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An evidence summary of Paediatric COVID-19 literature

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This post is a rapid literature review of pertinent paediatric literature regarding COVID-19 disease. We are proud to have joined forces with the UK Royal College of Paediatrics and Child Health to provide systematic search, and selected reviews of all the COVID-19 literature relevant to children and young people.

Our search and review methods have changed as the pace and utility of the published literature has evolved over time. Our process involved a formal literature search (methods can be found here), followed by identification of all papers relevant to children/young people, then reading of every article by one of our team of doctors. Initially we produced a written review of all publications, however on April 17th 2020 we moved to a more selective review process. All articles were read in full, then if high enough quality, determined by consensus and involvement of a clinical academic, a written review was also produced.

As of June 30th 2020, we have again revised our process as the urgent need for rapid evidence synthesis has lessened, and the volume of research published remains extremely high, with much of it adding little to the current body of knowledge. Our search criteria has therefore narrowed, and of the articles identified as relevant, only those felt to be of exceptional quality or impact (as determined by consensus with involvement of a clinical academic) are selected for written review.

Our team of reviewers includes Alasdair Munro, Alison Boast, Henry Goldstein, Grace Leo, Dani Hall, Daniel Yeoh, Tessa Davis, Melody Redman, Sarah Sloan, Tricia Barlow, Anne Bean, Maeve Kelleher, Victoria Dachtler, Irnthu Premadeva, Lilian Nyirongo, Esther Alderson, Sunil Bhopal, Aimee Donald and Rachel Harwood.

Here we present the top 10 papers from each category (Paediatric clinical cases, Epidemiology and transmission, and Neonates). At the top is an Executive summary followed by all New and noteworthy studies.

If you have feedback please email us at hello@dontforgetthebubbles.com

Executive Summary (Updated 21st January 2021)

New and Noteworthy (Updated 11 April 2021)

Top 10 Neonatal Papers

Top 10 Clinical Papers

Top Papers on Co-morbidities

Top 10 Epidemiological Papers on Transmission

Top Epidemiological Papers on Disease Burden

Top 10 PIMS-TS / MIS-C Papers

paediatric-covid-data

First authorLast authorJournalArticle titleDate of PublicationCountryRegion(n) childrenStudy typePaper linkReview
Parri, NBuonsenso, DNEJMChildren with Covid-19 in Pediatric Emergency Departments in Italy01 May 2020ItalyEurope100Clinicalhttps://www.nejm.org/doi/full/10.1056/NEJMc2007617

This report is of confirmed COVID-19 infections in children under 18 years of age who presented to a research collaboration of 17 paediatric emergency departments in Italy between March 3rd and March 27th. The median age was 3.3 years and 57/100 were male. Children under 1 year were overrepresented (40%) followed by children >10yrs (24%).

Helpfully they categorise their patients according to criteria from Dong et. al (see review in Epidemiology top 10): Asymptomatic 21%, Mild 58%, Moderate 19%, Severe 1% and Critical 1%. Only 12% of patients appeared ill on assessment. Interestingly only 4% of patients had Oxygen saturations <94%. Only 38% of children needed admission for severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below

Clinical features: Fever 54%, Cough 44%, Feeding difficulty 23%, Sore throat 4%, Rhinorrhoea 22%, Diarrhoea 9%, vomiting 10%.

Bloods: Largely unremarkable (although reports of lymphopenia unclear – state 14 patients lymphopenic but that this is 28%? – perhaps only 50 children had bloods, but this is not reported). Procalcitonin <0.5ng/L in 29/23 patients.

Radiology: Chest x-rays performed for 35 children, of which 14/35 had interstitial abnormalities, 6/35 consolidation and 1/35 pleural effusion: remaining 15/35 normal.

Comorbidities: There were 27/100 children with comorbidities – although it appears most had mild illness (did not require respiratory support). This included 6 with cystic fibrosis, 4 neurological, 4 haematological, 4 with a syndrome, 3 with prematurity, 2 with cardiac conditions, 2 immunological, 2 oncological and 1 metabolic disease.

Of the few patients who required respiratory support (9/100) a significant number had comorbidities (6/9), although the rage was broad. This included 2 children with “epileptic encephalopathy”, one of whom also had CHARGE syndrome, a child with autism, a child with a VSD, a child with propionic acidemia, and a child with thrombocytopenia and frequent respiratory infections.

One of the strengths of this study is comparisons across other studies of clinical features of COVID-19 in children. In comparison to Dong et al, CDC data and Lu et al, most features are broadly comparable. Some notable differences are a significantly larger number of infants in the Italian data (40% <1yr compared to 18% in Lu, 12% in Dong and 15.5% in CDC) and a slightly higher number of asymptomatic children (21% compared to 16% Lu, 13% Dong and 1.3% CDC). This most likely represents differences in which population cohorts presented for testing among the different studies – comparisons between cohorts is always difficult currently due to broad differences in the demoninators used. Notably there is no apparent difference in severity according to age in this Italian data, whereas CDC noted increased hospitalisation in children <1yr and Don’t et al noted higher rates of severe or critical illness in infants <1yr.

Broadly speaking this study confirms findings from China and the USA regarding significantly milder illness in children than adults with COVID-19, including many asymptomatic children. Note is made of overrepresentation of children with comorbidities in this cohort (similar to CDC data), although most of these still had mild illness - it is unclear if these children become more unwell, or are more likely to present to be tested.

Tsao, HFearon, DPediatrics Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics01 May 2020USANorth America1Clinicalhttps://pediatrics.aappublications.org/content/early/2020/05/19/peds.2020-1419/tab-e-letters?versioned=true

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2. A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Diorio, CTeachey, DBlood AdvancesEvidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.8 Dec 2020USANorth America50Clinical - Clinical Featureshttps://ashpublications.org/bloodadvances/article/4/23/6051/474421/Evidence-of-thrombotic-microangiopathy-in-children

This study investigated a group of 50 hospitalised paediatric patients with acute SARS-CoV-2 infection, classified into 3 groups (minimal COVID-19, severe COVID-19 and MIS-C), to assess whether these children met the clinical criteria for diagnosis of thrombotic microangiopathy (TMA). TMA (endothelial cell damage to small blood vessels, leading to haemolytic anaemia, thrombocytopaenia and, in some cases, organ damage) has been associated with SARS-CoV-2 infection in adults, causing thrombotic complications in severe COVID-19. A proposed mechanism for SARS-CoV-2-mediated TMA is via complement activation, which results in unregulated formation of the C5b9 membrane attack complex. An initial smaller study by these researchers of 20 of these paediatric patients (published in the Journal of Clinical Investigation on 30th July 2020), which compared clinical features and cytokines between the three groups, showed that soluble C5b9 (sC5b9), a biomarker of complement activation and TMA, may be elevated across the spectrum of manifestations of COVID-19.

Study design and population: From 3rd April to 7th July 2020, 112 patients admitted to the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania, USA were prospectively screened with 58 enrolled; the analysis comprised the 50 patients for whom complete sC5b9 data were available. All had either a positive SARS-CoV-2 RT-PCR from upper respiratory mucosa or a positive SARS-CoV-2 antibody test. Minimal COVID-19 (n=21/50, median age 13 yrs, IQR 5-17 yrs, range 2.5-23 yrs) was defined as those patients with an incidental finding of COVID-19 during routine testing before admission/procedure or those with mild COVID-19 symptoms not requiring respiratory support. All patients in the minimal group had comorbidities, including 5/21 sickle cell disease, 2/21 nephrotic syndrome, 2/21 B-ALL, T-ALL, medulloblastoma, osteosarcoma and asthma. Severe COVID-19 (n=11/50, median age 15 yrs, IQR 14-17 yrs, range 0.13-18 yrs) was defined as patients requiring new or escalation of respiratory support. All patients in the severe group had comorbidities, including 3/11 obesity, 2/11 prematurity, 3/11 hypopituitarism, HIE, hypertension, B-ALL and asthma. MIS-C (n=18/50, median age 9 yrs, IQR 7-13 yrs, range 5-17 yrs) was defined as per CDC criteria. All patients in the MIS-C group were previously healthy or had minimal comorbidities (2/18 asthma, 1/18 obesity, 12/18 previously healthy). All 21 (100%) of the minimal group and 18 (100%) of the MIS-C group were discharged. 2/11 (18%) of the severe group died and 2/11 (18%) remained hospitalised. A control group of discarded plasma samples from 26 otherwise healthy children who had been evaluated for symptoms of a bleeding disorder was obtained from the CHOP coagulation laboratory.

Data collection and criteria for thrombotic microangiopathy: Data collected from patient charts included demographic information, comorbid conditions and most extreme laboratory values from blood tests within the first 2 weeks of the positive SARS-CoV-2 test or admission for MIS-C (mostly within 48 hours of admission), plus assessment of 7 criteria for TMA (adapted from Gloude et al): raised LDH, schistocytes on blood smear, thrombocytopaenia, anaemia, proteinuria, hypertension and elevated sC5b9. The diagnosis of TMA was defined as 5 out of 7 of these criteria during the hospital admission for COVID-19 or MIS-C. A subsequent analysis used a simple set of clinical criteria (thrombocytopaenia, anaemia, schistocytes (fragmented red blood cells) and organ dysfunction) to define TMA in settings where more sophisticated diagnostics may be unavailable. Patients were assessed for renal dysfunction using the KDIGO (Kidney Disease: Improving Global Outcomes) criteria: acute kidney injury (AKI) was defined as KDIGO stage 2 or higher.

sC5b9 levels: Median sC5b9 level in control subjects (57 ng/mL, IQR 9-163) was significantly lower than minimal COVID-19 (392 ng/mL, IQR 244-622), severe COVID-19 (646 ng/mL, IQR 203-728) and MIS-C (630 ng/mL, IQR 359-932) (p<0.001 in each case). There were no statistically significant differences between the 3 disease groups. One patient with concomitantly diagnosed SLE had highly elevated sC5b9 (1568 ng/mL), therefore the analysis was repeated excluding patients with comorbidities associated with complement dysfunction (lupus, cancer, sickle cell disease, renal disease or inflammatory disease): levels of sC5b9 remained elevated in the 3 disease groups compared to the control group (p<0.001). Analysis of correlations between sC5b9 and markers of inflammation, haemolysis and coagulopathy in patients with severe COVID-19 and MIS-C (there was a high proportion of missing data in the minimal group) showed no significant correlations with ferritin, CRP, LDH, PT, PTT, fibrinogen, D-dimer, AST, Hb or platelets. Levels of SARS-CoV-2 IgG, IgM and IgA did not significantly correlate with sC5b9 levels (testing the hypothesis that raised sC5b9 in SARS-CoV-2 could be related to classical pathway activation from antiviral antibody-antigen complexes, rather than the alternative pathway complement activation of TMA).

TMA findings: Of the 19/50 (38%) patients with complete clinical criteria available, 17/19 (89%) met criteria for diagnosis of TMA, comprising 2/2 (100%) minimal COVID-19 patients, 4/4 (100%) severe COVID-19 and 11/13 (85%) MIS-C. sC5b9 levels were elevated in patients who both did and did not meet criteria for TMA. Out of the total study group (31/50 (62%) had missing data, which was counted as negative), 24/50 (48%) met criteria for TMA, comprising 4/21 (19%) minimal COVID-19 patients, 9/11 (82%) severe COVID-19 and 11/18 (61%) MIS-C. A sensitivity analysis in which sC5b9 was not included in the criteria for TMA was performed (testing the hypothesis that sC5b9 elevations could be caused by an unknown pathophysiological process other than TMA in SARS-CoV-2 patients): 15/50 (30%) patients still met the criteria for TMA (5/6 or 6/6 criteria met), 9/50 (18%) were indeterminate (4/6 criteria met) and 26/50 (52%) did not meet the criteria (3/6 or less criteria met). For 34/50 patients with peripheral blood smears, 13/34 (38%) met simpler clinical criteria for TMA (microangiopathic haemolytic anaemia, thrombocytopaenia and evidence of organ damage). Schistocytes were present in 5/11 (45%) peripheral blood smears in the minimal group, 7/8 (87%) in the severe group and 13/15 (87%) in the MIS-C group.

Renal dysfunction: There was evidence of AKI in 2/21 (10%) of the minimal COVID-19 group, 4/11 (36%) of the severe COVID-19 group and 5/18 (28%) of the MIS-C group. Only 1 child (in the severe group) required dialysis. There were significantly higher plasma sC5b9 levels in those with AKI (717 ng/mL, IQR 404-1232) than in those without AKI (433 ng/mL, 232-706) (p=0.374). Elevations in sC5b9 correlated statistically significantly with creatinine, blood urea nitrogen and GFR, but not with age.

Levels of IL-8: IL-8 levels, a marker of endothelial dysfunction, were similar in MIS-C and severe COVID-19 patients; both were significantly higher than the minimal group. IL-8 didn’t correlate with sC5b9 levels.

Limitations identified by authors: The high incidence of TMA seen in patients with complete data is confounded by ascertainment bias, since some markers (e.g. LDH) are more frequently measured in sicker children (although even when the children with missing data were included, with missing values assumed to be negative, nearly half met criteria for TMA). The hospitalised children in the minimal COVID-19 group were, by definition, admitted because of other comorbidities, which could independently cause elevated sC5b9 (this group would ideally have been asymptomatic or mildly symptomatic SARS-CoV-2 children without comorbidities). The healthy control group were patients being investigated for a bleeding disorder, which the authors believe will not affect complement activation, but this group would also ideally have been without comorbidities.

Conclusions: In all 3 presentations of SARS-CoV-2 studied (minimal COVID-19, severe COVID-19 and MIS-C), the final common pathway of complement activation was seen. Interpretation of the group called “minimal COVID-19” is difficult, due to an extremely mixed cohort of children with supposedly mild disease who were still hospitalised due to their illness, or children hospitalised for a variety of other conditions which are likely to confound the results. IL-8 was elevated in severe COVID-19 and MIS-C compared to minimal COVID-19, implying more severe endothelial damage in the 2 more clinically severe groups. The majority of children with complete clinical and laboratory data measured met the criteria for thrombotic microangiopathy, as did most patients with acute kidney injury. Elevated sC5b9 correlated with renal dysfunction, but was independent of inflammatory markers. The short- and long-term implications of complement activation in children with SARS-CoV-2 are unclear. It is not possible to generalise the results of this study to children with minimal or no symptoms in the community.

Marlais, MTulus, KArchdischildCOVID-19 in children treated with immunosuppressive medication for kidney diseases21Dec2020worldwideInternationalClinical - Clinical Featureshttp://dx.doi.org/10.1136/archdischild-2020-320616

Introduction: Initial reports of COVID-19 from the Wuhan province showed significant differences in the outcomes between children and adult patients. In children, the reported mortality rates were far below 1% while for people above the age of 70 years it was 5% or higher. It also became clear that in adult patients a number of comorbidities contributed to a worse outcome.

Based on those early findings, many children taking immunosuppressive medication were advised to ‘shield’. As well as being demanding authors have cautioned against its indirect ‘side-effects’, both physical and psychological. It is therefore important to accurately define the group of people who are extremely vulnerable to severe disease if infected with SARS-CoV-2.

However, the impact of immunosuppression is yet to be determined in this group. The multinational authors’ study aimed to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess their disease severity.

Methods: This was a voluntary-based survey on children with immunosuppressive treatment for kidney disease reported to be infected with SARS-CoV-2. It was hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. The members of these societies and the members of the PedNeph listserver were asked to include any child in their care fulfilling the inclusion criteria.

Inclusion criteria were all children (<20 years and under paediatric services) who have an underlying kidney disease and take immunosuppressive medication, with a diagnosis of COVID-19 (either laboratory confirmation with PCR or serology testing, or clinically highly suspected). The study was open for 16 weeks from 15 March 2020 to 05 July 2020 and included 8 separate reminders sent electronically to the memberships of the above organisations. Anonymised data were collected through an online platform including details of demographics, underlying kidney conditions, comorbidities and current immunosuppressive medication. Their symptoms at presentation were recorded, along with the method of COVID-19 diagnosis (laboratory or clinical). The severity and outcome of their COVID-19 was also reported.

Results : 113 children were reported in this study from 30 different countries. 104 cases were confirmed as COVID-19 by PCR or antibody testing, the remaining 9 being clinically suspected. The median age of the participants was 13 years (49% were male). The main underlying reasons for immunosuppressive therapy were: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Patients’ immunosuppressive medications included: glucocorticoids (76%), Mycophenolate Mofetil (MMF) (54%), Tacrolimus/ciclosporine A (58%), Rituximab/Ofatumumab (11%). Mean duration of immunosuppressive therapy prior to study was 9.5 months (IQR 3-39 months).

78% of the patients required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries (3 India, 1 South America) with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications. There was a difference in the severity of the disease with older children tending to have more severe disease but this did not reach statistical significance. No children developed PIMS-TS in this study.

Conclusions

The authors’ global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection.

They suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.

They find no evidence of any association between immunosuppressive medication number and the severity of COVID-19 in children.

They suggest children who are in the first few months immediately post-transplant may need some stricter social distancing measures (as were in place for many centres prior to COVID-19) as published data in this small subgroup are still limited.

Melé, MLaunes, CjinfLow Impact of SARS-CoV-2 infection among Paediatric Acute Respiratory Disease Hospitalisations21.10.20202SpainEurope110Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30655-1/fulltext

Observational study of children admitted to a Barcelona hospital with acute lower respiratory disease (ALRD) during the first pandemic peak (mid-March to mid-May), comparing those who were SARS-CoV-2 (+) to those who were SARS-CoV-2(-).

Key points

• 125 children with ALRD admitted, 110 consented to be in study

• Only 7 (6%) were SARS-CoV-2 (+)

• SARS-CoV-2 (+) children’s median age was 16.9y: the median for the SARS-CoV-2(-) children was 3.7y

• Co-morbidities: in 2 of the SARS-CoV-2 (+) (1 leukaemia, 1 obesity): in SARS-CoV-2(-) 44% had pre-existing respiratory issues and 13% neurological

• No significant differences were found in the clinical presentation of the 2 groups

• SARS-CoV-2 (+) group had significantly lower WBCs and platelets

• The SARS-CoV-2 (+) child with leukaemia had graft-versus-host and a co-infection with Influenza B and unfortunately died

The children were tested for SARS-CoV-2 when presenting at the hospital. In the 9-week period of the study, 960 children with fever &/or respiratory symptoms were seen and tested and only 56 (6%) were SARS-CoV-2 (+). The authors have then looked at detail at those children requiring admission with ALRD.

Bolanos-Almeida, CSegura, OPIDJ Clinical and epidemiological analysis of COVID-19 children cases in colombia PEDIACOVID20/10/20Colombia South America 5062Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_and_Epidemiologic_Analysis_of_COVID_19.95988.aspx

This is a retrospective study of 5062 children <18 years of age (until June 2016) who tested positive for SARS-CoV-2 and were reported to the National Institute of Health in Colombia. This cohort represented 9.2% of total cases in Colombia.

Cases were classified as symptomatic, asymptomatic, mild, moderate or severe. All children admitted to hospital with clinical or laboratory features of SARS-CoV-2 (eg. changes on chest imaging, elevated inflammatory markers, lymphopaenia) and who were characterised as an at risk or vulnerable population were classified as severe.

Majority of cases were mild (79.4%) or asymptomatic (16.8%). Overall, only 26 children required admission to intensive care (ICU) (0.51%) and 146 hospital admission (2.88%). There was a reported case fatality rate of 1.59 per 1000. Younger children were more likely to have more severe disease requiring hospital or ICU admission.

This retrospective study is the largest published cohort of children from South America and is consistent with findings from other geographical regions.

Goss, MGoss, JPaediatric TransplantationThe pediatric solid organ transplant experience with COVID‐19: An initial multi‐center, multi‐organ case series18 Sept 2020United StatesNorth America26Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/petr.13868

Five transplant centres in the United States report the outcome of 26 children ≤ 18 years of age (range 5-18 years) 16 of whom were male who developed Covid 19 between 1st April and 20th July 2020. Six were heart recipients, 8 kidney, 10 liver, and 2 lung.

The 26 COVID‐19‐positive transplant recipients had variable clinical presentations. The most common symptom was cough (n=12 (46%)) followed by fever (n=9 (35%)), dry/sore throat (n=3 (12%)), rhinorrhoea (n=3 (12%)), anosmia (n=2 (8%)), chest pain (n=2 (8%)), diarrhoea (n=2 (8%)), and dyspnoea and headache in 1 patient each (4%). Six patients (23%) did not have any symptoms (4 kidney, 1 liver, and 1 lung recipients). Eight (31%) were hospitalized, 3 of whom were already admitted for unrelated problems. None required supplemental oxygen. All patients with COVID‐19 symptoms at the time of diagnosis recovered with full resolution of symptoms within a median of 3 days. No patient experienced progressive deterioration or death.

Only two children required reduction in their post-transplant immunosuppression.

The authors conclude “Our multi-institutional experience suggests the prognosis of paediatric transplant recipients infected with COVID-19 may mirror those of immunocompetent children, with infrequent hospitalization and minimal treatment, if any, required”

Rekhtman, SGarg, AJ Am Acad DermatolMucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children18 Dec 2020USANorth America31Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585496/pdf/main.pdf

This cohort study describes the mucocutaneous features of COVID-19 and MIS-C patients hospitalised in a tertiary children’s hospital in New York. Sample size was small, but the authors observed a trend towards milder disease in those patients with rash and/or mucositis.

All patients aged 18 years or younger, admitted between 11 May and 5 June 2020 to the Cohen Children’s Hospital New York, with a diagnosis of COVID-19 or MIS-C, were included. Diagnostic criteria for MIS-C included: clinically severe illness, multisystem involvement, positive for SARS-CoV-2 on PCR/serology or exposure to positive COVID-19 case, and no alternative diagnosis. All patients in the COVID-19 group were SARS-CoV-2 PCR positive. There were 31 patients in total, 12 with COVID-19 and 19 with MIS-C. 61% of patients were male (50% of the COVID-19 group and 68% of the MIS-C group). Median age of COVID-19 patients with mucocutaneous disease was 5 years (1.75, 10) and without was 10 years (7.25, 16). Median age of MIS-C patients with mucocutaneous disease was 8 years (7, 10) and without was 10.5 years (10, 13).

Mucocutaneous features in COVID-19 group: 33% of the COVID-19 patients had a rash and/or mucositis. The rashes observed were non-specific erythema and morbilliform. The mucositis seen was limited to lip cracking. There was a trend towards younger age and milder disease in patients with mucocutaneous features compared to those without.

Mucocutaneous features in MIS-C group: 47% of MIS-C patients had a rash and/or mucositis. The pattern of rash seen was heterogenous including non-specific erythema, urticarial, purpuric and oedematous. Mucositis included lip cracking, tongue papillitis and conjunctivitis. As with the COVID-19 group, there was a trend towards milder disease in those MIS-C patients with mucocutaneous features compared to those without.

Discussion: This descriptive study is a useful addition to the literature, providing information on the prevalence of mucocutaneous disease amongst COVID-19 and MIS-C patients, as well as its morphologic pattern and distribution. The observed trend towards milder disease in those patients with mucocutaneous features is interesting and raises the question of whether this could be a prognostic indicator. The sample size is too small to draw any firm conclusions, but the study provides a good basis for further research.

Ludvigsson, JLudvigsson, JActa PaediatrCase report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-1917/11/20Sweden Europe5Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/apa.15673

This is a case report and systematic review of long-term symptoms experienced by children following acute SARS-CoV-2 infection. Although there are a number of reports of persistent symptoms in adults, this is the first systematic review of the currently available paediatric data. Long-term or persistent symptoms were defined as those lasting over 2 months from the onset of symptoms.

The case report is of 5 Swedish children identified by personal contact of their parent with the author of the manuscript. The 5 children had a median age of 12 years (range 9-15 years) and 4 were female. All were clinically diagnosed with COVID-19 without PCR confirmation and were managed conservatively, without hospitalisation. Subsequent SARS-CoV-2 serology in 4 of the 5 children was also negative. Symptoms reported by the child and/or parent most commonly included fatigue, dyspnoea, heart palpitations, dyspnoea, headaches, poor concentration, muscle weakness, dizziness and sore throat. Symptoms remain persistent 6-8 months following acute illness and none of the children have returned to school (at the time of manuscript publication).

The systematic review identified 19 articles which were relevant, however none contained further information on persistent symptoms following SARS-CoV-2 infection in children.

Although there is growing concern about persistent symptoms following acute COVID-19 infection in adults, there remains a paucity of data on children. This case report is limited by lack of PCR confirmed SARS-CoV-2 infection and selection bias. Future prospective research is required in both adults and children with a well-defined case definition to better delineate the long-term effects of SARS-CoV2.

Dannan, HRamsi, MBMJClinical course of COVID-19 among immunocompromised children a clinical case series15 Oct 2020United Arab EmiratesMiddle East5Clinical - Clinical Featureshttps://casereports.bmj.com/content/bmjcr/13/10/e237804.full.pdf

A case series of five immunocompromised children 2 boys 3 girls, aged 3-12 years from the United Arab Emirates who developed Covid-19 during 2020. They either had mild symptoms or were asymptomatic. They all had a benign course of their illness. None needed a change in their treatment regime nor had a relapse of their underlying condition. The children had prolonged duration of virus shedding post Covid 19 infection. The authors conclude “immunocompromised paediatric patients may not be at a higher risk of developing severe Covid-19.”

Kumar, LPandey, A.K Int J Pediatr OtorhinolaryngolLoss of smell and taste in COVID-19 infection in adolescents13/01/2021IndiaAsia141Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804378/pdf/main.pdf

This prospective study aimed to evaluate the prevalence of olfactory and taste dysfunction (OTD) in adolescents with mild-moderate COVID-19 who presented to a hospital in India between May and August 2020. The inclusion criteria was adolescents, aged 10–19 years, who presented to ESIC Medical College and Hospital in Faridabad with “influenza like illness (ILI)” and were detected COVID-19 positive by RT-PCR. These patients were followed up by telephone or ENT clinic consultation and the clinical course and outcomes of their OTD were documented. All the symptoms were self reported by the patients. Exclusion criteria included patients with severe COVID-19 disease, psychiatric or neurological disorders or those with existing conditions affecting their taste and smell.

Age/gender: 141 patients were included in the study, 58.9% were male and 41.1% were females. The age varied from 10 to 19 years with an average of 15.2 years.

Clinical features: 40 (28.4%) of the 141 patients in the study had olfactory or taste dysfunction. Of these 40 patients, 24.1% had olfactory dysfunction, 24.1% had an alteration in taste and 19.8% complained of both. Other common symptoms recorded by the patients were fever (48.2%), cough (20.6%), sore throat (19.9%) and malaise (14.2%). OTD was the first noted symptom in 13.9% of the patients. The duration of OTD varied from 2 to 15 days with an average of 5.7 days. There was no significant difference in OTD in different age groups or genders. All the patients reported complete recovery of their smell and taste sensations.

Conclusion: Olfactory and taste dysfunction is known to be a common presenting feature in adult patients with COVID-19. This prospective study in India shows a prevalence of OTD in 28.4% of COVID-19 adolescent patients. It concludes that the identification of OTD in the adolescent population may help in early diagnosis and reduced transmission of COVID-19 infection. Note is made of the limitations of the study including a lack of objective tools in evaluating olfactory and taste dysfunction (these were self-reported). Secondly, the study was limited to patients presenting to hospital with mild-moderate COVID-19 infection; a further study looking at the prevalence of OTD in well children found to be COVID-19 positive via community testing may be of use.

Millen, GKearns, PBr J CancerSeverity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project10 Dec 2020United KingdomEurope54Clinical - Clinical Featureshttps://doi.org/10.1038/s41416-020-01181-0

BACKGROUND: Data from adults with cancer suggests that they have an increased risk of contracting SARS-CoV-2 and develop a more severe COVID-19 illness.

AIM: To document the incidence and outcomes from SARS-CoV-2 infection in children with cancer attending all hospitals treating this population across the UK.

METHODS: Data were collected on children under 16 years of age with a diagnosis of cancer who were receiving hospital-based care who tested positive for SARS-CoV-2 from 12th March 2020 until 31st July 2020. Cases were confirmed by RT-PCR to SARS-CoV-2.

Prospective data collection started on 7 April 2020. The data were gathered as part of the UK Paediatric Coronavirus Cancer Monitoring Project, set up to record the effects of COVID-19 in children with cancer attending the 20 hospitals designated as the Principal Treatment Centres (PTCs) for the care of children with cancer in the UK. Paediatric Oncology Shared Care Units (POSCUs) linked to PTCs were encouraged to submit data. Children who had received an allogeneic stem cell transplant were excluded as data on this group of patients were being separately collected.

RESULTS: 54 children tested positive for SARS-CoV-2 during the data collection period and had complete datasets submitted. 98% of all patients had minimum of 4 weeks of follow-up data from their initial positive test result.

29 boys and 25 girls were affected with a median age of 5 years 0 months (range 10 months to 15 years, 9 months). 44% had a diagnosis of acute lymphoblastic leukaemia (ALL). 33% of children were from a black or minority ethnic background (BAME), who form 9% of the incidence of children with cancer in the UK.

Severity of illness: 49 of the 54 (91%) had mild (34) or asymptomatic (15) infections. The illness in one was moderate, in another was severe and in 3 was critical. All recovered. The cancer diagnosis in the 5 patients with moderate to critical illness were a mixture of haematological cancers and solid tumours. 87% of all symptomatic patients presented with fever while 62% had either cough or coryzal symptoms at presentation. 10% had gastrointestinal symptoms at presentation.

13 were hospitalised because of COVID-19, others 27 were in hospital for unrelated reasons, 14 were not hospitalised.

Treatment data were available for 38/54 patients (70%): 21% were receiving very myelosuppressive chemotherapy (either induction/delayed intensification chemotherapy for ALL or chemotherapy for AML). 29% were receiving less intensive chemotherapy. The remaining 50% were receiving a range of other more standard chemotherapy regimens. 26% were receiving targeted or immune therapy with or without conventional chemotherapy. None had received high dose chemotherapy within the 28 days preceding their positive SARS-CoV-2 result. The patients with moderate to critical infections were receiving oncological treatment of assorted intensities. One patient died of progressive cancer.

CONCLUSIONS: The authors of this study, carried out across all UK paediatric oncology centres, concluded that children with cancer who contract COVID-19 are not at any more risk of serious infection than children in the general population. These results are in keeping with emerging international reports. There was no trend of more serious infection in those receiving more intensive therapies. The limitations are that the numbers are small, that there was no consistent testing policy during the period of data collection, there is likely underestimation of children who have been asymptomatic or had mild symptoms. There also limitations derived from the limited sensitivity of the PCR test. The data presented are from children with a complete data set (apart from type of oncological treatment) and it is not known what proportion they make up out of all children with SARS-CoV-2 under hospital oncological care. These limitations, however, are unlikely to weaken the overall finding that children with ongoing cancer treatment are not at risk of a more severe COVID-19 illness. As a result, some of the more stringent shielding recommendations for this group of patients have been eased.

Foster, CCampbell, JRjpidsA Surge in Pediatric Coronavirus Disease 2019 Cases: The Experience of Texas Children's Hospital from March to June 202010 Dec 2020USANorth America1215Clinical - Clinical Featureshttps://doi.org/10.1093/jpids/piaa164

Methods: The Authors performed a retrospective chart review of all children, ≤ 21 years of age, presenting to the Texas Children’s Hospital (TCH) system in the greater Houston area, Texas with testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcription-polymerase chain reaction (RT-PCR) from March 10, 2020 to June 28, 2020. The children either presented to TCH or the community hospitals or clinics within the TCH system. Demographics were recorded for all patients undergoing testing and clinical characteristics and outcomes were recorded for children with positive tests. Data was sourced from charts, notes and Epic (the common electronic health record for the TCH system)

Results: Of 16,554 unique patients who were tested for SARS-CoV-2, 1215 (7.3%) patients tested positive. Infants under 1 year of age and patients aged 18-21 years had the highest percent of positive tests at 9.9% (230/2329) and 10.7% (79/739), respectively.

Children aged 1-5 years had the lowest percent of positive tests (335/5842, 5.7%). Fifty-one percent of patients with positive tests were male

Hispanic children accounted for 66% (802/1215) of positive tests, though they only represented 42.1% (6972/16554) of all children tested for SARS-CoV-2.

Of the 1215 children with a positive test, 55.7% had fever, 40.9% had cough, 39.8% had congestion or rhinorrhea, 21.9% had gastrointestinal complaints, and 15.9% were asymptomatic. Only 97 (8%) patients were hospitalized (of which 68% were Hispanic). Most patients (89/97, 91.8%) were admitted within 1 day of the collection date of the SARS-CoV-2 positive test

Most hospitalized patients had underlying medical conditions (62/97, 63.9%), including obesity.

Gastrointestinal complaints were present in 21.9% (266/1215) of patients. Almost 16% of children were asymptomatic (193/1215). Most children (90.8%) had no chest imaging.

Forty (41.2%) patients were admitted for a non-COVID-19 diagnosis including 12 (12.4%) patients admitted with acute appendicitis

Thirty-one hospitalized patients (31/97, 32%) required respiratory support and nine patients (9/97, 9.3%) received SARS-CoV-2 antiviral therapy. Two patients died. One patient had underlying congenital heart disease and developed acute respiratory distress syndrome secondary to COVID-19. The other patient expired from complications related to a new oncologic diagnosis.

Conclusions: A relatively high percentage of Hispanic children tested positive for SARS-CoV-2 and were hospitalized. Most children with detection of SARS-CoV-2 had uncomplicated illness courses, some children were critically ill, and two patients died.

The authors found that a relatively low percentage of patients with SARS-CoV-2 were hospitalized (97/1215, 8%) and furthermore over 40% of the admitted patients had a primary diagnosis other than COVID-19. Interestingly, 12 patients were hospitalized with acute appendicitis. They note there are case reports detailing clinical presentations of COVID-19 mimicking appendicitis. Appendicitis is the most common pediatric surgical diagnosis, however, and the relationship between SARS-CoV-2 and appendicitis remains unclear and warrants further investigation. Both pediatric and adult reports have found lymphopenia to be a common laboratory finding in patients with COVID-19, though this finding was only present in 30.7% of the study’s patients.

Alfraij, AAlghounaim, MJ Infect Public HealCharacteristics and outcomes of coronavirus disease2019 (COVID-19) in critically ill paediatric patients admitted to the intensive care unit: a multi-center retrospective cohort study.10 12 2020Kuwait/Saudi ArabiaMiddle East25Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120307668

This study was done in 8 paediatric centres (providing services to 12 million people) across Kuwait and Saudi Arabia from 1st March to 1st August 2021. The aim of the study was to better understand the dynamics of critical COVID-19, improve the quality of care and evaluate predictors of mortality and intubation.

From records, 43 children were identified as being admitted to ICU with positive SARS-CoV-2 PCR done on respiratory samples. 18 of these children were excluded (9 with confirmed MIS-C, 7 with asymptomatic infections identified when children admitted to ICU for other reasons, and 2 duplicate entries) leaving a study cohort of 25 children. 4 of these children died.

The authors have gathered a mass of demographic, clinical, laboratory and radiological data which is presented in tables. However, there are few findings that reach statistical significance. Interesting findings are:

Median age 2.78y

Only 3 patients were previously healthy before ICU admission

22 children were admitted to ICU because of respiratory failure, 2 for neurological compromise and 5 because of circulatory compromise

Death was significantly associated with thrombocytopaenia and circulatory collapse at time of admission: elevated procalcitonin and comorbidities were also associated with fatal outcome

Malhotra, AGaur, SPediatr Infect Dis JPediatric COVID-19 and Appendicitis: A Gut Reaction to SARS-CoV-208 Dec 2020United StatesNorth America48Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Pediatric_COVID_19_and_Appendicitis__A_Gut.95943.aspx

This study collected data on all SARS-CoV-2 positive patients admitted to a tertiary children’s hospital in New Jersey, USA during the first wave of infection, as well as on patients admitted with appendicitis. They report a temporal association between SARS-CoV-2 infection and appendicitis and suggest that is may represent another post-infectious manifestation.

Cohort demographics: Inclusion criteria were all patients admitted to the children’s hospital between 29 March and 26 July 2020 with confirmed SARS-CoV-2 infection, either by PCR or antibody testing. During this time, the hospital was admitting patients up to the age of 25 years, so this study included some patients not generally considered paediatric. There were 48 admissions, but 7 patients were excluded at the outset as they were asymptomatic. Of the remaining 41 patients, 18 were female (44%) and the median age was 9 (IQR 0.2, 17). The majority of patients were of Hispanic ethnicity (51%), with 22% black, 17% white and 10% ‘other’.

Results: The authors divided patients into 4 diagnostic categories for comparison: Pneumonia (16 patients); MIS-C (10 patients); Appendicitis (10 patients); and ‘Unconventional’ (5 patients) (defined as having symptoms and signs consistent with SARS-CoV-2 but not fitting into the other 3 categories).

The ‘Unconventional’ patients were significantly younger than patients in the other categories (median age 2 years, IQR 0.2-1.5 years). This category of patients was not included in further analysis, beyond comparison of demographic features.

Of the pneumonia patients, 94% were PCR positive and 6% (1 patient) antibody positive. This compared to 60% of MIS-C patients being antibody positive, 30% being PCR positive and 10% being both PCR and antibody positive. The appendicitis patients showed a similar pattern to the pneumonia patients, with 70% PCR positive, 20% antibody positive and 10% positive on both tests. The authors include a nice figure showing weekly admissions patterns during the study period. The shows the majority of the Pneumonia cases occurring during the first half of the study period, and correlating with the peak in SARS-CoV-2 infections in the region, whereas the MIS-C and Appendicitis cases predominated in the latter 2/3 of the study period.

The authors present data on a number of features such as severity, duration of fever, and inflammatory markers for their 3 main diagnostic categories (Pneumonia, MIS-C and Appendicitis), and these are consistent with what is already known. However, of particular interest in this study is the analysis of appendicitis in the context of SARS-CoV-2, and comparison with appendicitis patients without co-existing SARS infection. Although not statistically significant, there was the suggestion of an ethnic bias in the patients with appendicitis and SARS - 90% were Hispanic, compared to only 45% Hispanic the non-SARS infected appendicitis patients. There was also a trend to more severe disease in the SARS-infected appendicitis patients, with a 50% appendiceal rupture rate in this group compared to only 36% rupture rate in the non-SARS group.

Discussion: This study adds to the body of evidence on clinical features of SARS-CoV-2 infection in children and adds some interesting data on appendicitis in the context of SARS. The authors highlight the similarity of the temporal relationship they found between appendicitis and MIS-C in SARS-CoV-2 infected patients and suggest this may represent another post-infectious manifestation. Unfortunately, the data is not fully supportive of this conclusion as 70% of their appendicitis patients were PCR positive, consistent with current SARS-CoV-2 infection (unlike the MIS-C patients, who were, as expected, mostly antibody positive). What we also don’t know from this study is how the pattern of appendicitis presentations compares to normal (i.e. non-COVID) years and whether there is any difference.

Although it’s not possible to draw any firm conclusions from the data presented, this paper raises a number of interesting questions with respect to appendicitis and SARS-CoV-2 infection. Further studies into a possible correlation would be valuable.

Mizrahi, BSegal, ENat. CommunLongitudinal symptom dynamics of COVID-19 infection04 12 2020IsraelEurope862Clinical - Clinical Featureshttps://www.nature.com/articles/s41467-020-20053-y

In this study from Israel, data from electronic health records (EHR) from primary care visits to Maccabi Health Services 9MHS) was combined with longitudinal voluntary nationwide survey data on self-reported symptoms to explore the symptom dynamics of SARS-CoV-2 infection. Data on SARS-CoV-2 PCR testing was extracted from the EHR along with symptoms according to ICD-9 codes as documented by the primary care physician. Adults, but not children, were invited to participate in the nationwide survey via text or email to all members of MHS. Data from March 1st to June 7th, 2020 were analysed.

Data on symptoms was available for 206,377 individuals of whom 2471 had a positive SARS-CoV-2 PCR. For adults, there was relatively poor agreement between symptom report from survey and EHR data; most symptoms were more likely to be self-reported than recorded in the EHR. In SARS-CoV-2 positive adults, cough (11.6%), fever (10.3%), myalgia (7.7%) and fatigue (5.9%) were the most prevalent symptoms recorded in the EHR. Cough (21%), fatigue (19%, rhinorrhoea (17%), and headache (16%) were the most common self-reported symptoms. Loss taste of smell was self-reported in 10% of SARS-CoV-2 positive adults and was significantly associated with confirmed SARS-CoV-2 infection (OR 11.18, 95% CI 6.43-19.44) - this was the most discriminatory symptom for diagnosis of SARS-CoV-2.

Of 21,567 children included in the analysis, 862 (4%) were positive for SARS-CoV-2 on PCR. From EHR data, a smaller proportion of children had symptoms documented compared with adults. Fever (7%), cough (5.5%), abdominal pain (2.4%) and fatigue (2.3%) were the most prevalent symptoms amongst SARS-CoV-2 positive children. Most other symptoms were rarely documented (<1% of SARS-CoV-2 positive children); only 0.2% of children had documented loss of smell or taste. No individual symptom had a statistically significant association with confirmed SARS-CoV-2 infection in children. Fever (OR 0.3) and cough (OR 0.4) were in fact negatively associated with SARS-CoV-2 infection, likely due to the prevalence of other common paediatric infectious diseases resulting in primary care presentation during the study period.

Duration of illness, calculated from first positive SARS-CoV-2 PCR to a second consecutive negative PCR, was significantly shorter in children compared with adults in a Cox regression analysis (HR 1.18 95% CI 1.01-1.39).

The paediatric data in this study is limited by the reliance on EHR documentation of symptoms and the translation of this documentaion into ICD-9 codes. Thus, the reported proportions of SARS-CoV-2 positive children with each symptom are likely underestimates, as was evident in the discrepancy between the EHR and self-reported symptoms in adults. Nonetheless, the EHR data is consistent with the accumulating body of evidence that children experience a milder course of SARS-CoV-2 infection with fewer symptoms compared with adults. In addition, based on PCR data, children in this study appeared to experience a shorter duration of illness compared with adults.

Bain, RBrodie,MJournal of Cystic FibrosisClinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.03 December 2020Multinational 13 CountriesInternational105Clinical - Clinical Featureshttps://www.cysticfibrosisjournal.com/article/S1569-1993(20)30931-0/fulltext

This is a particularly important multinational study for the Cystic Fibrosis community. The authors describe 105 children, age 0-18years (median 10), 54% male, 41% homozygous for F508del CFTR mutation, from 13 countries in N and S America, S Africa, Europe, and Russia who had Sars-COV-2 between 1 February 2020 and 7 August 2020. The diagnosis of COVID 19 was made by a positive PCR test in 95 children.

Twenty nine percent of the children were asymptomatic. Of those with symptoms 73% had a fever, 38% altered cough, 30% dyspnoea, 23% gastrointestinal symptoms and 19% myalgia. The majority (71%) were managed in the community, and only one child needed intensive care. The children who were hospitalised had lower lung function and body mass index z-scores compared to those treated in the community. Of all the children 29% required new supplemental oxygen and about 1/3 had additional oral antibiotics and another 1/3 intravenous antibiotics. Fourteen percent of children had experimental antiviral therapy.

No child required ECMO and two children needed none invasive ventilation. No deaths very associated directly with COVID 19 though one child died 6 weeks after testing positive, but this was deemed to be due to worsening underlying cystic fibrosis.

What would have been interesting but has not been documented in the study would be a comparison of ppFEV1 prior to and after COVID 19 infection.

The authors conclude “SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have a pre-existing severe lung disease.”

Hizal, MCeyhan, M Pediatr PulmonolDiagnostic Value of Lung Ultrasonography in Children with COVID-1921 Oct 2020TurkeyEurope and Asia40Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.25127

This prospective multi-centre study was performed between April and May 2020 at four tertiary paediatric hospitals in Turkey. 40 children up to 18 years of age with confirmed COVID-19, both symptomatic and asymptomatic, had lung ultrasound performed compared to their other chest imaging (x-ray and/or CT) performed at the discretion of their treating clinician.

To minimise bias, bedside point of care lung ultrasounds were performed by a paediatric respiratory physician (‘pulmonologist’) blinded to the child’s symptoms and imaging findings. The ultrasound recordings were independently reviewed by a pulmonologist and radiologist, and when their findings were discrepant, they agreed in consultation on the findings. Chest x-rays and CTs were requested by the child’s treating physicians who were blinded to the lung ultrasound findings and were reported by an ‘experienced’ radiologist blinded to the lung ultrasound findings and clinical presentation. Lung ultrasound findings considered normal included: multiple horizontal A-lines and normal sliding. The presence of three or more B-lines (comet-tail artefacts, representing interstitial syndrome), or confluent B-lines was considered abnormal.

Of the 40 children, median age was 10.5 years with an age range of 0.4 to 17.8 years. Five (12.5%) were under 2 years and 12 (30%) were under 5 years.

All 40 children had both chest x-ray and lung ultrasound performed. Four children (10%) had abnormal chest x-rays with consolidation, lung opacity and pleural effusion.

Twenty-eight (70%) of the children had a chest CT, 12 (43%) of which were abnormal. Bilateral ground glass opacification and consolidation were the most frequent abnormalities seen on CT, mostly in the posterior and lower lung zones.

Lung ultrasound took between 4 and 10 minutes to perform. Eleven (27.5%) of the ultrasounds were abnormal.

Of the 12 children with abnormal CT scans, lung ultrasound was also abnormal for 10 (83.3%). Of the 10 children with abnormal ultrasound and CT, 7 (70%) had normal chest x-rays. Of the two children with abnormal CT but normal ultrasound, the lesions seen on CT were under 1cm in size.

Of the 16 children with normal CTs, ultrasound was also normal in 15 (93.8%).

All 12 children who did not have a CT had normal ultrasounds.

The two most unwell children had abnormal findings on CT, chest x-ray and ultrasound imaging.

Using CT as a standard for ‘disease positive’, ultrasound was found to have the following sensitivity, specificity, positive predictive value and negative predictive values:

CT positive CT negative

Lung US positive 10 1 PPV = 10/11 = 90.9%

Lung US negative 2 15 NPV = 15/17 = 88.2%

Sensitivity

= 10/12 = 83.3% Specificity

= 15/16 = 93.8%

The authors conducted further statistical analysis, including area under the ROC curve and confidence intervals. Confidence intervals were universally wide. The authors compared sensitivity and area under the curve for chest x-ray and lung ultrasound; these were statistically different (McNemar's test: p-value 0.016 and 0.001 respectively). Compared to CT, chest x-rays were falsely negative in 75%, while lung ultrasound was falsely negative in 16.7%.

The authors concluded that although bedside point of care lung ultrasound is not as sensitive as CT, it is still useful in the diagnostic work-up of COVID-19 in children with the undisputable advantage of reducing radiation exposure, minimising nosocomial spread of COVID-19 to other patients and staff by minimising movement around the hospital, and by using easily to disinfect portable ultrasound probe and mobile phone, which can be wrapped in cling film to further minimise contamination.

This study does have several limitations, particularly in that it was a small study, with no control group. The sensitivities, specificities, PPV and NPV have wide confidence intervals (detailed in the paper). A selection bias is also very possible as sicker children are more likely to have been more extensively investigated: some asymptomatic or only minimally symptomatic children did not have CT imaging (although the authors rightly point out that it would have been unethical to have performed CT chests on children in whom their primary clinician didn’t feel it was indicated). And, although portable probes and mobile phones are beneficial from an infection control perspective, the authors say that the image quality may have been compromised.

So what’s the study bottom line? This paper adds to the evidence that although not as sensitive as CT, lung ultrasound is a viable imaging modality in the investigation of COVID-19 in children, with fewer false negatives than x-ray and the benefit of not exposing children to ionizing radiation.

Freeman, MCWheeler, SEJ Pediatric Infect Dis SocImmunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center01 Oct 2020USANorth America485Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa123/5922694

Study of seroprevalence in 485 immunocompromised children at a paediatric quaternary centre in Pittsburgh, USA, between March and July 2020 (median age 11.9 years, range 0.79-18.9). Testing was done on residual serum taken for other reasons, and the authors point out that this limits the capacity to compare infection rates from their results to the entire paediatric population or to make comparisons between groups. 5 patients (1%) had SARS-CoV2-IgG antibodies (control population from same institution, 0.6%). 27.2% reported prior febrile or respiratory symptoms. 15.7% had a nasopharyngeal swab. 2 patients had rheumatological conditions, 2 solid organ transplant, and 1 solid organ malignancy. None required respiratory support, intensive care, or died. Only 2 patients had a positive NPS and one of these was seronegative (though the time interval between symptoms and blood test may have allowed waning of antibody levels in this case). In this study, all paediatric patients with exposure to SARS-CoV-2 based on the presence of IgG antibodies had relatively minor illness in contrast to reports in immunocompromised adults who seem more likely to be admitted and to have poorer outcomes than children.

Denina, MGarazzino, SPediatr Infect Dis JSequelae of COVID-19 in Hospitalized Children: A 4-Months Follow-Up29 Sep 2020ItalyEurope25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Sequelae_of_COVID_19_in_Hospitalized_Children__A.96024.aspx

This paper is a short report of a study that followed up children hospitalized with COVID-19 in a children’s hospital in Turin, Italy over a 4 month period, and assessed them for sequelae of infection.

Patient cohort: 25 of the 28 patients admitted with COVID-19 between 1 March and 1 June enrolled in the study, 13 male and 12 female. The age range was 0.4 to 15 years, with a median age of 7.75 years. All patients had a SARS-CoV-2 positive nasal swab on admission; 28% were described as having mild disease, 56% moderate disease and 16% severe disease. 52% of the patients had an abnormal lung ultrasound on admission showing a diffuse interstitial pattern, with 38% of these also having multiple area of subpleural consolidation. None were diagnosed with related multi-system inflammatory syndrome.

Follow-up: Patients were followed up 2 weeks post-discharge by telephone, with a subsequent medical examination together with bloods, lung ultrasound and nasal swab on average 35 days (IQR 19-46 days) after discharge. The authors report further follow up by telephone, and in person in some cases, up to 4 months post-discharge.

Imaging: 5 children continued to have abnormal lung ultrasound scans at first follow up, with 2 having persisting consolidation. Of these 2, one had resolved on repeat scan a month later. The other patient had cystic fibrosis and the ongoing lung abnormalities were felt to be related to this underlying condition.

Blood analysis: Most blood markers had normalised at first follow up, with the exception of 5 patients who continued to have some raised inflammatory markers (fibrinogen, ferritin, ESR, D-dimer). These were reported to have normalised on 2nd follow up at 6 weeks post-discharge.

SARS Co-V-2 detection: All nasal swabs were negative for SARS-CoV-2 at first follow up. 20 patients (out of 24 tested) were IgG positive on follow up, 4 were negative (despite positive nasal swabs on admission).

Summary: The findings of this study are positive and reassuring, with the authors reporting complete recovery of all patients and no sequelae of infection 4 months after discharge. This paper is a short report and the authors focus on presenting their laboratory and imaging findings. There is no information about what questions were asked at follow up and what the medical examination involved, so we have a somewhat limited picture of overall health outcomes. This study covered a broad age spectrum, however the cohort was small. Data supportive of these findings from a larger number of children is needed to add weight to the evidence that the prognosis of COVID-19 in children, even those needing hospitalisation, is good.

Bixler, DKoumans, ECDC MMWRSARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 202018 Sep 2020United StatesNorth America121Clinical - Clinical Featureshttps://www.cdc.gov/mmwr/volumes/69/wr/mm6937e4.htm

This Morbidity and Mortality Report from the CDC describes the deaths in children and young adults (<21 years of age) associated with SARS-CoV-2 in the United States (US).

Overall, 121 SARS-CoV-2-associated deaths have been reported in the US to July 31st 2020. When stratified by age: 10% occurred in children <1 year, 20% in children 1-9 years and 70% in children and young people 10-20 years of age. Of the 121 deaths, 63% occurred in males, and the most common ethnicity was Hispanic (45%) followed by non-Hispanic Black (29%). The definition of a “SARS-CoV-2” associated death was left to the jurisdictions reporting the deaths, so it is unclear precisely how this is defined; a not-trivial issue given half of deaths in the UK of children who had tested positive for SARS-CoV-2 were deemed not attributable to the virus (being infected was incidental).

Comorbidities were present in 75% of children who died. The most frequently reported medical conditions included asthma (28%), obesity (27%), neurological and developmental conditions (22%) and cardiovascular conditions (18%).

This report is consistent with previously published data showing higher mortality in individuals of Hispanic or Black ethnicity and in those with comorbidities.

Biko, DMRapp, JBPaediatr RadiolImaging of children with COVID-19: experience from a tertiary children’s hospital in the United States18 Sep 2020USANorth America313Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04830-x

This study looked at 313 SARS-CoV-2 positive children from Children's Hospital Philadelphia and affiliated hospitals with specific attention to radiological imaging performed. Only 55 had any imaging performed, with 51 children having chest X-ray and US, MRI or CT was performed for 23. children Of the 55 children with imaging, 10 met criteria for MIS-C (PIMS-TS).

Of the chest x-ray findings, one third showed abnormalities. The most common finding was related to pneumonia with interstitial opacities or alveolar opacities (total 32 cases). The interstitial opacities were mostly diffuse 10/16. Alveolar opacities were seen in 27% (14/51) of children with xrays. Children with MIS-C were more likely to have interstitial opacities (8/16) and/or pleural effusions (4/5) on chest x-ray.

Of the ten ultrasounds performed, aside from one showing acute appendicitis and another with non-obstructing renal calculi; there were no acute abnormalities.

Treatment data was also collected for the 55 patients who had imaging. Almost all (89%) required hospital admission (range 1->76days), broad spectrum antibiotics were given to 12 (22%).

Overall, most children with SARS-CoV-2 did not require hospital admission or further imaging during their care.

Vann, AMullan, CAm J Emerg MedA case series of pediatric croup with COVID-1915 Sep 2020North AmericaNorth America3Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490245/pdf/main.pdf

This series of three cases from Children's Hospital of the King's Daughters and New York Presbyterian Hospital were found through a retrospective review of children with positive SARS-COV-2 nasopharyngeal RT-PCR swab who also required nebulised non racemic epinephrine (NRE, also known as 1:1000 nebulised adrenaline) in ED. It is important to note that at the time frame searched from 1st March to July 31st 2020, the practice at these hospitals was not to perform SARS-CoV-2 testing for children if they were deemed to have a viral illness and were able to be discharged.

The three cases identified were an 11mo African American boy, 2 year old caucasian female and a 9yo female. All cases were negative for other common viral causes of croup at the time. The presentations appeared to be more prolonged and less responsive to nebulised treatment than usual croup cases with all requiring hospital admission, receiving 3 or more doses of nebulised epinephrine and all receiving >1 dose of dexamethasone due to prolonged time to resolution of stridor at rest. The 11mo boy had 1 day history of symptoms no known sick contacts and the 2 yo girl had two family members with URTI symptoms) (unknown SARS-CoV-2 status and presented with 2 days of symptoms. However the 9yo girl had a mother with positive SARS-COV-2 test 3 days prior to developing symptoms but had been advised not to present to ED until developing respiratory distress- so was seen in ED 7 days from time of symptoms onset. She was the most severe case and was initially managed in an adult ED with racemic epinephrine, codeine and lorazepam iwith initial improvement but represented 12 hours later with return of stridor at rest. She was subsequently transferred to the paediatric hospital, admitted to ICU, failed a trial of BiPap but had improvement after a second trial of Heliox with IV midazolam for anxiolytics. She required 22 hours of helix and dexmedetomidine infusion. She received 6 hours dexamethasone, had an initial dose of Ceftriaxone and given 5 days of IV Remdesivir. She required 4 days of PICU admission with intermittent helix and benzodiazepines for air hunger and respiratory distress and was able to be discharged the subsequent day. She had recovery by one week after discharge. Following these findings, the hospitals have subsequently started testing for SARS-CoV-2 in all children presenting with croup. Whilst more data is required to further understand the presentation of children with SRS-CoV-2 and croup, these cases suggest children with SARS-CoV-2 who do require nebuliser epinephrine tend towards more severe courses of illness.

Chong, CThoon, KClin Infect DisSaliva is not a useful diagnostic specimen in children with Coronavirus Disease 201914 Sep 2020SingaporeAsia18Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1376/5905581

This important pre-print letter from Singapore describes 18 children, 12 asymptomatic, mean age 6.6years, 10 of whom were boys. 53 paired samples of saliva and nasopharyngeal swabs were taken between 22 June and 22 July 2020 during the children’s admission, mean 3.1 paired samples per child.

The detection rate of COVID-18 was significantly lower in saliva than in nasopharyngeal samples with the best sensitivity of only 52.9% in the saliva samples taken between days 4-7.

The authors conclude that “saliva is not a useful specimen for diagnosing COVID-19 in children”

Nino, GLinguraru, GMPediatr PulmonolPEDIATRIC LUNG IMAGING FEATURES OF COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS14 Sep 2020Systematic review and metanalysisSystematic review and metanalysis1026Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25070

Nino et al conducted a systematic review of the literature using PubMed from 1st December 2019 to 11th July 2020 to describe lung imaging features of COVID-19 in children. They included studies that were peer-reviewed and including children aged 0-18 years with confirmed SARS-CoV-2 on reverse transcription PCR with chest imaging. If a study described both adult and paediatric cases, it was only included if paediatric cases were reported separately. Single case reports and literature reviews were excluded. 3278 articles were found and after various exclusions, the authors were left with 29 studies. They found chest x-ray descriptions were not consistently reported, with no studies describing ultrasound findings, and so when they extracted data for meta-analysis they chose to only analyse CT findings. The 29 studies had a pooled sample size of 1026 children with a mean age of 6.57 years (range 1.5 – 14.5 years).

Their findings boil down to:

• Just over a third of children had normal CT chests (35.7%l; 95% CI: 27.5%-44%). The authors compared this to a recent meta-analysis of lung CT changes in adults, stating that children are 3 x more likely to have a normal CT.

• Just under a third had bilateral lung involvement (27.7%; 95% CI: 19.9%-35.6%).

• The most common finding was ground glass opacities, reported in a little over a third of cases (37.2%; 95% CI: 29.3%-45%), somewhere in the region of half as common as in adults with COVID-19.

• The second most common finding was consolidation or pneumonic infiltrates in approximately one fifth of cases (22.3%; 95% CI: 17.8%-26.9%).

• All other lung CT findings reported in adults with COVID-19 were very uncommon (e.g. halo sign, interstitial changes, interlobular septal thickening, bronchovascular bundle thickening, crazy paving pattern, lymphadenopathy, pleural effusion or pleural thickening).

• Findings typically found in other paediatric respiratory infections, such as hyperinflation, were not seen.

The authors describe several limitations, the biggest being that only CT findings were described, despite the fact x-ray is more frequently used in children. They were also unable to correlate imaging findings with disease severity due to the lack of clinical data in the papers studied. Although the data analysed was from multi-national datasets, the majority were from China, particularly near Wuhan, and so were less international than on first appearances. The authors also explain that radiologists from different parts of the world use different terminology, giving the example “shadow” being often used to describe lung opacities, without specifying whether these were ground glass opacities, pneumonic infiltrates or something else. Perhaps more topically, there were no studies including lung imaging findings in Pediatric Inflammatory Syndrome.

What can we take away from this paper? There are two messages:

• lung CT findings in children with COVID-19 are less frequent and less severe than in adults

• typical changes seen in other paediatric viral respiratory infections do not seem to be present in children with COVID-19

This information may not be particularly useful in clinical practice, except in severely unwell children with COVID-19. Given the risks associated with ionising radiation, plus the not infrequent need for sedation, CT is not commonly used in children with COVID-19, except in extreme cases.

Han, MSChang, SHJAMA PaediatrClinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea28 Aug 2020KoreaAsia91Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2770150

This Korean case series examined children aged 0-18 years with COVID-19 who presented across 22 facilities (20 hospitals) from February 18-March 31st 2020. It focuses on clinical features and duration of SARS-CoV-2 RT-PCR detection. A total of 91 were identified by SARS-CoV-2RNA RT-PCR on nasopharyngeal/oropharyngeal or sputum swabs due to testing for one of the following reasons: symptomatic, close contact with a confirmed case, testing as apart of outbreak or screening on return from overseas.

Demographics included 53 (58%) male cases, with the median age being 11 years (range 27 days - 18 years). The majority (85, 93%) were previously well. Of the 6 with underlying medical conditions, 3 had asthma and epilepsy respectively.  Exposure was from a household contact in 57 (63%) of cases, with 15 (17%) imported, 11 (12%) cluster-associated, 4 from another contact and 4 remaining an unknown source.

Cases were mostly mild (46, 51%) or asymptomatic 20 (22%). There were 20 moderate, 2 severe cases and 3 unclassified. No children required mechanical ventilation. Fever ≥  38 as seen in 27 (30%) of patents, 54 (60%) had cough or coryza , 8 had loss of smell or taste, 5 had anosmia and 16 (18%) had gastrointestinal symptoms including diarrhoea and abdominal pain. Only one patient had gastrointestinal symptoms without fever or respiratory symptoms. Two thirds of children had symptoms prior to diagnosis (median time 3 days). The duration of symptoms for cases lasted a median of 11 days (range 1-36 days).

The children were tested for SARS-CoV-2 repeatedly to determine cessation of virus RNA detection, however intervals were not standardised, with a median of 3 days (range 1-15 days). Children who were asymptomatic had virus RNA detectable for an average of 14.1 days, and those with URTI or LRTI symptoms, at 18.7 and 19.9 days respectively (difference between these groups was not significant). Twelve children were given treatment with lopinavir-ritonavir and two with hydroxychloroquine. There was no difference in detection between the groups treated with the antiviral lopinavir-ritonavir or not.

This study confirms what many previous studies have demonstrated, which is that children with SARS-CoV-2 can remain PCR positive for prolonged periods. This study adds that this is also the case for children who do not develop symptoms. What is unclear is for how long this represents live virus with replicative potential. Culturable virus has not been detected beyond day 8 of symptoms. The authors of this study did not provide ct values which would enable some estimate of the presence of culturable virus (low ct values usually represent viral fragments).

Oterino Serrano, CBret-Zurita , MEur J RadiolPediatric chest x-ray in covid-19 infection26 Aug 2020spain Europe44Clinical - Clinical Featureshttps://www.ejradiology.com/action/showPdf?pii=S0720-048X%2820%2930425-3

Introduction: This is a radiological case series of the chest x-rays of 44 paediatric patients with confirmed SarsCoV2 infection from a tertiary paediatric hospital in Spain.

Patients <16 years from, 13th March to April 6th 2020, with positive PCR who had a clinical need for a chest x-ray were included. The indication for x-rays were not reported, so the precise nature of this cohort is unclear. All patients were admitted to hospital, so these findings likely represent the most unwell children with COVID-19. Two paediatric radiologists retrospectively and independently reviewed the chest x-ray films to determine the abnormality, distribution and evolution, if repeat x-ray was available.

Patient demographics : Of 44 patients, 29 were male (65.9 %). Median age was 79.8 months (2 weeks – 16 years). 23 (52.3%) had an underlying condition; cardiomyopathies (13.6 %), nephropathies (9%), history of prematurity (6.8 %), liver and renal transplantation (4.5 %), and neoplasm (4.5 %).

Radiological findings : 38 (86%) x-rays had peri-bronchial thickening, mainly perihilar (81%). Ground glass opacities (GCO) occurred in 40%. Consolidation was seen in 8, and a pleural effusion in 4. Four children had a normal chest x-ray. Most children recovered quickly and were discharged. Persistence or worsening of symptoms was observed in 15.9 % of the patients (7/44), they had new consolidation or worsening of features on their repeat x-ray. Unfavourable outcomes were more frequent when initial X-ray had bilateral involvement, diffuse affectation and combination of peri-bronchial cuffing and GGOs.

Conclusion: Most children with symptomatic COVID 19 requiring admission to hospital had some chest x-ray abnormalities, mainly perihilar thinking and ground glass opacities. In general the chest X-rays of children with Covid 19 are non-specific, and not sensitive to the disease.

Yonker, LFasano, AjpedsPediatric SARS-CoV-2: Clinical Presentation, Infectivity and Immune Responses19 Aug 2020USANorth America192Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31023-4/fulltext

This is an observational cohort study from Massachusetts General Hospital, Boston, USA

192 "children" (ages were 0-22 years) were enrolled when they presented with possible Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) at urgent care clinics (with symptoms or because of contact with a case) or were hospitalised with confirmed/ suspected SARS-CoV-2 or Multisystem Inflammatory Syndrome in Children (MIS-C). Dates of enrolment are not given.

Samples were collected after consent/assent: Nasopharyngeal swabs (83 samples), oropharyngeal swabs (105) and blood (100). Viral load was determined from respiratory and plasma samples, and ACE2 expression in the upper airways from the swabs.

Results

125(65%) children were SARS-CoV-2 negative, 49(26%) had acute SARS-CoV-2 infection and 18(9%) had MIS-C. MIS-C children were more likely to be younger and male.

.80% of the SARS-CoV-2(+) children had a known household contact but so did 44% of the SARS-CoV-2(-) and 45%of the MIS-C children. SARS-CoV-2(+) and (-) children presented similarly with non-specific symptoms, and anosmia occurred in 20% of the SARS-CoV-2 (+) group. MIS-C children most commonly had fever, followed by nausea and vomiting, and rash. There was no significant prevalence of any co-morbidities in any of the groups

Viral load in the respiratory samples of the SARS-CoV-2(+) was comparable to adults despite mild or absent symptom even in the youngest children. A comparison is made between children within 2 days of symptom onset and hospitalised adults after 7 days of symptoms, which is unhelpful as these time points are clearly not comparable (viral load rapidly decreases after onset of symptoms).

SARS-CoV-2 antibody response data is presented and is said to show a generalised enhancement of humoral immune responses as a marker of severe MIS-C

ACE2 gene expression of the upper airway was quantified by NP/OP swabs from both infected and non-infected children. ACE2 levels were higher in those with infection of SARS-CoV-2 and those with MIS-C (difference 10-4 – 10-5 log, p=0.004), and there was an increase of ACE2 expression with age, although with high variability. There was no association between ACE2 expression and viral load.

In summary, this study confirms a number of already known elements regarding children with COVID-19 or MIS-C, including that viral loads appear comparable to adults and that many symptoms are non-specific. This study confirms increasing ACE2 expression with age, which may in part explain reduced susceptibility to acquiring infection. Of interest is lack of correlation between viral load and ACE2 expression. Despite strong claims about transmission by the authors, the study does not address this question or add new information on this point.

Carter, MShankar-HariNat MedPeripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection18 Aug 2020United KingdomEurope25Clinical - Clinical Featureshttps://www.nature.com/articles/s41591-020-1054-6.pdf

This study examines the peripheral leukocyte phenotype of children with multi-system inflammatory syndrome in children (MIS-C).

A total of 25 children with a median age of 12.5 (range 7.7-14.4) were included. Clinical features of MIS-C were most commonly gastrointestinal symptoms (72%), polymorphous non-blanching rash (48%), and bilateral non-purulent conjunctivitis (40%). Only 2 (8%) children met criteria for Kawasaki Disease. Of note, 7 (30%) had coronary artery aneurysms. Treatments during admission included high-dose corticosteroids (80%), intravenous immunoglobulin (92%) and biologic agents (56%). Majority (84%) required admission to the paediatric intensive care, however only 2 (8%) of children required mechanical ventilation. Only 1 child (4%) was positive for SARS-CoV-2 PCR, however 17 (68%) were SARS-CoV-2 IgG antibody positive.

Leukocyte phenotyping was done during the acute (n=23), resolution (n=14), and convalescent (n=10) phase of illness. In the acute phase of illness, elevated levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T an B cell subset lymphopaenia were observed. In addition, there were decreased levels of HLA-DR and CD86 expression on antigen-presenting cells. Interestingly, the differential expression of these markers and elevated cytokines resolved as the child recovered.

This important study demonstrates that MIS-C is a distinct immunopathogenic illness. Future studies including larger cohorts of children will be critical in rational development of future therapies for this condition.

Swann, OSemple, MBMJClinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study17 Aug 2020UKEurope651Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/370/bmj.m3249.full.pdf

This large prospective observational study from 260 hospitals in the UK examines the clinical characteristics of children (<19yo) hospitalised with laboratory confirmed SARS-CoV-2 infection between 17th January and 3rd July 2020; as part of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK cohort. The main outcome measures were admission to critical care, in-hospital mortality and MIS-C.

Results;A total of 651 children admitted to 138 hospitals were included; median age was 4.6 (IQR 0.3-13.7); 35% were <12 months of age. Of patients with recorded ethnicity 57% were white, 12% south asian and 10% black. 56% were male and 42% had identified co-morbidities. 

Symptoms;The most common symptoms were fever (70%), cough (35%) nausea / vomiting (32%) and dyspnoea (30%). Three distinct clusters of symptoms were identified:- a discreet respiratory illness - cough, fever, dyspnoea, coryza and wheeze- a mucocutaneous enteric illness - headache, myalgia, sore throat, vomiting, abdominal pain, diarrhoea, fatigue, rash, lymphadenopathy and conjunctivitis- a rarer neurological ilness - seizures and confusion

Critical care and mortality;Critical care admission occurred in 18% (116/632); 8% received inotropic support; 9% received non-invasive and invasive ventilation respectively. Children of black ethnicity had higher odds of critical care admission (OR 2.82). Infants <1mo (OR 3.21, 95% CI 1.36-7.66) and children 10-14 yo (OR 3.23, 95% CI 1.55-6.99) were also more likely to be admitted to critical care. Co-morbidities including prematurity, respiratory and cardiac co-morbidities and obesity were more common in those with critical care admission compared with those receiving ward care.Six (1%) of patients died in hospital, all had serious comorbidities; 89% of children had been discharged alive and 10% remained in hospital at the time of reporting.

MIS-C;Based on the preliminary WHO case definition, 11% (52/456) of admitted children fulfilled diagnostic criteria for MIS-C. Children with MIS-C were older than those without (median 10.7 yo vs 1.6 yo) and were more likely to be of non-white ethnicity (64% vs 42%); obesity was also more common amongst those with MIS-C (10% vs 2%). Children with MIS-C were more likely to require critical care admission (73% vs 15%), receive inotropes (51%), invasive (27%) and non-invasive (35%) ventilation. There were no deaths due to MIS-C.

Of children with MIS-C differences were noted between those who were SARS-CoV-2 PCR positive (acute phase of infection - 56%) and those who were antibody positive (post-acute phase of infection - 44%). Antibody positive MIS-C patients were more likely to be of non-white ethnicity (90% vs 45%), less likely to be obese (0% vs 19%), and more likely to have conjunctivitis (71% vs 16%) and abdominal pain (95% vs 44%) compared to those who were PCR positive. Dyspnoea was more common in PCR positive patients (52% vs 14%). Cardiac complications were also more common in the antibody positive group (75% vs 35%).

Conclusion;The findings of this large prospective study are consistent with previous studies indicating that children represent a small proportion of hospitalised cases of COVID-19 (0.9% here), that outcomes in children are generally favourable and that death due to COVID-19 in children is rare. Similar to previous studies, fever and cough were the most common symptoms, although gastrointestinal symptoms (35%) were more common in this cohort; the identification of a mucocutaneous-enteric symptom cluster with overlap with WHO MIS-C criteria is a novel finding here. Children of black ethnicity were over-represented in overall cases, as well as amongst children admitted to critical care units, consistent with adult data from the UK. Similarly, obesity was associated with increased risk of critical care admission. 

The association of MIS-C with older age and non-white ethnicity are consistent with previous studies. In addition to current WHO criteria, fatigue, headache, myalgia, sore throat and low platelet count were all associated with MIS-C.  The demographic and clinical differences identified between MIS-C patients who were antibody positive compared with those who were PCR positive suggest a spectrum of clinical presentation that varies according to phase of infection and immune response.

Liu, XChen, JJ Infect DisClinical and epidemiological features of 46 children under 1 year old with coronavirus disease 2019 (COVID-19) in Wuhan, China: a descriptive study 06 Aug 2020ChinaAsia46Clinical - Clinical Featureshttps://watermark.silverchair.com/jiaa472.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArgwggK0BgkqhkiG9w0BBwagggKlMIICoQIBADCCApoGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMRenTM0H7AWkHfH5OAgEQgIICa-S2TrctCjayBEO6MxumGRv8cRCshq5YspREyle7HGSz423KjAOkoj9JVSjYnFYK-4AQk_PsUNKgNEiFcKtzxQmmPcFQb4_qXmXXRN7VEKAErKU6bCp94py_9BedSlJbOqx2wvSTyzCA3lx5EpyXjnzmnkGejTdhXYkihOkNa25518np1FWNH7Q3yt3fdkYKfpw-iC8JoXgTZeJUTVn3gwt2t62nwQFHoHNkpQN4lkSFOLRJgvs_n1BJODja2d5JhsOn8kwMg0iQNMzsqNjtaeRa9DjqjejOXaabpQIBrBHGf6HmCENuAy3DkuJTHMSPhMzvScKHa3aTV6n6ue80OZIFX__w-ak7J6YVTNidfBkPIWXL0dX3jVSJlz43rmZLjNi6ybjK5MJA3nBqcN0_ooufj4DNH649asuiXPGEYzuhWfKaIcszBlAIDDIofvOdkMo5B5f1FKWwO-dugrZaOeuO94nPclWiKD5_B_qZX45eBO_a00oSKZYejJho2I6-z19l7qtekqRqIb9ETv4zrSqcguK2sP7wctnmntr3DirqK6Pdp3xs7UCoS_TOvmZgV2o8K8KEMZWHykkK-Zt_Aw5bJNT6_T8-WqNd9saE5ic49bnVRsItNtTaiOqmTjWaOzwvdObd69sTvy6acaya1fL2N5e0fveNorCnz-5AJZtgg0cXZH9mh1Y72xmTPA8EaGRhPoIZ8tNbSfWs21pVDfFoGJNRUhMM1HpJ6V62jpoQ1mDPS-_QD3KqpStGg4QOgyv60xYT3iPz0MND03xLjlqIbbqH-dXQ7w6vuBS_PTgaW7Wa_pduFkGIY_c

This restrospective case series study analyses the clinical features of 46 infants less than 1 years old who were confirmed to have COVID-19 at Wuhan Children’s Hospital (China) between the period 26th January 2020 to 15th March 2020. It was not described how these patients were identified for the study. 25 patients (54.35%) were male and 21 (45.65%) were female. The median age was 5 months (IQR 2-7 months). The authors classed 2 patients (4.35%) as having severe or critical disease, 40 patients (86.96%) as moderate disease, 2 patients (4.35%) as mild disease, and 2 patients (4.35%) as asymptomatic. Sadly one patient (2.17%) died (age 10 months), and the remaining 45 (97.83%) were discharged home.

Cough (n=27; 58.7%) and fever (n=16; 34.78%) were the predominant features, with a minority of other patients experiencing vomiting (n=5; 10.87%); Nasal congestion and rhinorrhoea (n=3; 6.52%); dyspnoea (n=1; 2.17%); tachypnoea (n=1; 2.17%); diarrhoea (n=1; 2.17%); and sneezing (n=1; 2.17%).

With regards to complications, the following were found: liver dysfunction (n=20; 45.45%); cardiac injury (n=38; 86.36%); acute gastroenteritis (n=3; 6.52%); multiple organ dysfunction syndrome (n=1; 2.17%); required mechanical ventilation (n=2; 4.35%).

Common laboratory findings included: Lymphocytosis (n=13; 28.26%); raised ALT (n=11; 25.00%); raised AST (n=20; 45.45%); raised lactate dehydrogenase (n=23; 52.27%); raised creatine kinase (n=10; 22.72%); raised creatine kinase MB (n=38; 86.36%); raised CRP (n=8; 19.05%); raised CD3+ T cell (n=10; 28.57%); raised CD4+ T cell (n=14; 40.00%); raised CD19+ B cell (n=16 patients; 47.51%); raised IL-10 (n=15; 44.12%).

Caro-Dominguez, Pvan Rijn, RPediatr RadiolThoracic imaging of coronavirus disease 2019 (COVID-19) in children: a series of 91 cases04 Aug 2020Spain, Italy, France, Iran, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico International91Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04747-5

This international multicentre retrospective study of 91 children with confirmed SARS-CoV-2 describes the radiological findings of their chest imaging. Data was included from Spain, Italy, France, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico. Chest x-rays were reviewed independently by 3 senior paediatric radiologists. Chest CT images were evaluated by a different group of 3 senior paediatric radiologists. Impressions were shared and consensus reached for each image.

Of the 91 children, 11% had severe symptoms requiring PICU and 30 (33%) had coexisting medical conditions including 16 immunocompromised children, 7 children with congenital heart disease and 7 with long-term respiratory conditions. Six (7%) children were asymptomatic.

81 (89%) of the children in the study had chest x-rays. Of these, 10% were entirely normal despite the children being SARS-CoV-2 positive. None of the children with a normal x-ray required PICU admission. The most common abnormal x-ray findings were increased central peribronchovascular markings, bronchial wall thickening (47, 58%) and consolidation (28, 35%). Ground glass opacities and interstitial changes were less common in 16 (19%) and 13 (16%) children respectively. Pleural effusion (6, 7%), pneumothorax (2, 2%) and atelectasis (2, 2%) were uncommon.

24 (26%) of the children had a chest CT, mostly adolescents. The most frequent indication for CT was as a screening tool where the wait time for PCR testing was long. 22 (92%) of the CT scans were abnormal. The two most common CT changes were lower lobe ground glass opacification (21, 88%) and consolidation (14, 58%). The patterns seen on CT mirrored those described in adult studies: peripheral ground glass opacities in early stages, with ground glass with consolidation with or without interlobular septal thickening in more severe cases.

Only 3 children had lung ultrasound. One is described in the article as showing the characteristic B lines in the posterior and lateral left lung and pleural thickening. One asymptomatic child had an MRI for another reason which showed characteristic changes of COVID-19. Following this scan she was tested for COVID-19 on the recommendation of the radiologists.

paper contains numerous examples of x-rays, CTs and lung ultrasound images. The authors make several conclusions, which can be summarised in six points: In contract to adult studies, “bilateral, peripheral and subpleural ground glass opacities and/or consolidation” is not the typical chest x-ray finding of COVID-19 in children.Instead, chest x-rays of children with COVID-19 are nonspecific, frequently demonstrating peribronchovascular markings and airspace consolidation, seen in many other lower airway inflammatory disorders, viral infections and pneumonia. They therefore cannot be used to differentiate between COVID-19 and other childhood lung infections and should not be used as a screening tool for diagnosis of COVID-19 If radiographic imaging is required in symptomatic children, chest x-ray should remain the first imaging modality of choice, to assess for infection or pneumonia.Paediatric COVID-19 CT patterns are predominantly lower lobe ground glass opacity, as in adults, plus a more centrilobular or peribronchovascular pattern, not seen in adults, although it is not clear if this is directly due to COVID-19 or coinfection with other respiratory infectious agents. These findings are nonspecific and resemble other lower respiratory tract infections.CT should be reserved for complex cases or when there is clinical concern to assess for possible complications.In general, paediatric lung ultrasound image quality is superior to that in adults due to a thinner thoracic wall, however the role of lung ultrasound in children with suspected COVID-19 is unclear. The authors suggest lung ultrasound should be evaluated as a potential radiographic tool in paediatric COVID-19.

Heald-Sargent, TKociolek, LKJAMA PaediatrAge-Related Differences in Nasopharyngeal SevereAcute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) Levels in Patients With Mild toModerate Coronavirus Disease 2019 (COVID-19)30 Jul 2020AmericaNorth America97Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2768952

This research letter looked at 145 patients aged 1 month to 65 years old who were symptomatic and had positive SARS-CoV-2 RT-PCR on nasopharyngeal swab at a paediatric hospital in Chicago between March 23 and April 27th, 2020. Included were 46 children aged <5 years, 51 aged 5-17 years of age and 48 adults. Cycle threshold values of RT-PCR were measured and compared across the three age groups. A significant difference was found with children under 5 having lower cycle threshold values than children aged 5-17 and adults. The older children and adults had no significant difference found in cycle threshold.

These findings are at odds with most other studies of viral loads in children, which have shown little clinically relevant difference to levels found in adults (or if anything slightly lower levels). The reason is unclear, but this study confirms what was already known, that children carry viruses in their nasopharynx which is potentially transmissible (previous studies have found culturable virus in children). To what extents this correlates with how infectious children may be remains unknown.

Pavel, A.BYassky, EEJACISARS‐CoV‐2 receptorACE2 protein expression in serum is significantly associated with age29 Jul 2020USANorth AmericaClinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/all.14522

This is a peer review letter to the editor of Allergy, where ACE2 protein expression was measured in children and adults with and without atopic dermatitis using a previous cohort and their samples.

Angiotensin converting enzyme 2 (ACE2) is an integral component of the renin angiotensin system SARS COV2 cell entry is facilitated by ACE2. It is proposed that lower prevalence and maturity of ACE2 in children is one of the reasons for less illness, and less illness severity in children .

Methods: This study used samples from a previous published cohort of 19 healthy infants and toddlers and compared to 17 healthy adults and compared to 29 infants/toddlers and 55 adults with moderate to severe atopic dermatitis. Those with atopic dermatitis are not known to have increased susceptibility to SARS COV2. This cohort was generally healthy with no history of cardiovascular disease. None of paediatric control or AD groups had asthma. None of the control adults, but 17 of the AD adults had asthma.

They also investigated Cathepsin L/CTSL1 in both infant/adult and healthy/AD cohorts. CTSL1 is a protease which cleaves and primes SARS-Cov-1 spike protein, and is hypotheseized to play a similar role in SARS-CoV2.

Results: Adults had more ACE 2 expression than infants/toddlers. AD did not influence ACE2 expression. Males expressed ACE2 more than females. In a sensitivity analysis there was a trend towards increased expression of ACE2 in African American adults, and both African American and Asian toddlers.

CTSL1 was significantly greater in adults than infants/toddlers and was positively associated with ACE2 expression.

Conclusion: These results reflect what is already known, that ACE2 expression is higher in adults than infant/toddler and in men rather than women. It also suggests, and reflects what is seen clinically, that atopy does not increase risk of morbidity or mortality for Covid -19

Moraleda, CTagarro, AClinical infectious DiseasesMulti-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain25 Jul 2020SpainEurope252Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa1042

Clusters of children with a multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) have been reported in Europe and the USA. The authors describe the epidemiological and clinical features in a case series of children with MIS-C in Spain from March 1st to June 1st, 2020. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection. Children younger than 18 years with infection due to SARS-CoV-2 and attended at 49 hospitals were included in this registry. Inclusion criteria included positivity in real-time polymerase chain reaction (RT-PCR) positive, IgM or IgG in lateral-flow rapid test, ELISA or immuno-chemiluminescence serology, or severe disease suggestive of MIS-C and recent household contact with a confirmed patient with COVID-19.

Results; In the study period, 312 patients attended 49 hospitals, and 252 participants were hospitalized. Of them, 181 (72%) were admitted due to causes directly or likely related to SARSCoV-2. The remaining 71 (28%) were admitted due to causes not related with SARS-CoV-2, but were screened and found to be infected with SARS-CoV-2. A total of 31/252 (12%) children were diagnosed as MIS-C and/or Kawasaki disease by their physicians.

 

The peak of MIS-C cases were one month after the peak of admissions for other COVID-19 related reasons and decreased afterward.

Median age and interquartile range were 7.6 [4.5; 11.5] years. A total of 30 (97%) children had microbiological or serological evidence of SARS-CoV-2 infection, and the remaining patient, an 11- year old boy with incomplete Kawasaki disease and pericardial effusion, had epidemiological household contact with a COVID-19 adult patient, his father.

The World Health Organization recently released diagnostic criteria for this condition. All the described patients fulfilled the WHO case definition for MIS-C, except for 1/31 patients (3%). Rash or bilateral non-purulent conjunctivitis, or muco-cutaneous inflammation signs were found in 21/31 (67%) patients; hypotension or shock in 15/31 (48%), features of myocardial dysfunction 25/31 (80%) consisting of pericarditis, valvulitis, arrhythmias or coronary abnormalities in 19/31 (61%); 6 (19%) additional children had only an elevation of a biochemical marker of heart dysfunction (NT-proBNP); evidence of coagulopathy (specifically, elevated D-dimers) was found in 29/30 (97%), and acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain), in 27/31 (87%). No other apparent microbial cause of inflammation as sepsis or staphylococcal or streptococcal shock syndrome was found.

One child already on oral steroids for interstitial lung disease did not fit the WHO criteria for raised inflammatory markers but was included as all other criteria were met.

Thirteen children (45%) fulfilled the criteria of complete or incomplete Kawasaki disease.  Twenty (65%) patients needed admission to the Paediatric Intensive Care Unit, and 6/31 (19%) invasive mechanical ventilation. Cardiac complications consisted of myocardial dysfunction (15/31; 48%), pericardial effusion (6/31; 19%); valvular dysfunction (9/31; 29%), arrhythmias (7/31; 23%) and coronary abnormalities (3/31; 10%, among them 1 aneurysm). Four patients (13%) had renal failure.

Two (6%) patients received Remdesivir and 7/31 (23%) Lopinavir/Ritonavir. A total of 21/31 (68%) children received corticosteroids: 19 of these received methylprednisolone (13 patients received doses of 1 to 2.5 mg/kg/day; 2 patients boluses of 8 and 30 mg/kg/day for 3 days; 4 had dosing unavailable), 20/31 (65%) patients received 2 gr/kg of intravenous immunoglobulin (IVIG) and 13/31 (42%) patients received both IVIG and corticosteroids. All but three patients received broad spectrum antibiotics.

One patient with acute leukaemia and bone marrow transplant died, and one 6-month-old patient (with Downs Syndrome) developed anterior-descendant coronary aneurysm (z-score +9). The rest recovered without sequelae.

Limitations of this study include that some cases without microbiological, serological or epidemiological links may not have been included in this registry. 

The authors conclude SARS-CoV-2 could be a relevant trigger for a delayed cytokine storm and an inflammatory condition, with potentially severe consequences. Coinfections as hMPV may be present and might play a role in triggering the immune response. It is possible that some particular patients with special features such as chronic immunosuppressive treatment influencing inflammatory markers - may have MISC but not fulfil all WHO criteria.

Conclusion The authors concluded MIS-C is a potentially severe condition that presents in some children after SARS-CoV-2 infection. Physicians should be aware of this severe condition in children during COVID-19 epidemics. More studies are necessary to clarify the physiopathology of this syndrome and its treatment. 

Comment Even when removing the child without serological evidence of COVID-19 and the child which did not meet WHO criteria in this study, 29/252 or 11.5% of hospitalised patients developed MIS-C which is significant One death was reported in a patient with leukaemia and one complication in a patient with Downs syndrome but the rest of the patients (27/29, 93%) recovered without sequelae.

Prata-Barbosa, ACunha, AJ Pediatr (Rio J)Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study19 Jul 2020BrazilSouth America79Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0021755720301923

Date, patient identification and location. Between 1st March 2020 and 31st of May 2020, 79 patients aged 1 month to 19 years consecutively admitted to 19 pediatric intensive care units in Brazil with confirmed COVID-19 (RT-PCR in 72/79 and IgM and/or IgG antibodies in the other 7/79) and were included. 10 of these patients including 5 that only had positive antibodies had multisystem inflammatory syndrome (MIS-C) .

Age: median age 4 years( range 1 to 10.3 years)

Gender:43/79( 54%) male.

Ethnicity: 58% were white,25% mixed race, 15% black and 1% Asian.

Comorbidities:32/79( 41%) had previous comorbidities with neuromuscular disease predominant (28%) and chronic respiratory disease 19% , congenital heart disease 16%, diabetes 6% , undernutrition 6% and obesity 3%.

Clinical features : most common symptom was fever 59/79 (76%), followed by cough 40/79(51% ), tachypnoea 39/79 (50% )low oxygen saturation 23/79 (29%) , runny nose 17/79 (22%), diarrhoea 16/79(21%), vomiting 16/79(21%) and red throat 3/79(4%).

In MIS-C (n=10) : presentation included Kawasaki like disease 6/10 (60%), acute cardiac dysfunction 2/10(20%), toxic shock syndrome 1/10(10%), Macrophage activation syndrome 1/10(10%).

.Radiology: 42/68 (62%) had abnormal chest radiographs with 25/42(60%) having diffuse interstitial infiltrate. Chest CT with ground glass opacities in 19/38 (50%).

Bloods: Lymphopenia in 21/59(36%) of non MIS-C group and 5/10(50%) of MIS-C group.

Inflammatory markers including ESR,CRP,LDH,D-dimer, procalcitonin and ferritin were tested in varying number of cases but mainly in MIS-C group and were elevated in most tested patients.

Outcome: 32/79(41%) needed only oxygen therapy. Invasive mechanical ventilation was needed in 14(18%) for median of 7.5 days . Comorbidities were independently associated with the need for invasive mechanical ventilation (OR 5.5). Antibiotics , Oseltamivir and corticosteroids were used in 76%, 43%, and 23% respectively . The median intensive care length of stay was 5 days . There were 2 deaths (3% ) both in none MIS-C group. Age less than 1 year was not associated with a worse prognosis and patients with MIS-C had more severe symptoms, high inflammatory biomarkers but only comorbidities and chronic disease were independent predictors of severity.

Comment and Justification: this is the first study on COVID-19 in Pediatric CIU patients in Brazil which currently has one of the highest rates of infection .It has shown that the characteristics of the disease in Brazil are similar to other countries except age less than 1 year was not associated with a worse prognosis.

Kainth, MLorry, GRPediatricsEarly Experience of COVID-19 in a US Children's Hospital17 Jul 2020USANorth America65Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/07/15/peds.2020-003186

is the first comprehensive report from a major US paediatric centre. It describes all admitted cases of COVID-19 in children and young people (CYP) aged 0-22 years, from 23 Jan to 23 April 2020. It comes from the Cohen Children’s Medical Centre, just outside New York City, which serves a relatively deprived urban population. All had SARS-CoV-2 PCR positive antigen tests.

results are broadly similar to earlier reports from China and Europe, but with some interesting detail. Of the 65 admissions, the median age was 10.3 years, but there was a bimodal distribution, with 29% being infants of < 3 months, and 48% older than 12 years. Those with an underlying medical condition were over-represented (55%).

disease severity was considered mild in 60%, moderate in 26% and severe in 14%. Mean duration of hospital stay was 3.2 days. 23 (35%) went to intensive care. The older CYP did worse than the infants: 44% of 16 previously healthy CYP required any sort of respiratory support (1 ventilated), compared to 26% of 19 infants (none ventilated).

with either immunocompromise (e.g. cancer treatment) or chronic illness (e.g. chronic lung or neuromuscular disease) were identified separately. Although over-represented in the admissions, most did well: 21% of the 14 immunocompromised required oxygen or any respiratory support (3 ventilated), as did 44% of the 16 chronically ill (5 ventilated). There was one death, a toddler with advanced neuromuscular disease. Only one developed multisystem inflammatory syndrome (MIS-C).

esity was a significant risk for admission (but not for severity): 58% of the previously healthy children were obese, more than expected for the population.

expected, the most common presenting symptoms and signs were fever (86%), upper respiratory signs (34%), lower respiratory signs (60%), anorexia (40%), myalgia (34%), abdominal pain (17%) and headache (17%). Two had seizures. Anosmia was rare (1). Interestingly, only 4/10 with known asthma presented with wheezing.,

estigation findings were similar to earlier reports. Increased CRP and white cell counts were seen, showing strong associations with disease severity. Chest X-ray abnormalities were more common than might be expected from clinical status: 21 of 43 X-rayed had abnormal findings.

iviral ‘treatment’ of some sort was given to 40%, including hydroxychloroquine, remdesevir, anakinra and corticosteroids. Outcomes so far were good: 83% discharged well, 5% discharged with ‘sequelae’, 11% still inpatients.

this is further evidence, this time from an American population, that Covid-19 is less dangerous in children than adults, and that the prognosis is good in the vast majority. This is in spite of this population’s high prevalence of underlying serious conditions, obesity, and relative deprivation.

Derespina, KRMedar, SSJ PediatrClinical Manifestations and Outcomes of Critically Ill Children and Adolescents with COVID-19 in New York City.16 Jul 2020USANorth America70Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S002234762030888X

This multicenter retrospective observational study from New York City, USA, considers admissions of patients up to 21 years of age to 9 paediatric intensive care units (PICU) in New York City between 14 March 2020 and 2 May 2020. The authors consider 70 patients who are critically ill with COVID-19 positive nasopharyngeal swabs, and present their clinical manifestations, factors associated with PICU admission, and length of hospital stay. The data collection occurred prior to the definition of the multisystem inflammatory syndrome in children, therefore this presentation is not represented in this study.

he median age of patients included is 15 (IQR 9, 19). 61.4% are male. 74.3% had at least one comorbidity. 72.9% presented with fever, and 71.4% presented with cough. Bi-lateral infiltrates were the most common chest X-ray finding (50%). CRP, procalcitonin, lactate, pro-BNP and IL-6 were elevated. ARDS was associated with significantly longer duration of admission. Back/Latino race was associated with higher probability of discharge home by day 28.

NOTE – Some duplication of data :31 out of the 70 patients who are described in this paper have been discussed in other published reports.

Gaborieau, LMadhi, FJ Clin Med 9(7)Epidemiology and Clinical Presentation of Children Hospitalized with SARS-CoV-2 Infection in Suburbs of Paris14 Jul 2020FranceEurope192Clinical - Clinical Featureshttps://www.mdpi.com/2077-0383/9/7/2227

This paper presents the demographic characteristics, presenting symptoms, co-morbidities, and clinical progression of 192 children hospitalized with either confirmed nasopharyngeal PCR for SARS-CoV-2 (157) or strongly suspected but negative PCR (35) in the Ile-de-France département, in and around Paris, during their period of lockdown, from 23/03/20 to 10/05/20. The male:female ratio was 1.3:1. Those aged <1 made up 49% of the group, and those under ≤1 month, 17.7%. 29.2% had an underlying medical condition. Twenty four (12.5%) required PIC, 19 required ventilatory support (12 by mechanical ventilation) and 3 died.

Wardell, HDixit, AJ Pediatr Infect DisSARS-CoV-2 Infection in Febrile Neonates09 Jul 2020USANorth America4Clinical - Clinical Featureshttps://academic.oup.com/jpids/article/doi/10.1093/jpids/piaa084/5869489

Case reports of 4 term male neonates presenting with fever and testing positive for SARS-CoV-2, in Boston, USA, between 17/04-06/05/20. All infections were likely to have been acquired postnatally from close household contacts. Two had co-infection (1 E. coli UTI, 1 human metapneumovirus). All made a full recovery after a brief illness but 1 was still shedding virus when last tested (20 days). One had evidence of myocardial dysfunction which was postulated to be consistent with a pulmonary immunovascular coagulopathy model. This neonate did not have any co-infection and was treated with remdesivir; claimed to be the first reported use of this drug in a neonate. The only neonate with lymphopenia was that co-infected with hMPV. Authors advise continuing to screen febrile neonates for other infections even when there has been close contact with a proven case of SARS-CoV-2 and the neonate itself is positive.

Yudan, DWenbin,GFront PediatrClinical Characteristics of Children With COVID-19: A Meta-Analysis03 Jul 2020ChinaAsia396Clinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00431/full

This is a meta-analysis of papers published between 1 January and 1 April 2020 undertaken by Chinese authors. The authors undertook a literature search and identified 121 papers worldwide, only 33 studies met the inclusion criteria and more than half these were case reports. Interestingly all the included papers were from China.

396 children in total were identified with an age range 0-17 years (mean 5.5 years), just over 60% were >5 years old, 58% were male. 6.1% of all the included children had underlying diseases. In terms of the transmission route, 86.4% of the children with COVID-19 had close contact with family members with COVID-19 and 10% tested positive for other pathogens, such as influenza virus types A and B and Mycoplasma pneumoniae.

Fever (51.2%) and cough (37.0%) were the most frequent symptom, 17.4% of the children had asymptomatic infections. Furthermore, 66.7% had pneumonia, and 19% had radiologic features of pneumonia but were asymptomatic. Five developed severe or critical illness and required intensive care. The authors report that as of April 1, 2020, two child deaths were recorded in China (a 10-month-old child and a 14-year-old boy) but do not say if these two children were part of the study cohort.

The most frequent abnormal laboratory findings were leukopenia/lymphopenia (28.9%) and increased creatine kinase (20.%). Ground glass opacities were observed on CT scans in 53.9% of the children diagnosed with pneumonia.

The nineteen case reports included 25 patients. Their mean age was 4.6 years 48% were male, and 36% were older than 5 years. 76% of these were in a family cluster. No cases had underlying diseases or other pathogenic infections. Common clinical manifestations included fever (60%), nasal congestion/rhinorrhoea (28%), cough (24%), and digestive tract symptoms (24%). In addition, 11 (47.8%) of the 25 patients had pneumonia, four (16%) were asymptomatic but with imaging features of pneumonia, and one (4%) was critically ill. No deaths were reported. Five (25%) children had GGO on their CT scan. The most prevalent abnormal laboratory finding was increased creatine kinase (58.3%), followed by increased procalcitonin (55.6%), increased LDH (44.4%), and increased white blood cells/lymphocytes (36.8%)

In their discussion the authors conclude “Children are at a lower risk of developing COVID-19 and likely have a milder disease compared with adults. However, the evidence presented in this study is not satisfactory. Further investigations are urgently needed, and our data will be continuously updated.”

Denina,MGarrazino,SPEDIATRICSLung Ultrasound in Children With COVID-1901 Jul 2020ItalyEurope8Clinical - Clinical Features https://pediatrics.aappublications.org/content/early/2020/06/12/peds.2020-1157

Between March 18th and 26th 2020 8 children (age range 3 months to 10 years), 5 of whom were boys were admitted to Regina Margherita Children’s Hospital, Turin with Covid 19 respiratory tract infections. All 8 children had linear array chest ultrasound during routine medical examination. Although the number of patients analysed was small, the high concordance between radiologic and LUS findings suggested that ultrasound may be a reasonable method to detect lung abnormalities in children with COVID-19. The advantage of LUS was that the investigation could be done at the bedside, thus preventing transport of a potential infectious patient through a hospital

Wu, QXing, QPediatricsCo-infection and Other Clinical Characteristics of COVID-19 in Children 01 Jul 2020ChinaAsia74Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/05/04/peds.2020-0961

This retrospective study from 2 hospitals in China examines the clinical and epidemiological characteristics of 74 children with confirmed SARS CoV-2 infection. Consistent with other studies, the majority of children experienced a mild course of illness with only one severe case requiring non-invasive ventilation. All recovered.

Cough was present in 32%, fever in 27% and 40% were asymptomatic at the time of testing. Lymphopenia was present in only 5% of cases. Abnormal CT imaging was observed in 50%, but only 12% showed typical changes of COVID-19.

Of those tested for other respiratory pathogens 19 of 34 had co-infection. Mycoplasma pneumoniae (16) and RSV (3) were the most common pathogens. It is not clear how these pathogens were identified. The significance of Mycoplasma in particular is not entirely clear as asymptomatic upper respiratory tract carriage in children is well recognised; similarly in interpreting serology, false

positives can be problematic.

For cases where exposure history was available 65/68 were household contacts of a confirmed adult case. There was no evidence of transmission from children to others.

This data is consistent with larger paediatrics studies demonstrating a milder course of COVID-19 in children compared with adults. Notably co-infection was not uncommon, illustrating that the presence of another respiratory pathogen should not preclude SARS-CoV-2 testing in children.

Abdel-Mannan, OHacohen, YJAMA NeurolNeurologic and Radiographic Findings Associated With COVID-19 Infection in Children01 Jul 2020UKEurope55Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamaneurology/fullarticle/2767979

This is a retrospective case-series from the United Kingdom of children with neurological symptoms, identified from a larger cohort (n = 55) of SARS-CoV-2 positive children. Of the 55 children, 27 had features of paediatric multisystem inflammatory syndrome (PIMS-TS) and of these, 4 had neurological symptoms.

Clinical Features: The four children had a median age of 12 years (range 8-15 years) and interestingly, two children were of South Asian ethnicity and two of Afro-Caribbean ethnicity. Of the neurological symptoms reported, encephalopathy (4/4), headache (3/4) and brainstem signs such as dysarthria or dysphagia (2/4) were most common. Peripheral nervous system involvement was present in all patients and included proximal muscle weakness (4/4) and decreased reflexes (2/2). Neurological symptoms occurred alongside a range of systemic symptoms but were part of the initial presentation in 2 children.

Investigations: The four children had a range of investigations, including a lumbar puncture (2/4), EEG (3/4), EMG (3/4), MRI (4/4). The CSF was acellular and SARS-CoV2 negative, mild excess of slow activity was seen on EEG, and EMG showed mild myopathic and neuropathic changes. Interestingly, MRI findings were consistent in all four children, and included signal changes in the splenium of the corpus callosum. Three of the four children also had T2 hyperintense lesions associated with restricted diffusion.

Treatments: Therapeutics given varied. Three children received treatment for PIMS-TS more broadly, including methylprednisolone (2/4), dexamethasone (2/4), IVIG (2/4), anakinra (2/4), and rituximab (1/4).

Outcome: At the time of follow-up (median 18 days, range 11-13 days), 2 patients remain in hospital and have residual lower limb weakness and require a wheelchair to mobilise, and 2 patients have been discharged ambulating without support.

Overall, this paper provides a thorough description of neurological features associated with SARS-CoV-2 infection in the setting of multisystem inflammation.

Li, JDai, XJ Med Internet ResIdentification of Symptoms Prognostic of COVID-19 Severity: Multivariate Data Analysis of a Case Series in Henan Province30 Jun 2020ChinaAsia12Clinical - Clinical Featureshttps://www.jmir.org/2020/6/e19636/pdf
Acker, KHan, JClin Pediatr (Phila)Infectious Diseases Diagnoses of Children Admitted With Symptoms of Coronavirus Disease 2019 During an Outbreak in New York City27 Jun 2020North America North America42Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820944399?journalCode=cpja

This is a retrospective review of children with symptoms consistent with COVID-19 who were admitted at a single institution in New York City from March 12th to March 26th. Forty-two children were identified and had symptoms including fever (31), cough (21), increased work of breathing (17) and rhinorrhoea/congestion (16).

Of the 42 children, 5 (12%) had SARS-CoV-2 on nasopharyngeal swab, 15 (36%) had rhinovirus/enterovirus, 4 (10%) had human metapneumovirus 4, and 4 (10%) had bacterial infections. Overall, majority of children (25; 60%) had an infectious agent identified and were SARS-CoV-2 negative. Of the 5 children with SARS-CoV-2, two were neonates discharged within 72 hours with negative bacterial cultures, one was a 7 year old with MRSA bacteraemia and SARS-CoV-2 bacteraemia, one was a 14 year old with leukaemia who presented with fever, and the final patient had acute respiratory distress and required intubation, but was also positive for rhinovirus/enterovirus.

This small study demonstrates that even in the height of the outbreak in New York City, SARS-CoV-2 was responsible for a minority of admissions in children with respiratory symptoms. This highlights the importance of including SARS-CoV-2 in the list of differential diagnoses but ensuring appropriate investigations for viral and bacterial coinfections.

Götzinger, FTebruegge, MLancetCOVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study25 Jun 2020Europe (Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the UK)Europe582Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30177-2/fulltext

This European multi centre cohort study recruited from participating centres from  the Paediatric Tuberculosis Network European Trials Groups, to look at 582 cases of paediatric (<18 years old) SARS-CoV-2 infection in 21 countries with 77 healthcare centres. Centres from five additional countries reported no SARS-CoV-2 cases at the time of the study. The breakdown of centres included 454 (78%) tertiary, 54 (9%) secondary and 74 (13%) primary healthcare providers.

Cases were collected retrospectively from known cases prior to 1st April and prospectively between 1-24th April. Diagnosis was made on RT-PCR of SARS-CoV-2 alone. The age group of the population was young, with a median age of 5 (IQR 0.5-12) and 230 (40%) under 2 years of age. Just over half were male (n=311, 53%).

Index case data from history was included, with parents being the suspected index case for 324 patients (56%) and siblings accounting for 24 cases (4%). However a large number of cases (n=234, 40%) were either from someone outside of the immediate family or of unknown transmission.

The most common symptoms patients presented in were fever (n=379, 65%) and respiratory symptoms (n=313, 54% URTI and n=143, 25% LRTI). 128 (2%) had gastrointestinal (GI) symptoms and 40 (7%) had GI symptoms without respiratory symptoms. Asymptomatic patients accounted for 16% of all cases (92). There was confirmed viral co-infection in 5% (n=29) of patients. The study did not capture laboratory values. Chest x-ray was performed in 34% (n=198) of patients. Almost half of the x-rays showed findings consistent with pneumonia and ten (5%) of ARDS.

Of the patients in the study, a quarter (145) had pre-existing medical conditions. Twenty nine patients had pre-existing respiratory conditions (asthma accounting for 16) and malignancy was known in 27 patients. The study collected data on antiviral treatments administered however numbers were small and depended on local practice.

Across the cohort 363 patients (62%) required hospital admission, 48 (8%) required ICU admission. Factors increasing risk of ICU admission (n=48) were found to be age <1 month (n=7/48, 14.6%) the presence of any pre-existing medical condition (n=25/48 52%) and presence of lower respiratory tract infection signs at time of presentation (n=35/48, 73%). Mechanical ventilation was required by 25 patients (4%) and echo was used for 1 patient. Data on treatments given included antivirals: hydroxychloroquine (n=40, 7%), remdesivir (n=17, 3%), lopinavir-ritonavir (n=6, 1%) and oseltamivir (n=3, 1%). Other immunomodulators used were corticosteroids in 22 (4%), IvIG in 7 (1%), tocilizumab (n=4, 1%), anakinra (n=3, 1%) and siltuximab (n=1).

There were 4 deaths (0.69%), all of which were in children >10 years of age. Of the four deaths, one was an out of hospital cardiac arrest.

and two had pre-existing medical conditions; one patient had a stem cell transplant 15 months prior and another patient was managed palliatively due to their pre-existing illness. By time of end study 553 patients had made a full recovery and 25 patients had ongoing symptoms.

Overall, this is one of the first multi-national European studies of SARS-CoV-2 in children. Common symptoms included respiratory and fever but gastrointestinal symptoms were present in over one fifth of cases. Although eight percent of children required ICU admission, the case fatality rate was low at 0.69%. Children at greater risk of intensive care admission had pre-existing medical conditions, were less than 1 month old, or presented with lower respiratory tract symptoms. Asymptomatic infection occurred in 16% of cases. Given that at the time of the study, there were varying practices for screening criteria, it is likely that the true proportion of asymptomatic patients is higher (and true case fatality rate lower).

Zheng, G. Guo, Y.Pediatric PulmonologyClinical Characteristics of Acute Respiratory Syndrome with SARS-CoV-2 Infection in Children in South China.24 Jun 2020China Asia52Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24921
Rossoff, JMuller, WJPediatric blood and cancerBenign course of SARS‐CoV‐2 infection in a series of pediatric oncology patients23 Jun 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/pbc.28504
Gonzales Cortes, Rde Carlos-Vicente, JCIntensive Care Med A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units22 Jun 2020SpainEurope50Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00134-020-06146-8

The Spanish Paediatric Intensive Care Society have published their findings of 50 children admitted to 47 PICUs in Spain between 1st March 2020 and 1st May 2020 with SARS-CoV-2. More than 90% of PICUs in Spain were represented in this national database. During the study period there were no deaths from SARS-CoV-2 in children admitted to PICU in the participating PICUs.

The authors divided the children into two groups: those requiring ventilation and those not requiring ventilation, to assess for different characteristics between these groups. Fourteen (28%) of the children were ventilated. Twenty-seven (54%) of the 50 children in the study had suspected PIMS-TS; these children were less likely to require mechanical ventilation (4 of the 27 required ventilation) than those without PIMS-TS. Statistical significance between the two groups was found for age (median age of 2.8 years in the ventilated group, compared to 8.6 years in the non-ventilated group); co-morbidities (12, 24%, of the 50 children had comorbidities; 8 of these were ventilated); and clinical presentation with respiratory difficulties or an ARDS-type picture.

Overall, of the 50 children, 23 (46%) had haemodynamic instability, 20 (40%) had respiratory difficulties and 1 (2%) had neurological symptoms. Shock was present in half of the children (25, 50%), renal failure in 8 (15%) and cardiac dysfunction in 17 (34%).Across the 50 children, white cell count (median 9.26, IQR 5.64-14.46), lymphocytes (median 1.02, IQR 0.42-2.59) and CRP (median 13.9, IQR 4.9-27) were not statistically different between ventilated and non-ventilated children.

These are the preliminary findings from this national registry of children with SARS-CoV-2 admitted to PICU in Spain. Further results and analysis will provide more information regarding critically unwell children with COVID-19.

Rosenzweig, JKaicker, SPediatric Blood and CancerSARS‐CoV‐2 infection in two pediatric patients with immune cytopenias: A single institution experience during the pandemic21 Jun 2020USANorth America2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/pbc.28503
Hildenwall HHerleniusActa PaediatricaPaediatric COVID‐19 admissions in a region with open schools during the two first months of the pandemic21 Jun 2020SwedenEurope63Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303651/
Colmenero ITorello ABritish Journal of DermatologySARS‐CoV‐2 endothelial infection causes COVID‐19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases 20 Jun 2020SpainEurope7Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19327

Anecdotally, chilblains seem to be associated with Covid-19 in children and young adults. This case series from Madrid describes 7 children (age 11-17) presenting with chilblains on their toes during the pandemic. None had underlying conditions likely to cause chilblains, and in Spain, cold weather wasn’t responsible. The chilblains looked typical, caused only minor pain and itching, and all resolved spontaneously. All had skin biopsies, which showed a variety of inflammatory and vasculitic changes on histology, typical of chilblains: they also looked specifically for SARS-CoV-2 particles in the endothelium of the dermal vessels using immunohistochemistry and electron microscopy and found the virus in all of them.

What is remarkable is that all the children were systemically well, had either mild or no respiratory symptoms; and of the 6 that had nasal and pharyngeal swabs, all were negative for SARS-CoV-2 PCR. Only 4/7 had Covid-19 positive household contacts.The implication is that children can harbour demonstrably invasive coronavirus with minimal symptoms and negative swabs. This has epidemiological as well as clinical significance.

In conclusion, the presence of SARS-CoV-2 in the endothelium of dermal vessels in skin biopsies of children and adolescents with acute chilblains confirms that these lesions are a manifestation of COVID-19. Their clinical and histopathological features are similar to those of chilblains of other aetiologies, and virus-induced vascular damage could explain their pathophysiology. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a role in the pathogenesis of severe forms of the disease. More studies are needed to understand the reasons why previously healthy children, adolescents and young adults present

Heinz, NMartinez, MPaediatr TransplantA Case of an Infant with SARS-CoV-2 hepatitis early afterLiver Transplantation19 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/petr.13778
Xiong, XIp, PJ Pediatr.A Comparison Between Chinese Children Infected with COVID-19 and with SARS18 Jun 2020ChinaAsia244Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301144/

In this study, 244 children with SARS-CoV-2 infection from Wuhan, China are compared to 44 children diagnosed with SARS (SARS-CoV-1) in in Hong Kong in 2003. The clinical details of this series of patients from Wuhan, previously described elsewhere, are compared with those of those of children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 montsh vs 160 months). Compared with SARS-CoV-1 patients, children with SARS CoV-2 were less likely to have symptoms (20.9% asymptomatic vs 0% of SARS-CoV-1), including fever (40.2% vs 97.7%), myalgia (37.6% vs 0.8%), and chills (32.6% vs 3.7%).

Fewer children with SARS-CoV-2 required supplemental oxygen (4.7% vs 18.6%) and few in either cohort required mechanical ventilation (1.6% vs 2.3%). A single death occurred in a patient with SARS-CoV-2 (a 10 mo with intussusspection) and no cases of PIMS-TS / MIS-C were identified amongst the 244 SARS-CoV-2 infected children from Wuhan.

The most striking difference is the milder clinical illness and relative lack of symptoms in children with SARs-CoV-2 compared with those with SARS-CoV-1. The lack of asymptomatic infections in SARS-CoV-1 is also notable, similar to findings in adults. Whilst the role of asymptomatic patients in the spread of SARS-CoV-2 is unresolved, the milder clinical illness in the majority of patients along with the demonstrated earlier peak in viral shedding relative to symptom onset and resultant role of pre-symptomatic transmission are likely major reasons for the continuing widespread transmission of SARS-CoV-2, where the outbreak of SARS-CoV-1 in 2003 was more readily contained.

Del Barba, P.Barera, G.Pediatr PulmonolCOVID-19 cardiac involvement in a 38-day old infant18 Jun 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24895

First (single) case report of an infant with biochemical and echocardiographic evidence of mild cardiac involvement due to SARS-CoV-2 infection. The 38 day old male infant presented to hospital on 27/03/20. Neither the centre nor the country is identified but is likely to be in Italy. Pregnancy had been unremarkable. No delivery details given. Baby was formula fed. Both mother and father were +ve for SARS-CoV-2. He presented with a fever of 37.6oC and rhinitis but no respiratory distress and did not require oxygen therapy. Nasal and nasopharygeal swabs were +ve for SARS-CoV-2. Haemoglobin, lymphocyte count, CRP, ESR, electrolytes, liver transaminases, INR and PTT were normal. Abnormal results: LDH “mildly increased”, platelet count 525,000/μl, procalcitonin 3.28ng/ml, troponin T 8.2ng/dl, creatine kinase-MB 9.8μg/L, D-dimer 13.3 μg/ml, pro-brain natriuretic hormone 208pg/ml, fibrinogen 1.28g/L. CXR showed increased bronchovascular markings but no parenchymal changes (CT not done). A resting heart rate of 140bpm and a transient peak rate of 200bpm were the only cardiac signs (serial ECGs and 24hr recording). First echocardiogram showed no abnormalities but cardiac MR scan showed a “minimal amount” of pericardial effusion with no myocardial edema. Follow up echo 3 days after the first confirmed a 2mm effusion. A panel of other viruses linked to pulmonary and/or cardiac problems in infants was negative. He required no treatment and was discharged after 14 days. Swabs were -ve 21 and 22 days after presentation.

Meethal, LBKociolek, LKj.pedsSARS-CoV-2 Infection in Infants Less than 90 Days Old17 Jun 2020USANorth America18Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30750-2/fulltext
Ekbatani, M. S.Mamishi, S. British Journal of Biomedical Science Atypical and novel presentations of Coronavirus Disease 2019: a case series of three children.16 Jun 2020Iran Asia3Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/09674845.2020.1785102?scroll=top&needAccess=true
Li, YLi, Jpaediatric pulmunologyImmune-related factors associated with Pneumonia in 127 children with Coronavirus Disease in 2019 in Wuhan.16 Jun 2020chinaAsia127Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24907
Stewart, DStojanovic, JLancet. Child & adolescent healthRenal dysfunction in hospitalised children with COVID-1915 Jun 2020UKEurope52Clinical - Clinical Featureshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30178-4.pdf
Ranabothu, SVeerapandiyan, AActa Paediatr.Spectrum of COVID‐19 in Children15 Jun 2020USANorth America1353Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15412
Lanyon, NPeters, MArch Dis ChildhCritical paediatric COVID-19: varied presentations but good outcomes15 Jun 2020United KingdomEurope11Clinical - Clinical Featureshttps://adc.bmj.com/content/early/2020/06/28/archdischild-2020-319602

In this letter from Great Ormond Street Hospital for Children, London, 24 children, who tested positive for Covid-19, were admitted to the intensive care unit between 26th March 2020 and 31st May 2020. Thirteen of these had PIMS-TS. This letter describes the clinical features of the remaining 11.

These 11 had a median age of 5 years (range 0.4-11), 9 were boys, 9 had pre-existing medical conditions, and 4 came from the BAME community. The primary presenting feature was cough 6, apnoea 3, fever 10, gastrointestinal 6 and seizures 3 In all 11 inflammatory markers were raised, median ferritin 898 (range 254-1991), CRP 158 (27-449), LDH 1594 (802-4264) D-Dimer 158 (27-449). 4 children fulfilled the criteria for paediatric acute respiratory distress syndrome, the remaining 7 were admitted to PICU for other reason than respiratory failure. A variety of different forms of respiratory support were provided, invasive mechanical ventilation 9, prone position 4, inhaled pulmonary vasodilators 4, HFOV 2 and ECMO none. 5 children received remdesivir and 6 prophylactic anticoagulation.

All 11 children survived to hospital discharge. The authors conclude “While children can present to PICU with a pattern of illness similar to adult COVID-19 disease this is rare and three quarters of them had risk factors for respiratory infection. A larger number were found to be SARS-COV-2 coincidentally.”

Kanthimathinathan, KJyothish, DHospital PediatricsCOVID-19 - a UK Children's Hospital Experience15 Jun 2020UKEurope45Clinical - Clinical Featureshttps://hosppeds.aappublications.org/content/hosppeds/early/2020/06/06/hpeds.2020-000208.full.pdf
Pan, YZhang, LJIDEpidemiological and Clinical Characteristics of 26 Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Carriers15 Jun 2020ChinaAsia26Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/12/1940/5823633
Lee,HLytrivi,IPediatr TransplantVarying Presentations of COVID-19 in Young Heart Transplant Recipients:a Case Series15 Jun 2020United States of AmericaNorth America4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/petr.13780?af=R

This is a peer reviewed prepublication case report on the experience of Covid-19 among a population of young heart transplant patients from a tertiary centre, Columbia University Irving Medical Centre, New York.

Period Covered: first 3 months of the New York Covid pandemicHospital/Region Covered: the tertiary transplantation programme is one of the largest in the USA covering “hundreds” of patients.

Identification of Patients: 4 patients under the care of the hospital for heart transplantation are included. Case 1 was admitted after referral from secondary care with Covid symptoms and an oxygen requirement.. Cases 2 and 4 presented from home and case 3 was diagnosed during a planned admission for heart biopsy.

Age/Gender: there is a wide age range: case 1 (F)15 years, case 2 (F)25 years, case3 (M)13 months, case 4(F) 29 months.

Comorbidities and immunosuppression: The authors highlight the questions of whether the comorbidities (including immunosuppression) associated with heart transplantation lead to worse outcomes with Covid infection? Also whether immunosuppression has a protective or aggravating effect on outcome and how regimes should be managed?

Two patients (1 and2)also had renal transplants. Case 2 had connective tissue disease (elevated IL-2).

All patients were on various combinations of immunosuppressants (1,2 and 3 on steroids).In only one case (1) was this withheld during infection because of neutropenia.Clinical Features: 3 patients (1,2,3) had symptoms of acute Covid-19 and were nasal/nasopharyngeal positive. Case 1 required supplemental oxygen but no other treatment for 3 days and was then discharged.Cases 2 and 3 did not require admission. Cough: 3/3. Fever: 3/3.Sore throat: 1/3. Abdominal pain: 1/3. All remained well on follow up.

Patient 4 is likely to have had Covid-19 4 weeks prior to admission (symptoms and family history). She presented with a probable post Covid anaemia and hepatitis. She had a rash (acral papular) She was negative on nasal and hepatic Covid assay. Her liver biopsy was consistent with viral hepatitis. Her Covid serology was positive and other viral hepatitis serology negative. She received a blood transfusion

Reported Imaging: CXR:1/4. Normal. Cardiac echo:2/4. No deterioration.

Laboratory: Case1: WCC low 1460/ul, neutropenia (800/ul). ?secondary to immunosuppression or Covid. Elevated inflammatory markers: CRP, ferritin. D-dimer, pro- BNP elevated.

Case 2: no report. Case 3: normal FBC, CRP and LFTs.

Case 4: Hb 6.2 g/dl. Peak ALT elevated 1807 U/L. Peak AST 1070 U/L.

Comment: The centre maintains surveillance (telehealth) of most of it’s patients. Despite possible risk factors of comorbidities and immunosuppression only 4 cases presented. In the acute cases the illness was either mild (2,3) or moderate (1). This is the first report from a paediatric transplant centre and it will be necessary to examine the experience in other centres worldwide.

Case 4 developed hepatitis, anaemia and a rash 4 weeks after probable Covid infection. It is possible that this was Covid related. Viral hepatitis has been reported in a child post liver transplant with acute Covid infection.

Colonna, C.Gelmetti, C.Pediatric dermatologyChilblains in children in the time of Covid‐19: new evidence with serology assay13 Jun 2020ItalyEurope8Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14269
Kesici,SBayracki,BESCFulminant COVID 19 related Myocarditis in an infant12 Jun 2020TurkeyAsia1Clinical - Clinical Featureshttps://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa515/5856627

Clinical Features: 2 year old previously healthy male in contact with Covid19, hospitalized with nausea, vomiting and lethargy. On Day 2 of admission deteriorated with Respiratory distress, filiform pulse and blood pressure was not measurable. There was hepatomegaly. Child was intubated in PICU, while preparing for ECMO went into cardiac arrest. 30 minutes of CPR was performed. During ECMO biopsy of myocardium was taken.

Radiology: Initial CXR – bilateral interstitial infiltrates. Day 2: CXR Cardiomegaly with pleural effusion. ECHO: Severe heart failure

Bloods: Initial bloods negative for inflammatory markers but Troponin was elevated 30 times normal on Day 2.

PCR for viruses were negative including RT PCR for Sars_COV_2 Myocardial Biopsy showed local inflammation, Positive for RT_PCR for COVID 19

Conclusion: Single case report showing the effect of COVID 19 causing heart failure secondary to myocarditis without Kawasaki like syndrome

Zeng, QLYu, ZJTransbound Emerg DisClinical course and treatment efficacy of COVID-19 near Hubei Province, China: a multicentre, retrospective study12 Jun 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/tbed.13674
Jafari, RJavanbakht, MTravel Med Infect DisA 6 months old infant with fever, dyspnea and poor feeding, diagnosed with COVID-1911 Jun 2020IranMiddle East1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1477893920302799
Marhaeni, WR. S. Mapianto,Indian J PediatrThalassemic Child Presenting with Anosmia due to COVID-19.09 Jun 2020Indonesia Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281692/pdf/12098_2020_Article_3370.pdf
González-Dambrauskas, SKarsies, TPediatricsPediatric Critical Care and COVID1909 Jun 2020InternationalInternational17Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/06/05/peds.2020-1766.full.pdf

In preprint, González-Dambrauskas et al describe 17 children with COVID-19 admitted to international PICUs in Chile, Colombia, Italy, Spain and USA, in April 2020. These are interim results from the CAKE (Critical Coronavirus And Kids Epidemiologic) Study, recruiting between April and December 2020 from almost 60 PICUS in 20 countries. As well as describing the clinical details of each child in detail, this paper also describes four children with myocarditis associated with covid-19.

The 17 children predominantly presented with cough and fever (53% had cough, 76% had fever). Comorbidities were common in 71% of children, including underlying respiratory, cardiac, renal, liver or neurological disorders. Six children (35%) had gastrointestinal (GI) symptoms at presentation.

Of the four children with myocarditis, all were based in Europe, none had previous cardiac disease, and all presented with fever and GI symptoms. One also had a rash and conjunctivitis. These children all developed myocarditis early in their clinical picture, with average duration of symptoms prior to presentation of 3.5 days. All four children received IVIG. Three of these children also required inotropic support; one child also developed ARDS and acute kidney in addition to myocarditis, requiring non-invasive ventilation but not renal replacement therapy. None of the four children with myocarditis required mechanical ventilation. All four children survived to discharge home, with a mean hospital length of stay of 13.5 days.

Cen YLiu Y HClin Infect Dis.Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019 - a multi-centre observational study.08 Jun 2020ChinaAsia5Clinical - Clinical Features https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30341-4/fulltext
MAK, PQKwan, MPediatr.Infect.Dis.J.Anosmia and Ageusia : not an uncommon presentation of COVID-19 infection in children and adolescents.08 Jun 2020USANorth America3Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/.
Trogen, BShust, GPed. Infectious Disease J.COVID-19-Associated Myocarditis in an Adolescent08 Jun 2020USANorth America1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/COVID_19_Associated_Myocarditis_in_an_Adolescent.96126.aspx

This case report details the admission to PICU of a 17-year-old obese male (BMI 30kg/m2) with spondylolysis and a distant history of asthma (not requiring medication for > 5 yrs) who presented to a hospital in New York City during the third week of April with septic shock, after a week’s history of fever, GI symptoms and neck pain.

Clinical features: 7 day history of fever and neck pain and a 6 day history of diarrhoea and vomiting (non-bloody, non-bilious). No neck stiffness, headache, photophobia or respiratory symptoms. At presentation he was febrile, tachycardic and hypotensive (79/66 mmHg) with diffuse abdominal pain. His cardiovascular status remained labile after initial fluid resuscitation and he was admitted to PICU.

Initial bloods: Lymphocytes 0.9 x 103/L, CRP 167 mg/L, ferritin 1275 ng/mL, D-dimer 1218 ng/mL, initial Troponin I level 2.97 ng/mL rising to 6.17 ng/mL 2 hrs later, brain natriuretic peptide 2124 pg/mL, sodium 128 mmol/L, creatinine 1.25 mg/dL, creatine kinase 761 U/L, LDH 346 U/L, INR 1.5, IL-6 28 pg/mL

Microbiology: Nasopharyngeal swab RT-PCR SARS-CoV-2 positive. Other respiratory and GI pathogen PCRs negative, including enterovirus, adenovirus, CMV, EBV, HHV-6, parvovirus B19.

Radiology: Abdominal USS essentially normal. CXR: low lung volumes, normal cardiothymic silhouette and mild, hazy ground glass opacities at the lower lobes bilaterally.

ECG: T-wave inversion particularly in inferior leads.

Cardiac imaging: Initial transthoracic echocardiogram: LV ejection fraction mildly depressed with no obvious intracardiac clots or pericardial effusion. Cardiac MRI: normal sized LV & RV, LVEF 40%, RVEF 39%, area of mid-wall late gadolinium enhancement at inferior LV-RV junction corresponding to area of increased T2 signal as well as an area of hypokinesia, consistent with myocarditis.

Treatment in PICU: Blood pressure normalised on day 1, but remained febrile and tachycardic until day 4. Required 2 days of oxygen via NC. Received anticoagulation, paracetamol/ibuprofen and 48 hrs of piperacillin/tazobactam until blood cultures reported negative. No other anti-inflammatories or IVIg given. Initially started on hydroxychloroquine which was stopped on day 3 when serial ECG demonstrated prolonged QTc interval not present initially. Serial Troponin I and BNP levels normalised by discharge.

Outcome: Discharged on day 5 with 2 week course of anticoagulation (apixaban). Echocardiogram at follow-up one week after discharge demonstrated normal ejection fraction (59%) with qualitatively improved function. However, tissue Doppler imaging signals of the mitral valve annulus were still abnormally diminished with low global longitudinal strain rate, consistent with residual myocardial dysfunction. Repeat ECG showed persistent T-wave inversion in lead III.

The authors conclude with a discussion of the possible mechanisms of cardiac injury secondary to COVID-19, including viral entry via the ACE2 receptor causing direct damage to myocardiocytes, immune-mediated injury secondary to cytokine release or T-cell dysregulation, microvascular damage, endothelial shedding/dysfunction, hypoxia-mediated injury and abnormal coagulation, including DIC, increasing the risk of thrombosis and ischaemic events.

Du, WQ. LiJ Infect Public HealthPersistence of SARS-CoV-2 virus RNA in feces: A case series of children07 Jun 2020ChinaAsia10Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304913
Chen, YXiao, XJ Infect Public HealthRe-evaluation of retested nucleic acid-positive cases in recovered COVID-19 patients: Report from a designated transfer hospital in Chongqing, China07 Jun 2020ChinaAsia4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275981/
Foster, CCampbell, JJ Pediatric Infect Dis Soc.Coronavirus Disease 2019 in Children Cared for at Texas Children’s Hospital: Initial Clinical Characteristics and Outcomes06 Jun 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa072/5854294
Xing, CXu, ZWorld J Clin Cases Serial computed tomographic findings and specific clinical features of pediatric COVID-19 pneumonia: A case report06 Jun 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281042/
Li, C. Wu, B Medicine A 3-month-old child with COVID-19: A case report.05 Jun 2020China Asia1Clinical - Clinical Featureshttps://journals.lww.com/md-journal/fulltext/2020/06050/a_3_month_old_child_with_covid_19__a_case_report.92.aspx
Sun, D., XLiu, Z., SWorld Journal of Pediatrics SARS-CoV-2 infection in infants under 1 year of age in Wuhan City, China05 Jun 2020ChinaAsia36Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs12519-020-00368-y
Gorkem,SCetin,BDiagn Interv RadiolCOVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT05 Jun 2020TurkeyEurope1Clinical - Clinical Featureshttps://www.dirjournal.org/en/covid-19-pneumonia-in-a-turkish-child-presenting-with-abdominal-complaints-and-reversed-halo-sign-on-thorax-ct-167964

This is a case report of a 15 year old girl with Covid-19 from Turkey in an Epublished letter ahead of print with an early description of the “reversed halo sign”(RHS) on chest CT scan in. RHS is described as a central ground glass opacity (due to septal alveolar inflammation) surrounded by denser granulomatous airspace consolidation in the shape of a crescent or ring. It was identified in adult Covid -19 patients in early studies from Wuhan.

The patient presented with abdominal pain (epigastric tenderness). She had no respiratory symptoms and was apyrexial. Covid-19 was identified on nasopharyngeal swab. WCC 4.01x109, lymphocytes 1.92x109, CRP 1.6 mg/l rising to 10 mg/l after five days. Oxygen saturation remained above 95% in air.

Initial abdominal CT identified bilateral patchy alveolar infiltrates in the lower lobes and so an unenhanced low-dose thorax CT was performed. This identified multi focal RHS lesions within bilateral upper, middle and lower lobes. There were multiple multisegmental peripherally located alveolar infiltrations and scattered ground glass opacities.

The patient received hydroxy chloroquine. Interestingly, she did not develop any respiratory symptoms, making an uneventful recovery and was discharged after 8 days.RHS is a distinctive sign on chest CT. As well as occurring in pneumonia (including community acquired pneumonia) it can also be associated with fungal infections, immunosuppression, pneumocystis, TB, sarcoidosis, pulmonary neoplasms and pulmonary infarction. Therefore it can pose diagnostic challenges and management is guided by the clinical history. Although RHS is recognised in the adult Covid-19 literature this is a first report in a paediatric patient.

Mohammadi, A Mirza‑Aghazadeh‑Attari, MJpn J RadiolClinical and radiological characteristics of pediatric patients with COVID-19: focus on imaging findings04 Jun 2020IranMiddle East27Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293432/
Kerber, AYoussef, MIntnl J of DermatologyChilblains-like dermatologic manifestation of COVID-19 diagnosed by serology via multidisciplinary virtual care04 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/ijd.14974
Lin, EShah, AJAMA SurgeryIncidence of COVID-19 in Pediatric Surgical Patients Among 3 US Children’s Hospitals04 Jun 2020USANorth America12Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamasurgery/fullarticle/2766924
Zachariah, PSalman, LJAMA PediatricsEpidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York03 Jun 2020USANorth America50Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766920
Wu, HXiang, YJAMA Netw OpenClinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China03 Jun 2020ChinaAsia157Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2766670

In this retrospective case series from Wuhan, China, the clinical and immunological characteristics of children admitted to hospital with confirmed SARS-CoV-2 infection are examined. Details are provided for the 148 children with mild or moderate disease.

The median age was 84 months (IQR 18-123). Fever (40.5%) and cough (44.6%) and vomiting or diarrhoea (21.6%) were the most common symptoms. SARS-CoV-2 PCR became negative at a median of 7 days (IQR 4-11 days).

Lymphopenia was present in only 4.5% of patients; CD 4 lymphopenia in 1.9%. Elevation in CRP (32.4%) and procalcitonin (47.3% elevated; median 0.05 (IQR 0.04-0.08)) was observed in fewer than half of patients. Liver transaminases and LDH were significantly higher in moderate versus mild cases but the vast majority of levels fell within normal range.

Levels of inflammatory cytokines including IL2, IL6, TNG-a and IFN.y were largely normal; the authors note that one patient with severe disease had elevated IL-6 (3869 pg/mL). IL-10 was increased in 14%.No deaths occurred amongst mild and moderate cases and all 148 patients were discharged.

In this large case series of children with mild or moderated SARS-CoV-2 infection, laboratory measures of inflammation were largely normal. Specifically the significant elevations in IL-6, D-dimer, and ferritin characteristic of severe COVID-19 in adults and also PIMS-TS / MIS-C in children were absent in these milder cases. The authors postulate that the relative preservation of CD4 T-cells and the higher levels of IL-10 compared with adults with severe COVID-19 may indicate these as important components of a protective immune response.

As yet our understanding of the drivers of variation in individual immune response to SARS-CoV-2 remains incomplete.

Parri,NLazzerini,MEur J Pediatr Characteristic of Covid-19 infection in paediatric patients: early findings from two Italian Pediatric Research Networks 03 Jun 2020Delayed access or provision of care in Italy resulting from fear of COVID-19Europe130Clinical - Clinical Features https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269687/pdf/431_2020_Article_3683.pdf

This study is published as a short communication describing the clinical presentations and outcomes in children with identified Covid-19 in 61 centres in Italy between 3rd and 26 March 2020.Study Design: A retrospective study coordinated by the CONFIDENCE and COVID-19 Italian Paediatric Study Network’s involving 53(86.9%) hospitals and 8(13.1%) outpatient centres in 10 mainly northern regions. All children (0-18 years) diagnosed positive on screening and testing for Covid-19 by nasal/nasopharyngeal RT-PCR assay were entered into the study. Clinical, laboratory and imaging data was collected on standardised forms.

Study Population: 130 children and adolescents recruited (112 hospital;18 outpatient). <2 years 41 (31.5%), 2-9 years 35 (26.9%)’10-17 years 45 (34.6%). Male 73 (56.2%). Female 57(43.8%) p=0.47.Comorbidities 34 (26.2%) most frequent cardiovascular, respiratory and neuromuscular. No information on ethnicity. One patients data unobtainable.

Disease Severity: The majority of subjects were categorised as being asymptomatic or having mild disease 98/130 (75.4%). 11 (8.5%) were moderate severity, 11 severe and 9 (6.9%).critical. 75 (57.7%)were hospitalised with 15.(11,5%)needing respiratory support (5 needing oxygen, 2 non invasive ventilation and 2 mechanical ventilation). 9 cases were admitted to ICU with 6 being less than 6 months. 3 of the latter were less than 2 months and did not require respiratory support. Children less than 6 months had an increased risk of critical disease than older children: 6/35 (17.1%) vs 3/86 (3.5%) p=0.34. OR 5.6 CI 1.3 to 29.1.

Symptoms: Common symptoms were fever 67(51.5%), dry cough 38(29.2%) and productive cough 16(12.3%). Other symptoms were rhinorrhoea25(19.2%), respiratory distress 17(13%), vomiting 15(11.5%);diarrhoea 10(7.6%); sore throat 9(6.9%). Thoracic pains (3%), somnolence, febrile convulsions (1.5%) and lower limb pains (1.5%) were reported as novel symptoms.

Oxygen saturation at presentation: 91-92% 1(0.8%). <90 1(0.8)

Radiology: 41 (31.5%) of children had CXRs. These were normal in 15 (36.6%). The commonest abnormalities were ground-glass opacities in 17 (41.5%). Focal consolidation was seen in 4 (9.8%). Laboratory: 71 children were reported to have had laboratory tests. The authors report leukopenia (WCC %<5.5x109) and lymphopenia (<1.2x109) in 7/19 patients and 3/19 patients, respectively. They report elevation in aspartate transaminase >50U/l in 11/60 (18.3%) and alanine tranasaminase >45U/l in 8/68 (11.8%).

Outcomes: There were no deaths and all children were reported to have recovered. Comment: The study obtained data on all but one child found Covid-19 positive in this largely hospital based population. The authors acknowledge that there is a bias toward more ill patients with their population than community studies and this may explain the 57.7% admission rate. Also this is reflected in the amount of comorbidity. However, the majority of patients were either asymptomatic or had mild disease and small numbers required respiratory support or ITU. The authors identify the increased likelihood of critical disease in those less than 6 months and their being the majority of ICU cases. They also comment on new presenting symptoms (thoracic pain, somnolence, febrile convulsions and lower limb pains).

Pandey UDien Bard JMedRxIVPediatric COVID-19 in Southern California: clinical features and viral genetic diversity02 Jun 2020CaliforniaNorth America35Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.05.28.20104539v2.full.pdf

A study of 35 children age range 18 days to 18.5 years (median12.5), 57% of whom were boys, seen over an 8 week period in Southern California. Patients were identified by nasopharyngeal swabs submitted to Los Angeles Children’s Hospital between 11 March 2020 and 11 May 2020. 37% were hospitalised with a median inpatient stay of 4 days. Symptoms were diverse with fever and cough being the most common, 1/3 were symptomless. Whole genome sequencing was undertaken on Covid-19 samples. There was an association between disease severity and viral load. Children < 5 years age had a higher viral load and all were symptomatic. There was limited variation in the viral genome though a calculated evolutionary rate was like other RNA viruses. No correlation was identified between disease severity and genetic variation.

Frauenfelder, CBamford APediatricsInfant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir01 Jun 2020United KingdomEurope1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/06/16/peds.2020-1701
Escalera-Antezana, JP Rodríguez-Morales, AJLe Infezioni in MedicinaRisk factors for mortality in patients with Coronavirus Disease 2019 (COVID-19) in Bolivia: An analysis of the first 107 confirmed cases01 Jun 2020BoliviaInternational9Clinical - Clinical Featureshttps://www.infezmed.it/media/journal/Vol_28_2_2020_15.pdf
Manzoni, P Polastri, RoThe Pediatric Infectious Disease Journal: Uncommon Presentation of Coronavirus Disease 2019 Infection in a Child 01 Jun 2020italyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/Uncommon_Presentation_of_Coronavirus_Disease_2019.96134.aspx
Jones, B. A. ." . Slater, B. J. Journal of Pediatric Surgery Case ReportsNon-operative management of acute appendicitis in a pediatric patient with concomitant COVID-19 infection31 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261356/
Alsofayan, YAssiri, AJ Infect Public HealthClinical characteristics of COVID-19 in Saudi Arabia: A national retrospective study31 May 2020Saudi ArabiaMiddle East74Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304925
Valente, PBuzzonetti, LJournal of AAPOSOcular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report30 May 2020ItalyEurope27Clinical - Clinical Featureshttps://jaapos.org/article/S1091-8531(20)30115-4/fulltext?rss=yes

27 paediatric patients were identified between 16/03/2020 – 15/04/2020, from Bambino Gesù Children’s Hospital, Rome, Italy. It was not clear how patients were identified/recruited. The mean age was 84 months (range=8 days to 210 months). 74% were male (n=20); 26% were female (n=7).

Clinical features present: - Cough and/or dyspneoa = 15 patients (56%); - Vomiting and/or diarrhoea = 8 patients (30%); - Ocular manifestations consistent with viral conjunctivitis = 4 patients (15%);

In the abstract it states that "At admission, all patients showed ocular manifestations", however there is no other reference to further information in the paper.Radiology/bloods: N/a

Other investigations: Nasopharyngeal swab to COVID-19 tested positive in all 27 patients.Of the 4 patients with apparent viral conjunctivitis, 1 patient resulted positive for SARS-CoV-2 on RT-PCR from conjunctival swab.Of the other patients (n=23), two more patients had positive findings for SARS-CoV-2 in their conjunctival swab without developing clinical signs of conjunctivitis.Outcomes: 27 (100%) discharges. Other salient features: Some preliminary evidence to suggest that SARS-CoV-2 shedding is low in eye secretions/tears.

Olisova, OYShnakhova, LMDermatol TherCutaneous manifestations in COVID‐19: a skin rash in a child30 May 2020RussiaEastern Europe and Northern Asia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13712
Cai, JHe, GJ Med VirolClinical features and the treatment of children with COVID-19: a case series from Wenzhou, China30 May 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26092
Kakuya, FKinebuchi, TJapanese Journal of Infectious DiseasesThe first pediatric patients with coronavirus disease 2019 (COVID-19) in Japan; The risk of co-infection with other respiratory viruses29 May 2020JapanAsia3Clinical - Clinical Featureshttps://www.jstage.jst.go.jp/article/yoken/advpub/0/advpub_JJID.2020.181/_pdf
Zhao, WZhang, FClin PediatrCharacteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge28 May 2020ChinaAsia14Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820928057

In this study from Beijing, China, serial nasopharyngeal swabs were performed on children discharged between January 21st and April 18th 2020 following hospital admission with confirmed SARS-CoV-2 infection. Criteria for hospital discharge included clinical improvement and 2 negative RT-PCR tests for SARS-CoV-2 on consecutive nasopharyngeal swabs. Follow up swabs were performed fortnightly following discharge; the authors report on children with subsequent positive RT-PCR on follow up.

In total 14 children were followed, 7 of whom had a subsequent positive SARS-CoV-2 PCR result, none of whom had significant symptoms at the time (one with a temperature of 37.5). There were no significant clinical or laboratory differences between the group with subsequent positive tests compared with those who remained negative.

The authors refer to those who have subsequent positive SARS-CoV-2 PCR as having "reactivation" of infection. This is a misnomer as the persistent shedding of viral RNA has been well recognised in adult studies. This includes a large cohort of over 200 patients from Korea with positive tests following negative PCR results, similar to the children in this study. Importantly no onward transmission from these "re-positive" cases was found amongst 790 contacts in the Korean cohort, suggesting the viral RNA detected in patients with prolonged shedding is not viable. Indeed in a recent in vitro study including 90 SARS-CoV-2 PCR positive samples, only samples taken within 8 days of symptoms onset were capable of infecting cells. This is in keeping with contact tracing data suggesting peak transmissibility occurs before and immediately after symptom onset with limited transmission beyond 5 days of symptom onset.

The likely explanation of the "reactivation" described here is prolonged shedding of non-viable viral RNA with an interim "false negative" samples prior to hospital discharge. Given the available data, it is unlikely that these "re-positive" discharged patients represent an infection risk to others

Oualha, MRenolleau, SArchives de PédiatrieSevere and fatal forms of COVID-19 in children28 May 2020FranceEurope27Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0929693X20301172

The 27 children described here constitute the biggest series to date of children sick enough to need high dependency care during active COVID infection. The criteria for admission were oxygen requirement > 1L/min or underlying disease.

The cohort of 27 were admitted within days of onset of first symptoms and 24 were positive for COVID-19 by PCR of nasal swabs. This is consistent with active virus, rather than PIMS-TS, the Kawasaki like post-COVID syndrome.

24 had respiratory disease, mostly with radiological or CT findings consistent with COVID. 6 had cardiovascular disease and 4 renal problems.

9 required invasive ventilation with median duration 5 days. 10 received non-invasive ventilation and 23 were treated with oxygen. 4 received catecholamines, one ECMO and one renal replacement therapy. The median length of hospital stay was 6 days.

Mean laboratory findings in the group were of elevated CRP, procalcitonin, fibrinogen and D-dimers, consistent with an inflammatory and prothrombotic state. Neutrophil and lymphocyte counts were normal. T cell subsets and cytokine levels were not measured. 70% had underlying conditions, but the spectrum was different from adult experience, with neurological and respiratory problems or sickle cell disease being most common.Three of the five who died had previously been in good health. A teenage girl whose clinical course was suggestive of the cytokine storm seen in adults died within hours of admission. A teenage boy and a 6 year old girl co-infected with other pathogens both died after long PICU stays.

This description confirms that severe illness is rare in children with COVID and shows that even those admitted for HDU care had a shorter illness and better prognosis than that seen in adults. Nonetheless, occasional children do suffer a prolonged illness with multi-organ dysfunction.

Garcia-Salido, ASerrano-Gonzalez, APediatr Crit Care MedChildren in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital27 May 2020SpainEurope7Clinical - Clinical Featureshttps://journals.lww.com/pccmjournal/Abstract/9000/Children_in_Critical_Care_Due_to_Severe_Acute.98028.aspx
Kumar, KJayanthi, CRIJOPresence of viral RNA of SARS-CoV-2 in conjunctival swab specimens of COVID-19 patients25 May 2020IndiaAsia4Clinical - Clinical Featureshttp://www.ijo.in/temp/IndianJOphthalmol6861015-4225372_114413.pdf
Gefen, AMSethna, CPediatric NephrologyPediatric COVID-19-associated rhabdomyolysis: a case report23 May 2020USANorth America1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00467-020-04617-0
Torrelo AColmenero IPaediatric DermatologyErythema multiforme-like lesions in children and COVID-1923 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14246
Armann, J.Berner, R.Dtsch Arztebl IntHospital Admission in Children and Adolescents With COVID-1922 May 2020GermanyEurope128Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271745/
Docherty, ASemple, MBMJFeatures of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study22 May 2020United KingdomEurope310Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/369/bmj.m1985.full.pdf
de Ceano-Vivas, MCalvo CArch Dis ChildSARS-CoV-2 infection in ambulatory and hospitalised Spanish children22 May 2020SpainEurope58Clinical - Clinical Featureshttps://adc.bmj.com/content/archdischild/early/2020/05/22/archdischild-2020-319366.full.pdf

Study design: A retrospective case series of all children seen at a tertiary centre, who were found to have positive PCR for SARS-CoV-2. Testing for SARS-CoV-2 was only conducted in those children who had respiratory symptoms and “criteria for hospitalisation” or who had “underlying chronic pathology”. Children with mild symptoms were not tested even if there was a confirmed case in the household. Comparisons were made between the characteristics of those admitted to hospital and those treated as outpatients. The study was conducted between March 11th and April 9th 2020 at Hospital La Paz, Madrid, Spain.

Inclusion criteria: All children who underwent PCR for SARS-CoV-2 in nasopharyngeal smear, N=349. Of whom 58 (16.6%) had a positive PCR and were the cases analysed.

Key findings: Of the 58 cases: Male 37 (63.8%), Median age 35.5 months (range 3.3-146), Underlying conditions 23 (39.7%), Temperature >39.7degC 41 (70.7%), Cough 42 (72.4%), Rhinorrhoea 33 (56.9%), Breathing difficulty 10 (17.2%), Vomiting 9 (15.5%), Headache 8 (13.8%), Loss of taste 1 (1.7%), Anosmia 1 (1.7%).

Radiology: 40 (69%) had a CXR of which 35 (87.5%) were abnormal: Perihilar infiltrates, ground glass pattern, lobar or multilobar consolidation.

Bloods: 43 (74.1%) had a blood test, median WCC 9145/mm3, median lymphocyte count 2390/mm3.Outcomes: 33 were hospitalised and 25 were treated as outpatients. Of the inpatients, 14 (42.4%) received oxygen therapy for a median of 3 days. 5 were admitted to the PICU (15% of those hospitalised): 3 with severe COVID-19, 1 with a hypertensive crisis and 1 with diabetic ketoacidosis. 31 (53.4%) were treated with hydroxychloroquine, 3 patients were treated with remdesivir. 2 patients with an inflammatory syndrome were also treated with tocilizumab. There was 1 death of a 5/12 old infant with dilated cardiomyopathy and Hurler’s syndrome. The comparisons between the inpatient and outpatient group provide almost no additional useful information.

Comment: As the authors concede, the retrospective nature of the study is a significant weakness. Patients were selected for testing on the basis of symptoms and/or underlying conditions and many other children who could have been infected were never tested. The study is useful in describing the range of symptoms, treatment and outcome in the large selected group of children who tested positive for SARS-CoV-2. It does not, however, add anything new to what is already known about the condition in children.

Scheier, EBalla, UEur Rev Med Pharmacol Sci Lung ultrasound cannot be used to screen for Covid-19 in children21 May 2020IsraelMiddle East1Clinical - Clinical FeaturesCOVID-19 Associated Pediatric Multi-System Inflammatory Syndrome
Li, BYu, CIndian PediatricsRadiographic and Clinical Features of Children With Coronavirus Disease (COVID-19) Pneumonia21 May 2020ChinaAsia22Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1816-8.pdf
Leung, CLeung, CPediatric PulmonologyClinical characteristics of COVID‐19 in children: Are they similar to those of SARS?21 May 2020China Asia43Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/ppul.24855
Zachariah, PGreen, DClin Infect DisSymptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children20 May 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa608/5841161

This research letter details the viral loads of children with confirmed SARS-CoV-2 infection from Columbia University Irving Medical Centre in New York. All children admitted and discharged between March 14th to April 24th 2020 were included, timing of test relative to onset of symptoms, clinical severity along with viral load were compared between infants <1yo and children >1yo.Of 57 patients with positive SARSCoV-2 PCR, 20 (35%) were under 1yo. Compared with older children, viral load was higher amongst infants <1yo (mean cycle threshold 21.05 vs 27.25, p<0.01 - where lower cycle threshold=greater viral load). Infants were tested earlier on average (2 vs 3.8 days from symptom onset) and fewer had severe disease compared with older children (5% vs 32.4%).

In this small hospital-based study symptomatic infants appear were found to have higher viral loads and milder disease compared with older children. This is in contrast to data from some adult studies where a higher viral load correlated with more severe illness.

Amongst several possible explanations for this observation are that:- infants were more likely to be tested early in illness when viral load peaks - declining thereafter- thresholds for hospital presentation may differ between infants and older children- test performance and sample quality may differ between infants and older children- there may possibly be differences in host biology according to age

Although some data suggest that higher SARS-CoV-2 viral load is associated with the presence of viable virus / in vitro infectivity, the exact implications of the findings here in terms of risk of transmission from infants compared with older children is unclear. Further studies examining SARS-CoV-2 viral load dynamics and correlation with clinical course in children are required to better understand potential variation between different age groups.

Venturini, EGalli, LJ PaediatrSevere neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection 19 May 2020ItalyEurope2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236669

This case report from the Meyer Children University Hospital, Florence, published as a letter describes two infants with SARS-CoV-2 with transient severe neutropenia (<0.5 x109/l) Clinical Features: The two female infants, aged 23 days and 39 days were admitted with mild respiratory symptoms and low grade fever. Nasopharyngeal swans were positive for Covid-19. There was no clinical deterioration in their condition during admission.

Radiology: not described

Treatment: not described.

Haematology: leukocytes and neutrophils normal on admission. At 5 days neutrophil counts fell to 0.244 x 109/lnand 0.482 x 109/l. Subsequently both improved.

Apart from age and gender there is no other demographic information nor any on treatments.Although neutropenia is described in 6% of cases of Covid-19, severe neutropenia has not been described. In the report cases it was not associated with any change in clinical state. The authors suggest consideration of performing FBCs 5 to 7 days into the illness to identify neutropenia.It requires further studies to see if these findings are replicated and whether they are clinically significant. The severity of the neutropenia could be age dependent reflecting bone marrow maturity as one patient was in the neonatal range and the other just beyond it.

Xiong XTam, PGutComparative study of the clinical characteristics and epidemiological trend of 244 COVID-19 infected children with or without GI symptoms19 May 2020china Asia244Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/05/19/gutjnl-2020-321486.info
Dallan, CSahyoun, CLancetSeptic shock presentation in adolescents with COVID -1919 May 2020SwitzerlandEurope3Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30164-4/fulltext
Giacomet, VZuccotti, GPIDJAcute inflammation and elevated cardiac markers in a two-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with cardiac symptoms 19 May 2020ItalyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/ACUTE_INFLAMMATION_AND_ELEVATED_CARDIAC_MARKERS_IN.96157.aspx
Dugue, RMishra, NNeurologyNeurologic manifestations in an infant with COVID-1919 May 2020USANorth America1Clinical - Clinical Featureshttps://n.neurology.org/content/neurology/early/2020/05/18/WNL.0000000000009653.full.pdf
Shaw, RYuki, KJ Pediatr Surg Case Rep.Intubation precautions in a pediatric patient with severe COVID-1918 May 2020USANorth America1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S2213576620301299
Guarneri, CNunnari, GThe Lancet, Infection diseasesSilent COVID-19: what your skin can reveal18 May 2020Italy (assumed) Europe3Clinical - Clinical Featureshttps://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30402-3/fulltext#coronavirus-linkback-header
Yoo, SKim, D Pediatrics InternationalReactivation of SARS-CoV-2 after Recovery18 May 2020KoreaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ped.14312
Li, YWu, BBMC PediatricsChest CT imaging characteristics of COVID-19 pneumonia in preschool children: a retrospective study18 May 2020ChinaAsia8Clinical - Clinical Featureshttps://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-020-02140-7
Turbin, RNimchimsky, EOrbitOrbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-1918 May 2020USANorth America2Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/01676830.2020.1768560
Wang, Y.Li, L.The Journal of Infectious DiseasesClinical Outcomes in 55 Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Who Were Asymptomatic at Hospital Admission in Shenzhen, China17 May 2020ChinaAsia15Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/11/1770/5807958
Voinsky, IGurwitz,DJ Infect.COVID-19 Associated Pediatric Multi-System Inflammatory Syndrome. J Paediatric Infect Dis Soc16 May 2020IsraelMiddle East933Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30303-0/fulltext

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Duramaz, BTurel, ODermatol TherAppearance of Skin Rash in Pediatric Patients with COVID-19: Three Case Presentations15 May 2020TurkeyWestern Asia, Southeastern Europe20Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/dth.13594
Diotallevi, FOffidani, AJ Med VirolSkin Involvement in SARS-CoV-2 Infection: Case Series15 May 2020ItalyEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/jmv.26012
He, GCai, JIndian PediatricsSerial Computed Tomography Findings in a Child with Coronavirus Disease (COVID-19) Pneumonia15 May 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1824-8.pdf
Mastrolonardo, MFoti, CDermatologic TherapyThe management of the outbreak of acral skin manifestationsin asymptomatic children during COVID-19 era14 May 2020ItalyEurope38Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13617
Craver, RFinger, LFetal Pediatr PatholFatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c)13 May 2020USANorth America1Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/15513815.2020.1761491
Cordoro, KMMcCalmont, THPediatric DermatologyClustered Cases of Acral Perniosis: Clinical Features, Histopathology and Relationship to COVID‐1912 May 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14227
DeBiasi, RWessel, DJ Pediatr.Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region12 May 2020United StatesNorth America177Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30581-3/fulltext

This is retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at Children’s National Hospital, Washington DC US. Children and young adults were detected through symptomatic presentation at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalised, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features associated with hospitalisation, or critical care.

Of note this hospital served as a regional centre for providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. Overall patient age range was from 0.1 - 34.2 years, with a median of 9.6years. Of the total group 12/177 were > 20 years of age, and 37/177 were between age of 15 – 20years.

Results: Age; There was no significant difference in age between the hospitalised and non-hospitalised patients, however in the hospitalised cohort, the critically unwell group were significantly older than the non-critically unwell hospitalised group (17.3 years versus 3.6 years; P =.04) Sex; There was equal representation in total cohort showed (n = 177 52% male, 48% female), as well as the hospitalised cohort (n=44 50% male, 50% female). However males made up 67% of the critically ill cohort (n =9, 67% male, 33% female); but this was not statistically significant (p=0.26)Race/ethnicity: data not provided, authors describe plans to do so in follow up analysis Underlying conditions; 39% of positive patients had an underlying condition (classified as asthma, diabetes, neurological, obesity, cardiac, haematological, oncological). Though asthma was the most common underlying condition (35/177 20%), it was not more common in hospitalised patients (7/44 16%), nor of those admitted, those who were critically unwell (2/9, 22%). Though the numbers where small, specific underlying conditions such as neurological, cardiac, haematological, or oncological underlying conditions were more common in the hospitalised cohort than the non hospitalised cohort. But were not more common in the hospitalised critically ill compared with the hospitalised non critically ill. The authors noted there was no underlying condition present in 96/177 (55%) of overall SARS-CoV-2 infected patients overall, 16/44 (37%) of hospitalized patients and in 2/9 (22%) of critically ill patients.Symptoms; 76% of infected patients presented with respiratory symptoms (rhinorrhea, congestion, sore throat, cough or shortness of breath) with or without fever. Fever was present in 116/177 (66%) but was not more common in the infected hospitalized cohort (34/44, 77%) compared with the non-hospitalized cohort (82/133, 62%; p=0.46). 

Shortness of breath was more common in the hospitalized cohort (11/44, 26%) compared with non-hospitalized (16/133, 12%; p=0.04). Patients in the critically ill cohort were not more likely to have fever or any other specific symptom compared with the non-critically ill cohort.

Critical Care: 9 patients required critical care; which represented 5% (9/177) of total cohort and 20% (9/44) of admitted patients. 4 required intubation (3 ARDS, 2 multiple organ failure); 3 required BiPAP, 1 RAM cannula and 1 High flow nasal cannula. One patient had features consistent with the recently emerged Kawasaki disease-like presentation with hyper-inflammatory state, hypotension and profound myocardial depression; a 4 year male with no underlying conditions.

Summary: A very clear description of 177 patients with Sars CoV 2, in one large centre in Washington DC. 25% of patients needed hospitalisation and 5 % needed critical care. Older teenagers and adults who required admission, were then overrepresented in requiring critical care. Though underlying conditions were more common in hospitalised patients, they were not significantly more common in the hospitalised patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalised patients than non-hospitalised patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of recently described hyperinflammatory state.

Bai, KLi, CPIDJClinical analysis of 25 Novel Coronavirus Infections in Children 12 May 2020China Asia25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_Analysis_of_25_Novel_Coronavirus.96172.aspx
Brambilla, IMarseglia, GLThe Pediatric Infectious Disease JournalCOVID-19 in the Pediatric Population Admitted to a Tertiary Referral Hospitap in Northern Italy: Preliminary Clinical Data12 May 2020ItalyEurope17Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/COVID_19_in_the_Pediatric_Population_Admitted_to_a.96177.aspx
Brambilla, I.Ciprandi, G.Obesity: A research journalSpecial Issues for COVID‐19 in Children and Adolescents12 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22878
Meslin, PZemouri, NThe Pediatric Infectious Disease JournalCoronavirus Disease 2019 in Newborns and Very Young Infants a Series of Six Patients in France12 May 2020FranceEurope6Clinical - Clinical Featureshttps://journals.lww.com/pidj/Fulltext/2020/07000/Coronavirus_Disease_2019_in_Newborns_and_Very.33.aspx
Cai, XLi, WFront. PediatrClinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children12 May 2020ChinaAsiaClinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00258/full
Shekerdemian, LSBurns, JPJAMA PediatricsCharacteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units11 May 2020USA & CanadaNorth America48Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766037

This is a cross-sectional study of children admitted to 46 PICUs in North America. 48 children were admitted during the collection period (March 14 to April 3 2020). All had confirmed COVID-19 infection on PCR from a nasal swab.

Most patients presented with respiratory symptoms, but there were other presentations – three with DKA, and one with vaso-occlusive crisis (sickle cell). 86% of these patients had at least one comorbidity. 69% were severely or critically ill on admission, and 25% needed vasoactive drugs. 81% of patients needed respiratory support that exceeded their baseline.

61% had a range of therapies, including Hydroxychloroquine, Azithromycin, Remdisivir, and Tocilizumab. These were used as single agents or in combination with other therapies.

The overall mortality rate was 4.2% (both patients who died had pre-existing comorbidities and developed multisystem organ failure). 32% were still hospitalised at the time of publication (including one patient still receiving ECMO). 65% had been discharged.

This study reinforces what is known about the decreased burden of disease from COVID-19 in children compared with adults. Critically ill children had a less severe course of illness and better hospital outcomes than in adults. Children commonly had medically complex comorbidities. Overall the mortality is much lower in children (4.2%) than has been reported in adults (50-62%).

Chao, JMedar, SJ. Pediatr.Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City 11 May 2020USNorth America46Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30580-1/pdf
Wehl, G..Rauchenzauner, MKlin PadiatrCo-infection of SARS CoV-2 and influenza A in a Pediatric Patient in Germany.11 May 2020GermanyEurope1Clinical - Clinical Featureshttps://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1163-7385
Oberweis, MGarcia, IPediatr. Infect. Dis. J.Pediatric Life-Threatening Coronavirus Disease 2019 With Myocarditis11 May 2020LuxembourgEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Pediatric_Life_Threatening_Coronavirus_Disease.96160.aspx

In this case report from Luxembourg, the authors describe an 8yo boy of African ethinicity with COVID-19 complicated by myocarditis. Presenting features included fever, cough, fatigue and cervical adenopathy associated with painful erythematous swelling of the skin. Following admission, the patient developed renal failure and refractory hypotension necessitating ICU admission. CRP (151mg/L), ferritin (2869ng/mL), D-dimer and IL-6 were all elevated. Echocardiography demonstrated myocarditis with biventricular dysfunction and troponin was elevated. SARS-CoV-2 infection was confirmed on RT-PCR of nasopharyngeal swab and stool; serology (IgA and IgG) was also positive.

IVIG and tocilizumab (anti-IL-6 monoclonal antibody) were given along with supportive care including enoxaparin and inotropes. The patient made a full recovery with resolution of changes on repeat cardiac imaging and was discharged home on day 10.

This case, likely submitted prior to the description of PIMS-TS / MIS-C, fits with the definition for these syndromes. The myocarditis, refractory hypotension, overlap with features of Kawasaki Disease, laboratory findings suggestive of cytokine storm as well as the patient's African ethnicity are all in keeping with recent reports from UK, Europe and the US. The authors postulate that the "cardiac injury could be due to disproportionate host immune response to SARS-CoV2" and describe a rapid clinical response following administration of tocilizumab.

With emerging reports of PIMS-TS / MIS-C, our understanding of the pathophysiology of this condition will increase. At this stage the role of immunomodulatory agents remain uncertain in PIMS-TS / MIS-C; discussion with paediatric ID clinicians on a case by case basis is recommended.

Zhang, NZheng, XTransl PediatrAnalysis and suggestions for the preview and triage screening of children with suspected COVID-19 outside the epidemic area of Hubei Province10 May 2020ChinaAsia36Clinical - Clinical Features http://dx.doi.org/10.21037/tp.2020.03.08
Andina, D.Torello, A.Paediatric DermatologyChilblains in children in the setting of COVID-19 pandemic09 May 2020SpainEurope22Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14215
Locatelli, ASena, PJ Eur Acad Dermatol VenereolHistologic features of long lasting chilblain‐like lesions in a pediatric COVID‐19 patient09 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16617

This retrospective single case report describes clinical and pathological signs of chilblain-like lesions whilst the patient was asymptomatic. He did not have any signs of autoimmune conditions including on histological examination. The lesions persisted for several weeks whilst he remained positive for SARS-CoV-2 on nasopharyngeal swab. The authors highlight young people with this sign could be carriers of the virus.

A 16-year-old male patient attended Papa Giovanni XXIII Hospital, Italy. His nasopharyngeal swab was positive for SARS-CoV-2. His mother was admitted to hospital for SARS-CoV-2 management following his presentation.

Clinical features: Diarrhoea and dysgeusia were experienced 3 days prior to the onset of skin lesions described as “multiple asymptomatic erythematous oedematous partially eroded macules and plaques on dorsal aspects of the fingers”. A lesion was also noted on second toe.

Radiology: None discussed.

Bloods: "Routine bloods autoimmunity, cryoglobulins, viral serologies all negative or within normal limits"

Treatments: None

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: Histopathological examination demonstrated oedema of the papillary dermis, superficial and deep lymphocytic infiltrate in the perivascular and strong peri-eccrine pattern. Images are provided.

Diercks, GRKwolek, CJInternational Journal of Pediatric OtorhinolaryngologyAsymptomatic COVID-19 infection in a child with nasal foreign body08 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205643/pdf/main.pdf
Fu, BFu, XMed Clin (Barc)Clinical characteristics of 11 asymptomatic patients with COVID-1908 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205640/pdf/main.pdf
Ma, Y.Zhang, Z.Microbes and InfectionCharacteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China07 May 2020ChinaAsia10Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204664/pdf/main.pdf
Zhang, YSun, BCell Mol ImmunolProtective humoral immunity in SARS-CoV-2 infected pediatric patients07 May 2020China Asia6Clinical - Clinical Featureshttps://www.nature.com/articles/s41423-020-0438-3

This is a study looking at the immune responses of 6 children with Sars-CoV-2 infection and comparing it to controls, in hospitals in China, in “areas other than Wuhan”. The clinical characteristics of the children were described previously (Cai et al Clin. Infect. Dis. 2020). All six children had positive respiratory samples RT PCR positive for Sars-Cov-2. All had a mild respiratory illness, needing no supportive treatment.

It is somewhat difficult to interpret exactly what immunological tests were done on which child from the study report. However, flow cytometry analysis analysing T and B cells was performed on 4 of the positive patients and was compared to five uninfected controls, admitted to the same hospital for non Sars-CoV-2 related reasons. There was no significant difference in lymphocyte count, or percentage of CD3+, CD4+, and CD8+ T cells between positive or control groups. The percentage of IgG+ in total B cells was higher, though not significantly, between groups but the percentage of IgG+ memory B cells was significantly higher in infected group.

The authors used Nucleocapsid protein and receptor binding domain of spike protein (spike-RBD) of SARS-COV-2 as antigen. All 6 infected children were tested for antigen specific antibodies, with 5 of 6 children producing antigen specific antibodies between 2 – 17 days post infection (it is unclear whether these were serial samples, or opportunistic sampling, therefore exact time of production of antigen specific antibodies is unclear). The team report that most of the IgM antibody for spike RBD Sars-CoV-2 was undetectable shortly after disease onset, suggesting class switching occurred within one week of virus exposure.

The team went on to select select serum from one patient with high concentration of spike RBD protein, and demonstrated in vitro it could block the receptor binding between spikeprotein and ACE2 protein, which is considered a vital pathway for Sars-CoV-2 to infect.

Authors conclude that the efficient humoral immune response might explain why the majority of children infected with SARS-CoV-2 had milder symptoms and recovered more easily than adults.

Papa, AVarrassi, GPain TherImages in Practice: Painful Cutaneous Vasculitis in a SARS-Cov-2 IgG-Positive Child06 May 2020ItalyEurope1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s40122-020-00174-4.pdf
Ma, H.Shao, J.BMC MedicineA single-center, retrospective study of COVID-19 features in children: a descriptive investigation06 May 2020ChinaAsia158Clinical - Clinical Featureshttps://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-020-01596-9
Zhang, BZhang SJ InfectionChildren hospitalized for coronavirus disease 2019 (COVID-19): A multicenter retrospective descriptive study06 May 2020ChinaAsia46Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204760/pdf/main.pdf
Wang, YSun, DPediatr Infect Dis JThe Risk of Children Hospitalized With Severe COVID-19 in Wuhan06 May 2020ChinaAsia43Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32384397
Colonna, C. Gelmetti, C.Paediatric DermatologyChilblains-like lesions in children following suspected Covid-19 infection06 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14210
Li, J.Song, S.Q.The Brazilian Journal of INFECTIOUS DISEASEAn infant with a mild SARS-CoV-2 infection detected only by anal swabs: a case report06 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S141386702030043X
Xiong, X.Tam, P.Med archivesAre COVID-19 infected children with gastrointestinal symptoms different from those without symptoms? A comparative study of the clinical characteristics and epidemiological trend of 244 pediatric cases from Wuhan05 May 2020ChinaAsia244Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.04.29.20084244v1
Lu, YDu, HPed Infectious Disease JSymptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan05 May 2020ChinaAsia110Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Symptomatic_Infection_is_Associated_with_Prolonged.96181.aspx

This retrospective study analysed demographic, clinical, laboratory, radiological and therapeutic data from the electronic medical records of 110 children hospitalised with “mild/ordinary” COVID-19 (classified as per the National Health Commission of People’s Republic of China National Recommendations for Diagnosis and Treatment of COVID-19, 7th edition) at Wuhan Children’s Hospital in Hubei, China between 30th January and 10th March 2020. Inclusion criteria: throat or nasopharyngeal swabs RT-PCR SARS-CoV-2 positive and patient discharged from hospital after recovery (an initial cohort of 127 children was reduced to 110 after exclusion of 2 critical cases and 15 children in whom the onset of disease could not be accurately determined).

Study design: Timings of onset of illness, most recent exposure (presumably to SARS-CoV-2-confirmed or symptomatic contacts, although this isn’t specified), diagnosis and discharge from hospital were recorded. Patients were discharged only once they had two consecutive RT-PCR SARS-CoV-2 negative swab results (separated by at least 24 hours). The authors calculated the duration of viral shedding for (a) symptomatic patients (81/110, 74%) as time from onset of illness to discharge and for (b) asymptomatic patients (29/110, 26%) as time from date of most recent exposure OR abnormal chest radiological imaging (reason for imaging not specified in these asymptomatic patients) to discharge. This definition of duration of viral shedding, with starting point presumably in most cases a retrospective parent-reported start of symptoms or exposure to an infectious contact, and end point two negative swabs leading to discharge from hospital, makes interpreting the duration figures problematic. Viral shedding in urine and faeces was not measured.

Clinical features: Median age of the 110 children was 6 years (IQR 2-9); 59/110 male (54%), 51/110 female (46%). Symptoms included: cough and dyspnoea 57/110 (52%), fever 56/110 (51%), GI (including diarrhoea, vomiting, poor feeding, anorexia, abdominal pain) 26/110 (24%), rhinorrhoea 10/110 (9%).Radiology: 64/103 (62%) had unspecified chest imaging reported as demonstrating pneumonia (55/75 symptomatic (73%) and 9/28 asymptomatic (32%)).

Bloods: Leucocytes < 4.0 x 109/L in 6/110 (5%) (all 6 were symptomatic). Leucocytes > 10.5 x 109/L in 12/110 (11%) (9 symptomatic & 3 asymptomatic). Lymphocyte ranges not specified. Haemoglobin < 110 g/L in 13/110 (12%) (all 13 symptomatic). Fibrinogen < 2.0 g/L in 34/90 (38%) (20 symptomatic & 14 asymptomatic). Hs-CRP > 3.0 mg/L in 21/110 (19%) (18 symptomatic & 3 asymptomatic). Procalcitonin > 0.05 ng/mL in 52/110 (47%) (43 symptomatic & 9 asymptomatic). AST > 50.0 U/L in 19/110 (17%) (all 19 symptomatic).

Treatment: None of the patients required oxygen therapy. All of them received antiviral therapy, mostly commonly nebulised interferon-. According to the data table 22/110 received Chinese medicine therapy, although no details are given and it’s not clear if this was pre-hospitalisation. Median duration of hospital stay was 10 days (IQR 8-13).

Conclusions: The median duration of viral shedding using the definitions above was 15 days overall (IQR 11-20 days, range 5-37 days): 17 days (IQR 12-23) in symptomatic patients and 11 days (IQR 9-13) in asymptomatic patients. Symptomatic infection, fever, pneumonia and lymphocyte counts < 2.0 x 109/L were reported to be associated with prolonged duration of shedding.

Garcia-Lara, G.Ruiz-Villaverde, R.Dermatologic TherapyChilblain-like lesions in pediatrics dermatological outpatients during the COVID-19 outbreak 05 May 2020SpainEurope27Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13516
Merza, MAbdulah, D.Diabetes Metab SyndrCOVID-19 outbreak in Iraqi Kurdistan: The first report characterizing epidemiological, clinical, laboratory, and radiological findings of the disease05 May 2020Iraqi KurdistanMiddle East4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199697/
Hong-Rui, C.Wan-Xin, C.The Pediatric Infectious Disease Journal:A CASE OF CHILDHOOD COVID-19 INFECTION WITH PLEURAL EFFUSION COMPLICATED BY POSSIBLE SECONDARY MYCOPLASMA PNEUMONIAE INFECTION05 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_CASE_OF_CHILDHOOD_COVID_19_INFECTION_WITH.96183.aspx
Peng, HXu, HJ Clin VirologyCoronavirus disease 2019 in children: Characteristics, antimicrobial treatment, and outcomes04 May 2020China Asia75Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204737/table/tbl0010/
Rahmanzade, RHashemian, SA A PractRespiratory Distress in Postanesthesia Care Unit: First Presentation of Coronavirus Disease 2019 in a 17-Year-Old Girl: A Case Report04 May 2020IranAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227797/pdf/acc-14-e01227.pdf
Morey-Olive, MGarcia-Patos, VAnales de pediatriaCutaneous manifestations in the current pandemic of coronavirus infection disease (COVID 2019)04 May 2020SpainEurope2Clinical - Clinical Featureshttps://www.analesdepediatria.org/en-cutaneous-manifestations-in-current-pandemic-avance-S2341287920300673
Nirenberg, M.Herrera, MDMRJ Am Podiatr Med Assoc.Foot Manifestations in a COVID-19 Positive Patient, A case study04 May 2020SpainEuropeClinical - Clinical Featureshttps://www.japmaonline.org/doi/pdf/10.7547/20-088
Zheng, ZLiu, JJ Cent South Univ (Med Sci)Chest CT findings and clinical features of coronavirus disease 2019 in children03 May 2020ChinaAsia9Clinical - Clinical Featureshttp://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202003236.pdf
Sun, JWang, YJ Infect Dev CtriesDifferent outcome of COVID-19 in members of a family03 May 2020ChinaAsia1Clinical - Clinical Featureshttps://jidc.org/index.php/journal/article/download/12792/2248
Steinberger, SLittle, B PAm J RoentgenolCT Features of Coronavirus Disease (COVID-19) in 30 Pediatric Patients 01 May 2020ChinaAsia30Clinical - Clinical Featureshttps://www.ajronline.org/doi/10.2214/AJR.20.23145
Qiu, LLuo, XPediatr Infect DisA Typical Case of Critically Ill Infant of Coronavirus Disease 2019 With Persistent Reduction of T Lymphocytes01 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_Typical_Case_of_Critically_Ill_Infant_of.96189.aspx
Tsao, HFearon, DPediatricsThrombocytopenia (ITP) in a SARS-CoV-2 Positive Pediatric Patient01 May 2020USANorth America1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/05/19/peds.2020-1419.full.pdf

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2.

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications.

A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Zhu, XCiu, LVirusResCo-infection with respiratory pathogens among COVID-2019 cases30 Apr 2020China Asia11Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0168170220303531
Yu, X.Fu, C.Transboundary and Emerging diseasesEpidemiological and clinical characteristics of 333 confirmed cases with coronavirus disease 2019 in Shanghai, China29 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/tbed.13604
Casas, CGarcia-Doval, IBr J DermatologyClassification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases29 Apr 2020spainEurope0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19163

This article from a team in Spain aimed to classify cutaneous manifestations of COVID-19 and relate them to other clinical findings.

From 3rd of April 2020 to 16th of April 2020 they collected 429 cases but excluded 54 leaving a sample of 375 patients. A standardised questionnaire was used, photographs were taken and the questionnaires and photographs were independently reviewed by 4 dermatologists.

Data was collected by Spanish dermatologists from across the country most of whom had been redeployed from their usual dermatology posts.

Patients with an eruption of recent onset (previous 2 weeks) and no clear explanation, plus suspected or confirmed COVID-19 were included.They describe 5 cutaneous manifestations.

Acral areas of Erythema-oedema with some vesicles or pustules: 19% of cases. These were more likely in children.

Other vesicular eruptions: 9%. May also affect the limbs and have a haemorrhagic content, and become larger or diffuse.

3 Urticarial lesions: 19%. Mostly distributed in the trunk or disperse. A few cases were palmar.

Other maculopapular: 47%. Some showed perifollicular distribution and varying degrees of scaling, Some had been described as similar to pityriasis rosea.Livedo or necrosis: 6% Strengths of this study are the large number of patients recruited and that four dermatologists independently reviewed the images. It adds to the understanding of skin manifestations of COVID-19, which may give additional information when trying to make a clinical diagnosis of COVID-19 if other symptoms are non-specific, also the cutaneous manifestations may persist for some time once other symptoms have resolved.

A weakness is the authors did not specify the age of the patients involved so the usefulness for paediatric patients is limited. Also, in some areas, diagnosis of COVID-19 infection could only be made clinically, based on symptoms as the ability to test patients was limited during the height of the pandemic.

Chacon-Aguilar, R.Perez-Moneo, B.An Padiatric (Engl Ed)COVID-19: Fever syndrome and neurological symptoms in a neonate27 Apr 2020SpainEurope1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183976/
Nathan, NCorvol, HLancetAtypical presentation of COVID-19 in young infants27 Apr 2020FranceEurope5Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30980-6/fulltext

This correspondence in the Lancet describes the clinical features of 5 infants with COVID-19 who were admitted to a Paris hospital during the first week after imposed population quarantine in France (from 17th March 2020). At this time at Trousseau Hospital, children needing admission with fever or respiratory symptoms (or both) were admitted to a dedicated SARS-CoV-2 infection unit: during this week 14 infants under the age of 3 months were admitted and of these 5 out of 14 were confirmed SARS-CoV-2 positive on nasopharyngeal swabs.

Age/gender of infants: All 5 of these previously healthy infants with COVID-19 were boys; ages ranged from 1.6 to 2.7 months (median 2.1). All of their parents had mild signs of viral infection (including fever, cough, rhinitis), which could have been indicative of undiagnosed COVID-19.Clinical features at presentation: 5/5 fever (range 37.4 to 38.5 C), 4/5 neurological signs (drowsiness/hypotonia/abnormal “moaning” cry), 4/5 mottled skin, 4/5 runny nose, 4/5 cough, 0/5 dyspnoea, 5/5 normal SpO2, 0/5 digestive symptoms.

Investigations: FBC, CRP & procalcitonin largely unremarkable, with the exception of lymphopaenia in 2/5. Lumbar punctures in 4/5 babies with abnormal neurology reported normal (including negative for RT-PCR SARS-CoV-2). Chest X-rays performed in 4/5 essentially normal.

Outcomes: All 5 showed rapid clinical improvement and received no drugs other than paracetamol. Inpatient stays ranged from 1 to 3 days and duration of fever ranged from 1 to 5 days (max 39C). The infants were followed up for 2 weeks post-discharge with a daily phone call from a paediatrician using a standardised questionnaire.

Conclusion: This encouraging report of a small cohort of SARS-CoV-2 positive infants under the age of 3 months presenting Atypical presentation of COVID-19 in young infantswith fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.

Piccolo, VBassi, AJournal of the European Academy of Dermatology and VenereologyChillblain-like lesions during COVID-19 pandemic: a preliminary study on 63 patients24 Apr 2020ItalyEurope63Clinical - Clinical Featureshttps://doi.org/10.1111/jdv.16526

This is a report of chilblain like lesions observed during the COVID-19 pandemic, collected through a survey issued to Italian dermatologists and Paediatricians. This is a preliminary report as data collection still ongoing.

Importantly – very few patients in this cohort were tested for COVID-19 (11/63) and only 2 of these patients were positive. It is therefore difficult to extrapolate these findings to paediatric COVID-19 specifically, but is worth being aware of.

63 patients have been reported on with a median age of 14 years (IQR 12 – 16yrs) with feet alone being bar far the most commonly affected area (85/7%) followed by feet and hands together (7%). In uploaded pictures from 54 patients, erythematous-oedematous lesions were most common (31/54) followed by blistering lesions (23/54) and pain and itch were common, although a quarter of lesions were “asymptomatic”. Median time of onset of rash to diagnosis was 10 days. The lesions were generally stable and no other cutaneous signs observed. GI symptoms were the most common co-existing (11.1%) with surprisingly low levels of respiratory symptoms (7.9%).

This is basically a description of a common skin manifestation which coincided with COVID-19, and looked like it could be infectious in origin. Few patients tested, and even fewer positive. An interesting series worth bearing in mind given increasing reports of skin manifestation of COVID-19.

Racalcati, SFantini, FJ Eur Acad Dermatol VenereolAcral cutaneous lesions in the time of COVID-1924 Apr 2020ItalyEurope11Clinical - Clinical Featureshttps://doi.org/10.1111/JDV.16533

This pre-print Letter to the Editor reports on a series of unusual dermatological manifestations presenting to the Dermatologic Unit in Alessandro Manzoni Hospital, Italy in March and April 2020. The authors observed 14 cases, of which 11 were children with a mean age of 14.4 years and a range of 13-18 years. Of the 14 cases, 6 (43%) were male. 3 pairs of cases were siblings.

None of the cases had systemic symptoms (other than mild itch in 3 cases), there was no association with cold exposure, co-morbidities or drug intake, and there was no family history of COVID-19 related symptoms. 3 cases reported cough and fever 3 weeks prior to the onset of the lesions.

The authors believe that these dermatological findings are related to COVID-19 due to the rapid outbreak and clustering of these unusual skin lesions occurring at the same time as the COVID-19 outbreak. In support of this they report multiple similar cases being described from other areas affected by the pandemic. They hypothesise that the skin lesions may represent late manifestations of COVID-19 infection in young, healthy subjects, possibly due to an immunologic response targeting the cutaneous vessels. They accept that this hypothesis cannot be tested until a reliable serological test for antibody response to COVID-19 has been developed.

Clinical features: Acral eruption of erythemato-violaceous papules and macules, with possible bullous evolution or digital swelling. Lesions were found on the feet in 8 cases, hands in 4 cases, and on both sites in 2 cases. 2 children developed erythemato-papular targetoid lesions on the hands and elbows after a few days.

Histology: Lesions on fingers showed diffuse dense lymphoid infiltrate of the superficial and deep dermis, with a prevalent perivascular pattern and signs of endothelial activation. Targetoid lesions on elbows showed mild superficial perivascular dermatitis.

Bloods: Normal FBC, CRP, LDH and D-dimer. Serology was negative for EBV, CMV, Coxsackie and Parvovirus B19.

Outcomes: In all cases the lesions resolved without treatment after 2-4 weeks. It is worth noting that this study is limited both by the small number of cases, but more particularly by the lack of evidence linking these skin lesions with a proven COVID-19 infection.Piccolo et al (Clinical)

Landa, NAguirre, TInternational Journal of DermatologyChillblain-like lesions on feet and hands during the COVID-19 pandemic24 Apr 2020SpainEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ijd.14937
Wu, PNie, SGraefes Arch Clin Exp OphthalmolA child confirmed COVID-19 with only symptoms of conjunctivitis and eyelid dermatitis24 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00417-020-04708-6
Zhang, BZhang SJ InfectPositive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19)23 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30233-4/fulltext

In this case series from Dongguan, China, three normally fit & well children aged 14y, 13y and 10m were followed up after positive throat swab for SARS-CoV-2. All three had a subsequent negative throat swab within approximately 7 days, and fully recovered, however 7-9 days later all three had rectal swabs which were positive. These findings raise the question of whether apparently well COVID-19 patients continue to carry and possibly shed the virus. If this was found to be the case in larger and more comprehensive studies, there may be an argument for introduction of strategies to increase avoidance of transmission via the faecal-oral route.

Huang, LZhou, JClin ImagInitial CT imaging characters of an imported family cluster of COVID-1923 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175903/#!po=31.2500
Kan, MJGreenhow, TLJ Ped Inf Dis SocFever without a source in a young infant due to SARS-CoV-222 Apr 2020United States North America1Clinical - Clinical Featureshttps://doi.org/10.1093/jpids/piaa044
Carrabba, GLocatelli, MLancetNeurosurgery in an infant with COVID-1922 Apr 2020Italy Europe1Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30927-2/fulltext
Genovese, GMarzano, AVPediatr DermatolVaricella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?21 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14201

This single case report describes an 8 year old girl presenting on a hospital in Milan, Lombardy region, Italy, on 21 March 2020 with a painless, non-pruritic papulovesicular rash on the trunk developing 3 days after onset of a mild cough. The rash was predominantly papular with some vesicles with crusting, similar in appearance to chickenpox. Limbs, face, genitalia and mucous membranes were spared. She developed a mild fever 5 days after the onset of the rash, and tested positive for SARS-CoV-2. She had bloods including FBC, renal function, liver function and CRP, all of which were normal with the exception of a mild thrombocytopenia with platelets of 105 x 109/L, which subsequently normalised. The rash lasted 7 days, by which time systemic symptoms had resolved. The young girl had a history of varicella infection a year previously.

The authors quote other case reports of cutaneous manifestations associated with COVID-19: petechial rash, widespread urticaria and varicella-like rash predominantly involving the trunk. Although unable to confirm that the rash was definitely associated with COVID-19, they feel it is likely given the child’s previous history of varicella infection and lack of pruritis to suggest the lesions were insect bites. They suggest papulovesicular eruptions be included in the spectrum of exanthems possibly associated with COVID-19.

Li, HXu, QJ Infect The Profile of Peripheral Blood Lymphocyte Subsets and Serum Cytokines in Children With 2019 Novel Coronavirus Pneumonia20 Apr 2020China Asia40Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0163445320302073?via%3Dihub

This was a retrospective observational study, studying lymphocyte subsets and serum cytokines of 40 children admitted with 2019-nCoV pneumonia to Wuhan Children’s Hospital between 24 January and 22 February 2020. These were compared against the lymphocyte subsets and serum cytokines of 16 children admitted with RSV pneumonia to the same hospital between 10 December 2019 and 22 February 2020. Study authors report they could not compare 2019-nCoV pneumonia to healthy controls, as the city was in lockdown.

It is not described how these patients were selected from all patients admitted with 2019-nCoV pneumonia, and RSV pneumonia, and what proportion the included patients were of the total admitted patients with these conditions.

There were 40 children with 2019-nCoV pneumonia, diagnosed by real time PCR. The mean age was 5.07 years (4.71 SD). 23 were male, with 17 females. All 40 children had a CT performed, 16 had unilateral changes, 26 had bilateral changes, and 1 had no changes. Severity was classed as needing ICU admission, only 1 out of 40 was classed as “severe”.

There were 16 children with RSV pneumonia included with mean age of 1.36 years (0.85 SD). 10 were male, 6 were female. All had CT chest, with 3 unilateral changes, 12 bilateral changes, and 1 with no changes. 2 out of 16 required were classified as severe and needed ICU admission.

Lymphocyte subsets were drawn within first 3 days of admission. Those treated with glucocorticoids (3 2019-nCoV and 4 with RSV pneumonia) had them taken before steroids were administered. They compared mean and % between patient groups. Mean CD3+ CD8+ are higher in 2019-nCoV patients; mean 933N/µL(SD 421) than RSV patients mean 675 N/µL (SD 426) (p = 0.044), CD3+ CD8+ % were also significantly higher in 2019-nCoV pneumonia patients. IL10 levels were significantly lower in children with 2019-nCoV pneumonia, though exact figures were not given. The child with severe 2019-nCoV had serial lymphocyte subsets. The authors concluded that immune responses could play a significant role in the disease and influence the severity of response.

The limitations of the study discussed were the small numbers, the very few patients with severe illness and the lack of a normal control. The authors did not comment on the significant age differences between the groups, and how these patients were selected.

Richardson, SDavidson, KJAMA networkPresenting Characteristics, Comorbidities and Outcomes among 5700 patients hospitalized with COVID-19 in the New York City area20 Apr 2020USANorth America34Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2765184

This is a paper from New York, USA, looking at the presenting characteristics, comorbidities, and outcomes of 5700 patients who were hospitalized with Covid-19. These were patients who were admitted to one of 12 Northwell Health acute care hospitals between 01/03/2020 and 04/04/2020. Clinical outcomes were monitored until 04/04/2020. All patients who were sufficiently medically ill to require hospital admission with confirmed severe acute respiratory syndrome coronavirus 2 infection by positive result on PCR testing of an NPA were included. The median age of patients was 63 years (IQR 52-75), 39.7% were female.

At presentations, 30.7% of patients had a temperature of over 380C. 20% had oxygen saturations of less than 90%. 43.1% of patients were considered tachycardic with a heart rate of over 100.

The majority of patients white cell count and differentials were within normal range. The mean white blood cell count was 7 (IQR 5.2-9.5). Neutrophil count 5.3 (IQR 3.7-7.7), however some patients were mildly lymphopenic, median 0.88 (IQR 0.6-1.2). Most patients had a low CRP, the mean result was 16 (IQR 6.4-26.9). Most patients had a raised ferritin, the mean result was 798 (IQR 411-1515), with 15-400 being considered normal range. Of note lactate dehydrogenase was tested in 70% of the patients and was significantly raised in most patients, the mean being 404 (IQR 300-551) with the normal considered to be 50-242.

A venous lactate was recorded in 44% of patients and all results were normal- <2. The most common comorbidities were hypertension (56.6%), obesity (41.7%) and diabetes (33.8%).

At the study end point 2634 patients had been discharged or had died during hospitalisation. Of these 14.2% were treated in ICU, 12.2% of them received mechanical ventilation, and 21% of these patients died. At the end point of the study of those patients who had received mechanical ventilation 3.3% were discharged alive, 24.5% died, 72.2% were still in hospital. There were no deaths in the under 18 age group (34 patients).

Of the patients who died, those with diabetes were more likely to have received mechanical ventilation or care in the ICU compared to those who did not have diabetes. Interestingly of those who died, those with hypertension were less likely to have received invasive mechanical ventilation than those without hypertension.

As most patients were still in the hospital at the endo point of the study (53.8%) this biases rates toward including patients who died early in their hospital course. The researchers point out that as these patients complete their hospital course, reported mortality rates will decline.

This study was slightly limited by the fact that the data was collected from the electronic heath record database and not the medical notes, from which a greater level of detail may have been established, however it was using this method that allowed for such a large number of patients to have been included and reviewed over a relatively short space of time. It is also limited by the fact that the study population only included patients from within the New York metropolitan area which may underrepresent some ethnic minorities.

Li, HXu, JJournal of Medical VirologyPositive result of SARS-CoV-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu, China20 Apr 2020ChinaAsia0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25905
Du, AZhang, ZInfectionClinical characteristics of COVID-19 in children compared with adults in Shandong Province, China16 Apr 2020ChinaAsia14Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs15010-020-01427-2
Xing, YXing, QJ InfecDynamics of faecal SARS-CoV-2 in infected children during the convalescent phase16 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30177-8/fulltext
Jiang, SYu, XClin Chem Lab MedCoinfection of SARS-CoV-2 and multiple respiratory pathogens in children16 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://www.degruyter.com/view/journals/cclm/ahead-of-print/article-10.1515-cclm-2020-0434/article-10.1515-cclm-2020-0434.xml
See, K CIbrahim Hinternational journal of infectious diseasesCOVID-19: Four paediatric cases in Malaysia15 Apr 2020malaysia Asia4Clinical - Clinical Featureshttps://www.ijidonline.com/article/S1201-9712(20)30181-8/fulltext
Shi, BXu, HClin PediatrSevere pneumonia due to SARS-CoV-2 and respiratory syncytial virus infection: a case report15 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820920016?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&#articleCitationDownloadContainer
Chen, JHuang, AGenes Dis.The clinical and immunological features of pediatric COVID-19 patients in China14 Apr 2020ChinaAsia12Clinical - Clinical Featureshttps://reader.elsevier.com/reader/sd/pii/S2352304220300507?token=631DD2FAEE11F02D80D1CC96D2AB2621AA7960348DA5FFDD2FAB802D188A0726E724273D5014403A376291F4BD637C50

This early study from Chongqing, China describes the features of 12 children diagnosed with COVID-19. All had a mild course of illness. CT imaging was abnormal in 10 of 12 with patchy ground glass opacity the most common finding. Lymphopenia was present in 2 children.

The authors also compare the "immune profile" (including lymphocyte counts, immunoglobulins, complement, CRP and IL6 levels) of the 12 children with a group of 20 adults patients. Aside from a lower CRP in children (mean 11.5 vs 23.3mg/L) and expected age-related differences in absolute lymphocyte numbers, there were no significant differences between the groups.

liu, J.Lu, B.JMVDetection of SARS‐CoV‐2 by RT‐PCR in anal from patients who have recovered from coronavirus disease 201914 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25875
Shen, LLan, JJournal of InfectionClinical and laboratory-derived parameters of 199 hospitalized patients with coronavirus disease 2019 in Xiangyang, Hubei Province, China10 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.038
Wang, H.Lu, XiaoxiaPediatric Infectious Disease JournalRehospiatlization of a recovered coronavirus disease 19 (COVID-19) child with positive nucleic acid detection09 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/onlinefirst/Rehospitalization_of_a_Recovered_Coronavirus.96214.aspx
Lazerrini, MTrobia, GLancet Child and Adolescent HealthDelayed access of provision of care in Italy resulting from fear of COVID-1909 Apr 2020ItalyEurope12Clinical - Clinical Featureshttps://doi.org/10.1016/S2352-4642(20)30108-5

This is a report of case studies during the COVID-19 pandemic in Italy of children whose presentations were thought to have been delayed due to parental fears of coming to the hospital. They report from 5 hospitals between March 1st and March 27th 2020, where paediatric presentations were reduced between 73–88%.

During this period, in the week of March 23rd to 27th 12 children are identified whose parents reported avoiding accessing hospital due to concerns over SARS-CoV-2 infection . 6 of these were admitted to PICU and there were 4 deaths. The cases include 2 children with DKA, 2 with acute leukaemia, 2 children with cerebral palsy and complex needs, 1 with pneumonia and febrile convulsions, 1 with pyelonephritis, 1 with pyloric stenosis, 1 with a Wilm’s tumour, 1 with vomiting and hypoglycaemia and 1 with a congenital syndrome on dialysis.

This case series highlights the concerns of many paediatricians that more deaths will be seen in children from collateral damage born from the COVID-19 response, than will die of COVID-19. Delayed presentations is a major concern around the world currently, and whilst these cases certainly raise concerns, evidence is needed to ascertain the true presence and extent of this problem.

Zhu, CZhu, LPediatric PulmonologyClinical characteristics of a case series of children with coronavirus disease 201908 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24767

This is a case series of ten paediatrics patients aged 1 – 17 years with confirmed Covid 19. These cases were retrospectively selected from 3 hospitals in Jiangsu, a coastal province approx 700 km east of Wuhan. Cases were collect from 24th January 2020 to 22nd February 2020. All cases were confirmed by RT-PCR anal or throat swabs. 70% of children presented with symptoms, and 30% were asymptomatic, but were screened due to contact with confirmed family member.

The most common symptoms on presentation were fever (40%), cough, (20%) and headache (20%). There was no report of whether children had underlying conditions. All children had a CT chest completed. Half of the cohort had CT changes. There were 2 cases of bilateral pneumonia, and 3 cases of unilateral pneumonia, 2 of which were in asymptomatic patients. Bloods were unremarkable, one child aged 1 year had Lymphocytosis, all others had normal lymphocyte counts. CRP was not raised in any child. Only one patient in the cohort required oxygen, and there were no ICU admissions. Five children were treated with antiviral medication including lopinavir/ritonavir (n=4) interferon α‐2b (n = 4), and oseltamivir (n = 1).

Of note, 5 children were still in hospital at the end of the case series.

Yuan, JLiu, LClinical Infectious DiseasesPCR assays turned positive in 25 discharged COVID-19 patients08 Apr 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa398
Shen, QZhou, ZPediatric PulmonologyNovel coronavirus infection in children outside of Wuhan, China07 Apr 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24762

This retrospective study examines the clinical characteristics of children admitted to Public Health centre of Changsha, Hunan, China. There were 9 children admitted during the study period 08/01/2019 and 19/02/2020 who tested positive for COVID-19. All had a confirmed contact case with COVID-19. Median age was 8 years, with a minimum age 1 year and oldest was 12 years. Children were predominantly female (6/9, 66%). There was no information provided about co-morbidities.Clinical features: 2/9 were asymptomatic, 1/9 had cough, 4/9 had fever, 1/9 had sore throat and 2/9 had diarrhoea.

Radiology: 2 patients had chest CT that were described as ground glass opacities. No further information was provided about the indications.

Bloods: 1/9 had lymphocytosis in whom other infectious causes were excluded. 1/9 had raised CRP, 4/9 raised ESR, 1/9 raised LDH, 2/9 had raised AST with 0/9 ALT abnormalities. All abnormalities were mild.

Treatments: All (9/9) children were treated10/2.5 mg/kg lopinavir/ritonavir twice daily, orally. 5/9 children received 10 mg/kg azithromycin once a day. One child received meprednisone and immune globulin therapy for febrile convulsion. No additional information regarding treatments were provided.All children required oxygen therapy. None required intensive care or mechanical ventilation.Outcomes: At the end of data collection 3/9 remained under hospital care and were positive for COVID-19. The remainder (6/9) were discharged from hospital. The time spent in hospital varied between 11 and 22 days (median 13.5 IQR 10.75-14 days).

Other salient features: 6/9 children were RT-PCR negative at discharge. The time between initial contact and a negative test varied between 9 and 20 days (median 13.5 IQR 10.75-14 days).

All averages were calculated by the reviewer from the data provided within the article.

Lei, PJiao, JJournal of X-ray Science and TechnologyClinical and computed tomographic (CT) images characteristics in the patients with COVID-19 infection: what should radiologists need to know?07 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://content.iospress.com/articles/journal-of-x-ray-science-and-technology/xst200670
Han, YFang, YJournal of Medical VirologyA comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults06 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1002/jmv.25835

This retrospective study compares the clinical characteristics of 25 adults and 7 children with acute respiratory disease confirmed as COVID-19. Cases were retrospectively identified from patients admitted to Xian Eighth Hospital in Shaanxi, China, between 31st January and 16th February 2020. The mean age of the children was 1.3 years with a range of 2 months to 13 years, and 4 (57%) were male. None had any co-morbidities.

Clinical features: 5/7 (71%) children had cough, 3/7 (43%) had shortness of breath, 5/7 (71%) had fever, 1/7 (14%) had sore throat and 4/7 (57%) had diarrhoea and/or vomiting.

Radiology: 5/7 (71%) children had “positive findings suggestive of pneumonia” reported on CXR and/or CT. Examples of these findings were ground glass opacities and segmental consolidation in bilateral lung fields, particularly peripherally.

Bloods: No children had a low lymphocyte count (<0.8). Raised lymphocyte counts were not mentioned but raised WCC was reported in 2/7 (29%) children. 2/7 (29%) had a raised CRP (>10). 4/7 (57%) had a raised AST (>50) or ALT (>37). 5/7 (71%) had increased Brain Natriuretic Peptide (>125). 4/7 (57%) had a raised CK Isoenzyme (>30).

Outcomes: All 7 cases in children were classified as mild and recovered within 1-2 weeks. None of the children were admitted to intensive care and none died.Comparison of clinical characteristics in adults and children: Children were more likely than adults to have diarrhoea and/or vomiting (57% vs. 8%, p=0.012). Adults more frequently had a reduced WCC, compared to a raised WCC in children, and raised CK isoenzyme was less common in adults.

Graselli, GPasenti, AJAMABaseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy06 Apr 2020ItalyEurope4Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2764365

This is a retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the regional ICU coordinator of the Lombardy ICU Network, and treated at one of the ICUs of the 72 hospitals in the network. Patients were recruited between 20/02/2020 and 18/03/2020 with follow-up on 25/03/2020. Data was collected via telephone. Of the nearly 1600 patients referred for ICU admission, only 4 were between 0 and 20 years of age, with a median age of 16 and interquartile range of 14 to 19 years of age. Three of the four patients (75%) were male and three of the four had comorbidities (specific details not given).

Two required mechanical ventilation. It’s important to note that the patients in this study were those admitted to ICU and not patients on medical wards, in the ED or in the community so the high percentage of ventilated patients in this study is not a reflection of the other patients in the region with SARS-CoV-2. These two patients had relatively low oxygen requirements with an FiO2 of 30% and 50%; relatively low PEEPs of 5 and 14 mmHg; and favourable PaO2/FiO2 ratios of 195 and 323, placing these two patients in the mild to moderate ARDS severity scores (for more information on PaO2/FiO2 ratios have a look at the LITFL explanation at https://litfl. com/pao2-fio2-ratio/). None of the four patients in the 0-20 year old category received ECMO. Information on disposition was only available for two of the four patients. None of these patients died. Two remained on ICU on 25/03/2020 at time of follow-up.What can we take from this study? As the study recruited patients admitted to ICU, the numbers of adolescent patients in this case series is low at only four, with an age range of 16 to 19. The data was collected retrospectively via telephone making it difficult to draw robust conclusions. However, we can see that compared to the older groups of patients in the study, ventilation requirements were lower. Three of the four adolescent patients had comorbidities, which might suggest that children and adolescents without comorbidities in the Lombardy region were less severely unwell and did not require ICU admission.

Lai, WLiu, JPediatr RadiolComputed tomography of the lungs in novel corona virus (COVID-19) infection06 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04664-7
Canarutto, DBarera, GPediatric PulmonologyCOVID-19 infection in a paucisymptomatic infant: raising the index of suspicion in epidemic settings06 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24754

This early single case report from Milan, Italy describes an infant with mild a mild case of COVID-19 who recovered without need for intervention. His father, the implied household index, had an upper airway infection with conjunctivitis without confirmatory testing.

Patient: 32 day old boy, presented to hospital symptomatic

Clinical Features: Cough, fever, rhinitis

Radiology: CXR normal

Bloods: reactive lymphocytes on film, monocytosis (1400/L) and neutrpenia (900/uL), CRP normal

Outcomes: Resolution of fever by day 3 of hospitalisation, full recovery without need for supportive therapy. Breast feeding maintained.

Lin, LShan, HGutGastrointestinal symptoms of 95 cases with SARS-CoV-2 infection02 Apr 2020ChinaAsia5Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/04/02/gutjnl-2020-321013
Xing, YXing, QJournal of Microbiology, Immunology and Infection.Prolonged viral shedding in feces of pediatric patients with coronavirus disease 201928 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://dx.doi.org/10.1016%2Fj.jmii.2020.03.021
Yin XLi HRadiology of Infectious Diseases A mild type of childhood COVID-19 - a case report27 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jrid.2020.03.004
Qui, HLancet: Infectious DiseasesClinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study25 Mar 2020ChinaAsia36Clinical - Clinical Featureshttps://doi.org/10.1016/S1473-3099(20)30198-5

Qui and colleagues retrospectively identified 36 children with an EMR diagnosis of COVID-19, during the period Jan 17 through March 1st, at three hospitals in Zhejiang, China, a province 900km to the east of Wuhan. Diagnosis was made by COVID-19 RT PCR for all patients presenting with fever, cough and radiographic presentation, or if there was a history of exposure to an infected individual.

For the mild cohort, 28% of patients were asymptomatic, with moderate cases more likely to have fever of 38oC or higher (47%), cough (24%), vomiting or diarrhoea (10%) or headache (10%). More than half (53%) of patients had ground-glass opacities on CT scan, meeting the case definition for Moderate illness. Key laboratory values of note include lymphopaenia, leukocytopaenia and increased procalcitonin as all associated with moderate illness. No patients in this cohort were hypoxaemic as a result of their pneumonia.

The authors also draw comparisons between adults and children with COVID-19 (less severe illness, less likely to have abnormal investigations), as well as comparing the clinical features and severity of COVID-19 with SARS (milder symptoms and severity) and H1N1 influenza (fewer symptoms, more frequent pneumonia) in children. Wisely, Qui & colleagues note the high rate of findings that are not clinically obvious, and the high proportion of asymptomatic cases make for very challenging case identification in the absence of clear epidemiologic information. “This finding suggests a dangerous situation if community-acquired infections occur.”

Su, LGai, ZEmerging Microbes and InfectionsThe different clinical characteristics of corona virus disease cases between children and their families in China - the character of children with COVID-1925 Mar 2020Asia9Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/22221751.2020.1744483

This study from the Jinan Infectious Disease Hospital retrospectively reviewed cases of nucleic acid-positive SARS-CoV-2 patients between 24th January to 24th February 2020 (detected using the (ORF1ab/N) nucleic acid detection kit by Bio-germ, Shanghai, China). Nine children and members of their family totalling 14 adults were included. Note that two family members missed enrollment as they were at another hospital. Of the 9 children, 6 were female (66%). The age group ranged from 11 months to 9 years and 9 months old (mean age 4.5 years). For eight of the nine children, there was history of their parents having travelled frequently, being in contact with someone from Wuhan or having worked or visited Wuhan. Of note, five of the discharged children were readmitted to hospital because their stool showed positive results in SARS-CoV-2 PCR.

Clinical Features (children): 3 of the 9 children had fever (33%) and one had cough (11.2%). Imaging (children): On chest x-ray and CT, two children had findings consistent with bronchitis (22.2%), one had bronchial pneumonia (11.1%) and a further one had pulmonary consolidation and ground glass opacity. From the two example images included,, findings appear to be bilateral but this was not specified in the body of the text. Bloods (children): 8 of 9 children (88.9%) had normal or decreased white blood cell counts. Six children (66.7%) had increased CK-MB. ALT, AST. All children had a normal CRP, PCT, ESR and IL-6. Clinical Features (adults): Of the 14 adults, 8 (57.1%) had fever, five had cough (35.7%), three had chest tightness or pain (21.4%), a further three had fatigue (21.4%) and one reported a sore throat (7.1%). Imaging (adults): Ten (71.4%) had abnormal imaging mainly pulmonary consolidation, with 7 (50%) having nodular shadow and 7 (50%) having ground glass opacities. Bloods (adults): Four (28.6%) had reduced whice cell count with seven (50%) having lymphocytopaenia.

Zheng, FJin, RCurrent Medical ScienceClinical characteristics of children with coronavirus disease 2019 in Hubei, China24 Mar 2020ChinaAsia25Clinical - Clinical Featureshttps://doi.org/10.1007/s11596-020-2172-6

This is a retrospective case series of 25 children <14 years of age hospitalised with COVID-19 from 10 hospitals across the Hubei province between February 1st and February 10th 2020. It is unclear how the cases were ascertained. 14/25 were male (54%) and the median age was 3yrs (IQR 2-9yrs). Most patients were <3 years (40%). 2 patients had a background of repaired congenital heart disease (both infants), although we have no more detail than this. Both of these children went on to develop critical illness.Clinical features: 13/25 (52%) had fever, 11/25 (44%) had cough, 3/25 (12%) had diarrhoea, and 2/25 (8%) had nasal congestion, vomiting, breathlessness or abdominal pain.

Bloods: Inflammatory markers were not particularly raised, with a median CRP of 14.5mg/L (IQR 0.93 - 25). 10/25 (40%) patients had lymphopenia.

Radiology: CT chest was normal in 8/24 (32%) with unilateral involvement in 5/24 (20%) and bilateral in 12/24 (48%). Changes typically showed patchy shadows. Younger children appeared more likely to have bilateral lung findings than older children.

Co-infection: Other organisms identified included Mycoplasma pneumoniae (3/25, 12%), Influenza B (2/25, 8%) and one of the 2 critically ill children had Enterobacter aerogenes.

Lou, XTian, YJournal of Paediatrics and Child HealthThree children who recovered from novel coronavirus 2019 pneumonia22 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://doi.org/10.1111/jpc.14871

This is a case series of 3 children diagnosed with COVID-19 and admitted in the Zhengzhou University Children’s hospital in Henan Province, China (dates not provided). They were 2 sisters aged 6 and 8yrs, and a 6m old infant. The children were all infected by a family member, although the family of the 6m infant had no link to Wuhan.

Clinical features: All 3 had a fever, 2 had nasal congestion and rhinitis alongside fatigue, diarrhoea, and headache. The 6yr old girl had a cough.

Radiology: All 3 patients had CT scans with bilateral infiltrates

Bloods: Not reported

Outcomes: No children required intensive care/intubation or had any severe complications. All have been discharged. The 2 sisters were treated with nebulized interferon.

Liu HLan WJournal of InfectionClinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children21 Mar 2020ChinaAsia4Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.007

This study is a review of CT imaging findings in children and pregnant women in a hospital in the Hubei Province. Four children with confirmed COVID-19 infection were included in the study. The bottom line is that pulmonary CT changes in children were mild, with either focal ground glass opacification or focal consolidation. Although CT has been reported as a useful screening tool in adults with suspected COVID-19 infection, the CT changes of the four children were non-specific; the authors conclude that exposure history and clinical symptoms are more helpful for screening in swab-negative children than CT. 41 pregnant women with either laboratory-confirmed or clinically-diagnosed COVID-19 infection were included in the study. All pregnant women had mild courses of their COVID-19 illnesses. Six of the 16 laboratory-confirmed pregnant women and 10 of the 25 clinically diagnosed pregnant women delivered during the study period. There were no cases of vertically transmitted COVID-19 in the neonates born to these pregnant women.

Case 1: 5 year old female with fever, cough and fatigue. No lymphadenopathy. Bloods: low WCC with raised lymphocytes and decreased neutrophil ratio. Normal CRP. CT: normal. Follow-up CT 9 days later remained normal.

Case 2: 11 month old male with fever and cough. No lymphadenopathy Bloods: normal WCC with raised lymphocyte count and decreased neutrophil ratio. Normal CRP. CT chest: single consolidation without peripheral predominance (unlike reported findings in adults).

Case 3: 9 year old female with fever but no cough. No lymphadenopathy. Bloods: normal WCC, low lymphocytes and normal neutrophil ratio. Normal CRP. CT chest: single ground glass opacity without peripheral predominance (unlike reported findings in adults).

Case 4: 2 month old male with cough but no fever. No lymphadenopathy. This infant was coinfected with RSV. Bloods: normal WCC with normal lymphocytes and normal neutrophil ratio. CRP raised (does not say how high). CT chest: multiple focal consolidations and pleural effusion. This infant’s CT findings were more severe than the other three children, thought to be due to coinfection with RSV.

Lu, XWong, GWKNEJMSARS-CoV-2 infection in children18 Mar 2020ChinaAsia171Clinical - Clinical Featureshttps://www.nejm.org/doi/full/10.1056/NEJMc2005073

This retrospective study examines the clinical characteristics of children with confirmed COVID-19 diagnosed at Wuhan Children’s hospital. There were 1391 children tested between Jan 28th and Feb 26th 2020 due to known contact with a case of COVID-19, of these 171 were confirmed to have SARSCoV-2. Median age was 6.7yrs, and there was a relatively even spread amongst age groups. Children were predominantly male (104/171, 60.8%).

Clinical features: 83/171 had cough, 79/171 had pharyngeal inflammation (sore throat), 71/171 had fever. 15/171 had diarrhoea and 13/171 had rhinorrhoea. 49/171 were tachypnoeic on admission and 72/171 were tachycardia. Only 4/171 had Oxygen saturations <92% during hospitalisation. 0/31 infants <1yr were asymptomatic in this cohort, with rates of asymptomatic infection increasing with age. There were higher rates of pneumonia in infants (25/6), but the definition of this is unclear. We also have no information regarding co-infection with other viruses or bacteria.

Radiology: Not delineated into CXR or CT, but descriptions sound like CT findings. The most common was bilateral ground glass opacity (56/171) followed by unilateral patchy shadowing (32/171) and bilateral patchy shadowing (21/171). There were several children with radiographic pneumonia who were asymptomatic.

Bloods: The supplementary appendix contains lab results. Only 6/171 patients had lymphopaenia, the vast majority were in normal range (Med 2.9×109/L, IQR 2.2 – 4.4). CRP was elevated (>10mg/L) in 33/171 (Med 4, IQR 1.3 – 8) of which 27/33 had pneumonia.

Outcomes: 3 patients required ITU admission and intubation. All 3 had comorbidities, including hydronephrosis, leukaemia and intussusception. The child with intussusception suffered multiorgan failure and died after 4 weeks. The cause of death is not clear from the report. As of writing 149 patients had been discharged with 21 stable in the general wards.

Cui, YZha, YJournal of Infectious DiseasesA 55-day-old female infant infected with 2019 novel coronavirus disease: presenting with pneumonia, liver injury, and heart damage17 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa113/5807961

This is a case report of a 55 day old with SARS-CoV-2 who was admitted to hospital in China on February 2, 2020. She was treated with inhaled intereron-alpha-1b, amoxicillin, reduced glutathione, ursodeoxycholic acid, and traditional Chinese medicine lotus qingwen. The child was initially well, although her respiratory status worsened on day 2-6, and she required supplemental oxygen via nasal cannulae. Anal swabs on day 11 and 13 were positive on day 11-13 despite negative pharyngeal swabs.Note is made in the title of this study that the infant sustained liver injury and heart damage. This is on the basis of marginally elevated liver tranaminases and cardiac troponin measurements, for which it is unclear why the tests were performed. There is no indication of any clinical compromise demonstrated. It should be noted that a significant proportion of the child’s care (including investigations) would not be considered standard practice in UK/US/Aus paediatric medicine.

Zhang, CZhou, XMedRxIVClinical characteristics of 34 children with coronavirus disease-2019 in the West of China: a multiple-center case series16 Mar 2020ChinaAsia34Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.12.20034686v1

A pre-print, the information should be treated with caution until it has undergone peer review.This is a further retrospective case study looking at 34 children with confirmed COVID-19 between Jan 1st and Feb 25th 2020 in 4 hospitals in Western China. They were aged 1 month to 12 years.

Clinical features: The most common symptom was fever (26/34) followed by cough (20/34), followed by vomiting (4/34) and diarrhoea (4/34). A significant number had co-infections (16/34) including Mycoplasma pneumoniae (9/34), influenza A or B (12/34) and 2/34 were mononucleosis. One child had a nephroblastoma and one had asthma. The median incubation period was 10 days (IQR 7.75 – 25.25) and median 3 days (IQ 2 – 4) from admission to fever resolution

Bloods: Lymphocytosis was most common (17/34). CRP was not significantly elevated (median 7.56ml/L, IQR 1.21 – 15.13), but was >5 for 20/34, and procalcitonin was not significantly elevated either (0.6, 0.03 – 0.07)

Radiography: On chest CT 14/34 had patchy shadows bilaterally, 14/34 unilaterally, and 6 had normal CT chest.

Ji, LJian, RWorld Journal of PediatricsClinical features of pediatric patients with COVID-19: a report of two family cluster cases16 Mar 2020ChinaAsia2Clinical - Clinical Featureshttps://dx.doi.org/10.1007/s12519-020-00356-2

This is a review of two confirmed paediatric cases of COVID-19 (both from oropharyngeal swabs) from two family clusters with recent travel to Wuhan. One child presented with fever and the other with diarrhoea.

Case one: 15-year-old boy presenting with a one-day history of fever. Clinical features: Temperature 37.9oC, pharyngeal congestion. Normal lung auscultation. Laboratory findings: mildly elevated white cell count at 11.82 x109/L, predominantly neutrophils (67.3%) and 25.7% lymphocytes. His CRP was mildly elevated at 35 mg/L. Radiological findings: normal unenhanced CT chest. Outcome: Symptomatic treatment. Symptoms disappeared after two days. Family information: both parents also tested positive for SARSCoV2.

Case two: 9-year-old boy presented with mild diarrhoea but no cough and no fever. Normal examination. Laboratory findings: normal white cell count and normal CRP. Radiological findings: normal unenhanced CT chest. Outcome. Treated with oral probiotic and symptoms disappeared after 2 days. Family information: Family members had negative COVID-19 swabs but were symptomatic. His mother presented with fever and cough with bilateral peripheral ground glass opacifications on CT chest. The child’s father and two-year old sister had normal CT chests but had mild symptoms consistent with COVID-19: his father had a cough for four days and his twoyear-old sister had a transient two-day low-grade fever.

Xu, YGong, SNature MedicineCharacteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding13 Mar 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1038/s41591-020-0817-4

This study presents the results of widespread screening for COVID-19 in Guangzhou in China. 745 children were screened of which 10 were positive for COVID-19. Their ages ranged from 2 months to 15 years.

Clinical features: 6/10 had a fever over 38oC. 5/10 had a cough. 4/10 had a sore throat. 2/10 had rhinorrhoea and 2/10 had diarrhoea.

Radiography: 7/10 had coarse lung markings on CXR with no pneumonia, and 3/10 were normal. CT scans revealed ground glass or patchy opacities in 5/10.Bloods: Basically normal in all cases

They made note that rectal swabs were frequently positive and that these swabs were positive for a longer duration than nasal swabs. The authors suggest on this basis that faecal-oral transmission may be possible, however this is very uncertain and will require further research to elucidate.

Xing, YXing, QmedRxivProlonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase13 March 2020ChinaAsia3Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.11.20033159v1

A pre-print, the information should be treated again with caution until it has undergone peer review.

This study of 3 paediatric patients with COVID-19 from Qingdao, China (aged 1.5, 5 and 6 years) all had fevers and none were severe. All children had elevated lymphocytes (>4.4 x 109/L) and 2 of 3 had abnormalities on chest CT (consolidation in one and ground glass changes in the other). The primary point made in the paper is that whilst respiratory swabs were negative within 2 weeks after children became afebrile, stool remained positive for over 4 weeks.

Liu, WLiu, YNEJMDetection of COVID-19 in children in early January 2020 in Wuhan, China12 Mar 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1056/NEJMc2003717

This letter to the editor describes a case series from Tongji hospital in Wuhan, China, taken from a cohort of 366 hospitalized children between January 7th and 15th 2020. 6 children were PCR Positive for COVID-19. Of the 6 patients, age range 1-7 years. All had fever >39oC, cough and 4/6 had vomiting. All had lymphocytopenia, with 4/6 leukopenia and 3/6 with neutropenia. One child required an ICU admission, receiving pooled donor IVIG. The median recovery time was 7.5 days. Authors surmise COVID-19 occurs in children with some moderate-severe episodes of illness.

Li, WLi, SPediatric RadiologyChest computed tomography in children with COVID-19 respiratory infection11 Mar 2020ChinaAsia5Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04656-7

This study describes five children with confirmed COVID-19 who had CT chest scans in a large tertiary level hospital in China. Three of the five children had patchy ground-glass opacities on their CT scans but these changes were less severe than those seen in infected adults. The treatment is not detailed in the paper, so presented as published in this summary.

Case 1: 17 month old asymptomatic male. Bloods: CRP 9.4, WCC 9.2. Radiology: CT chest performed on day 4 showed patchy ground glass opacities. Repeat CT on day 9 after treatment had normalised (antiviral, anti-infective, immunoglobulin, interferon and Lianhua qingwen granules). No CXR.

Case 2: 10 month old asymptomatic female. Bloods: CRP 0.9, WCC 14.8. Radiology: Day 2 scan: normal. Not repeated. No CXR.

Case 3: 3 year old male with coryza, productive cough, sore throat and fever after 3 days. Bloods: CRP 0.7, WCC 15.0. Radiology: Day 9 CT showed patchy ground-glass opacities. Repeat CT on day 16 had normalised after treatment (antiviral, anti-infective, immunoglobulin). No CXR.

Case 4: 4 year old asymptomatic male. Bloods: CRP 0.2, WCC 6.6. Radiology: Day 2 CT chest showed patchy ground-glass opacities. Repeat CT on day 7 had normalised after treatment (montelukast, immunoglobulin). No CXR.

Case 5: 6 year old asymptomatic male. Bloods: CRP 0.6, WCC 5.3. Radiology:

Day 3 CT was normal. No CXR.

Xu, R.Hu, XQuantit Imag Med and SurgCT imaging of one extended family cluster of corona virus disease 2019 (COVID-19) including adolescent patients and "silent infection" 10 Mar 2020China Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136726/
Bahar, BDelaney, MJ Peds Kinetics of viral clearance and antibody production across age groups in children with severe acute respiratory syndrome coronavirus 2 infection09 Mar 2020United StatesNorth America641Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31114-8/fulltext

This is a retrospective study of SARS-CoV-2 viral clearance and antibody production in children. Children with who were tested with a nasopharyngeal SARS-CoV-2 RT-PCR test from March to June 2020 at Children’s National Hospital Washington, US were included.

Overall, there were 641 positive RT-PCR tests in 592 patients (median of 1 test per patient, max 6 tests) and 5777 negative tests (median of 1 test per patient, max 15 tests). 68 patients had more than 1 RT-PCR test. Of the 238 serological tests done, 69 were positive in a total of 58 patients (median of 1 test per patient).

The median duration of RT-PCR positivity was 19.5 days. Of note, children aged 6-15 years had a longer duration of RT-PCR positivity compared with older children (16-22 years) (median 32 vs 18 days). The median time to achieve positive serology was 18 days, however, to reach sufficient levels of neutralising antibodies was 36 days. IgG class antibodies against the S1 and S2 glycoproteins were detected in blood samples of children prior to viral clearance.

This study provides further insight into the kinetics viral clearance and the antibody response in children infected with SARS-CoV-2. The prolonged period of RT-PCR positivity is consistent with other studies in children and adults. Importantly, it is unknown whether this period of PCR positivity correlates with ongoing shedding of viable virus particles capable of transmission. Unfortunately, this study did not include details of symptoms associated with the laboratory results.

Xia, WHu, DPediatric PulmonologyClinical and CT features in pediatric patients with COVID-19 infection: different points from adults05 Mar 2020ChinaAsia20Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24718

A case series of 20 paediatric patients with COVID-19 infection identified with COVID-19 NAT on pharyngeal swabs from Wuhan Children’s Hospital. It reviews the clinical information and co-infections.

Clinical features: two thirds had a clear contact history. Incubation 24hrs28 days of life. 13/20 had a cough, 12/20 had a fever. Bloods: 11/20 had (N) CRP, i.e. less than 3mg/L and 80% had PCT >0.05.

Radiology: On CT: Subpleural findings were seen in all 20 patients. 50% had bilateral findings, with a further 6/20 with unilateral findings. Consolidation with a halo in 50% of cases, considered as atypical signs in paediatric patien. Chloral hydrate was the primary sedative for CTs These were predominantly mild cases in the paediatric patients, with CXR adding little diagnostically. An early chest CT exam seemed to be necessary. 9/20 had coinfection, most commonly with mycoplasma (4/9) – although the ‘flu B,’flu A or RSV accounted for almost all of the remainder

Despite this, the physical chest symptoms were mild, with retraction in one case, and another case with cyanosis.

The average length of stay 12.9 days. Some patients were managed on the basis of their CT alone. These are similar to those seen in adults.

Lan, L.Xu, H. Korean J Radiol Early CT Findings of Coronavirus Disease 2019 (COVID-19) in Asymptomatic Children: A Single-Center Experience.04 Mar 2020China Asia4Clinical - Clinical Featureshttps://kjronline.org/Synapse/Data/PDFData/0068KJR/kjr-21-919.pdf
Zhu, YFeng, SJournal of Infection Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)03 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.033
Dong YJiang ZPediatrics Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China01 Mar 2020ChinaAsia2143Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/03/16/peds.2020-0702/tab-figures-data?versioned=true

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Kai-qian, KThoon, KCClinical Infectious DiseasesA well infant with coronavirus disease 2019 with high viral load28 Feb 2020SingaporeAsia1Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa201

This was a case report of a single 6-month-old with a positive nasopharyngeal swab until D16 of admission to hospital. There had been household transmission. There was a positive NPA with rt-PCR on D1 of admission although the child was asymptomatic – daily swabs remained positive until D17. The child was febrile once during the course of admission although they remained asymptomatic. Blood and stool tests were positive on D2.

They had essentially normal investigations except for a neutropenia.

Cai, JZeng, MClinical Infectious DIseasesA case series of children with 2019 novel coronavirus infection: clinical and epidemiological features28 Feb 2020ChinaAsia10Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa198/5766430

This retrospective study examines 10 children diagnosed with confirmed COVID-19 between 19th Jan and 3rd February 2020 at the Children’s hospital in Shanghai. The age range is from 3 months to 11 years. None had comorbidities. There were no severe cases.

Clinical features: The assumed incubation period (time from exposure to index case to developing symptoms) was between 2 – 10 days, but median (and mode) 7 days. With regard to symptoms, 7/10 had fever >38oC, 6/10 had a cough, 4/10 had a sore throat, 3/10 had nasal congestion, 2/10 had rhinorrhea and 2/10 were sneezing.

Radiology: The chest x-ray was normal in 6/10. The rest had unilateral opacities.

Bloods: Lymphocyte counts were normal in 9/10, raised in one case. CRP ranged from 0.5mg/L to 35mg/L but was <10 for 7/10. Procalcitonin was normal (<0.25) in all children. 2 patients had a mild elevation of ALT (100U/L) or AST (142U/L and 51U/L) Detection of SARS-CoV-2: Virus was found in NP/throat swabs in all patients, and the duration of shedding ranged from 6-22 days (Median 12 days). Stool shedding was prolonged, over 30 days in one patient. No urine was positive, and no serum positive.

Chen, CWang, FLancet pre-print serverCoronavirus disease-19 among children outside Wuhan, China25 Feb 2020ChinaAsia31Clinical - Clinical Featureshttp://dx.doi.org/10.2139/ssrn.3546071

A pre-print, the information should be treated with caution until it has undergone peer review. This is a prospective case series of 31 paediatric cases of COVID-19 diagnosed at the Shenzen Third Peoples hospital between Jan 16th and Feb 19th 2020. This made up 7.9% of all cases diagnosed in Shenzen. They were all confirmed by PCR. None had been exposed to the seafood market in WUhan. The patients received nebulised interferon and, IV ribavirin or oral lopinovir/ritonavir. The median age was 6.75, with most patients (41.9%) aged 5-9. Followed by 0-4yrs (32.2%) and 10-14yrs (19.4%). 41.9% were male.Clinical features: 12/31 Children were asymptomatic. Fever was observed in 14/31, Cough in 13/41, Sore throat in 2/31, Rhinorrhoea in 22/31 and diarrhoea in 2/31. Median duration of fever was 2 days, with a range of 1–9 days. Bloods: Lymphopaenia was not observed. Lymphocytosis occurred in 17/31 patients. CRP was elevated in 4/31 patients. Radiology: On admission 64.5% of CT were normal, with 25% having unilateral pneumonia and 9.7% having bilateral. During hospitalization one child developed a unilateral pneumonia whose radiography was initially normal. Outcome: 23 children had been discharged at the time of writing, and the remainder were well and afebrile.

Xu, XWLi, LJBMJClinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: a retrospective case series19 Feb 2020ChinaAsia2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pubmed/32075786

This study looks at a group of 62 patients with COVID-19 in a province outside of Wuhan (Hubei). 2 of these were children, aged 10 and 11. There is a lot of clinical data in the paper but it is not broken down by age, so we cannot make any inference on behalf of the paediatric patients.

Wei, MLiu, YJAMANovel coronavirus infection in hospitalized infants under 1 year of age in China14 Feb 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1001/jama.2020.2131

This is a case series of, from Dec 8 2019 to Feb 6 2020, from China of 9 infants – all of whom had been hospitalised.

Clinical presentation: 4/9 fever, 2/9 mild URTI symptoms, 1/9 were asymptomatic. All had family members that were COVID-19 positive. There were no severe complications or ICU admissions.

Parri, NMasi, SPediatrics COVID-19 in 17 Italian Pediatric Emergency Departments09 Jan 2020ItalyEurope170Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/09/21/peds.2020-1235

This is a retrospective review of 170 children with confirmed SARS-CoV-2 who presented to Italian emergency departments between March and May 2020. Children in this cohort had a median age of 45 months and 38 (22%) had a comorbidity. Interestingly, under half (70; 41%) had a family member with confirmed SARS-CoV-2, while 21 (12%) had travelled to areas with documented community transmission. Seven (4%) children were infected from an unknown source.

Similar to other cohort studies, the most common symptoms at presentation were fever (48%), cough (43%), decreased feeding (35%) and rhinorrhoea (20%). Of the 13 children (8%) who required respiratory support, 6 had a pre-existing comorbidity. 17% of children who were SARS-CoV-2 positive were asymptomatic.

A chest X-ray was done in 62 children (36%) and showed unilateral patchy infiltrate with ground-glass changes in 20 (32%) and pneumonia in 14 (32%). Chest CT was done in 3 children and 2 had interstitial abnormalities. Point-of-care lung ultrasound was used in 13 (8%) children as an alternative to other imaging modalities, and as an adjunct in 2 children. Of these, 11 (84%) had sonographic features of interstitial disease and 5 showed an additional consolidation.

Three children in this series met criteria for MIS-C. All were febrile with elevated inflammatory markers and received intravenous immunoglobulin and steroids.

This retrospective cohort study is comparable to other similar studies describing cohorts in China, Europe and the United States. Of note, this series included a larger proportion of children <1 year of age and who had only mild symptoms or were completely asymptomatic, likely explained due to differences in testing criteria between countries. The utility of point-of-care ultrasound was demonstrated for diagnosing more severe disease without exposing children to radiation.

Brisca, GMoscatelli, AActa PaediatrClinical course of COVID‐19 in children with pre‐existing medical conditions21 12 2020ItalyEurope37Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15730

This is a short report of a study (the authors call it a prospective study) of the clinical course of 37 children with pre-existing medical conditions who were diagnosed with COVID-19 after they presented at the children’s hospital in Genoa, Italy. This is a subset of the total 167 children who presented between 21st March and 15th November 2020, the other 130 having no identified pre-existing condition. Data was extracted from their electronic record.

The data is presented in a table in the supplementary information. Generally, the mild course but diverse clinical features of COVID-19 in children was seen.

• 10 of the children had known respiratory disease (9 asthma) but there was a diverse range of other pre-existing conditions

• 13 were admitted to HDU, 16 to a general paediatric ward and 8 did not require admission. None required ICU

• 30(81%) of the children had no respiratory symptoms and only 2 required oxygen support

The authors state that although the risk of severe COVID-19 was low in their cohort, children with pre-existing conditions need to be carefully assessed and monitored. They note that further data is required to define management guidelines for high-risk children.

The children in this study presented over an 8-month period and there is no reference to the fact that knowledge of the course and treatment of COVID-19 in children increased during that period and the authors references are all from the earlier period of the pandemic.

Tsankov, BJacobson, KIntnl J of Inf DisSevere COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis.20 Nov 2020WorldwideInternational285014Clinical - Comorbiditieshttps://www.ijidonline.com/article/S1201-9712(20)32475-9/fulltext

This systematic review and meta-analysis, published on 20th November 2020, of 42 studies (totalling 275,661 children without comorbidities and 9,353 children with comorbidities), investigated the effects of paediatric comorbidities on COVID-19 severity.

Study selection: The authors of this review, who are based in Canada (mainly at BC Children’s Hospital in Vancouver), searched PubMed, Medline and Embase databases for articles published between 1st January and 5th October 2020 about SARS-CoV-2 infection in paediatric patients (defined as under 21 years of age), in accordance with PRISMA recommendations. An initial 13,310 articles were screened: of the remaining 808 assessed for eligibility, 98 articles in English had paediatric study participants with pre-existing comorbidities and COVID-19 for which clear outcomes were reported. After literature grading 86 were analysed, of which only 42 studies had paediatric case-control participants without comorbidities with either severe COVID-19 and/or COVID-19-associated mortality. 5 studies only examined children who died from COVID-19 and were therefore only included in the mortality analysis. Studies were from the USA 18/42 (43%), China 4/42 (10%), Italy 4/42 (10%), Spain 4/42 (10%), France 3/42 (7%), UK 2/42 (5%), Iran 2/42 (5%), Austria 1/42 (2%), Brazil 1/42 (2%), India 1/42 (2%), Turkey 1/42 (2%), Uruguay 1/42 (2%). Extracted data included disease severity, PICU admission and mortality. Severe COVID-19 was defined as any SARS-CoV-2 infection requiring supplemental help to normal breathing and/or PICU admission.

Study patient characteristics: From the 42 articles 285,014 paediatric patients with laboratory-confirmed SARS-CoV-2 infection were identified, of which 9,353 (3.3%) had at least one underlying comorbidity. Data on gender was available for 280,999 patients: 50.7% female, 49.9% male. Age category data was only available in 362 children. The comorbidities break down as follows: chronic respiratory 49%, immune 8.1%, cardiovascular 6.6%, metabolic 5.9%, obesity 5.4%, neurological 2.3%, renal 1.5%, haematological 1%, cancer 0.9%, hepatobiliary 0.8%, allergy 0.5%, GI 0.3%, other 17.4%.

Relative risk of paediatric comorbidities on severe COVID-19: Severe COVID-19 and/or PICU admission in paediatric patients with SARS-CoV-2 infection: with comorbidities 481/9,353 (5.1%) versus without comorbidities 579/275,661 (0.21%). Relative risk of severe COVID-19 and/or PICU admission among children with comorbidities relative to those without: 1.79 (95% CI 1.27–2.51; 𝜒2=602.31 (P < 0.001), I2=94%) (37/42 studies included in this analysis since 5 studies only examined COVID-19-associated deaths). 7 studies had a higher risk ratio of severe COVID-19 among those without comorbidities versus those with. Individual exclusion of each of the 37 studies from the analysis didn’t significantly influence the risk ratio in either direction.

Relative risk of paediatric comorbidities on mortality associated with COVID-19 infection: 19/42 articles reported children who died with COVID-19. Across these 19 articles, only 77/274,647 (0.03%) paediatric patients without comorbidities died across 8 studies versus 134/8,960 (1.5%) with comorbidities across 15 studies. Relative risk of mortality among paediatric patients with comorbidities and COVID-19 relative to those without: 2.81 (95% CI 1.31–6.02; 𝜒2 = 97.85 (P < 0.001); I2 = 82%). In only 5 of the studies did children with comorbidities have a lower risk of mortality during the course of COVID-19. Again, subsequent sensitivity analysis confirmed that no one article significantly affected the relative risk ratio.

Relative risk of obesity on severe COVID-19: Defined as BMI greater than or equal to the 95th percentile for children of the same age and sex. Analysis performed only on the 6 studies including case-control participants. Relative risk of severe COVID-19 in children with obesity relative to children without comorbidities: 2.87 (95% CI 1.16–7.07; 𝜒2 = 7.81 (P = 0.17); I2 = 36%).

Limitations identified by authors: There will be variation in PICU admission criteria across the studies and there may be selection bias of PICU admissions in favour of children with underlying conditions. There is a high degree of study heterogeneity and many studies were of small sample size. The meta-analysis was not able to capture the relative risk that comorbidities other than obesity contribute to severe COVID-19, because of the sub-population heterogeneity of comorbidities, which limits the ability to draw accurate comparisons between the studies. Testing of asymptomatic and pauci-symptomatic children is very limited, so mild cases among children with comorbidities are likely to be underrepresented.

Conclusions: Children with comorbidities have a higher risk of severe COVID-19 and associated mortality than children without underlying disease. Childhood obesity was shown to be associated with a more severe course of disease.

Nepogodiev, DBSJFavourable perioperative outcomes for children with SARS‐CoV‐219 Oct 2020United KingdomInternational88Clinical - Comorbiditieshttps://bjssjournals.onlinelibrary.wiley.com/doi/10.1002/bjs.12038

To better understand the surgical risks for children with confirmed SARS-CoV-2, CovidSurg, a multicentre, observational, international cohort study summarised observations of paediatric SARSCoV-2 surgical patients whose diagnosis had been made from 7 days before to 30 days after surgery and in whom surgery was carried out between 1st January and April 30, 2020. On the ground surgical interventions for children were commonly being delayed or cancelled during the foregone Covid-19 pandemic wave due to concerns for risk of nosocomial SARS-CoV-2 infections, concern for perioperative complications and constrained resources for routine surgery. The authors concerns expanded to include health complications when children’s surgical treatments were delayed or cancelled.

Fifty-two hospitals in 21 countries participated. Assessed were 5,388 patients, of whom 88 were children were under 16 years of age, 56 (63.6%). Diagnosis of SARS-CoV-2 was preoperative was in 48(56%) of the children.The majority (89%) of the children required emergency surgery. The distribution of the disease conditions included benign conditions (81%), trauma (11%) and cancer (8%). There was one death (1/88) in the 30 day post-operative period, low compared to confirmed SARSCoV-2 adult post-operative mortality of 23.8% referred to in this research letter. Pulmonary complications (pneumonia/acute respiratory syndrome or unexpected post-operative ventilation problem) occurred in 12 of the 88 (13.6%) children, also considered low compared to adult pulmonary complications of 51.2% in confirmed SARS-CoV-2 post-operative adults reported in the research letter.

This research letter informs but it probably only begins asking the question whether less restrictive surgical rationing policies should be considered for children. The authors’ call for further studies toward answering the question raised is supported. Due to the likelihood of the influence of age and other likely confounders in the adult perioperative SARS-CoV-2 confirmed patients referred to by the authors in the research letter, observation of matched cohorts of perioperative paediatric surgical patients with confirmed SARS-CoV-2 and those without may be a further worthwhile scenario to explore

Kabesch Msingle authorPed Allergy ImmunologyShielding against SARS‐Cov‐2 infection is not justified in children with severe asthma05 Aug 2020EuropeEurope0Clinical - Comorbiditieshttps://doi.org/10.1111/pai.13327

In the UK, severe asthma was one of the diagnoses which mandated ‘shielding’, i.e. remaining at home at all times, during the lockdown, for children and adults. Some doubted whether this was necessary. This brief report suggests that the doubters were right. Using a database which was originally designed to monitor the use of biologic treatments in severe asthma, the author surveyed 37 major asthma centres in 25 European countries. None of the centres were aware of any symptomatic COVID-19 case from March-July 2020 in any of the roughly 1000 children included.

So was this because shielding prevented it? No, because they compared the 4 countries with strict shielding policies (including the UK) with the others where precautions for asthmatics were the same as everyone else. There was no difference.They conclude that shielding is unnecessary, even in the most severe asthmatics.

Wilkes, MRapaport RJ of PediatricsSevere COVID-19 in Children and Young Adults.23 Jun 2020USANorth America10Clinical - Comorbiditieshttps://www.jpeds.com/article/S0022-3476(20)30764-2/pdf
Kulkarni, RKJadhav, TIndian Journal of PaediatricsFatal Covid-19 in a Malnourished Child with Megaloblastic Anemia17 Jun 2020IndiaAsia1Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297666/
Yuksel, MAriKan, CEur J Gastroenterol HepatolImmune monitoring of a child with autoimmune hepatitis and type 1 diabetes during COVID-19 infection16 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://journals.lww.com/eurojgh/Abstract/9000/Immune_monitoring_of_a_child_with_autoimmune.97545.aspx
Akcabelen, Y. M.Yarali, N.Pediatr Blood Cancer: e28443.COVID‐19 in a child with severe aplastic anemia15 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28443?af=R
Cesaro, S.Petris, MGPaediatr Blood CancerScreening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy15 Jun 2020ItalyEurope282Clinical - Comorbiditieshttps://doi.org/10.1002/pbc.28466

Observational study of nasopharyngeal presence of SARS-CoV-2 in a cohort of 282 paediatric oncology patient presenting for scheduled care at 14 specialist centres in Italy between 20/02/20 and 19/04/20. Median age for oncology cases (n=247) was 7 years (range 0-17.9) and for stem cell transplant (SCT) patients (n=35) was 9.6 years (range 0.3-17.6). 10/334 swabs from the oncology group were +ve and 0/56 from the SCT group. Only 2/10 NPS +ve patients had any symptoms (both "mild fever").

Chemotherapy was paused for all NPS +ve patients until 2 clear swabs were obtained 24 hours apart. No adverse outcomes were recorded up to the study end but follow up was only reported up to 30/04/20. This study demonstrates that paediatric oncology patients can remain asymtomatic whilst carrying SARS-CoV-2 in the nasopharynx, and recover spontaneously, without any apparent increased rate of adverse outcomes. Researchers raise the question of whether routine chemotherapy needs to be paused for asymptomatic NP carriage of SARS-CoV-2 but present no evidence for the safety of this course of action.

Flores, VLenica A, CAnn Hematol.SARS-CoV-2 infection in children with febrile neutropenia12 Jun 2020MexicoSouth America3Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289627/

This letter to Annals of Hematology offers a brief description of three children with ALL who presented with febrile illness and were found to be SARS-CoV2 PCR positive. The letter is of note as sadly one of the children died during this illness following cardiac arrest; the authors offer the paper to highlight the occurrence of SARS CoV2 in febrile neutropenic patients; however it prompts further analysis of those cases of severe infection in the context of immunosuppression.

The patients were identified at a centre in Mexico however the time period is not known. The three patients were aged 4yrs, 8yrs and 9yrs. All had ALL, two receiving consolidation chemotherapy and one on immunosuppression with mycophenolate and prednisolone. The latter patient had undergone HSCT for ALL, the time since HSCT was not provided, however this patient was admitted from the community suggesting she wasn’t in the immediate post-transplant period. All patients developed neutropenia either at time of fever or quickly following it and similarly evolved to have ‘respiratory symptoms’. All had negative blood cultures however results of other virology is not provided. Over-all pre-covid health status is not provided within the letter and this might be helpful in understanding the severity of symptoms in the patient who died.

The child who died was 8 years old and presented with febrile neutropenia, they were on mycophenolate and prednisolone following HSCT for ALL. The child quickly developed respiratory distress and required invasive mechanical ventilation; a heamodynamic deterioration led to cardiac arrest and resuscitation measures failed.

The distinguishing features of this child was her immunosuppression and history of HSCT, she was also more profoundly lymphopenic and thrombocytopenic. All other laboratory values were variable between all three patients. Further information on her overall cardiorespiratory status pre-SARS-CoV-2 would be helpful to understand her vulnerabilities and to guide management of children presenting with similar comorbidities in the future.

Gine, CLopez, MJ Laparoendosc Adv Surg Tech A .Thoracoscopic Bullectomy for Persistent Air Leak in a 14-Year-Old Child With COVID-19 Bilateral Pulmonary Disease11 Jun 2020SpainEurope1Clinical - Comorbiditieshttps://www.liebertpub.com/doi/abs/10.1089/lap.2020.0289
Anurathapan, U.Hongeng, S.Bone Marrow Transplantation; www.nature.com/bmt/Hematopoietic stem cell transplantation from an infected SARS-CoV2 donor sibling11 Jun 2020ThailandAsia2Clinical - Comorbiditieshttps://www.nature.com/articles/s41409-020-0969-3
Du, HGao, YAllergyClinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status10 Jun 2020ChinaAsia183Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1111/all.14452
Sabatino, JDi Salvo, GJ Clin MedCOVID-19 and Congenital Heart Disease: Results from a Nationwide Survey08 Jun 2020ItalyEurope4Clinical - Comorbiditieshttps://www.mdpi.com/2077-0383/9/6/1774
Alloway, B. C.Hardy, G.Radiology Case reports Suspected case of COVID-19-associated pancreatitis in a child.06 Jun 2020USANorth America1Clinical - Comorbiditieshttps://reader.elsevier.com/reader/sd/pii/S1930043320302569?token=2F2186726A3F368F41FAC9F6CCCAB2CE9CB00D44308E9ADA898D0795CFDBF9CC12EE79807C3C0390C107B51CF81D49EA
Wahlster, LSankaran, VG Pediatr Blood CancerCOVID-19 presenting with autoimmune hemolytic anemia in the setting of underlying immune dysregulation.03 Jun 2020USANorth America1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28382?af=R
Tennuri, UMiyatani, HClinics (Sao Paulo)Low Incidence of COVID-19 in Children and Adolescent Post-Liver Transplant at a Latin American Reference Center03 Jun 2020BrazilSouth America6Clinical - Comorbiditieshttps://www.scielo.br/pdf/clin/v75/1807-5932-clin-75-e1986.pdf
Mirzaree, SMMVossough, ARadiologyFocal Cerebral Arteriopathy in a COVID-19 Pediatric Patient 02 Jun 2020IranMiddle East1Clinical - Comorbiditieshttps://pubs.rsna.org/doi/pdf/10.1148/radiol.2020202197
Harman KGupta ALancetEthnicity and COVID-19 in children with comorbidities28 May 2020UKEurope12Clinical - Comorbidities https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30167-X/fulltext

Between 25 February 2020 and 28 April 2020, 12h children aged 0 to 16 years with confirmed COVID-19 who required admission to hospital were prospectively identified at Kings College Hospital London. 5 of these had known comorbidities (identified here as Group A) and 7 had no known comorbidities (Group B).

Age: Median age of Group A was 7.1yrs (range 0.2-15.3 with 2 <1 yr) and Group B was 4.8yrs (range 0-15.4).

Gender: 40% (n=2) in Group A and 71% (n=5) in Group B are male gender.

Ethnicity: 80% (n=4) in Group A and 71% (n=5) in Group B were from a black, Asian and minority ethnic (BAME) group.

Comorbidities: In Group A pre-existing comorbidities included cerebral palsy, prematurity, Wilsons disease, and dilated cardiomyopathy.

Clinical features: Most common symptoms on admission in group A and B respectively were fever (60%, n 3/5 and 86% n 6/7) and tachypnoea (60% n 3/5 and 71% n5/7). Liver dysfunction was observed in 4/5 patients in Group A but 2 had underlying liver conditions including one with Wilsons disease who has since had a liver transplant.

Radiology: In Group A radiological evidence of new infiltrates was seen in 50% (n2/4) of patients in Group A who had an x-ray because of clinical indication.

Bloods: In Group A 3 /5 patients had lymphopenia and thrombocytopenia, 3 /4 had raised CRP, 4/5 had liver dysfunction but 2 of these had underlying liver disease, 1/5 had renal dysfunction. None had symptoms that would be compatible with multisystem inflammatory syndrome. No blood data given for Group B.

Outcome: Median length of stay in hospital for Group A was 20 days (range 7-84 days) with 1child with liver transplant still an inpatient on 20th May 2020. For Group B the median stay was 3 days ( range 1-8 days); 1 admitted to hospital for safeguarding concerns and another was a neonate with vertical transmission of Covid-19.

Other salient feature: During this period 2288 adults were admitted to Kings College Hospital so children only formed 0.5% of total admissions. in Group A all children received antibiotics, 1 remdesivir and 1 hydroxychloroquine.

This case study presents data on 12 children with COVID-19 (5 of whom had comorbidities) admitted to Kings College Hospital London during 25th Feb-28th April 2020.

It is noteworthy that 75% of the total children admitted with Covid-19 and 80% of 5 children who had comorbidities were from a black, Asian, and minority (BAME) communities. Even keeping in mind that in Inner London 39% of the population is BAME, this data suggests that ethnicity in children may be an independent risk factor for severe disease. Conclusion is that Children from BAME communities particularly if they have comorbidities, may be at greater risk of severe disease from COVID-19. This is particularly significant given the ongoing investigation into the increased rates of severe COVID-19 infection in adults from BAME backgrounds.

This is a relatively new observation in children and although the numbers are very small, justifies considering this paper to be important.

Ferrari, ABalduzzi, APediatr Blood CancerChildren with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy26 May 2020ItalyEurope286Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28410

This Letter to the Editor describes the findings of 6 paediatric haematology and oncology centres in Lombardy during the 8 weeks after the COVID-19 pandemic began in Italy. Between 20th February 2020 and 15th April 2020 286 patients were tested for COVID-19 when accessing services at these centres: 74 were symptomatic, 25 had close contact with a diagnosed case and 187 were tested for screening purposes. Of these, 21 cases tested positive for COVID-19, with a median age of 6 years (range 1-17 years) and 48% were male.

Of the 21 cases 10 had leukaemia, 5 had soft tissue or bone sarcoma, 2 had lymphoma, two had hepatoblastoma, 1 had a CNS tumour and 1 had colon carcinoma. 15 patients were currently receiving treatment while 6 had completed treatment and were receiving follow up.

Clinical features: 1 patient (who had existing neurological respiratory impairment) developed aspiration pneumonia requiring respiratory support, and 1 developed atypical bilateral pneumonia with mild symptoms.

Outcomes: There were no deaths related to COVID-19 infection. Cancer treatment was modified in 10 cases (delaying chemotherapy, reducing drug doses and postponing surgery).

The authors observe that despite the overwhelming rate of COVID-19 in the general population in the region at the time, relatively few paediatric cancer patients were symptomatic, or tested positive for the virus, and that severe illness was rare. They suggest that these results may indicate that paediatric anti-cancer treatments could continue without major adjustments, especially as alterations may reduce their efficacy.

Of note, these centres experienced a reduction in newly diagnosed cancer cases to 55% of the expected rate, which may reflect delayed access to healthcare services.

Issitt, RWSebire, NJmedRxivCoronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population25 May 2020UKEurope166Clinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.05.20.20107904v1

A retrospective cohort study published by Great Ormond Street Hospital (GOSH), London, UK suggested children who are defined as vulnerable in the COVID-19 pandemic era do not appear to be at significantly increased risk of being admitted to hospital with COVID-19. In addition, the vulnerable group have similar outcomes to those who are COVID-19 negative. However, the authors do identify children undergoing chemotherapy or radiotherapy are ‘over-represented’ in the vulnerable group. Data was collected from the institution’s electronic health record system. The inclusion criteria were any patient admitted between 01/03/2020 and 15/05/2020 who was admitted with features suggestive of COVID-19 based on the attending clinician’s interpretation, of undefined grade, including fever, cough and “systemic symptoms”. Children were defined as COVID-19 positive by a positive PCR test for nucleic acid in respiratory or blood specimens performed at the referring or presenting hospital or a documented positive familial test. Patients were classified as vulnerable if they fulfilled the high risk shielded list from NHS digital or the institutions local policy that was not provided. Due to the nature of the specialist paediatric services the population of children were highly selected.

166 children fulfilled the criteria; 65 (38.7%) were COVID positive and 101 (60.8%) were negative. The average age for COVID positive group was 9 years [IQR 0.9-14] with 38 (58.5%) males. This compared to the COVID-19 negative group with an average age of 1 year [0.1-5.75], 58 (55.4%) male. The COVID-19 positive patients were significantly older (p<0.001). Differences in ethnicity frequency was statistically significant for Asian ethnicity: 12 (8.5%) COVID-19 positive compared to 6 (5.9%) in the COVID-19 negative group (p=0.02).

The number of vulnerable children who were COVID-19 positive totalled 31 (47.7%) compared to 73 who were COVID-19 negative (72.3%), demonstrating a lower number of vulnerable children were positive for COVID-19, (p=0.002).

Clinical features: Breakdown of symptoms were not provided

Radiology: N/A

Bloods (For those COVID-19 positive):

ALT 41.5 U/L [IQR 29-74], Albumin 32 g/L [IQR 27-36], AntiDNAse 310U/mL [80.8-402], AntiStreptolysin O 285 IU/mL [134-384], AST 70 U/L [43-100], CRP 28 mg/L [10-74], CK 63.5 U/L [35-214], Creatinine 23 umol/L [14-46], D-dimer 1876 ug/L [1043-3618], Ferritin 788 ug/L [445-1863], Fibrinogen 3.65 g/L [2.4-4.8], Interleukin-6 50 pg/ml [50-152], Interleukin-10 50pg/mL, LDH 848 U/L [654-1136], BNP 3550 pg/ml [626-6992], Lymphocytes 1.44 X10^9/L [0.64-2.49], Neutrophils 3.90X10^9/L [1.46-8.6], WBC 8X10^9/L [3.38-13.2], Troponin I 54 ng/L [13-157], Prothrombin time 12 seconds [11.3-13], bilirubin 6 umol/L [3-10], Triglycerides 2.48 mmol/L [1.65-3.56].

The results highlight the difference in results between the COVID positive and negative groups but do not define further differences between vulnerable and non-vulnerable groups. These include a statistically higher average CRP (p=0.002, fibrinogen (p<0.001), albumin (p0.02) neutrophil (p<0.001) and white blood cell count (p<0.001) and a lower LDH (p=0.002),

Treatments: Patient were treated following national or speciality specific guidance. No further information was provided.

Outcomes: Mortality for those who were COVID-19 was 1 (1.5%) who was in the vulnerable group. Additional comments described the primary focus of treatment was aspiration pneumonia. This compared to 4 (4%) in the non-COVID-9 group, all of whom were in the vulnerable group. The difference in mortality rates was not statistically significant.

There was no difference in the proportion of vulnerable patients based on their COVID-19 status: 61% of vulnerable patients who were COVID-19 positive compared to 64.3% who were negative, (p = 0.84). Overall, comparing all patients, a significantly lower proportion of COVID-19 positive patients required mechanical ventilation (27.7%) than COVID-19 negative patients (57.4%), (p<0.001). The individual number of patients were not provided.

The average ICU length of stay for those with COVID-19 was 4 days [2.4-10.6]. For those in the vulnerable subgroup the average was 11 days [3.7-15.1]. The significance of the difference between the vulnerable and non-vulnerable group was not described. However, vulnerable non-COVID-19 patients had a 6 [2.8-12.2] day stay in ICU. The difference between vulnerable COVID-19 positive and negative groups demonstrated no significance (p=0.3).

The average total hospital stay for vulnerable patients with COVID-19 was 16.2 days [3.8-20.8]. This compared to vulnerable COVID-19 negative patient were in hospital for 12.3 days [5.2-19.8]. The difference in duration was not significant (p=0.94).

Other salient features: Breaking down conditions that comprises vulnerable children there was a significant increased number of children with cancer undergoing active chemotherapy or radiotherapy who were admitted to hospital with symptoms and COVID-19 positive status compared to with symptoms but COVID-19 negative [7 VS 3 (p=0.01)]. There was no statistical differences between the COVID-19 positive and negative categories with on the national transplant, transplant medication, haematological cancer, respiratory and rare genetic, metabolic and autoimmune conditions lists or local severe respiratory conditions, rare diseases immunosuppressive therapies and other potential factors lists.

Barsoum, ZSN Comprehensive Clinical MedicinePediatric Asthma & Coronavirus (COVID-19)-Clinical Presentation in an Asthmatic Child—Case Report19 May 2020Northern IrelandEurope1Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s42399-020-00310-3.pdf
Hains, DKrammer, FJAMAAsymptomatic Seroconversion of Immunoglobulins to SARS-CoV-2 in a Pediatric Dialysis Unit14 May 2020USANorth America3Clinical - Comorbiditieshttps://jamanetwork.com/journals/jama/fullarticle/2766215
Boulad, FBouvier, NJAMA Oncol.COVID-19 in Children With Cancer in New York City13 May 2020USNorth America20Clinical - Comorbiditieshttps://jamanetwork.com/journals/jamaoncology/fullarticle/2766112

This research letter reports the results of SARS-CoV-2 screening of patients and caregivers from one of the largest paediatric cancer centres in the US (Memorial Sloan Kettering Cancer Center, New York) in a region with very high levels of community SARS-CoV-2 transmission.

From March 10th to April 12th 2020, inpatients and outpatients with either symptoms of or exposure to SARS-CoV-2 infection underwent RT-PCR testing. Asymptomatic patients were also tested prior to admission, deep sedation and or myelosuppressive chemotherapy, as were caregivers of children being admitted.

Overall 11% (20/178) of paediatric patients returned a positive SARS-CoV-2 result; including 29.3% in the symptomatic / exposed group and 2.5% in the asymptomatic group. In contrast 14.7% (10/76) of asymptomatic caregivers were positive. Despite close contact, 5 of the 10 children of caregivers with SARS-CoV-2 were uninfected.Only 1 of the 20 paediatric patients required hospitalisation for COVID-19 symptoms, without need for critical care.

This data provides reassurance that children with cancer may not be more vulnerable to complications of SARS-CoV-2 infection compared to other children. The lack of specific clinical detail in this report limits the ability to draw more definitive conclusions regarding risk.

The lower rate of asymptomatic carriage in children relative to their caregivers provides further evidence that children, including paediatric cancer patients, may be less susceptible to SARS-CoV-2 infection compared with adults.Clearly infection control strategies must consider the risk of nosocomial spread from infected caregivers as well as paediatric patients, particularly in areas with high levels of community transmission.

Marlais, MTullus KLancet Child Adolesc HealthThe severity of COVID-19 in children on immunosuppressive medication13 May 2020Multi-countryMulti-region18Clinical - Comorbiditieshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30145-0.pdf
Bush, R.Upadhyay, K.Am J TransplantMild COVID-19 in a Pediatric Renal Transplant Recipient13 May 2020USANorth America1Clinical - Comorbiditieshttps://pubmed.ncbi.nlm.nih.gov/32406181/
Zhao, YGao, GPediatr Infect Dis JFIRST CASE OF CORONAVIRUS DISEASE 2019 IN CHILDHOOD LEUKEMIA IN CHINA12 May 2020ChinaAsia1Clinical - Comorbiditieshttps://journals.lww.com/pidj/Abstract/9000/FIRST_CASE_OF_CORONAVIRUS_DISEASE_2019_IN.96166.aspx
Angelletti, AForno, RClin TransplantRisk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study12 May 2020ItalyEurope64Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ctr.13889

Giannina Gaslini Children’s Hospital, Italy undertook this prospective observational study of patients, who received a kidney transplant between January 2010 and March 2020, with stable graft function and were taking chronic immunosuppressant therapy. They were interviewed weekly between 24th February and 12th April 2020 for 7 weeks, using a 12-point structure questionnaire contained in the appendix, to evaluate the health status of themselves and their cohabitants. The data for adults and children were combined presenting a median age of 20 (2-30) years. The demographics were reported as a combined total; 93 were male.

2 patients, an adult (information not included) and 1 girl aged 13, had co-habitants who were positive for SARS-CoV-2. The 13-year-old had a kidney transplant aged 9 years old. At the time of study, she was taking a combination of steroid, calcineurin inhibitor (CNI and mycophenolate mofetil (MMF) and had investigations including a white cell count and haemoglobin within normal limits.

She tested negative for SARS-CoV-2 using a nasopharyngeal swab (test not declared) and did not develop any symptoms in the subsequent 21 days, declared as the incubation period. Anti-SARS-CoV-2 antibodies were also negative at an undefined time point.

Clinical features: No patients developed any clinical symptoms.

Radiology: None discussed.

Bloods: None discussed for patients who were positive for SARS-CoV-2.

Treatments: None.

Outcomes: None.

Other salient features: The authors recommend avoiding altering the immunosuppressive therapy in young transplant recipients who do not have symptoms of SARS-CoV-2 including those who are exposed to positive close contact. Despite observing a relatively large population of kidney transplant recipients, a small number, 2 (1 child) were exposed to SARS-CoV-2, upon which has the conclusions are based.

Koczulla, RAKneidinger, NAmerican Journal of TransplantationSARS-CoV-2 infection in two patients following recent lung transplantation12 May 2020GermanyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.15998
Blanchon, SRochat, IPediatr PulmonolCOVID-19: A Message of Hope From a Young Girl With Severe Cystic Fibrosis11 May 2020SwitzerlandEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24812
Brenner, EUngaro RGastroenterologyCorticosteroids but not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Pateitns with Inflammatory Bowel Disease: Results from an International Registry. 08 May 2020USANorth America30Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0016508520306557

This is a pre-proof article and therefore has not yet undergone final editing and review.This is an article from America (Carolina) aiming to characterise the clinical course of COVID-19 on patients with inflammatory bowel disease (IBD) and evaluate the association between demographics, clinical characteristics and immunosuppressant treatments of COVID-19 outcomes.

The authors created a surveillance database and healthcare providers were encouraged to voluntarily report all cases of Polymerase Chain Reaction (PCR)-confirmed COVID-19 patients with IBD. A website was developed to enable international contributions. Contributors were asked to report cases a minimum of 7 days from symptom onset and after sufficient time had passed to observe disease course through to resolution of acute illness or death.

525 patients from 33 countries were reported. 7% had severe COVID-19, 31% were hospitalised, 3% of patients died. The median age of patient was 41 years (from 5 to 90). The majority of patients had Crohns Disease (59.4%) and IBD disease activity was classed as remission in 58.9% of cases. The most common class of treatment was TNF antagonist therapy (43.4% of patients).

63.5% of patients had no comorbidities other than IBD. Most patients who died had other co-morbidities. Only 3 paediatric patients (10% of paediatric cases) required hospitalization. After controlling for all other covariates use of systemic corticosteroids and ASA/sulfasalazine use were strongly associated with more serious outcomes after infection with COVID-19 but there was no significant association seen between TNF antagonist use and adverse outcomes.

The authors observed an age-standardized mortality ration of approximately 1.5-1.9 as compared to the general populations of China, Italy and the U.S.

They state it is reassuring that the most commonly used treatment- TNF antagonists- appears not to lead to increased adverse outcome for patients infected with COVID-19.

This study has strength in that it includes data from many countries although how comparable that data can be between countries is debatable. The authors did not look at dosing regimens or what was done in terms of continuing or postponing treatment which may well have varied from one country to another. There may also be some bias towards patients who were unwell enough to present to hospital, there may have been other patients who were infected but not unwell enough to require hospital treatment/testing for COVID-19 who would not have been included in this study population.

de Rojas, TPerez-Martinez, APediatric Blood and CancerCOVID-19 Infection in children and adolescents with cancer in Madrid08 May 2020Italy Europe15Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28397
Andre, NGandemer, VPediatr Blood CancerCOVID-19 in pediatric oncology from French pediatric oncology and hematology centers: High risk of severe forms?08 May 2020FranceEurope33Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28392
Morand, AFabre AArchives de PediatrieChild with liver transplant recovers from COVID-19 infection. A case report. 06 May 2020franceEurope1Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0929693X2030110X

This a case report form France of a 2-and-a-half-year-old girl who recovered from COVID-19 infection, 5 months after a liver transplant; she had co-infection with Epstein-Barr virus (EBV).

The child had received a living donor transplant (father) as she had developed portal hypertension post Kasai portoentemrostoy performed at 53 days of age for biliary atresia.

She had been discharged home 20 days post procedure on tacrolimus immunosuppression therapy and had no immunization against EBV before transplantation.

On day 96 post transplant she was found to have primary EBV infection linked to the transplant- her father was EBV positive- but was asymptomatic of this.

The first developed rhinitis which developed into a fever, cough and tachypnoea. In the few days before this her mother had been hospitalized with pneumonia and found to be COVID-19 positive on nasopharyngeal swab. On day three of the illness the child was referred to hospital where she was found to be positive for COVID-19 on NPA.

On admission she was tachypnoeic with no other signs of respiratory distress, her CRP was low (3). A chest CT showed focal alveolar condensation of the ligula and a stable mediastinal enlargement. Her liver function tests had deteriorated (GGT and AST). An US of the liver showed aggravation of the transplanted biliary tract stenosis and an elevated EBV blood viral load. She was managed symptomatically, and she did not receive any COVID-19 specific treatment.

She recovered from COVID-19 infection despite the high level of immunosuppression caused by her tacrolimus treatment. NPA test samples became negative on day 11. The authors report they reduced the dose of tacrolimus but do not state at which point in the illness nor for how long. They do not state how long it took for her LFTs to return to previous levels nor if there were any consequences of the raised EBV viral load.

The authors suggest liver transplantation is not associated with COVID-19 symptom severity development even when there is high level immunosuppression on tacrolimus. Moreover COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.

It is difficult to draw conclusions based on one case study. Particularly as other studies have shown the severity of COVID-19 is increased when present with other co-morbidities. This particular patient, due to the nature of her original liver insult and the fact that she is a young patient, did not have other co-morbidities, this is often not the case for other patients who have required a liver transplantation.

Michelena, XMarsal, S.Med archivesIncidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs05 May 2020SpainEuropeClinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.04.30.20086090v1.full.pdf
Sieni, EFavre, CBritish Journal of HaematologyFavourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression05 May 2020ItalyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16781

This retrospective single case report discusses the progression and treatment of a child with high risk acute myeloid leukaemia having undertaken the third chemotherapy cycle of the induction phase following AIEOP LAM 2013 protocol.

13-month-old female patient attended routine clinic at Myers Hospital, Florence, Italy following completion of the chemotherapy. Routine investigations revealed a low white cell count, haemoglobin and platelet count which necessitated admission for transfusions. The need for admission was the initial reason for testing for SARS-CoV-2. RT-PCR was performed for nasal and pharyngeal swabs. Faecal PCR testing was also positive.

Clinical features: Fever starting on day 3 (the combination of fever and low WCC suggested neutropenic sepsis), vomiting and diarrhoea with negative stool culture.

Radiology: CXR on day 3 showed bilateral reticular markings. A repeat prior to discharge demonstrated “no significant modification from baseline”.

Bloods: Day 0 showed low WCC (80/mmc), haemoglobin (7.9g/dL) and platelet (5000/mmc) count. The elevated CRP was highest at day 5 (7.2mg/dL) and normalised by day 10 (<0.5mg/dL). Additional laboratory investigations included LDH which was highest by day 13 (401 IU/L) and ferratin maximally raised on day 9 (3000 mg/mL). Immunoglobulins were low throughout the illness. On day 3 the results were: IgG 258 mg/dL, IgA 18.7 mg/dL, IgM 7 mg/dL. IL-1β, IL-6, IL-10, TNFα and cardiac enzymes were normal.

Blood microbiology was negative.

Additional laboratory investigations, including cytokines (IL-1β, IL-6, IL-10 and TNFα) and cardiac enzymes, were normal; lactate dehydrogenase slightly increased (up to 401 IU/L at day 13), whereas ferritin values showed moderate elevation from day 9

Treatments: Treatment for neutropenic sepsis with piperacillin-tazobactam and fluconazole was commenced on day 3 due to fever. Hydroxychloroquine day 3-11. On day 4 lopinavir/ritonavir stopping day 12

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: There was a undetectable viral plasma load by day 16, however nasal swab for SARS-CoV-2 remained positive beyond discharge at day 26. There is no data to suggest a negative test to publication date.

It is unclear if the low WCC, anaemia and thrombocytopenia requiring transfusion was due to the chemotherapy, underlying acute myeloid leukaemia or COVID-19 infection, however, on discharge these values had normalised and were maintained by day 26.

Summary: This case describes a high-risk young patient with acute myeloid leukaemia undergoing chemotherapy presenting with febrile neutropenia. Whilst the symptoms were initially vague, subsequent investigations suggested the underlying cause was SARS-CoV-2. Early anti-viral treatments were commenced. Given the patient’s immunosuppression the authors discuss fears regarding seroconversion, viral dissemination and inflammatory responses which did not occur.

Melgosa, MPerez-Beltran, VPed NephrolSARS-CoV-2 infection in Spanish children with chronic kidney pathologies01 May 2020Spain Europe16Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s00467-020-04597-1.pdf
Odièvre, MCorvol, HAm J HematologyDramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome01 May 2020FranceEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1002/ajh.25855

The authors of this case study are based at two hospitals in Paris; in this correspondence they describe the treatment of a 16 year old girl with homozygous sickle cell disease (SCD) admitted to ICU with acute chest syndrome (ACS) and pulmonary emboli complicating COVID-19 pneumonia, in particular the use of Tocilizumab, a humanised anti-IL-6 monoclonal antibody (usual indications include use as immunosuppressant therapy in rheumatoid arthritis and giant cell arteritis in adults and juvenile idiopathic arthritis in children).

Course of SCD prior to admission: The patient had a history of recurrent vaso-occlusive crises and abnormal transcranial dopplers between the ages of 5 and 11 years old, necessitating treatment with exchange transfusions. At 11 years of age she was commenced on daily hydroxyurea with resolution of vaso-occlusive events. She had no history of ACS or pulmonary hypertension; respiratory function and chest radiography were previously normal.

Presentation with COVID-19-19: She presented with isolated fever, with nasophyaryngeal swabs subsequently confirmed as RT-PCR SARS-CoV-2 positive. 7 days later she developed acute chest pain associated with respiratory distress (SpO2 85%).

Radiology: CT pulmonary angiogram (CTPA) showed bilateral pulmonary emboli and bilateral consolidation with right-sided halo sign.

Treatment in ICU: Included non-invasive ventilation, anticoagulation and red cell exchange transfusion followed by simple transfusion (lowest Hb 64 g/L). Based on recent experience in adult SCD patients with COVID-19 disease she also received a single infusion of Tocilizumab (8 mg/kg). The authors report rapid clinical improvement after Tocilizumab with repeat CTPA 5 days later showing complete resolution of pulmonary emboli and consolidation on the right and decrease on the left. She was discharged from hospital 11 days after admission to continue oral anticoagulation for 6 weeks.

Conclusions: Inflammatory cytokines such as IL-6 and TNF- are elevated in COVID-19. COVID-19 pneumonia can cause ACS in SCD patients; there have been several recent reports of successful treatment using Tocilizumab.

Inci Yildirim, ATurkmen Karaagac, AIndian PediatricsCOVID-19 in a Young Girl with Restrictive Cardiomyopathy and Chronic Lung Disease30 Apr 2020TurkeyWestern Asia, Southeastern Europe1Clinical - Comorbiditieshttps://www.indianpediatrics.net/june2020/577.pdf
Russell M.Reardon LThe Journal of Heart and Lung TransplantationCOVID-19 in a paediatric heart transplant recipient: Emergence of donor-specific antibodies 29 Apr 2020UKEurope1Clinical - Comorbidities https://www.jhltonline.org/article/S1053-2498(20)31532-1/fulltext

This is a case report of a 3 year old child who had received a heart transplant at 11 months of age for congenital dilated cardiomyopathy.

Her post-transplant course had been unremarkable except for persistent Ebstein Barr Virus (EBV) viremia. She was on tacrolimus monotherapy.

Her initial symptoms were productive cough with rhinorrhea and nasal congestion, she was not tested for COVID-19 at this point as she had no Centres for Disease Control risk factors for infection and testing was not widely available.

A week later a follow-up telehealth visit was performed and there was improvement in symptoms.Surveillance blood tests demonstrated the following de novo Class II donor specific antibodies: DQ4, DR8 and DQA1*04.

One week later the patient was scheduled for routine admission for intravenous immunoglobulin administration, because of the history of cough had a nasal swab sent for reverse transcriptase polymerase chain reaction testing for COVID-19. Other than an intermittent wet cough she was well, and her observations were within normal limits. She received the immunoglobulin infusion overnight. The next morning the nasal swab was reported as positive for COVID-19 infection.

The patient remained well without symptoms of respiratory distress. Repeat COVID-19 nasal polymerase chain reaction testing was planned for 2 weeks with IVIG administration repeated every month for 2 more months. The authors report that although the patient tolerated IVIG administration with concurrent COVID-19 infection without any notable reaction they would be hesitant to attempt more aggressive forms of desensitisation with active infection until more clinical knowledge of COVID-19 is available.

Climent, F. J.Pérez-Martínez, ARev Esp Cardiol (Engl Ed). Fatal outcome of COVID-19 disease in a 5-month infant with comorbidities27 Apr 2020SpainEurope12Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183979/pdf/main.pdf
Schwierzeck, VKampmeier, SClin Infect DisFirst reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit27 Apr 2020GermanyEurope13Clinical - Comorbiditieshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa491/5825509

This paper presents the results of an outbreak investigation following a member of staff on a paediatric dialysis unit developing confirmed COVID-19. Detailed contact tracing was carried out and found that 48 cases in total were involved - this included 13 patients, 28 healthcare workers and seven 'accompanying persons'. Of note, of the 3 traced who children tested positive for SARS-CoV-2, only one had symptoms; given these children's high-risk status, their asymptomatic presentations are noteable. The paper discusses hygiene measures put in place to avoid further spread.

Chen, YHuang, KDiabetes CareClinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication24 Apr 2020ChinaAsia3Clinical - Comorbiditieshttps://care.diabetesjournals.org/content/early/2020/05/13/dc20-0660
Poli, PBadolato, RJ. Cyst FibrosAsymptomatic case of COVID-19 in an infant with cystic fibrosis14 Apr 2020ItalyEurope1Clinical - Comorbiditieshttps://www.cysticfibrosisjournal.com/article/S1569-1993(20)30096-5/fulltext#%20

This is the first case report of confirmed SARS-CoV-2 infection in a child with cystic fibrosis. The 1 month-old, from Italy, was diagnosed with CF on newborn screening. SARS-CoV-2 infection was confirmed on nasopharyngeal swab PCR as part of contact tracing following exposure to COVID-19 through his grandfather.

The infant remained asymptomatic throughout follow up and did not require hospital admission.This is one of a limited number of reports of SARS-CoV-2 infection in people with CF. A better understanding of the course of illness in this group will likely emerge with data from ongoing collaborative studies.

Hrusak, OSchrappe, MEur J CancerFlash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment07 Apr 2020International (first author from Czechia)International9Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141482/

This is the report of a data from an international survey of paediatric haematology and oncology clinicians to assess the frequency and severity of SARS-CoV-2 infection amongst children with cancer. The survey, conducted from 16th-17th March 2020, had over 35 respondents from 25 countries. Of an estimated 10,000 patients at risk and over 200 tested, 9 children were positive for SARS-CoV-2. Clinical details are provided for 8 cases, 6 of whom had solid tumours and 2 with acute lymphoblastic leukaemia. 7 had mild or asymptomatic disease, 1 patient required low flow oxygen. Fever was the presenting symptom in 6 patients and one patient also had diarrhoea. All 7 patients with outcome data available made a full recovery.

The interpretation of these data is clearly limited by the study design as well as the relatively early stage of the pandemic during which the survey was conducted. Notwithstanding these limitations, the absence of severe COVID-19 cases in this report provides some early reassurance. More detailed clinical studies are needed to draw firm conclusions about the risk of severe disease in children receiving chemotherapy.

Balduzzi, ABiondi, ALancet pre-print serverLessons after the early management of the COVID-19 outbreak in a pediatric transplant and hemato-oncology center embedded within a COVID-19 dedicated hospital in Lombardia, Italy02 Apr 2020ItalyEurope5Clinical - Comorbiditieshttps://dx.doi.org/10.2139/ssrn.3559560

This report from a paediatric haematology unit in Lombardia, Italy, includes the Italian experience of COVID-19 in children with malignancy so far. At their particular unit, they have had no children with malignancy test positive for COVID-19 (they admit this is dependent on testing criteria, requiring hospitalisation at their institute). They are aware of 5 cases of paediatric cancer patients who have had COVID-19 and have all suffered a mild course, with 3 managed at home and 2 in hospital.

This small case series provides further reassurance for at risk paediatric populations.

Lagana, SMLefkowitch, JHArchives of Pathology & Laboratory MedicineCOVID-19 associated hepatitis complicating recent living donor liver transplantation02 Apr 2020USANorth America1Clinical - Comorbiditieshttps://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2020-0186-SA

This retrospective single case report examines the histopathological features of liver associated COVID-19 in a child admitted to Columbia University Medical Centre, USA. The female child, 6 months old, was admitted for a liver transplant for treatment of biliary atresia. COVID-19 was diagnosed in the donor on post-operative day 2 and confirmed in the patient day 4 post-operatively. The type of test used was not described.

Clinical features: Increased work of breathing requiring CPAP, fever and diarrhoea were developed on post-operative day 4.

Radiology: CXR on post-operative day 4 was described as “no significant changes compared to prior exam with only patchy areas of atelectasis in irregularly aerated lungs”. CXR on day 6 demonstrated “patchy lung opacities bilaterally, mildly increased in the right upper lobe and left lung base”. Bloods: Deranged LFTs exacerbated from baseline on post-operative day 1: AST (maximum 908U/L from 163U/L), ALT (maximum 980U/L from 215U/L), GGT (maximum 473U/L from 174U/L), ALP (maximum 578U/L from 388U/L).

Treatments: Treated with hydroxychloroquine from day 4 post-operative. She required CPAP for an undefined time period. Undefined immunosuppressant treatment was provided for acute transplant rejection, however liver enzymes worsened when commenced.

Outcomes: Remains on a hospital ward without supplemental oxygen.

A liver biopsy was performed on post-operative day 7 demonstrating portal tract expansion through a mixed inflammatory infiltrate which consisted of lymphocytes, rare plasma cells, and interspersed eosinophils, lymphocytic cholangitis, reactive changes in the interlobular bile ducts and mild portal venulitis. These were interpreted as acute cellular rejection.

Other findings of moderate acute hepatitis including an “azonal pattern of clusters of apoptotic hepatocytes” and singly dispersed apoptotic hepatocytes. Other features of interest include large fragments of cytoplasmic debris described as “crumbling” hepatocytes, few mitotic figures, regions of Kupffer cell prominence with sinusoidal and central vein endotheliitis. The authors commented that the extent of hepatocyte apoptosis and large clusters were unusual and not a usual feature of acute cellular rejection (ACR). Central endotheliitis may also be a feature of COVID-19 hepatitis, with the presence of more Kupffer cells and less plasma cells than ACR.

Summary: COVID-19 hepatitis likely presents as a moderate acute hepatitis with prominent clusters of “crumbling” apoptotic hepatocytes. Other features may be lymphohistiocytic inflammation of sinusoidal and central vein endothelium, with the presence of more Kupffer and less plasma cells when compared to ACR.

Turner, DRussel, RJournal of Pediatric Gastroenterology and NutritionCOVID-19 and paediatric inflammatory bowel diseases31 Mar 2020InternationalInternational8Clinical - Comorbiditieshttps://doi.org/10.1097/MPG.0000000000002729

This article outlines the experience from Asia and Europe so far of children with inflammatory bowel disease given the COVID-19 pandemic. This is of particular interest because many of these children receive immunosuppression as part of their treatment, and so could be considered high risk for complications of the disease.

It appears to have been routine practice to suspend treatment for IBD during the outbreak of COVID-19, which resulted in a large number of relapses. No children with IBD contracted COVID-19 in China in the period covered by the survey.

In South Korea treatment for IBD was not suspended. They also have had no cases of COVID-19 in children with IBD.

In the PORTO IBD group of ESPGHAN (covering Europe, some centres in Canada and Israel) treatment was not suspended in 31/32 centres. 7 children with IBD, who were on immunosuppression, had COVID-19. They all suffered a mild illness with no flare of their IBD. There is an additional child case from an international IBD database identified who also experiences mild symptoms (no hospitalisation required).

This survey provides further reassurance that treatment with immunosuppression does not appear to significantly increase the risk of severe disease from COVID-19 in children.

D'Antiga, LLiver transplantationCoronaviruses and immunosuppressed patients: the facts during the third epidemic20 Mar 2020ItalyEurope3Clinical - Comorbiditieshttps://doi.org/10.1002/lt.25756

This letter is from a liver transplant centre in Lombardy, Italy, reporting their experience of patients (including children) with immunosuppression and COVID-19. They have had 3 children post liver transplant test positive for SARS-CoV-2, and none have developed clinical pulmonary disease. They believe due to the widespread nature of infection that many other of their patients may also be infected, but not developed clinically apparent disease.

This provides the first official reports of vulnerable paediatric populations with COVID-19, which so far does not appear to be any more severe than the rest of the population in that age bracket. Further data is awaited.

Weisberg, SFarber, DNat ImmunolDistinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.5 Nov 2020USANorth America47Clinical - PIMS-TShttps://doi.org/10.1038/s41590-020-00826-9

This study, published online on 5th November 2020, investigates the SARS-CoV-2 antibody response and its protective capacity in 32 adult and 47 paediatric patients seen at New York-Presbyterian/Columbia University Irving Medical Center hospital and the Morgan Stanley Children’s Hospital of New York during the height of the COVID-19 pandemic in New York City from March to June 2020. Children with SARS-CoV-2 infection are often asymptomatic and rarely have severe respiratory symptoms, but may very rarely present with multisystem inflammatory syndrome in children (MIS-C), typically 2-4 weeks after infection with SARS-CoV-2. Adults are more likely to experience respiratory symptoms of varying severity, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (particularly in older adults and those with comorbidities such as diabetes). The authors aimed to investigate the immune response after SARS-Co-2 infection in adults and children with a range of clinical presentations, by analysing antibodies specific for the major SARS-CoV-2 antigens, including the S protein (which binds the cellular receptor for viral entry) and the N protein (necessary for viral replication). They also analysed the neutralising activity of these antibodies in blocking viral infection, which correlates with their protective capacity (only a small fraction of antibodies raised against viral antigens will have neutralising activity).

Study population: There were 4 patient cohorts in the study (2 adult and 2 paediatric, one each of mild and severe disease in each age group) totalling 79 individuals, defined as having been SARS-CoV-2-infected based on symptoms, positive PCR and/or serology:

1. 19/79 (24%) adult convalescent plasma donors (CPDs): recovered from mild COVID-19 respiratory disease without hospitalisation and recruited from the community via web tool as part of convalescent plasma trial (telephone screening to determine eligibility as plasma donors), median age 45 yrs (range 28-69), 10/19 (53%) male, ethnicity: 53% white, 32% Asian, 11% Pacific Islander, 5% Hispanic/Latin American, 5% other/unknown. Median time from onset of symptoms consistent with COVID-19 to sampling during outpatient donation of blood: 24 days (IQR 19-37).

2. 13/79 (16%) adults hospitalised with severe COVID-19 ARDS (COVID-ARDS): median age 62 yrs (range 19-84), male 11/13 (85%), ethnicity: 31% Hispanic/Latin American, 23% Black/African American, 15% white, 38% other/unknown. Co-morbidities: diabetes 4/13 (31%), hypertension 4/13 (31%), current/former smoker 3/13 (23%), COPD 2/13 (15%), chronic neurological disease/dementia 1/13 (8%). Median time from onset of respiratory/COVID-19 symptoms to sampling (after diagnosis of ARDS requiring intubation and admission to ICU): 16 days (IQR 14-21). 30-day in-hospital mortality 6/13 (46%), 4 patients remained hospitalised.

3. 16/79 (20%) children hospitalised with MIS-C (paediatric MIS-C): median age 11 yrs (range 4-17), male 7/16 (44%), ethnicity: 44% Black/African American, 44% white, 25% Hispanic/Latin American, 6% other/unknown. Asthma 4/16 (25%) (no other co-morbidities). Median time after onset of symptoms of MIS-C to sampling on admission to PICU: 6 days (IQR 4-7). 30-day in-hospital mortality 0%, 1/16 (6%) developed respiratory failure/ARDS.

4. 31/79 (39%) children infected with SARS-CoV-2 who didn’t develop MIS-C (paediatric non-MIS-C): median age 11 yrs (range 3-18), male 17/31 (55%), ethnicity: 48% white, 42% Hispanic/Latin American, 13% Black/Latin American, 23% other/unknown. Co-morbidities: asthma 1/31 (3%), chronic kidney disease 1, hypertension 1. Clinical presentation: surgical 9/31 (29%), COVID-19 symptoms 7/31 (23%), psychiatric 4/31 (13%), trauma 3/31 (10%), fever (non-COVID) 2/31 (6%), other 6/31 (19%). Asymptomatic 15/31 (48%). Median time from symptom onset or from confirmed COVID-19 exposure (reportable data for 16 individuals) to sampling during clinical care (including routine screening for admission and procedures): 29 days (IQR 17-44). 30-day in-hospital mortality 0%, 1/31 (3%) developed respiratory failure/ARDS. These samples were obtained from the Columbia University Biobank after screening for appropriate age and exclusion of confounders such as immune deficiency, malignancy and genetic abnormality.

SARS-CoV-2 specific antibodies for each cohort: Blood samples were collected from all 4 cohorts during the same 60 day time window. Levels of antibodies to SARS-CoV-2 S (spike) and N (nucleocapsid) proteins were measured in patient plasma samples (and in a negative control pre-pandemic plasma) using serial dilutions in an indirect ELISA assay to detect anti-S IgG, anti-S IgM, anti-S IgA and anti-N IgG. Detailed results and graphs are reported in the article, together with statistical comparisons between cohorts. Anti-S antibodies were present as IgM (primary response), IgG (prominent in serum) and IgA (prominent in secretions) classes in adult CPDs and COVID-ARDS, with significantly higher concentration in COVID-ARDS patients for all classes. By contrast, anti-S antibody titres and isotype predominance in both paediatric cohorts (MISC-C and non-MIS-C) were similar to each other and to the adult CPDs, showing predominant anti-S IgG, low titres of anti-S IgM (similar to the negative control) and variable titres of anti-S IgA antibodies. The specificity of anti-S IgG for SARS-CoV-2 S protein compared to other coronavirus strains was assessed using a cell-based ELISA: plasma IgG from subject samples (but not pre-pandemic control plasma) bound SARS-CoV-2 protein and the common circulating D614G S protein variant, but did not significantly bind S protein from SARS-CoV-1 or MERS coronaviruses. Anti-N IgG titres were significantly lower in both paediatric cohorts compared to the two adult cohorts. The low titres of anti-N IgG in children were similar in MIS-C and non-MIS-C cohorts. The higher titres of anti-N IgG in adults were similar in CPDs and COVID-ARDS cohorts, suggesting that production of anti-N antibody is age- but not symptom-dependent.

Effect of age on antibodies in each cohort: No significant correlation between age and anti-S IgG in adults or paediatric MIS-C cohort; modest but significant negative correlation between age and anti-S IgG in paediatric non-MIS-C cohort (younger children having higher anti-S titres than teens). Significant correlation between age and anti-N IgG in adult CPDs (younger adults having lower anti-N titres than older adults). Both paediatric cohorts had low anti-N titres across all ages.

Effect of time post-symptom onset on antibodies in each cohort: Significant correlation between anti-S IgG titres and increased time post-symptom onset for both paediatric cohorts and the adult COVID-ARDS cohort, suggesting an evolving response over time. No correlation between anti-S IgM and time post-symptom onset in any cohort.

Neutralising activity of antibodies in each cohort: A pseudovirus assay was used to measure neutralising activity. Both paediatric cohorts exhibited significantly lower neutralising activity than the two adults cohorts, with no difference between MIS-C and non-MIS-C cohorts. Plasma from adult COVID-ARDS patients showed the highest neutralising activity. No correlation between age and neutralising activity in either adult cohort. Significant decline of neutralising activity with age in the paediatric non-MIS-C cohort, similar to the decrease in anti-S IgG observed during the teenage years. Neutralising activity within each cohort did not correlate with time post-symptom onset except in the adult COVID-ARDS cohort. 10/16 (62.5%) MIS-C patients maintained the same anti-S IgG titres and neutralising activity when followed up 2-4 weeks post hospital discharge based on paired analysis, suggesting that lower levels of functional antibody responses in paediatric SARS-CoV-2 infection compared to adults is age-associated and not related to infection course.

Additional analysis to better define how antibody responses relate to age and disease severity: Multivariable linear regression analysis was performed to control for the effects of demographic and clinical covariates. Consistent with the grouped analysis, analysis of all paediatric and adult data showed that the paediatric age group was a significant predictor of lower SARS-CoV-2 neutralising activity, anti-S IgM and anti-N IgG, independent of time post-symptom onset, clinical syndrome or sex. ARDS was a significant independent predictor of higher neutralising activity, anti-S IgG and anti-S IgM.

Observations: Self-selection bias may apply to the CPDs cohort, since they volunteered via the internet to be plasma donors. Timing of onset of symptoms was subjective and the paediatric non-MIS-C cohort included 48% asymptomatic patients whose symptom onset to sampling time interval was calculated based on days since confirmed COVID-19 exposure (with reportable data for only half the cohort). The paediatric MIS-C cohort symptom onset to sampling time interval is based on onset of MIS-C symptoms, not potential initial COVID-19 symptoms or COVID-19 exposure. Samples from COVID-ARDS and MIS-C patients were obtained within 24-36 hours of being admitted to ICU/PICU or intubated for respiratory failure; this was not always before the initiation of therapeutic interventions. Treatments received by the 13 COVID-ARDS patients included: convalescent plasma 4/13 (31%) (1/13 sampled post-treatment), hydrocortisone 6/13 (46%) (1/13 sampled post-treatment), methylprednisolone 9/13 (69%) (8/13 sampled post-treatment), monoclonal antibodies 7/13 (54%) (6/13 sampled post-treatment), remdesevir 6/13 (40%) (2/13 sampled post-treatment). 16 MIS-C patients: hydrocortisone 3/16 (19%) (3/13 sampled post-treatment), intravenous immunoglobulin 14/16 (88%) (6/16 sampled post-treatment), methylprednisolone 15/16 (94%) (10/16 sampled post-treatment), monoclonal antibodies 3/16 (1/16 sampled post-treatment), remdesevir 1/16 (1/16 sampled post-treatment). 31 non-MISC-C patients: intravenous immunoglobulin 2/31 (6%) (both sampled before treatment), methylprednisolone 1/31 (3%) (1/31 sampled post-treatment), remdesevir 1/31 (3%) (1/31 sampled post-treatment).

Conclusions: This study demonstrates quantitative and qualitative differences between children and adults in the anti-SARS-CoV-2-specific antibody response in both mild and severe disease. The anti-SARS-CoV-2 antibody response in children was found to be predominantly anti-S IgG antibodies, with low neutralising activity compared to adults. Children with and without MIS-C had similar antibody profiles (suggesting that the adaptive immune response is not in itself associated with MIS-C pathogenesis), in contrast to the adult cohorts, where those with the most severe disease had higher abundance, breadth and neutralising activity of anti-SARS-CoV-2 antibodies compared to adults who recovered from mild disease. Anti-N antibody titres were low in children compared to adults, which is consistent with a milder course of infection in children (release of N proteins requires lysis of virally infected cells). This effect was also seen in the adult CPDs cohort, where anti-N antibodies increased with age, consistent with an increase in severe and prolonged disease in older adults. Testing platforms using anti-N IgG to identify previous infection may have decreased sensitivity in children, since children were shown to predominantly generate IgG antibodies specific for the S protein, but not the N protein. Age was the major factor distinguishing antibody profiles (independent of sex, disease severity and time post-symptom onset). The authors note the opportunity to study primary immune responses across all ages afforded by the sudden and widespread emergence of SARS-CoV-2 as a new pathogen; the majority of primary exposures to common viral respiratory pathogens occur in infancy and childhood, so that virus-specific immune memory is established by adulthood, and therefore differences between primary immune responses in children and adults are currently unknown. The authors postulate that the reduced functional adaptive antibody response in children compared to adults may be due to efficient immune-mediated viral clearance resulting in fewer respiratory symptoms and less severe disease. Children may have more naïve T cells available to respond to new pathogens or more recently acquired T cell memory to related coronaviruses due to more recent and frequent respiratory illnesses. Defining the nature of the antibody response to SARS-CoV-2 infection as a function of age and disease severity will improve age-targeted screening and protection in the form of therapeutics and vaccines.

García-Salido, AGonzález Cortés, RCrit Care 24(1): 666Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain26 Nov 2020SpainEurope74Clinical - PIMS-TShttps://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03332-4

Multicentre registry-based study of 74 children admitted to 47 PICUs in Spain with SARS-CoV-2-related disease, from 01/03-15/06/20, comparing cases with a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) with non-MIS-C cases. MIS-C cases were more likely to be older, to not to have any prior medical condition, to present with fever, fatigue, GI symptoms and to develop cardiac dysfunction and shock, and to need vasoactive drugs, antibiotics and immunomodulatory drugs than were non-MIS-C cases. They had lower lymphocyte counts and LDH levels but higher neutrophil counts and pro-calcitonin and CRP levels. They were less likely to present with cough, respiratory distress or rhinorrhoea, to need non-invasive or mechanical ventilation, or blood product support. All 3 deaths were in non-MIS-c cases with significant underlying medical conditions. Whereas non-MIS-C cases were admitted reasonably regularly throughout the 1st pandemic wave, MIS-C admissions showed a delayed peak compared to national case numbers. MIS-C cases were more likely to have negative PCR for SARS-CoV-2 than non-MIS-C cases, though many had other immunological evidence of infection. The authors point out that the findings of this study are only applicable to PICU populations and do not reflect the full spectrum of MIS-C disease, since milder cases will not have been admitted to a PICU.

Anderson, EHensley, SJPIDSSARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-1902 Dec 2020USANorth America29Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa161
Lucio Verdoni, MD Lorenzo D'Antiga, MDThe LancetAn outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study 13th May 2020ItalyEurope10Clinical - PIMS-TShttps://doi.org/10.1016/S0140-6736(20)31103-X

This is the second published manuscript on the increase in a Kawaski-like illness (now termed PIMS-TS) during the SARS-CoV-2 pandemic.

This is a retrospective study of children with a diagnosis of Kawasaki Disease (KD) in the Bergamo province of Italy, an area which was significantly affected by SARS-CoV-2. Overall, 10 children were diagnosed with KD during the pandemic (Feb 18 to April 20,2020), compared with 19 children prior to the pandemic (Jan 1 2015 to Feb 17 2020). Interestingly, 8 of 10 children were positive for SARS-CoV-2 IgG, IgM or both.

The two groups of children were compared, and those with KD during the SARS-CoV-2 pandemic were found to be older, have a higher rate of KD and were more likely to present with KD shock syndrome or Macrophage Activation Syndrome. Overall, there was a 30 fold increased incidence of a KD-like illness during the pandemic.

Prieto, LMBlazquez, DClin Microbiol Infect Cardiovascular magnetic resonance imaging in children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and heart dysfunction10 Oct 2020SpainEurope5Clinical - PIMS-TShttps://doi.org/10.1016/j.cmi.2020.10.005

The authors (from the Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid) describe their recent experience with five patients affected by PIMS-TS from April 28 to May 11, 2020. The exact mechanisms of how SARS-CoV-2 causes this transient myocardial dysfunction in children with PIMS-TS are not well understood. Cardiovascular magnetic resonance imaging (CMRI) has become the diagnostic tool of choice for patients with evidence for acute non-ischemic myocardial injury, including myocarditis in the last decade. CMRI allows for targeting several features of myocardial injury: inflammatory hyperemia and edema, necrosis/scar, contractile dysfunction and pericardial effusion. CMRI is also a predictor of functional and clinical recovery. They state CMRI allows for a robust assessment of the extent of injury and dysfunction in clinically acute scenarios of myocardial injury but the diagnostic value of echocardiography for myocardial injury is limited by the fact that many patients with less severe disease have a normal echocardiogram and the highly variable echocardiographic findings lack specificity.

Presenting features and investigations

All were previously healthy children, with a median age of 7 years old of varying racial backgrounds, [interquartile range (IQR), 5-12 years]. They presented at admission with fever, tachycardia and hypotension. The median white cell count was 9100 cells/mm3 and the median lymphocyte count was 1700 cells/mm3. Other ancillary tests revealed elevated cardiac biomarkers [median troponin T was 66.6 ng/l (IQR: 3.2-75.2) and NT-proBNP of 14,407 pg/ml (IQR: 3988–16,150)], and markedly increased inflammatory biomarkers like C-reactive protein and procalcitonin [10.2 mg/dl (IQR: 9.4-26.9) and 10.5 ng/ml (IQR: 3.4-14.8), respectively]. The median ferritin was 421 μg/l (IQR: 369-639) and the median interleukin 6 was 63.5 pg/ml (IQR: 27.2-216.2). The echocardiography revealed mild to moderate heart dysfunction in all of the patients. All of them had a positive serology against SARS-CoV-2 (Ig anti receptor-binding domain) and met criteria for PIMS-TS according to UK, WHO and CDC definitions. Z-score for coronary artery diameters were also standardly assessed.

Treatment

Patients received IVIG, and in three cases steroids were added because of persistent fever 48 hours after IVIG administration.

Outcome

They were all discharged home with total recovery of the heart function.

A cardiovascular magnetic resonance imaging (CMRI) was performed after discharge [median day after admission: +16, (range 9-17)]. The protocol performed included steady-state free precession cine 2D sequences (short axis, 4, 3 and 2 Chamber views); study of edema (Inversion Recovery sequence in short axis), hyperemia and capillary leak (early gadolinium enhancement) and myocyte necrosis and fibrosis (late gadolinium enhancement). Both ventricles had normal function and no edema or abnormalities in early and late gadolinium enhancement were observed in any cases.

Conclusions

CMRI did not show any myocardial damage in this small series of patients with PIMS-TS. CMRI is considered a highly sensitive technique to evaluate myocardial injury. Although the number of patients in this series was small, the authors felt that heart dysfunction did not seem secondary to myocardial viral injury in these children. They put forward an alternative hypothesis that the exaggerated inflammatory response observed in these children with PIMS-TS could be the cause of the heart dysfunction. The rapid recovery of the heart function after immunomodulatory treatment and the absence of myocardial abnormalities in CMRI support this hypothesis. They conclude that further studies to further elucidate the cause of myocardial dysfunction in children with multisystem inflammatory syndrome related to COVID-19 are warranted.

Minocha, PSingh, RClinical PediatricsCardiac Findings in Pediatric Patients With Multisystem Inflammatory Syndrome in Children Associated With COVID-1925 Sep 2020USANorth America33Clinical - PIMS-TShttps://doi.org/10.1177/0009922820961771

Methods: The authors retrospectively reviewed the clinical course and cardiac testing results in paediatric patients hospitalized with Multisystem Inflammatory Syndrome in Children (MIS-C) at 2 large hospital systems in the New York City metropolitan area over 3 months between March 1st and June 8th 2020. A standardized pathway was used to evaluate suspected cases of MIS-C and patients with acute respiratory COVID-19 infection were excluded.

Data on patient demographics, clinical course, testing results, treatment, and outcomes was collected. Patients were assessed for prior COVID-19 exposures and COVID-19 infections. All patients were tested with SARS-CoV-2 nasopharyngeal (RT-PCR) on admission. After introduction of SARS-CoV-2 serological testing on May 12, 2020, all patients with MIS-C received SARS-CoV-2 IgG (immunoglobulin G) antibody testing on admission.

For this study, MIS-C patients with positive cardiac testing were defined as having an abnormality of one or more of the following on admission: electrocardiogram (ECG), serum troponin, brain natriuretic peptide (BNP), and/or echocardiogram (echo). Left ventricular (LV) systolic function was calculated by 5/6 area length method and LV dysfunction was defined as a LV ejection fraction (LVEF) <55%.LV diastolic function was assessed by E/A wave ratios of mitral valve inflow Doppler interrogation, tissue Doppler imaging, and/or strain analysis. The classification of coronary artery dilation, aneurysm size, and Kawasaki disease were based on the 2017 American Heart Association statement. Appropriate ethical approval of the study was gained.

Results: 33 patients (median age 2.8 years) were in the study cohort There was a male predominance (58%) with Hispanics constituting the largest ethnic group (36%). Comorbidities included obesity (21%) and asthma (15%). Median duration of symptoms prior to admission was 5 days (IQR: 3-6 days). The most common symptoms were fevers (100%), rash (58%), conjunctivitis (36%), and diarrhea (36%). Three (9%) patients met the criteria for Kawasaki disease, while 10 (30%) patients met the criteria for atypical Kawasaki disease. SARS-CoV-2 RT-PCR testing was positive in 11 (33%) patients. Of the 23 patients who underwent SARS-CoV-2 IgG antibody testing, 14 (61%) were IgG positive. Inflammatory markers on admission were elevated with a median C-reactive protein (CRP) of 85 mg/L (IQR: 33-196 mg/L), median D-dimer of 649 ng/mL (IQR: 362-1093 ng/mL), and median ferritin of 206 ng/mL (IQR: 105-633 ng/mL)

24 (73%) had at least one abnormality in cardiac testing: abnormal electrocardiogram (48%), elevated brain natriuretic peptide (43%), abnormal echocardiogram (30%), and/or elevated troponin (21%).

The most common ECG changes seen were T wave (24%) and ST segment abnormalities (18%). Prolonged QTc was seen in 3 (9%) patients.

All 4 patients with LV dysfunction had normal systolic function on follow-up echos (LVEF = 66%, IQR = 64% to 69%). The median time to documented normalization of LV function was 2 days (IQR = 1.5-8.5 days). Mitral valve insufficiency and dilation of the LMCA all normalized on follow-up echos within 2 weeks of hospitalization. ST segment and T-wave abnormalities resolved on follow-up ECGs.

On univariate testing, BNP >100 pg/mL (P = .012) and CRP >50 mg/L (P = .023) were associated with an abnormal echo. There was no statistically significant association between D-dimer (P = .26), ferritin (P = .45), troponin (P = .20), or EKG findings (P = 1.0) with an abnormal echo.

Treatment: Eleven (33%) patients required ICU-level care. Most patients were treated with intravenous immunoglobulin (IVIG; 72%) and glucocorticoids (55%). Median hospital length of stay was 4 days (IQR: 3-6 days). All patients have been discharged except for one critically ill patient with a history of persistent fevers despite IVIG, glucocorticoids, and Anakinra (interleukin-1 receptor antagonist). Patients were sent home on low-dose aspirin (3-5 mg/kg/day) that was stopped after a normal echo at 6 weeks post-MIS-C diagnosis. Electrocardiogram and echocardiogram abnormalities all resolved by the 2-week outpatient follow-up cardiology visit.

Limitations of study: As a rare disease, the numbers of patients in this study is relatively small. This was a retrospective review and there was no standardization of care provided. The demographics both younger age and Hispanic preponderance may have affected the results. With its broad case definition, there may have been misclassification of patients with MIS-C who may have had these other diagnoses. Not all patients received SARS-CoV-2 antibody testing in this study due to the novel nature of this disease during our study period.

Comment: The authors conclude that there is a spectrum of cardiac disease in MIS-C and that not all patients are as severely affected as suggested previously. Obesity and Asthma were comorbidities in a significant proportion of patients. While 73% of pediatric patients with MIS-C had evidence of abnormal cardiac testing on hospital admission in the study, all cardiac testing was normal by outpatient hospital discharge follow-up. They also state that cardiac screening tests should be performed in all patients diagnosed with MIS-C given the high rate of abnormal cardiac findings in their study cohort.

Pang, JBreuer, JPediatricsSARS-CoV-2 Polymorphisms and Multisystem Inflammatory Syndrome in Children (MIS-C)01 Sep 2020United Kingdom Europe13Clinical - PIMS-TShttps://pediatrics.aappublications.org/content/early/2020/09/07/peds.2020-019844
Godfred-Cato, SBelay, EMorb Mortal Wkly Rep COVID-19–Associated Multisystem Inflammatory Syndrome in Children — United States, March–July 202007 Aug 2020United StatesNorth America570Clinical - PIMS-TShttps://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6932e2-H.pdf

On May 14th 2020, the CDC (Centre of Disease Dontrol) In the United states issued an alert on Multisystem Inflammatory Syndrome in Children, and asked clinicians to report any suspected cases to local and state health departments.

As of 29 July 2020, a total of 570 MIS-C patients with onset dates from March 2 to July 18, 2020, had been reported from 40 state health departments, the District of Columbia, and New York City. The median patient age was 8 years (range = 2 weeks–20 years); 55.4% were male, 40.5% were Hispanic or Latino (Hispanic), 33.1% were non-Hispanic black (black), and 13.2% non-Hispanic white (white). Obesity was the most commonly reported underlying medical condition, occurring in 30.5% of Hispanic, 27.5% of black, and 6.6% of white MIS-C patients. 364 (63.9%) of patients needed ICU care, and 10 children (1.8%) died.

Latent class analysis (LCA), a statistical modelling technique that can divide cases into groups by underlying similarities, was used to identify and describe differing manifestations in patients who met the MIS-C case definition. Indicator variables used in the analysis were presence or absence of SARS-CoV-2–positive test results by PCR or serology, shock, pneumonia, and involvement of organ systems.

This analysis divided the cohort of patients into three groups.

Class 1: 203 (35.6%) patients. Median age 9 years. These patients had the highest number of involved organ systems. Of this group, 99 (48.8%) had involvement of six or more organ systems; most commonly cardiovascular (100.0%) and gastrointestinal (97.5%). Compared with other Classes they had significantly more shock/abdominal pain/myocarditis/lymphopenia and markedly raised inflammatory markers. Coronary artery dilatation and aneurysm rate was 21.1%. 10 (4.9%) met full criteria for Kawasaki disease. 98% had positive Sars COV2 positive serology with/without positive PCR. 1 child from this group died (case fatality rate 0.5%)

Class 2: 169 (29.6%) patients. Median age 10 years. In this group, 129 (76.3%) had respiratory system involvement. These patients were significantly more likely to have cough, shortness, ARDS. Coronary artery dilatation and aneurysm rate 15.8%. 5 children (3%) met full criteria for Kawasaki disease. Most of this group (84%) had Sars CoV2 positive PCR without positive serology. This suggested Class 2 had severe acute Covid 19 disease. Nine children in this group died, giving the highest case fatality 5.8%

Class 3: 198 (34.7%) patients. Median age 6 years (significantly younger). This group had the highest prevalence of rash (62.6%), and mucocutaneous lesions (44.9%). Prevalence of coronary artery aneurysm and dilatations was 18.2%. 6.6% met criteria for complete Kawasaki disease. This group had the lowest prevalence of underlying medical conditions, organ system involvement, complications (e.g., shock, myocarditis), and markers of inflammation and cardiac damage. 63.1% had positive SARS-CoV-2 serology only and 33.8% had both serologic confirmation and positive RT-PCR results. None of these children died.

Comparison with UK report of PIMS-TS;The association of Covid 19 with an inflammatory syndrome has been reported in many countries across Europe following on from the peak outbreaks in the respective countries. In the UK, Whittaker et al, in JAMA in June, published a cohort of 58 children who met the criteria for PIMS-TS. These 58 children were reported as one group; however they were stratified by shock, Kawasaki disease, Kawasaki clinical criteria, coronary artery aneurysm, and prevalence of Sars CoV 2 infection (PCR or serology). Though direct comparison across the groups is somewhat difficult, some similarities and differences are apparent.

CDC Class 1 with shock abdominal pain and a somewhat older age group at presentation, with markedly raised inflammatory markers, is seen also in the UK group. The prevalence of abdominal symptoms is significantly higher in those where KD disease or clinical criteria is not met.

Similarly CDC Class 3 group of younger children with increase prevalence of mucocutaneous lesions, and rash were younger, and lower prevalence of shock is seen in the UK cohort when stratified.

CDC Class 2 with 76.3% respiratory involvement is not really reflected in the UK cohort, with respiratory symptoms only present in 26% of the total group, without wide variation when the UK group is stratified. It appears that this CDC Class 2 may be representative of acute severe Covid infection, which was not incorporated UK PIMS-TS cohort.

Coronary artery dilation and aneurysm was higher across all CDC classes compared with UK cohort prevalence of 14%.

Jhaveri SStern KJpeds Longitudinal Echocardiographic Assessment of Coronary Arteries and Left Ventricular Function Following Multisystem Inflammatory Syndrome in Children (MIS-C)02 Aug 2020United StatesNorth America15Clinical - PIMS-TShttps://www.jpeds.com/article/S0022-3476(20)30984-7/pdf
Diorio, CBassiri, HJCIMultisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-230 Jul 2020USANorth America20Clinical - PIMS-TShttps://www.jci.org/articles/view/140970#sd

According to the authors this is a prospective report comparing life threatening complications of SARS-CoV-2 in children.

Children admitted to the Children's hospital of Philadelphia between April 3rd and May 15th 2020 were prospectively screened and enrolled if there was evidence of past or present SARS-CoV-2 infection. After enrolment the children were categorised by clinical presentation as MIS-C, severe COVID-19 or minimal COVID-19.

Data collected included demographics, co-morbid conditions, sources of co-infection, treatments used and many laboratory investigations particularly looking for organ dysfunction and inflammatory markers.

26 children were enrolled, there was only sufficient data on 20. Of these 6 met the criteria for MIS-C (and 2 of these also met criteria for Kawasaki Disease), 9 severe COVID-19 and 5 minimal COVID-19. All 6 MIS-C patients had been previously healthy and were younger than the other groups. 8 of the 9 severe COVID-19 had pre-existing conditions and all 5 of the minimal COVID-19 had other infections or pre-existing conditions which were the reason for admission. Ethnicity showed no significant differences between the groups. Among the wealth of analyses, only TNF+IL-10 significantly distinguished between MIS-C and severe COVID-19 (p=0.036). Data also supports an infective aetiology for MIS-C.

This is a small study from early in the pandemic (enrolment was started before CDC alert on MIS-C in USA). Various hypotheses are mentioned but not statistically proven. The authors themselves state "We believe these results can inform hypotheses for future studies when larger cohorts are available and we would caution against broad generalisation of these results until such work is complete.

Lee, PYSon, MBFJ Clin Invest 2020Distinct clinical and immunological features of SARS-COV-2- induced multisystem inflammatory syndrome in children23 Jul 2020USANorth America28Clinical - PIMS-TShttps://www.jci.org/articles/view/141113

28 children with MIS-C and evidence of SARS-CoV-2 were identified at a tertiary referral unit in Boston, USA, between March and June 2020. Age range, 1 month–17 years; median, 9 years. 57% male. Statistically significant over-representation of black and Hispanic cases. 50% had pre-existing medical conditions. Comprehensive data is given on the clinical and immunological features, treatment and outcomes.

The pattern of MIS-C showed a clear distinction from both Kawasaki disease and Macrophage Activation Syndrome. Respiratory features were mild compared to adult MIS (none mechanically ventilated, 25% non-invasive support, 14% supplemental O2 only) but other organ systems were similarly affected (GI 54%, conjunctivitis 57%, rash 36%, low platelets 64%, low lymphocytes 75%, raised D-dimers 96%, acute kidney injury 21%, L ventricular dysfunction 39%). 61% required ICU admission, 54% due to hypotension/shock, but none developed ARDS. Intravenous immunoglobulin (71%), corticosteroids (61%), remdesivir (25%), anakrina (18%) and hydroxychloroquine (1 case) were given as immunomodulatory treatments, with clinical improvement in all cases. There were no deaths.

To, KKwan, MDiagnostic Microbiology and Infectious DiseaseFalse-positive SARS-CoV-2 serology in 3 children with Kawasaki disease17 Jul 2020ChinaAsia3Clinical - PIMS-TShttps://doi.org/10.1016/j.diagmicrobio.2020.115141

This retrospective case study of three children with typical Kawasaki disease reports the discrepancy between positive tests for SARS-CoV-2 anti-NP or anti-RBD IgG, and subsequent microneutralization assays which were negative in all three.

Clinical features: The study took place in Hong Kong, China. Three children were identified as having typical Kawasaki disease between January and April 2020. Two were aged 3 months and one was aged 6 months; two were girls and one a boy. None reported any epidemiological links to individuals with COVID-19 or any travel history in areas with COVID-19 outbreaks.

All three had fever, conjunctivitis, a maculopapular rash, cracked or erythematous lips and rhinorrhea. Two had in addition a cough and one had cervical lymphadenopathy. Two had abnormal echocardiograms (perivascular echogenicity and non-tapering coronary arteries) and one had a normal echocardiogram.

Each patient tested negative for SARS-CoV-2 and other common respiratory pathogens in nasopharyngeal aspirate polymerase chain reaction (PCR).

Bloods: One patient tested positive for SARS-CoV-2 anti-RBD and anti-NP IgG after 60 days; a second patient tested positive for SARS-CoV-2 anti-RBD and anti-NP IgG after 87 days; and the third patient tested positive for only SARS-CoV-2 anti-RBD IgG after 90 days.

All three patients subsequently tested negative for SARS-CoV-2 neutralising antibodies by microneutralization assay (a titre ≥10 was considered positive).

Outcomes: All three were treated with intravenous immunoglobulin and high dose aspirin (30–50 mg/kg per day), followed by low dose aspirin (3–5mg/kg per day) for 8 weeks. All made a full recovery including normal echocardiograms.

Comment: The authors speculate that the false-positive SARS-CoV-2 IgG could be due to cross-reactive antibodies triggered by Kawasaki Disease or triggered by other coronaviruses. They discount the possibility that the results were related to the administration of IVIG, which had been obtained from healthy Hong Kong blood donors months before its use, and long before the first case of COVID-19 was diagnosed in Hong Kong in late January 2020.

There needs to be caution in investigating pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), in the light of these results, The authors recommend patients with positive SARS-CoV-2 serology but negative PCR should be further tested by microneutralization assay for the presence of neutralizing antibodies.

Davies, PRamnarayan, PLancetIntensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study09 Jul 2020UKEurope78Clinical - PIMS-TShttps://doi.org/10.1016/S2352-4642(20)30215-7

This multicentre observational study examines 78 children with PIMS-TS, admitted to 21 of the 23 PICUs in the UK between April 1 and May 10, 2020. The study team analysed routinely collected de-identified data submitted by clinicians from the individual PICUs.

The median age of patients was 11 years (IQR 8–14). There were 52 male patients (67%) and 61 patients (78%) were from ethnic minority backgrounds.

Clinical features: Common presenting features were fever in 78 (100%), shock in 68 (87%), abdominal pain in 48 (62%), vomiting in 49 (63%) and diarrhoea in 50 (64%). Rash was seen in 35 (45%) and conjunctivitis in 23 (29%).

Bloods: Of 35 patients tested for SARS-CoV-2 IgG serology, 33 were positive, and one of the two negative serology patients was PCR positive. 32 patients were PCR negative, with unknown serology and without a known COVID-19 contact. Over the first 4 days of admission there was a reduction in C-reactive protein (from a median of 264 mg/L on day 1 to 96 mg/L on day 4) and ferritin (1042 μg/L to 757 μg/L), whereas the lymphocyte count increased to more than 1·0 × 109 cells per L by day 3.

Outcomes: 36 (46%) patients were invasively ventilated and 65 (83%) needed vasoactive infusions; 57 (73%) received steroids, 59 (76%) received intravenous immunoglobulin, and 17 (22%) received biologic therapies. 28 (36%) had evidence of coronary artery abnormalities (18 aneurysms and ten echogenicity). Three children needed extracorporeal membrane oxygenation, and two children died.

During the study period, the rate of PICU admissions for PIMS-TS was at least 11-fold higher than historical trends for similar inflammatory conditions. Using these data and extrapolating from international child sero-prevalence data (Spain ~3% of children being infected, equivalent to 456,000 children in the UK) this would result in a conservative estimate of the risk of a child infected with SARS-CoV-2 subsequently being admitted to PICU with PIMS-TS as just under 2 per 10,000 infections.

Dufort, EZucker, H NEJMMultisystem Inflammatory Syndrome in Children in New York State29 Jun 2020USANorth America99Clinical - PIMS-TShttps://www.nejm.org/doi/full/10.1056/NEJMoa2021756?query=featured_coronavirus

This is a case series of 99 children (<21 years of age) from New York State with multisystem inflammatory syndrome in children (MIS-C). Of note some of these cases have been reported in small series (Cheung et al JAMA 2020). New York State Department of Health required hospitals that provide paediatric medical or surgical care to report potential cases of Kawasaki’s disease, toxic shock syndrome, or myocarditis or who were suspected to have MIS-C among persons younger than 21 years of age admitted since March 1, 2020, through the NYSDOH Health Emergency Response Data System. The clinical and laboratory characteristics of these reports were studied. Between March 1 and May 10 2020 191 cases were reported of which 95 met the criteria for MIS-C and 4 further were suspected.

Case definition: Confirmed cases were defined by the presence of both clinical and laboratory criteria. Suspected cases had clinical and epidemiological criteria. Clinical criteria were children <21 years of age with fever and needing hospitalisation with either; 1 or more of hypotension or shock, features of severe cardiac illness, or other severe organ failure. Or 2 or more of; maculopapular rash, non-purulent conjunctivitis, mucocutaneous inflammatory signs or acute GI symptoms with an absence of other cause.

Laboratory criteria: 1. General Criteria; Two or more of raised inflammatory markers and 2. Either positive SARS CoV2 RNA at time of presentation or within 4 weeks or detection of specific antibody.

Epidemiological criteria: In 6 weeks prior to exposure close contact with a person with confirmed or clinically consistent Sars CoV2 infection or travel to or resident in an area with ongoing community transmission.

Baseline characteristics: 53 (54%) were male. Age range was 0-5 years (31%), 6 to 12 year (42%) and 13 to 20 years (26%). 78 patients had data on race with 29 (37%) were white, 31 (40%) were black, 4 (5%) were Asian, and 14 (18%) were of other races. 36 patients had a preexisting condition, 29 had obesity. 24 (24%) had a Covid-19–compatible illness a median of 21 days (interquartile range, 10 to 31) before hospitalization, 38 (38%) had exposure to a person with confirmed Covid-19, and 22 (22%) had direct contact with a person who had clinical Covid 19.

Symptoms : Described in detail in the study. Prevalence of dermatologic symptoms was highest among children 0 to 5 years of age, and the prevalence of myocarditis (diagnoses and clinical) was highest among the adolescents.

Treatment : Of 99 patients, 79 were treated in ICU. 69 had IVIG, 63 received systemic glucocorticoids, 48 received both systemic glucocorticoids and IVIG. 9 patients had coronary aneurysm

Outcome : As of May 15, a total of 76 patients (77%) had been discharged and 21 (21%) were still hospitalised. Unfortunately 2 patients died in the hospital. Both were intubated and ventilated, once received ECMO. Neither received IVIG, systemic glucocorticoids, or immunomodulators.p

Feldstein, LRRandolph, AGNEJMMultiststem Inflammatory Syndrome in U.S. Children and Adolescents29 Jun 2020USANorth America186Clinical - PIMS-TShttps://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.nejm.org%2Fdoi%2Ffull%2F10.1056%2FNEJMoa2021680&data=01%7C01%7CA.Munro%40soton.ac.uk%7C44a8f00e84024fc3091408d81ce42e9c%7C4a5378f929f44d3ebe89669d03ada9d8%7C0&sdata=bQRL8Sx61R5%2FkQST67%2FVl9CZj8puJPfyKJCftB6Q9ec%3D&reserved=0

This retrospective and prospective multi-centre cohort study from 53 participating hospitals in 26 states looked at 234 patients under 21 years of age that met criteria for multi system inflammatory syndrome in children (MIS-C), between March 15 and May 20th

The median age of the patients was 8.3years old and 62% (115) were male. Fifty one patients (27%) had an underlying medical condition. In terms of confirmation of SARS_CoV-2 infection - 70% were positive for RT-PCR and/or antibody testing. Of a small subgroup of 14 patients with Covid-19 symptoms before MIS-C, the median time between Covid-19 symptom to MIS-C was 25 days (6-51 days).

Criteria for MIS-C were based on CDC guidelines (in brief, requiring hospitalisation, at least two systems involved, fever of at least 24 hours and either lab confirmed SARS_CoV-2 infection (via RT-PCR or antibody testing) or an epidemiological link to a person with Covid-19 within 4 weeks before onset of symptoms).

Although MIS-C criteria was at least 2 system involvement, 71% had involvement of four organ systems or more. The most frequent systems in order were gastrointestinal (92%) followed by cardiovascular (80%), haematological (76%) and respiratory (70%). Blood changes observed included lymphocytopaenia in 80% of patients, and an elevated CRP in 91%.

Looking at similarity and overlap with Kawasaki disease, 40% of patients had either fever for at least 5 days and 4-5 of Kawasaki's disease-like features or 2-3 Kawasaki's disease-like features with additional lab or echocardiographic findings. Common symptoms similar to Kawasaki disease bilateral conjunctival infection in 103 (55%), oral mucosal changes in 78 (42%), peripheral extremity change in 69 (37%), rash in 110 (59%), cervical lymphadenoapthy (>1.5cm diameter) in 18 (10%). Differences between MIS-C and Kawasaki's disease groups include an older age group and a different cardiovascular involvement (more likely myocardial dysfunction) in MIS-C patients.

The majority of patients required ICU admission (n=148, 80%) with one in five patients needing invasive mechanical ventilation. Eight patients received ECMO support. Treatment included IVIG in 77% and systemic glucocorticoids in 49%. There were four deaths (two of which had received ECMO). At the time of writing the paper, 70% of patients had fully recovered with 28% still in hospital.

Felstein, LRandolph, ANEJMMultisystem Inflammatory Syndrome in U.S. Children and Adolescents29 Jun 2020USANorth AmericaClinical - PIMS-TShttps://www.nejm.org/doi/full/10.1056/NEJMoa2021680
Hameed, SJogeesvaran, K HRadiologySpectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19.25 Jun 2020UKEurope35Clinical - PIMS-TShttps://pubs.rsna.org/doi/10.1148/radiol.2020202543
Riollano-Cruz, MPaniz-Mondolfi, AJ Med VirolMultisystem Inflammatory Syndrome in Children (MIS‐C) Related to COVID‐19: A New York City Experience25 Jun 2020USANorth America15Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26224

This retrospective case series describes 15 patients presenting to Mount Sinai Hospital in New York between 24th April and 19th June 2020. Patients were identified by presentation to hospital with clinical features meeting the criteria for MIS-C (known in the UK as PIMS-TS) as defined by the Centers for Disease Control and Prevention Emergency Preparedness and Response, and the New York City Health Department. The mean age of the 15 patients was 12 years, with a range of 3 to 20 years. 11 patients (73%) were male, and 10 patients (66%) identified as Hispanic or Latino.

Clinical features: All patients had a fever at admission and 13/15 (87%) had gastrointestinal symptoms including abdominal pain, vomiting and diarrhoea. Respiratory symptoms were far less common, with cough or sore throat only occurring in 3/15 (20%) of cases. Other features at admission included rash in 7/15 (47%), conjunctivitis in 4/15 (27%) and swollen hands and feet in 4/15 (27%).

COVID-19 status: 7/15 (47%) tested positive for SARS-CoV-2 from a nasopharygeal or respiratory specimen during admission, and 2/15 (13%) had a positive test in the month prior to admission. 15/15 (100%) of patients were positive for COVID-19 antibodies.

Radiology: CXR at admission showed non-specific findings in 7/15 (47%), reactive airway disease in 4/15 (27%), pleural effusions in 4/15 (27%) and were normal in 3/15 (20%). Echocardiogram was abnormal in 12/15 (80%): 4/15 (27%) had reduced LV function, 3/15 (20%) had reduced biventricular function and 3/15 (20%) had coronary artery abnormalities.

Bloods: 13/15 patient (87%) presented with lymphopenia, and 14/15 (93%) had elevated fibrinogen. During admission 15/15 cases (100%) had a raised CRP and D-dimer, 14/15 (93%) had a raised ESR and 13/15 (87%) had a raised ferritin. IL-6 and IL-8 were elevated in 15/15 patients (100%) whereas 0/15 (0%) had an elevated IL-1 (which tends to be raised in Kawasaki disease).

Treatment: 15/15 patients (100%) received prophylactic enoxaparin until 2 weeks post-discharge. 12/15 patients (80%) received tocilizumab (anti-IL-6 antibody), 12 (80%) were given IVIG, 3 (20%) received steroids, 2 (13%) initially received Anakinra (IL-1 receptor antagonist),and 2 (13%) patients were treated with Remdesivir. Outcomes were not analysed according to treatment received.

Outcomes: 14/15 patients (93%) were admitted to PICU. 3 patients (20%) needed mechanical ventilation, another 5 patients (33%) required non-invasive ventilation, and 8 patients (53%) needed inotropic support. At the time of publication 13 patients had been discharged, 1 was still an inpatient and 1 had died.

Chiu, J. S., Samuels-Kalow, MPediatr Cardiol. Kawasaki Disease Features and Myocarditis in a Patient with COVID-1915 Jun 2020USANorth America1Clinical - PIMS-TShttps://link.springer.com/article/10.1007/s00246-020-02393-0
Capone, CDavidson, KJ. PediatrCharacteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection14 Jun 2020USNorth America33Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293762/

This is a single-centre retrospective case series of 33 sequentially hospitalized febrile paediatric patients with CDC case definition for Multisystem Inflammatory Disease of Childhood (MIS-C) and WHO criteria for Multisystem Inflammatory Syndrome (MIS) admitted to Cohen Children's Medical Center, Queens, NY from April 17, 2020 through May 13, 2020. All cases were positive for SARS-CoV-2 by detection of serum antibodies or nucleic acid from a nasopharyngeal specimen. Patients with COVID-like lower respiratory tract involvement were excluded. The peak of hospitalizations occurred approximately five weeks after the peak of hospitalizations with acute COVID-19. Patients were predominantly male (20, 61%) and non-Hispanic (24, 73%) with a median age of 8.6 years (IQR 5.5-12.6). Most patients were previously healthy but a higher proportion were overweight (2,6%) or obese (12, 39%) compared with the regional childhood obesity rate of 18%. 

Patients presented with a median of 4 days (IQR 3-5) of fever and almost all (32, 97%) had gastrointestinal symptoms (including diarrhoea, vomiting and abdominal pain) as well as other organ system involvement. 21 (64%) patients fulfilled complete criteria for KD and most patients with complete KD criteria, had shock (16, 76%). 

All patients had negative blood cultures and multiplex nucleic acid amplification test for multiple respiratory pathogens except 1 patient in whom influenza virus detected. 26 (79%) patients needed intensive care and 6 (18%) required mechanical ventilation. 58% had myocardial dysfunction and 76% required vasoactive medications. Coronary artery aneurysm was identified in 5 (15%) and dilation was detected in 3 (9%) patients.

All patients were treated with IVIG, 88% received aspirin, and 70% were given a corticosteroid and 42% were given Enoxaparin. 24% of patients exhibited a partial response to these treatments and received a biologic modifying medication (Anakinra, Tocilizumab, Infliximab). Most patients demonstrated rapid clinical improvement. No patients died. Median length of hospital stay was 4 days (IQR 4, 8). At hospital discharge, mild cardiac dysfunction was still present in 9 of 19 patients. This case series shares similarities with smaller international case series reported as Kawasaki-like disease and hyperinflammatory shock syndrome. In all these studies, most patients had antibodies against SARS-COV2 virus, suggestive of a post-infectious, immunologically mediated pathophysiology. The authors suggest that the latent period between the peak of paediatric cases of COVID-19 and MIS-C suggests that MIS-C has a post-infectious, possibly immunologically mediated pathogenesis.

Despite clinical similarities with KD, differences include the predominance of gastrointestinal symptoms, an older age range (8.6 year in MIS-C patients compared with a median age of 2.5 years for patients with KD), markedly elevated inflammatory markers, higher proportion of patients with shock and/or impaired cardiac function (76%) than in other KD studies (less than 3% shock reported), and the lack of thrombotic events in the case series patients. This suggests that MIS-C may be a syndrome distinct from KD. Acute COVID-19 with "cytokine storm" further complicates differentiation of these presentations.  

Further study is needed to shed light on the pathophysiology, treatment options, and outcomes of MIS-C.

Foong Ng, KTang, JWTJournal of Medical VirologyCOVID-19 Multisystem Inflammatory Syndrome in Three Teenagers with Confirmed SARS-CoV-2 Infection13 Jun 2020UKEurope3Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26206
Kaushik, SMedar, SJ PediatricsMultisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection: A Multi-institutional Study from New York City13 Jun 2020USANorth America33Clinical - PIMS-TShttps://www.jpeds.com/action/showPdf?pii=S0022-3476%2820%2930747-2

This retrospective observational study details clinical characteristics, therapies and outcomes of a multicentre cohort of 33 children with Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 admitted to PICUs at 3 tertiary care children’s hospitals in New York City between 23 April and 23 May 2020.Study design: Patients aged 1 month to 21 years admitted to 3 NYC PICUs (at Children’s Hospital at Montefiore, Mount Sinai Kravis Children’s Hospital and Jacobi Medical Center) with confirmed SARS-CoV-2 infection (positive nasopharyngeal swab RT-PCR or antibody assay) meeting criteria for MIS-C (US CDC case definition, formalised on 14 May 2020, used: age < 21 yrs presenting with fever, laboratory evidence of inflammation and evidence of clinically severe illness requiring hospitalisation, with 2 organ involvement, plus no alternative plausible diagnosis, plus positive for current/recent SARS-CoV-2 infection or COVID-19 exposure within 4 wks prior to onset of symptoms). During the study period there were additional suspected patients with similar presentations and management without confirmed SARS-CoV-2 infection/exposure who were excluded; only cases with confirmed infection by RT-PCR/antibody assay were included.

Study population: 33 children met the inclusion criteria at the 3 centres. Median age 10 years (IQR 6-13), 20/33 male (61%), median BMI 18.6 kg/m2 (IQR 15.9-22.9), 2/33 obese (6%, BMI > 30 kg/m2). 15/33 Hispanic/Latino (45%), 13/33 black (39%), 3/33 white (9%), 1/33 Asian (3%), 1/33 other (3%). 16/33 comorbidities (48%) (most common comorbidity was asthma). 8/33 (24%) had had contact with an ill person, 5/33 (15%) had had contact with a confirmed COVID-19 case.

Clinical features: Fever 31/33 (94%), mucocutaneous involvement 7/33 (21%), conjunctivitis 12/33 (36%), rash 14/33 (42%), abdominal pain 21/33 (64%), nausea/vomiting 23/33 (70%), diarrhoea 16/33 (48%), dyspnoea 11/33 (33%), dizziness 3/33 (9%). Duration of symptoms prior to admission 4.5 days (IQR 3-6). 21/33 (64%) were hypotensive on admission.

Admission blood results: Medians (IQR in brackets): WBC 11,000/L (8450-14,400), lymphocytes 1,100/L (600-1,300), CRP 250 mg/L (156-302), ESR 53 mm/hr (28-77), procalcitonin 5.4 ng/mL (1.8-16.7), ferritin 568 ng/mL (340-954), fibrinogen 627 mg/dL (455-782), D-dimer 3.7 g/mL FEU (2.4-5.1), BNP 388 pg/mL (75-1086), pro-BNP 4328 pg/mL (2117-13370), troponin T 0.08 ng/mL (0.02-0.17), IL-6 200 pg/mL (56.4-330), IL-8 41.7 pg/mL (25.1-54.4), creatinine 0.6 mg/dL (0.4-1.1).

CXRs: Cardiomegaly 10/33 (30%), focal or bilateral pulmonary opacities 11/33 (33%).

Echocardiograms: Performed in 32/33 (97%). Pericardial effusion 15/32 (47%), median LVEF 47% (IQR 40-53). LVEF < 30% 4/32 (13%), LVEF 30-50% 17/32 (53%), LVEF > 50% 11/32 (34%). 24/32 had a second echocardiogram prior to discharge: of those with initial LVEF < 50%, 20/21 (95%) had recovery of ventricular function with normal EF. Median pre-discharge LVEF 58% (IQR 55-62). A detailed table is supplied for the 21 patients with LVEF < 50%, including BNP/troponin levels, drug treatment by patient and the 8/21 who had prominent coronary arteries on echo.

Treatment in PICU: 18/33 received IVIg (55%), 17/33 corticosteroids (52%), 12/33 tocilizumab (35%), 7/33 remdesivir (21%), 4/33 Anakinra (12%), convalescent plasma therapy 1/33 (3%), 17/33 vasopressor/inotropes (52%) (median duration of vasopressor use 72 hrs (IQR 48-110), norepinephrine most commonly used agent), 8/33 aspirin (24%), 21/33 diuretics (64%). Anticoagulation was used in all patients: prophylactic dose enoxaparin 5/33 (15%),therapeutic dose enoxaparin 27/33 (82%), therapeutic dose unfractionated heparin 1/33 (3%). Empiric antibiotic coverage for < 48 hrs in 14/33 (42%) and > 48 hrs in 15/33 (45%). 5/33 (15%) required invasive mechanical ventilation. 2/33 (6%) required mechanical circulatory support: 1 ECMO (5-yr-old) and 1 intra-aortic balloon pump (20-yr-old).

Outcomes: 32/33 (97%) patients were discharged home with median PICU stay of 4.7 days (IQR 4-8) and hospital stay of 7.8 days (IQR 6-10). 1/33 (3%) died (ischaemic brain infarction with subarachnoid haemorrhage on day 6 of ECMO).The authors conclude that rapid, complete clinical and myocardial recovery was almost universal in their study. They hypothesise that this novel COVID-19 MIS-C is predominantly an antibody-mediated or other immune cell-mediated cytokine storm, with some contribution from direct myocardial injury. They note the lower morbidity in their cohort relative to recent European studies

Schnapp, AMolho-Pessach, VJ Eur Acad Dermatol VenereolIntroductory histopathologic findings may shed light on COVID19 pediatric hyperinflammatory shock syndrome13 Jun 2020IsraelMiddle East1Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16749
Ramcharan, TChikermane, APediatr Cardiol.Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital12 Jun 2020UKEurope15Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289638/

This retrospective case-series on the cardiac manifestations of PIMS-TS from a UK Paediatric Centre (Birmingham); reinforces and highlights some of the clinical features reported elsewhere.

15 patients meeting the definition of PIMS-TS were identified over one month, between 10th of April and 9th of May, at Birmingham Women’s and Children’s NHS Foundation Trust. Patient demographics were consistent with other larger reports; patient age 8.8yrs (IQR 6.4-11.2years); which the authors highlight is older than the average age of children affected by Kawasaki’s disease in the UK and consistent with previous literature on PIMS-TS. Furthermore; this cohort were predominantly male (11/15 (73%) and all (100%) were from African/Afro-Caribbean, South Asian, mixed or other minority ethnic groups; the authors highlight that this is disproportionate to the ethnic demographics of children within the region.

The paper focuses on cardiac investigations and highlights that all patients in this cohort had evidence of cardiac involvement. 60% (9/15) had ECG abnormalities;

primarily T-wave abnormalities; 93% (14/15) had coronary artery abnormalities on echo. Coronary abnormalities were detailed as ‘prominent’, ‘dilated’ or ‘aneurysmal’. Aneurysms were seen in only one patient. Left ventricular dysfunction was evidenced in 80% and this was reflected in the needs for cardiovascular support (necessary in 10/15 (67%) of patients and an equal number requiring PICU admission).

Reassuringly all patients survived and were discharged after a median hospital stay of 12 days (IQR 9-13days). In the 12 patients who had completed their first clinic review (1 week following discharge), all had stable cardiac function and no new coronary changes.

Pouletty, AMelki, IAnn Rheum Dis Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort11 Jun 2020FranceEurope16Clinical - PIMS-TShttps://ard.bmj.com/content/annrheumdis/early/2020/06/11/annrheumdis-2020-217960.full.pdf

This is a retrospective clinical case series, comprising 16 children from the Paris region, France, who were reported to two national networks of children with rare auto-immune and rheumatologic disorders between 7 and 30 April 2020. Median age was 10 years (IQR (4.7 to 12.5)) and sex-ratio was 1. Four children were overweight and 2 had asthma.

SaRs-CoV-2 was detected in either nasopharyngeal secretion or stool samples in 11 cases (69%), while the remaining five cases included in the series had close exposure to a SARS-CoV-2 PCR-positive individual.

Ten patients (62%) had Kawasaki Disease, defined by persistent fever over 5 days associated with at least four of the five following criteria: conjunctivitis, lymphadenopathy, skin rash, red and cracked lips, inflammation of hands and feet; whilst the remaining 6 were described as having “incomplete” Kawasaki Disease.

Clinical features: Cough and dyspnoea occurred in 2 (12%) and anosmia in 1 (6%), whereas 13 (81%) had gastrointestinal signs. Neurological signs (headache or aseptic meningitis) occurred in 9 (56%). Thirteen (81%) had skin rash, 11 (68%) had erythema/oedema of hands and feet, 15 (94%) had conjunctivitis, 14 (87%) had dry cracked lips and 6 (37%) had cervical lymphadenopathy.

Eleven (69%) children developed haemodynamic failure and 9 (56%) developed acute renal failure. 7 patients (44%) developed Kawasaki shock syndrome.

Laboratory investigations: Inflammatory biomarkers were highly elevated in all patients, with median C-reactive protein (CRP) 207mg/L (IQR 162 to 236). Ferritin (median 1067 μg/L (IQR 272 to 1709)) was abnormal in 12 of 14 tested patients, and highly elevated (>500μg/L) in 50% of cases. Myocardial enzymes were elevated in 11 patients.

Imaging: Only 5 (31%) children had an abnormal chest X-ray. Eleven (69%) had an abnormal cardiac ultrasound, including coronary artery dilatation and signs of myocarditis or pericarditis.Treatment: Fifteen patients (94%) were treated with intravenous immunoglobulin. Additional treatments included steroids in 3 (19%) and aspirin in 15 (94%). Seven children (44%) were admitted to ICU.

Outcome: Median duration of symptoms from onset until abatement of fever was 9 days (IQR 8 to 13). No patient died. All made a recovery, but two have persistent mild cardiac dysfunction due to myocarditis.

This paper makes an important contribution to the clinical literature about Paediatric Multisystem Inflammatory Syndrome temporally associated with COVID-19.

The authors compared their patients to an historical series of 220 French children diagnosed with Kawasaki disease between 2005 and 2020. The children in the historical series were significantly younger and had significantly higher platelet and lymphocyte counts. Importantly, the patients reported in the present study had a significantly higher frequency of cardiac complications than children in the historical series.

The authors also attempted to subdivide the small cohort into a severe and non-severe group, but the comparison does not appear to serve a useful purpose.

Blondiaux EDucou le Pointe HRadiologyCardiac MRI of Children with Multisystem Inflammatory Syndrome (MIS-C) Associated with COVID-19: Case Series09 Jun 2020FranceEurope4Clinical - PIMS-TShttps://pubs.rsna.org/doi/10.1148/radiol.2020202288

The authors describe 4 children who developed MIS-C who required admission to PICU because they had developed myocarditis and signs of cardiogenic and/or septic shock syndrome. One required mechanical ventilation. All 4 recovered.

Mean age was 9year (range 6-12years), and cardiac features developed <1 week after onset of covid-19 symptoms of abdominal pain and rash. 3 of the 4 had chelitis or conjunctivitis. None had experienced any respiratory symptoms.

Nasopharyngeal swabs and respiratory and stool samples were all negative for covid-19 using RT-PCR. All 4 had positive IgG to covid-19 and one also had positive IgM antibody. The clinical and laboratory findings and treatment given are tabulated, and a further table gives the cardiac MRI findings with images. MRI was undertaken during the acute phase in 3 and recovery phase in the 4th patient. The main MRI finding was of cardiac hyperaemia and oedema, without evidence of fibrosis. There were no coronary artery abnormalities.

The authors contrast the diffuse myocardial findings of MIS-C in children with the cardiac effects of covid-19 in adults, in whom it causes focal myocardial fibrosis/necrosis. They highlight that their findings point to inflammatory infiltration of the interstitial myocardium similar to that seen in Kawasaki disease. They suggest that this points to an inflammatory immune response to an antigen rather than to viral infiltration. The timescale of peak inflammatory response at 10 days after onset of symptoms and resolution by 20 days is also similar Kawaski disease. In contrast to Kawasaki disease, MISC-C affects an older age group and was not associated with arterial changes in this series.

Cheung, EMilner, JJAMAMultisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City08 Jun 2020USANorth America17Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2767207?appId=scweb

This is a case series of 17 children, admitted to a hospital in New York city, between April 18th and May 5th 2020 with features of Multisystem Inflammatory Syndrome Related to COVID-19.

Patients included in this series were i. less than 21 years old, ii. presented with a clinical syndrome characterized by prolonged fever, systemic inflammation, shock, end-organ dysfunction, or symptoms reminiscent of Kawasaki Disease or Toxic Shock Syndrome and iii. had evidence of recent (SARS-CoV-2) infection. The baseline characteristics of these children were; median age 8 years (1.8-16), 8 were male (47%); 12 were classified white (70.1%), 4 black (23.5%), 1 Asian (5.9%).

Presentation: All had fever, with median duration of 5 days. 14/17 had GI symptoms. Mucocutaneous findings were common (12 rash, 11 conjunctivitis, 9 lip redness/swelling). 3 were hypoxic at presentation, and 13 had shock. 8 met criteria for KD and 5 for incomplete KD.Investigations: 8 patients tested positive for SARS-CoV-2 by RT-PCR and 9 by serology.

Xrays: 14 had abnormal chest radiograph findings, most commonly bilateral, interstitial opacities.

Bloods: mean values for a wide variety of investigations shown in paper in table 2. Mainly group were lymphopenic with raised ferritin, d dimers, clotting times, and troponin. Cardiac: ECG of 16 patients showed nonspecific ST/T-wave abnormalities in 10 and attenuated QRS voltage in 1. Dysrhythmias were noted in 3. Admission echos showed normal to mildly decreased left ventricular function in 11, or moderate or more ventricular dysfunction in 6. All patients had normal coronary arteries by measurement, though coronary arteries were described as prominent or echogenic in 7. However one patient (aged 4 years) developed a medium-sized aneurysm (z score, 5.2) of the left anterior descending coronary artery. This patient presented with fever, diarrhea, and shock, with no additional features of KD.Treatment: 15/17 patients were admitted to PICU; vasoactive support was required in 10. Treatment was varied, 14 received steroids (either methylprednisone or hydrocortisone, prednisolone numbers of each not given). 13/17 received IVIG including 3 patients who did not receive steroids and 8 who met criteria for KD. One patient received tocilizumab.

Outcome: All patients discharged home with no fatalities.

Comparison with other PIMS TS cohorts:

Reports of hyperinflammatory syndrome in children during the Sars CoV2 outbreak has been reported in France, Italy, UK and US. (see https://dontforgetthebubbles.com/pims-ts/) This cohort used the CDC definition, which is broadly similar to RCPCH and WHO, though in the US paediatrics < 21 years of age.

Like the other cohorts, the age range is older than typically seen in Kawasaki Disease. Fever and GI symptoms are very common. Mucocutaneous signs were also common. Children presented very unwell, with many needing PICU care (88% in this study). Treatment used included IVIG and steroids.

Unlike other cohorts where black ethnicity was pronounced, 70% of this cohort was classified as white. It would be useful to know the demographic breakdown of the local paediatric population who attend this hospital.

Whittaker, ELevin, MJAMAClinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-208 Jun 2020UKEurope58Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2767209

This paper provides a detailed description of the clinical and laboratory features of 58 children diagnosed with PIMS-TS from 8 hospitals in England between March 23rd and May 16th 2020. All children fulfilling the UK, WHO or CDC criteria for PIMS-TS / MIS-C were included; evidence of SARS-CoV-2 infection was not required for inclusion. Features of this group were compared with previous data from children with Kawasaki Disease (KD), KD shock syndrome (KDSS) and toxic shock syndrome (TSS).

Of the 58 patients, 45 (78%) had evidence of SARS-CoV-2 infection (RT-PCR (15) and or IgG (40)). 33 (57%) were female. 22 (38%) were of black race, 18 (31%) asian. The majority were previously well; only 7 had co-morbidities (3 with asthma, 1 epilepsy, 1 neuro-disability, 1 sickle cell trait, 1 alopecia)

All patients had fever (range 3-19 days). Gastrointestinal symptoms were common (abdominal pain (53%), diarrhoea (52%), vomiting (45%)) whilst respiratory symptoms were relatively uncommon (21%) and 15 (26%) had headache. 

Only 13 (22%) of patients fulfilled criteria for KD; 8 (14%) had coronary artery aneurysm, 26 (45%) conjunctival injection, 30 (52%) rash, 17 (29%) mucous membrane changes, 9 (16%) lymphadenopathy, and 9 (16%) swollen hands and feet. Half of patients developed shock. Laboratory findings were consistent with marked inflammation (mean CRP 229 mg/L (IQR 156-338), ferritin 610 μg/L (359-1280), fibrinogen 5.7 g/L (4.4-7), D-dimer 3578 ng/mL (2085-8235)) with neutrophilia (13 x 10^9 (10-19)). Evidence of myocardial injury was common with troponin elevated in 34/50 (68%) and NT ProBNP in 24/29 (83%). Low haemaglobin (92 g/L (83-103)), lymphocyte (0.8 x 10^9 (0.5-1.5) and platelet levels (151 x 10^9 (104-210)) were also observed. 

Half of patients were admitted to a critical care unit; 25 (43%) requiring mechanical ventilation, 27 (47%) inotropes and 3 (5%) ECMO. A range of treatments were given including IVIG (71%), steroids (64%), anakinra (5%) and infliximab (14%). 13 (22%) recovered without immunomodulatory treatment, whilst 60% received >/= 2 and  16% >/= 3 agents. To the last date of follow up only one child had passed away. p

The authors suggest three clinical patterns of PIMS-TS based on the patients included in this series:   (1) persistent fever and elevated inflammatory markers (without KD, shock or organ failure) - 23 patients here  (2) fever and shock, often with myocardial dysfunction - 29 patients   (3) children fulfilling criteria for KD - 7 patients (13 if aneurysm included in criteria). 

Compared with children with KD, KDSS and TSS, children with PIMS-TS were older (median age 9 (IQR 5.7-14)) with higher CRP and lower haemaglobin. Compared with those with KD and KDSS, PIMS-TS patients in this series had higher neutrophil count, ferritin and troponin with lower platelet and lymphocyte counts. Compared with pre-COVID-KD cases children with PIMS-TS KD were older and had higher markers of inflammation and myocardial injury. 

This is the most detailed clinical report of PIMS-TS to date. The findings here demonstrate a syndrome with a wide spectrum of signs, symptoms and severity with some overlap with KD, KDSS and TSS. PIMS-TS is characterised by marked inflammation with myocardial dysfunction and often shock necessitating ICU admission for inotropic support, mechanical ventilation and, in a small number of patients, ECMO. Treatment with immunomodulatory agents similar to those used in KD has been employed and only one death had occurred at the time of the report. Differences in clinical and laboratory profile compared with KD, KDSS and TSS, suggests= that PIMS-TS is a unique entity, potentially arising from a maladaptive acquired immune response to SARS-CoV-2 infection. 

Toubiana, JAllali, SBMJKawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study03 Jun 2020FranceEurope21Clinical - PIMS-TShttps://www.bmj.com/content/369/bmj.m2094

This cohort study looks at a cluster of patients diagnosed with Kawasakis disease at a hospital in Paris between April 27th and May 11th. During this time they admitted 21 children with a diagnosis of Kawasakis or incomplete Kawasakis, with a median age of 7.9yr and 12/21 female.

Clinical features: All children presented with persistent fever and with initial GI symptoms (vomiting and diarrhoea) with over half fulfilling complete KD criteria (11/21, 52%). The majority were irritable (12/21, 57%) and myocarditis was common (16/21, 76%). Coronary artery dilation was seen in 5/21 (24%) but no aneurysms seen. 8/18 who had chest imaging had lung changes.Bloods: Inflammatory markers were significantly raised, with a median CRP of 253, PCT 22.5 and IL-6 170. Interestingly mean platelet count was 499 (but up to 838). Median troponin 282 and D dimer 4025 (up to 19330). Ferritin not reported.

COVID-19 status: 8/21 tested positive on swab and 19/21 had positive serology Treatment: All were given IVIg, following which 5/21 still had fever 36hrs afterwards. They were given a second dose of IVIg and steroids. 15/21 required inotropic support and 11/21 required intubation/ventilation.

Outcomes: Median length of stay was 8 days (rage 5 – 17). There were no deaths.Three subsequent studies have confirmed very similar presentations of this hyperinflammatory syndrome (PIMS-TS) in children, with initial abdominal pain, fever, diarrhoea and vomiting, progressing to a picture similar to Kawasakis disease but with a significant number developing shock and significant cardiac involvement.

Grimaud, MOualha, MAnnals of Intensive careAcute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children.01 Jun 2020FranceEurope20Clinical - PIMS-TS https://annalsofintensivecare.springeropen.com/track/pdf/10.1186/s13613-020-00690-8

This is a retrospective observational study of 20 children who were admitted to paediatric intensive care units across four academic tertiary centres in Paris, four weeks after the start of French lockdown. None of the children had existing co-morbidities nor a history of symptomatic COVID-19 infection.

All patients were less than 18 years old and presented with hypotensive shock and acute myocarditis.

All children had the same presenting complaint- severe abdominal pain, vomiting and fever, for an average of 6 days previously (1-10). On admission to PCIU all children had a raised CRP, (median 251) and procalcitonin, (median 46). p

All children had myocarditis, defined as: elevated troponin, ST segment elevation or depression on ECG and regional wall motion abnormalities with decreased left ventricular function on ECHO. Pericardial effusion was found in four children. All children but one required inotropic support for a median of 3 days (1-7). Eight children required mechanical ventilation for 1-7 days.

Fourteen children had transient acute renal failure but none required renal replacement therapy.

SARS-CoV-2 PCR and serology were positive for 10 and 15 children respectively. One child had a negative PCR and serology but typical SARS-CoV-2 chest CT scan changes. No other bacterial or viral infections were identified.

All children had at least one feature of Kawasaki disease along with a fever, skin rash (10), conjunctivitis (6), cheilitis (5), adenitis (2).

All children received intravenous immunoglobulin within 48hrs of admission and 18 were afebrile thereafter. Two children also received corticosteroids, the reason for this additional therapy is not documented in the article.

All children survived and were afebrile with a full left ventricular function recovery at the time of discharge from PICU.

Wolfler, AndreaZuccotti, GianvincenzoLancet Child Adolescent Health 2020Acute myocardial injury: a novel pattern in children with Covid-19 01 Jun 2020ItalyEurope9Clinical - PIMS-TShttps://doi.org/10.1016/s2352-4642(20)30168-1
Greene, ASinert, RAJEMToxic shock-like syndrome and COVID-19: A case report of multisysteminflammatory syndrome in children (MIS-C)31 May 2020USANorth America1Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274960/pdf/main.pdf
Miller, JMargolis, KGastroeneterologyGastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-C) that is related to COVID-19 a single center experience of 44 cases30 May 2020USANorth America44Clinical - PIMS-TShttps://www.gastrojournal.org/article/S0016-5085(20)34753-3/pdf

A retrospective case study of gastrointestinal symptoms in children with PIMS-TS (the authors call MIS-C). 44 children (age range 7months -20years, 20male), were identified with MIS-C between 18 April 2020 and 22 May 2020. The diagnostic criteria for MIS-C were not given. Gastrointestinal symptoms were present in 84.1% of children, all were febrile and 31/40 (70.5%) had a skin rash.

Importantly 13/44 (29.5%) of children had presented previously with only symptoms of different milder GI conditions.

22/44 50% children had cardiac dysfunction, 22/44 50% had shock requiring treatment with vasopressors, 13/44 29.5% had neurological symptoms, 11/44 25% needed supplemental O2, and 7/44 had acute kidney injury.

Investigations showed markedly elevated inflammatory markers in all and half the children had elevated transaminases. GI imaging was undertaken in 15, 10/12 children had abnormal ultrasounds and 2/3 abnormal CT/MR

The authors conclude that PIMS-TS (MIS-C) should be considered in children with prominent GI symptoms and a history of Covid-19 infection. They also suggest long term follow up may be warranted for IBD surveillance.

Choitos, KJohn, AJ Pediat Inf Dis SocMultisystem Inflammatory Syndrome in Children during the COVID-19 pandemic: a case series26 May 2020AmericaNorth America8Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa069
Chang, AHicar, MmedRxivKawasaki Disease serum responses against SARS-CoV-2.26 May 2020United StatesNorth America14Clinical - PIMS-TShttps://www.medrxiv.org/content/10.1101/2020.05.24.20111732v1
Labe, PMahe, EJ Eur Acad Dermatol VenereolErythema multiforme and Kawasaki disease associated with COVID-19 infection in children26 May 2020FranceEurope2Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16666

This is a retrospective case-series from the United Kingdom of children with neurological symptoms, identified from a larger cohort (n = 55) of SARS-CoV-2 positive children. Of the 55 children, 27 had features of paediatric multisystem inflammatory syndrome (PIMS-TS) and of these, 4 had neurological symptoms.

Clinical Features: The four children had a median age of 12 years (range 8-15 years) and interestingly, two children were of South Asian ethnicity and two of Afro-Caribbean ethnicity. Of the neurological symptoms reported, encephalopathy (4/4), headache (3/4) and brainstem signs such as dysarthria or dysphagia (2/4) were most common. Peripheral nervous system involvement was present in all patients and included proximal muscle weakness (4/4) and decreased reflexes (2/2). Neurological symptoms occurred alongside a range of systemic symptoms but were part of the initial presentation in 2 children.

Investigations: The four children had a range of investigations, including a lumbar puncture (2/4), EEG (3/4), EMG (3/4), MRI (4/4). The CSF was acellular and SARS-CoV2 negative, mild excess of slow activity was seen on EEG, and EMG showed mild myopathic and neuropathic changes. Interestingly, MRI findings were consistent in all four children, and included signal changes in the splenium of the corpus callosum. Three of the four children also had T2 hyperintense lesions associated with restricted diffusion.

Treatments: Therapeutics given varied. Three children received treatment for PIMS-TS more broadly, including methylprednisolone (2/4), dexamethasone (2/4), IVIG (2/4), anakinra (2/4), and rituximab (1/4).

Outcome: At the time of follow-up (median 18 days, range 11-13 days), 2 patients remain in hospital and have residual lower limb weakness and require a wheelchair to mobilise, and 2 patients have been discharged ambulating without support.

Overall, this paper provides a thorough description of neurological features associated with SARS-CoV-2 infection in the setting of multisystem inflammation.

Waltuch, TGill, PAm J Emerg MedFeatures of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department23 May 2020North AmericaNorth America4Clinical - PIMS-TShttps://www.ajemjournal.com/article/S0735-6757(20)30403-4/fulltext#t0005
Acharyya, BDas, DIndian Pediatr Novel Coronavirus Mimicking Kawasaki Disease in an Infant22 May 2020IndiaAsia1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00184.pdf
Deza Leon, MAsmar, BJPIDSCOVID-19–Associated Pediatric Multisystem Inflammatory Syndrome22 May 2020USANorth America1Clinical - PIMS-TShttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa061/5842067

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Leon, MAsmar, BPIDSCOVID-19 Associated Pediatric Multi-System Inflammatory Syndrome22 May 2020USANorth America1Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa061

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Tullie, LCurry, JThe Lancet. Child & adolescent healthGastrointestinal features in children with COVID-19: an observation of varied presentation in eight children19 May 2020EnglandEurope8Clinical - PIMS-TShttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30165-6/fulltext#articleInformation

This is a case series of eight children referred to a single UK centre with symptoms of atypical appendicitis before rapid deterioration requiring hospitalisation and, in some cases, intensive care support. All were found to have evidence of terminal ileitis on imaging and did not require surgical intervention. Although the term is not used by the authors, all children in this case series appear to meet the case definition for Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS). 4/8 children were PCR positive for Covid-19 on initial testing, increasing to 5/8 on repeat testing. Antibody testing is not reported.

Authors highlight the importance of imaging prior to surgery in suspected appendicitis during the COVID-19 pandemic. CT is superior to ultrasound in demonstrating a non-inflamed appendix.

Of note, 6 out of 8 were from Black or Asian ethnic group, this is in keeping with the increased rates of PIMS-TS reported among these ethnic groups. The weight of patients is not reported.

Clinical features: All patients presented with fever, abdominal pain, diarrhoea, and vomiting. All but one child had significantly raised CRP. Four patients developed multi-system inflammatory response with shock and required intensive care support, including one child with myocarditis who required ECMO.

Radiological features: Abdominal imaging demonstrated lymphadenopathy and presence of inflammatory fat throughout the mesentery, with thickening of the terminal ileum.Treatment: Four children were treated with IVIG and steroids for ‘atypical Kawasaki disease’, although two of these children did not have features of Kawasaki disease. All patients were treated with IV antibiotics and fluids.

Outcomes: At the time of writing 2 children had been discharged and the remainder were still hospitalised. There were no deaths.

Study period: 25 Apr 2020 to 2 May 2020

Age range: 4-16yr, mean: 10.6yr

This case series highlights that Covid-19, or PIMS-TS, may mimic appendicitis in children, due to inflammation of the terminal ileum. It is important to investigate appropriately to prevent unnecessary surgery on these children.

Licciardi,FMontin, DPediatricsSAR-Cov2-Induced Kawasaki -Like Hperinflamatory Syndrome: A novel Covid Phenotype in Children19 May 2020ItalyEurope2Clinical - PIMS-TShttps://pediatrics.aappublications.org/content/pediatrics/early/2020/05/19/peds.2020-1711.full.pdf
Belhadjer, ZWacker, JCirculationAcute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic17 May 2020France and SwitzerlandEurope35Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/abs/10.1111/ctr.13889

A multi-centred retrospective case series studied the early outcomes for children admitted to intensive care for cardiogenic shock, left ventricular dysfunction and severe inflammatory state. The study involved 14 centres in France and Switzerland. The inclusion criteria were admission between 22nd March and 30th April 2020 with fever (>38.5°C), cardiogenic shock or left ventricular dysfunction (left ventricular ejection fraction<50% in the presence of an inflammatory state (CRP> 100 mg/mL).

In summary, left ventricular systolic dysfunction was present in all patients who experienced a low systolic blood pressure. The authors contrast this to Kawasaki disease, in which diastolic dysfunction predominates and only a third of patients experience left ventricular systolic dysfunction.

The authors suggest the rapid resolution of systolic dysfunction in conjunction with a mild to moderate troponin rise implies the mechanism of cardiac impairment associated with SARS-CoV2 in the paediatric population differs to that seen in the adult population. Due to the high BNP levels present in the case series a mechanism of myocardial oedema or stunning is suggested. Very high levels of Interleukin-6 were also seen and may be related to vasoplegia. It was hypothesised these significantly raised results could be caused by stretched cardiomyocytes and cardiac fibroblasts in conjunction with macrophage activation. However, further research would be required to determine the immune mechanisms involved and potentially guide treatment choices.

35 patients were included with a median age of 10 years (IQR 2-16 years), 18 were male. 31 patients were confirmed SARS-CoV2 positive by either a nasopharyngeal RT-PCR, faecal RT-PCR, tracheal swab, or serology using Chemiluminescent Microplate Immunoassay-CMIA technique. 2 other patients were SARS-CoV2 negative, however, had CT chest appearances consistent with SARS-CoV2 changes.

10 of the patients had an identified co-morbidity: 3 (8.5%) had asthma, 1 (3%) had lupus and 6 (17%) were overweight with a BMI greater than 25. There was no data regarding ethnic origin included.

Clinical features: 35 (100%) had fever, 35 (100%) Asthenia, GI symptoms 29 (83%), rhinorrhoea 15 (43%), respiratory distress 23 (65%), adenopathy 21 (60%), rash 20 (57%), meningism 11 (31%), chest pain 6 (71%), cardiogenic shock 28 (80%), ventricular arrhythmia 1 (3%). A large proportion of the patients had shock with low systemic blood pressure with limited information.

Radiology: 2 patients had CT chest appearances “typical” for those with SARS-CoV2.Bloods: CRP 241 mg/mL (IQR150-311) mg/mL, Troponin I 347 (IQR 186-1267) ng/L (normal <26ng/L), Creatinine Kinase 174 U/L (IQR 110-510), NT-proBNP 41484 pg/mL (IQR 35811-52475) (normal <300 pg/mL), BNP 5743 pg/mL (IQR 2648-11909) normal <100 pg/mL), D-Dimer 5284 ng/ml (IQR 4069-9095), Procalcitonin 36 ng/ml (IQR 8-99), WCC 16 X 10^3/L (IQR 12-23), Neutrophil count 13 X 10^3/L (IQR 8-19), Interleukin 6 135 pg/mL (IQR 87-175) (normal <8.5 pg/mL)

Treatments: All patients required intensive care management with 10 (28%) needing V-A ECMO for an average of 4.5 days (range 3-6), 28 (80%) needing inotropic medication, 22 (62%) invasive ventilation and 11 (32%) non-invasive ventilation.

25 (71%) were given intravenous immune globulin with 1 (3%) patient given repeated IVIG due to persistent fever 48 hours after the first dose. 12 (34%) received intravenous steroids, dose unclear, due to grading them high-risk with symptoms similar to an incomplete form of Kawasaki disease and 3 patients received interleukin 1 receptor antagonist (anakinra) due to a persistent severe inflammatory state. 23 patients received therapeutic heparin.

Outcomes: No patients died. All 10 patients requiring V-A ECMO were weaned off successfully. The average hospital stay was 8 days (IQR 8-14) with ICU duration of 7 days (3.7-10 days). At the time of publication 7 (20%) patients remained as an inpatient or had residual left ventricular dysfunction.

Complete recovery of left ventricular function, [left ventricular ejection fraction > 60% at day 7] was seen in 25 patients (71%) by an average of 2 days after admission. 5 (14%) had residual mild to moderate left ventricular systolic dysfunction with a left ventricular ejection fraction greater than 45%. This was measured on the last follow up, an average of 12 days after admission.

Other investigations were undertaken to assess cardiac function.

ECG: 1 patient (3%) had ST elevation on ECG.

Echocardiography results: 10 (29%) of patients had an ejection fraction below 30% on admission whilst 25 (71%) had an ejection fraction between 30 and 50%. Global hypokinesis was seen in 31 (89%) with an additional 3 (9%) patients had segmental wall hypokinesis. 1 (3%) patient had Takotsubo syndrome presentation with akinesis of the apical segment Pericardial effusions were diagnosed in 3 (9%) patients.

Coronary artery dilatation, defined as Z-score >2 adjusted for body temperature, was present in 6 patients (17%): 5 patients (14%) had dilatation of the left main stem and 1 (3%) had dilatation of the right coronary artery. Right ventricular function was normal, and no thrombi were seen. No coronary aneurysms have been seen, however, ongoing follow up is planned. Data was not presented regarding SARS-CoV2 antibodies, however, within the discussion it was noted that those who were serologically positive for SARS-CoV2 already had IgG antibodies suggesting the patients included within the study had contact with the virus “more than 3 weeks before admission”.

Pain, CHedrich, CLancet RheumatolNovel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms15 May 2020United Kingdom Europe1Clinical - PIMS-TShttps://www.thelancet.com/action/showPdf?pii=S2665-9913%2820%2930137-5

This is a case report from Alder Hey Childrens Hospital, Liverpool of previously health 14 year old patient fitting criteria for PIM-TS, successfully treated with Anakinra.

Initial presentation : This patient initially presented with a a 3-day history of fever, abdominal pain, nausea, and vomiting, and no respiratory symptoms. A previous history of mild respiratory symptoms 3 weeks earlier was reported. On initial presentation patient had fever 38.1, was cardiovascularly stable, no respiratory distress, but had a tense abdomen with guarding in right upper and lower quadrant. Initial investigations conducted showed; bloods - lymphopenia (0·14 × 109 cells/L), CRP of 242mg/per L, urine – sterile pyuria (30cells), radiology – normal CXR, normal abdominal ultrasound. Nasopharyngeal Sars CoV2 PCR – sent (subsequently negative). A provisional diagnose of acute appendicitis was made, and patient started on Piperacillin-tazobactam.

Deterioration : Within 24 hours of admission, patient became visually more unwell, was tachycardic, had increased dyspnoea and cough, and developed a widespread maculopapular rash. Further investigations showed; Radiology – Ct chest, showed typical findings of SARS-CoV-2. Bloods showed; lymphopenia, anaemia, thrombocytopenia, raised CRP and Ferritin, raised serum interleukin (IL)-6 (1098 pg/mL [normal range<7]), coagulopathy with raised D Dimers and prolonged PR and APTT, raised increased liver enzymes, hypertriglyceridaemia, ANA negative, raised APL (anticardiolipin IgG 25·5 U/mL [normal range <20] and antiβ2-glycoprotein IgG 28·8 U/mL [normal range <20]) were positive, and low complement levels (C3 0·09 g/L [normal range 0·90–1·88], C4 0·12 g/L [normal range 0·18–0·42]). Patient also developed mild polyarticular arthritis.

Treatment and ongoing care : Initial oxygen requirement (8 L/min), finally escalating to CPAP ventilation support. IV Bolus for hypertension. Anti-inflammatory treatment with recombinant IL-1 receptor antagonist (Anakinra) was started after multidisciplinary discussion. It was commenced at 4 mg/kg per day s/c but increased to 8 mg/kg per day after 36 hours because patient required inotropic support for hypotension and rising lactate (6 mmol/L). Because of cardiovascular involvement (borderline LV systolic dysfunction, aortic regurgitation, progressive left coronary dilatation, enzyme leak with troponin-T 45 ng/L), aspirin was started (2 mg/kg) for its antithrombotic effects. Patient did not show additional clinical features of Kawasaki disease, and upon discussion IVIG nor corticosteroids were not given.

Outcome : SARS-CoV-2 IgG became positive (borderline day 6, positive day 11). In temporal relation with anakinra treatment, the patient’s respiratory status stabilised and clinical and laboratory variables returned to normal.

Cabrero-Hernandez, MSerrano-Gonzalez, APediatr Infect Dis JSevere SARS-CoV-2 Infection in Children With Suspected Acute Abdomen: A Case Series From a Tertiary Hospital in Spain10 May 2020SpainEurope5Clinical - PIMS-TShttps://journals.lww.com/pidj/Abstract/9000/Severe_SARS_CoV_2_Infection_in_Children_With.96141.aspx
Balasubramanian, SRamanan, AIndian PediatrHyper-inflammatory Syndrome in a Child With COVID-19 Treated Successfully With Intravenous Immunoglobulin and Tocilizumab10 May 2020IndiaAsia1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00180.pdf
Rivera-Figueroa, ESimpson. SIndian PediatrIncomplete Kawasaki Disease in a Child With Covid-1909 May 2020USANorth America1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00179.pdf
Riphagen, STheocharis, PLancet Hyperinflammatory shock in children during COVID-19 pandemic01 May 2020LondonEurope8Clinical - PIMS-TShttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31094-1/fulltext

This is the first case series to describe a cluster of children presenting with hyperinflammatory shock during the COVID-19 pandemic.

Eight children aged 4 to 14 years were identified by a paediatric retrieval service based in London in mid-April 2020. Interestingly, of the 8 children, 7 had weights >75th centile. Notably 6 were of Afro-Caribbean descent and 2 were Asian, with no Caucasian children in this cohort. 5/8 were boys. 4 children had exposure to family members with COVID-19.

The clinical presentation was similar to Kawasaki disease, with unrelenting fever, rash, conjunctivitis, peripheral oedema, and extremity pain, in addition to gastrointestinal symptoms. All children developed warm, vasoplegic shock and required inotropic support. Seven children required mechanical ventilation.

Small pleural, pericardial and ascitic effusions, also consistent with a diffuse inflammatory process were also observed. Vascular involvement was demonstrated with echo-bright coronary arteries seen in all children, with a giant coronary aneurysm in one patient. One child died from a large cerebrovascular infarct. Myocardial enzymes were significantly elevated.

A range of investigations were done in all children, and despite this no causative pathogen was identified. Adenovirus and enterovirus were isolated in one child. Four children had known exposures to SARS-CoV-2 in family members, but only two tested positive for SARS-CoV-2 (1 was positive only postmortem).

In addition to other supportive therapies, all children received IVIG and broad-spectrum antibiotics (ceftriaxone, clindamycin). Six children have been given aspirin. This clinical presentation may represent a new phenomenon associated with SARS-CoV-2 infection in children and has remarkable similarities to Kawasaki Disease. Following publication of this case series, Evelina London Children’s Hospital has managed >20 similar cases in children. Ten of these children were SARS-CoV-2 antibody positive (unclear which antibody or which test was used).

These findings have garnered particular interest due to the fact that children have otherwise been relatively spared from severe disease due to COVID-19, and here both the temporal association and high proportion of children with seemingly positive serology suggests a possible association with this hyperinflammatory syndrome. Anecdotally, clusters have also been noted in the USA (particularly NYC) and some centres in Spain and Italy. Reports are conspicuously absent from Asia, most notable as Kawasakis disease is more common amongst this population normally. Even more striking is the gross overrepresention of children with an Afro-Carribean background, which given current investigations into the increased incidence of severe adult disease in these communities seems even more pertinent.

As so little is currently known about “garden variety” Kawasakis, it will make defining this disease and its associated with COVID-19 that bit more difficult, but studies are currently ongoing to assess the nature and mechanism of this disease (https://www.diamonds2020.eu/). For now, this cohort doesn’t change the management of childhood COVID-19, nor does it change the management of hyperinflammatory shock or Kawasakis – although the RCPCH have produced excellent guidance for suggested investigations and processes to include these patients in ongoing research.

Jones, VMathew, RHospital PediatricsCOVID-19 and Kawasaki Disease: Novel virus and novel case07 Apr 2020AmericaNorth America1Clinical - PIMS-TShttps://hosppeds.aappublications.org/content/hosppeds/early/2020/04/06/hpeds.2020-0123.full.pdf

This is a case study from the USA of a 6m old child who presented with fever and fussiness with no history of respiratory symptoms. They had unremarkable flu swab and urine MC&S, diagnosed viral illness. She subsequently developed an erythematous non-pruritic and blotchy rash.

On day 4 of fever she presented with the rash, still no significant respiratory symptoms. She was tachycardic, irritable, had limbic sparing conjunctivitis and dry cracked lips with no lymphadenopathy and no extremity skin changes. She had normal platelets with high CRP (133mg/L). Chest x-ray showed faint opacity in the left lung, and respiratory PC negative. No unwell contacts, no travel.

She was admitted with suspected Kawasakis, and due to fever and CXR was swabbed for SARS-CoV-2. Upon arrival to the paeds ward she met all Kawasakis criteria and was treated with IVIG and aspirin. Normal Echo. Just before discharge her SARS-CoV-2 test returned positive.This case is highly pertinent given current media headlines about a collection of cases in the UK of a Kawasaki like syndrome, some testing positive for COVID-19 and some negative. This case seems a bit different, as the child had “barn door” classic Kawasaki syndrome, and had an otherwise unremarkable course.

Further details regarding these cases from London (and possibly elsewhere) will be needed to determine a link between COVID-19 and a systemic inflammatory response syndrome. 3 things are particularly interesting.

Kawasakis disease has been theorised to be triggered by viral infections. One could imagine if this is the case, then COVID-19 could also trigger a similar syndromeIt is well documented that some adults experience a systemic inflammatory response to COVID-19 (including cytokine storm) and whilst children generally suffer a much milder course, it seems within reason that a subset of children may develop a similar illnessReports from a paper in 2005 suggested a link between human coronaviruses in Kawasakis disease. A case control study found significantly higher rates of coronavirus in children with Kawasakis (72.7%) than a matched control group without Kawasakis (4.2%) The meaning of all this is still unclear – it doesn’t change the management of Kawasakis disease or COVID-19, but presents interesting research questions which can be addressed in the coming months.

Miron, ODavidovitch, NArch Dis Child.COVID-19 infections following physical school reopening.7 Dec 2020USANorth AmericaEpidemiology - Disease Burdenhttps://adc.bmj.com/content/early/2020/12/06/archdischild-2020-321018

This letter, published in Archives of Disease in Childhood on 7th December 2020, describes an analysis of COVID-19 incidence in Florida, USA, at ages 6-13 years (elementary school) and 14-17 years (high school) relative to school reopening in August-September 2020 (most schools in the USA were closed in March-April 2020 because of the COVID-19 pandemic). The analysis compares counties in Florida with physical learning in schools (in-person teaching) to those with remote learning; there were 3 counties with remote learning: Broward, Miami-Dade and Palm Beach (which are grouped together in south-eastern Florida on the coast). There are 67 counties in Florida (numbers of schools and pupils in the 3 remote learning counties and 64 physical learning counties are not supplied).

Collection of data: The authors, who are based in Boston, USA, and Israel, used a Florida database to extract COVID-19 incidence by county for the two age bands (6-13 and 14-17 years), using a 7-day moving average; these incidence figures were matched with each county’s date of school reopening (day 0), looking at the period from 10 days before reopening to 20 days after reopening. Rates were aggregated for counties with physical learning and for those with remote learning in order to compare trends.

Florida counties teaching physically: For ages 6-13 years, COVID-19 incidence decreased slightly from day -10 to day 4 (-0.5% daily change), to an incidence of 11 daily cases/100,000 at day 4 (95% CI 9.9-12), followed by a slight increase from day 4 to 12.8/100,000 at day 20 (95% CI 11.7-13.9). For ages 14-17 years, incidence decreased more steeply from day -10 to day 1 (-3.2% daily change), to an incidence of 16.1/100,00 at day 1 (95% CI 14.4-17.9) followed by an increase from day 1 of 1.4% daily change to an incidence of 20.5/100,000 on day 20 (95% CI 18.5-22.5).

Florida counties teaching remotely: For ages 6-13 years, COVID-19 incidence decreased from day -10 to day 4 (-5.6% daily change) followed by no significant trend up or down to day 20. For ages 14-17 years, incidence decreased from day -10 to day 6 (-4.3% daily change) followed by no significant trend up or down to day 20. The slope for both age groups in counties teaching remotely was significantly different from the slope in counties teaching physically.

Conclusions and limitations: The authors conclude that physical reopening of schools was followed by increased COVID-19 incidence at school ages over the first 20 days, especially in high schools. The 3 counties with remote learning did not have increased incidence; the authors note that this may also relate to their lower COVID-19 rates before school reopening, their public mask mandate and gathering limit or their socio-economic differences. A limitation noted is that some parents opted not to send their children to physical learning. A possible confounder for increased infections with physical learning could be that it enabled parents to go to work, which might increase infections in children.

Lee, EReilly, KJAMA Netw OpenRace/Ethnicity Among Children With COVID-19-Associated Multisystem Inflammatory Syndrome.30 11 2020USANorth America223Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.30280

The authors seek to gather the data “to contextualise the racial/ethnic distribution of MIS-C cases” as a higher proportion are reported to be in Black and Hispanic children.

It is a short but number/statistics heavy article

Population based cohort study: the method of identifying cases is described

Cases of MIS-C reported in New York City between 1st March and 30th June 2020 with a Median age of 7y. 22.4% had an underlying condition mostly asthma or obesity. Only 8.5% reported COVID-19 like illness in previous 4 weeks. 78.5% had lab evidence of COVID-19 infection, current or past.

34.4% of children were Black compared with 22.2% NY population and 19.9% COVID-19 admissions and 29.8% Hispanic compared with 35.6% NY population and 40% COVID-19 admissions. Compared to White children, MIS-C had a higher incidence in Black (IRR 3.2, 95%CI 2.0-4.9) and Hispanic (IRR 1.7, 95%CI1.1-2.7). No significant difference in IRR rates between White, Asian or Pacific Islander. Black and Hispanic children also had a higher COVID-19 admission rate compared to White children

Conclusions

There is a higher burden of MIS-C amongst Black and Hispanic children but it is unclear whether this is distinct phenomenon or because of the increased COVID-19 rates in Black and Hispanic communities. Ethnicity data is missing for 36 (16.5%) of these MIS-C cases and the authors report that it is mostly missing for confirmed, non-hospitalised and non-fatal COVID-19 cases in NYC which limits the possible analyses.

Bailey, LCForrest CBJAMA PedsAssessment of 135 794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States23 Nov 2020.USANorth America135794Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/10.1001/jamapediatrics.2020.5052

This study used the PEDSNet system to gather data on SARS-CoV-2 PCR testing on a large population of children and young people (CYP) throughout the US. PEDSNet includes 7 major children’s hospitals, and covers about 3% of the US child population. Data from 135 800 people under 25 years old who were tested between 1st January and 8th September were reported. There was no mass population testing, so the results reflect availability and access to tests, and local testing policies, as much as genuine disease prevalence. Paediatric care in the US can continue until young people are in their twenties.

They made some interesting observations: 290 per 10 000 population were tested, although this varied between centres (range 155-395). Overall 4% of those tested were positive, a much lower rate than that found in adults. Of the 5370 test-positive patients, 7% were hospitalised for Covid-related symptoms, and of these 28% required intensive care. Eight died (0.2% of test-positives).

CYP of non-white ethnicity were both less likely to be tested (odds ratios 0.6-0.7), and more likely to test positive: black CYP were nearly 3 times more likely to test positive (OR 2.66) and Hispanics nearly 4 times (OR 3.75). Older age increased likelihoods of testing positive (OR for 5-11 year-olds 1.25; for 18-24 year-olds 3.51). In the States, patients can be categorised according to whether their healthcare is commercially funded or publicly funded, as a proxy for deprivation: perhaps unsurprisingly, children relying on public funding were more likely to test positive (OR 1.43).

They also looked at pre-existing conditions, grouped together by systems: amongst others, malignant, haematological, cardiac, gastrointestinal, endocrine (types 1 and 2 diabetes) and mental health disorders all increased the risk of testing positive; curiously, however, the risk was reduced in respiratory disorders including asthma.

As a side issue, they tried to look at incidence of multisystem inflammatory syndrome in children, MIS-C (also known as paediatric inflammatory multisystem syndrome), thought to be associated with Covid-19. There was no diagnostic code for this new condition from which they could identify cases, so they looked for cases of Kawasaki Disease (KD), which it closely resembles, over the same time period: they found a 40% fall in incidence compared to the same period in 2018 and 2019. This might represent a genuine fall in incidence, but anyway it seems unlikely that clinicians are classifying MIS-C as KD.

This tells us little about true population prevalence of the virus, as many children with mild or no symptoms would never have been tested. But it does repeat the findings seen elsewhere: although they are less vulnerable generally, the stark social and ethnic differences seen in adults apply to children as well.

Roarty, CWaterfield, TLancet Infect DisKinetics and seroprevalence of SARS-CoV-2 antibodies in children 19 Nov 2020United KingdomEurope849Epidemiology - Disease Burdenhttps://doi.org/10.1016/S1473-3099(20)30884-7
Oved, KLustig, Yj.eclinmMulti-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation19 Nov 2020IsrealMiddle East688Epidemiology - Disease Burdenhttps://doi.org/10.1016/j.eclinm.2020.100651

Background; An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. They validated the performance of six commercially available automated IgG/total antibody serology products for SARS-CoV-2 and one ELISA format: Roche Cobas Total Ig (Roche), Abbott SARS-CoV-2 IgG (Abbott), BioMerieux VIDAS IgG (VIDAS IgG), Beckman Coulter Access IgG (Beckman), Siemens ADVIA IgG (Siemens), Diasorin Liaison IgG (Diasorin) and the RBD ELISA assay of Mt. Sinai (ELISA). Previous studies have been limited in the number of assays compared and the power and heterogeneity of the samples used, including small cohorts, lack of psadiatric samples, gender biases, and disease severity biases.

Methods; The diagnostic laboratories of all four Health Maintenance Organizations (HMOs) in Israel – Clalit, Maccabi, Leumit and Meuhedet and the Central Virology Laboratory of the Ministry of Health, participated in the study which was designed and executed during March-July 2020. Each lab obtained and tested serum samples from different cohorts of non-SARS-CoV-2 and SARS-CoV-2 patients collected from all regions in Israel. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed.

Results; Immunoassays’ sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (<15%) prevalence scenarios.

Specificity in children; Protective immunity in children might partially be due to cross-reactive immunity to past Coronavirus strains, the study specifically investigated the specificity in children and adolescents under 20 years (688 samples which compose 28.7% of our SARS-CoV-2 negative cohort). Results show that specificity in children and adolescents were similar to those overall: Abbott 99.7% (642/644: CI 98.9–99.9), Diasorin 98.0% (633/646: CI 96.6–98.8), Vidas VIDAS IgG 97.4% (330/339: CI 95.0–98.6), Roche 100% (367/367: CI 99.0–100.0), ELISA 98.6% (351/356: CI 96.8–99.4), Beckman 100% (12/12: CI 73.5–100.0) and Siemens 100% (20/20: CI 83.2–100.0).

No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies.

All patients were described as seronegative non-responders if they were tested with 4 or more independent assays and remained negative across all tests. The study found the proportion of this subpopulation to be 4.7% of the symptomatic PCR positive patients with blood collection 14 or more days after the positive PCR result. In patients who were negative in 3 or more different assays, the proportion increased to 6.5%.

The seronegative subpopulation was compared with seropositive patients to search for potential unique characteristics, but found no clear differences in age, hospitalization, disease severity, time from positive PCR and gender, although numbers are too small to rule out such differences. This measurement represents the first population-wide estimate using multiple commercially available tests and different antigens to quantify the proportion of seronegative non-responding patients at risk for re-infection.

Conclusions; The commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The study finds no decrease in antibody titers in the first 8 weeks in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The ~5% who were seronegative non-responders, using multiple assays in a population-wide manner, represents the proportion of patients that may be at risk for re-infection.

Therefore their impact on herd immunity or the healthcare system is expected to be limited; yet, these individuals are at increased risk for re-infection. The assay of choice for epidemiological assessments and diagnosis should be determined separately in each country and be based on the prevalence of SARS-CoV-2.

Seronegative non-responders are also expected at a certain proportion after immunization and the proportion of vaccine non-responders was traditionally higher than the natural disease itself. The study estimates that the proportion of vaccination failure in the Israeli population may be higher than 5% regardless of the vaccine identity.

Somekh, ISomekh, EClin Infect DisReopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.18 Jan 2021IsraelAsiaEpidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab035/6103916

This study, published on 18th January 2021, investigates the effects on the dynamics of SARS-CoV-2 infections in Israel of the reopening of schools and the easing of social distancing restrictions between March and July 2020.

Background: Israel’s schools were closed from 14 March 2020 as part of efforts to control the spread of COVID-19 (which included a complete lockdown from 25 March to 19 April). The peak of infections was at the end of March 2020 and schools were partially reopened on 3 May (for children in grades 1-3 and 11-12, with separate groups attending at different times on different days) and then completely reopened on 17 May for all day in-person learning (with social distancing and masks for children over 7 years of age, but no cohorting). When schools reopened, there was low incidence of SARS-CoV-2 infections in all age groups. On 20 May there was a partial easing of social distancing in the community, with the opening of synagogues and beaches to the public, followed by further easing on 12 June, when gatherings of up to 250 people at social events were permitted. The end of the academic year was 19 June for high school students (grades 7-12) and 30 June for elementary school students (grades 1-6).

Collection of data: Using data sources including the Israeli Center for Diseases Control, Ministry of Health and Israel Central Bureau of Statistics, the authors examined the nationwide weekly incidence, prevalence, numbers of SARS-Co-2 PCR tests, their positivity, COVID-19 hospitalisations and deaths, for 5 age groups: 0-9 years, 10-19 years, 20-39 years, 40-59 years and 60+ years. Incidence rates were adjusted for number of PCR tests: for each age group, incidence rate (weekly number of new cases/100,000 population in this age group) was multiplied by the proportion of this age group in the general population to the proportion of samples obtained from individuals in this age group. Patients classified as moderately and severely ill were included in hospitalisations data, to avoid bias from changing definitions of severity over the course of the pandemic and to exclude mildly ill patients who might have been hospitalised for quarantine, rather than medical reasons. Weekly data were used to avoid incidental daily fluctuations.

Temporal trends: The effects over time on the parameters examined of schools reopening in May, the easing of social restrictions such as permitted large scale gatherings from 12 June and then schools closing for the end of term in late June were investigated. Data on COVID-19 incidence, prevalence and PCR test positivity rates from the week prior to the implementation of the measure being analysed were compared to data at 14-20 days and 21-27 days after the implemented measure. For hospitalisations and mortality, the data at 14-27 days and 21-34 days respectively were analysed and compared with that prior to the implemented measure. The lag period of 21-34 days between possible exposure and mortality was based on an average of 17 days between symptoms and death, plus an additional 4-6 days for a child who was infected in school to infect an adult, extended to 34 days to allow for several rounds of infection.

Incidence, adjusted incidence and prevalence after school reopening: Incidence rates, adjusted incidence rates (adjusted for the number of PCR tests in each age group) and prevalence of SARS-CoV-2 infection gradually increased following complete school opening in both paediatric/adolescent age groups and the three adult age groups.

Increase in PCR testing following school reopening: During this period, the number of PCR tests performed also increased for all age groups, but particularly for the 0-9 and 10-19 years age groups. Weekly SARS-CoV-2 samples tested: 0-9 yrs 2133 17-23 May vs 15081 7-13 June (7.1-fold increase); 10-19 yrs 2073 17-23 May vs 16952 7-13 June (8.2-fold increase); 20-59 yrs 17917 17-23 May vs 45564 7-13 June (2.5-fold increase); 60+ yrs 10090 17-23 May vs 15889 7-13 June (1.6-fold increase).

Positivity rates of PCR tests following school reopening: Following complete school opening on 17 May, positivity rates increased gradually for the adult age groups, but not for paediatric/adolescent age groups, when comparing rates the week prior to schools reopening (10-16 May) with 14-20 days after (31 May – 6 June) and 21-27 days after (7-13 June). 0-9 yrs: 14/1950 (0.7%) samples positive 1-7 days prior to complete school reopening followed by 78/9853 (0.8%) positive 14-20 days after reopening and 158/15081 (1.0%) positive 21-27 days after reopening; RR (relative ratio) of 1.1 [95% CI 0.63-1.94] and 1.46 [0.85-2.51] respectively (compared to prior to reopening). 10-19 yrs: 33/2092 (1.6%) positive 1-7 days prior to reopening followed by 168/16431 (1.0%) 14-20 days after and 250/16952 (1.5%) 21-27 days after; RR of 0.65 [0.45-0.94] and 0.93 [0.65-1.34]. 20-39 yrs: 49/11169 (0.4%) positive 1-7 days prior to reopening followed by 229/19884 (1.2%) 14-20 days after and 396/26779 (1.5%) 21-27 days after; RR of 2.62 [1.93-3.57] and 3.37 [2.51-4.53]. 40-59 yrs: 32/9311 (0.3%) positive 1-7 days prior to reopening followed by 167/15626 (1.1%) 14-20 days after and 276/17568 (1.6%) 21-27 days after; RR of 3.1 [2.13-4.5] and 4.72 [3.26-6.83]. 60+ yrs: 35/13762 (0.3%) positive 1-7 days prior to reopening, followed by 64/14739 (0.4%) 14-20 days after and 111/15889 (0.7%) 21-27 days after; RR of 1.7 [1.13-2.58] and 2.75 [1.88-4.01].

Single cluster of COVID-19 in a high school in Jerusalem: There was a single peak of a high rate of SARS-CoV-2 infections in 10-19 year olds at the end of May 2020, related to a high school in Jerusalem (see Stein-Kamir et al, A large COVID-19 outbreak in a high school 10 days after schools’ reopening, Israel, May 2020, Eurosurveillance, published 23 June 2020), which resulted in a 6% sample positivity during 24-30 May in that age group. This outbreak has been postulated to be linked to the temporary lifting of restrictions requiring face masks in school due to a heat wave from 19 to 22 May. During the following 2 weeks, the positivity rate in 10-19 year olds reduced to 1.0% (31 May – 6 June) and 1.5% (7-13 June).

Adjusted incidence rate ratios (aIRRs) following school reopening: aIRRs were calculated by comparing incidence (adjusted for the number of PCR tests performed) 14-20 and 21-27 days after complete school reopening to adjusted incidence during the week prior to reopening. The adjusted incidence rate increased in all age groups, but mostly in adults. The largest increase 14-20 days after reopening was in 40-59 yrs (aIRR 6.22 [3.6-10.7]), followed by 20-39 yrs (aIRR 5.25 [3.5-7.8]). The smallest increase was in 0-9 yrs (aIRR 2.2 [1.6-3.1])and 10-19 yrs (aIRR 1.3 [0.9-1.8]), with 60+ yrs having an aIRR of 3.42 [1.8-6.7] 14-20 days after reopening. Higher aIRRs in adults compared to children were also seen 21-27 days after school reopening: 0-9 yrs aIRR 3.51 [2.5-4.9], 10-19 yrs aIRR 2.25 [1.7-3.0], 20-39 yrs aIRR 8.13 [5.5-12.0], 40-59 yrs 11.1 [6.5-18.7], 60+ yrs 6.73 [3.5-12.4].

Trends after schools closed in June at end of academic year: Incidence, prevalence, number of samples tested and their positivity all increased for all age groups at the end of term (this also coincided with the relaxation of social restrictions in the community). The highest increases in these parameters following the end of term were in 10-19 yr olds.

Positivity rates of PCR tests following easing of social restrictions: Following partial easing of social restrictions on 20 May, rates of test positivity were initially similar to those of school reopening, but after restrictions on large scale gatherings were lifted on 12 June, increased positivity rates were seen in all age groups. 0-9 yrs: 0.8% samples positive 1-7 days prior to permitted large events (5-11 June), followed by 2.3% 14-20 days after (26 June – 2 July) and 3.1% 21-27 days after (3-9 July); RR 2.77 and 3.64 respectively. 10-19 years: 1.1% 1-7 days prior, 5.5% 14-20 and 6.7% 21-27 days after; RR 5.13 and 6.25. 20-39 yrs: 1.2% 1-7 days prior, 5.2% 14-20 and 6.1% 21-27 days after; RR 4.31 and 5.07. 40-59 yrs: 1.3% 1-7 days prior, 4.4% 14-20 and 5.0% 21-27 days after; RR 3.34 and 3.84. 60+ yrs: 0.7% 1-7 days prior, 2.7% 14-20 days and 3.3% 21-27 days after; RR 3.99 and 4.86.

aIRRs following permitted large scale social gatherings: Adjusted incidence rates increased after large events of up to 250 people were permitted on 12 June in all age groups. 0-9 yrs: aIRR 3.11 14-20 days and 5.6 21-27 days after, compared to 1-7 days prior to lifting of restrictions on large scale gatherings. 10-19 yrs: aIRR 5.77 14-20 days and 9.6 21-27 days after. 20-39 yrs: aIRR 4.85 14-20 days and 7.8 21-27 days after. 40-59 yrs: aIRR 3.8 14-20 days and 5.99 21-27 days after. 60+ yrs: aIRR 4.5 14-20 days and 7.52 21-27 days after.

Hospitalisations and mortality following schools reopening: Weekly hospitalisations and deaths of COVID-19 patients did not increase following partial and complete school reopening. This lack of increased mortality was seen even up to 49 days after school reopening. However, the weekly deaths due to COVID-19 significantly increased following the end of the academic year. Risk ratios were 15.2 [5.5-41.9] 28-34 days after high school term ended and 17.2 [6.3-47.3] 28-34 days after elementary school term ended.

Hospitalisations and mortality following easing of social restrictions: No significant increases in SARS-CoV-2-related hospitalisations and deaths were seen following partial easing of social restrictions on 20 May. However, a significant increase in hospitalisations (risk ratio: 3.95 [3.2-4.8]) and deaths (risk ratio: 4 [1.9-8.3]) occurred at 21-27 days and 28-34 days, respectively, following permission to attend large scale events on 12 June. There were no deaths amongst SARS-CoV-2 infected children during the study period.

Conclusions: This national data from Israel suggests that the reopening of schools in May 2020 had a limited effect on the SARS-CoV-2 infection rate in children and adults and that it was not a major contributor to SARS-CoV-2-related mortality. It also suggests that the easing of restrictions on large scale gatherings may have been related to a resurgence of cases and associated increased mortality. The analysis adjusted for the number of PCR tests performed at different time periods in different age groups; this is important given the high proportion of asymptomatic and mildly symptomatic cases of SARS-CoV-2.

Somekh, ISomekh, EClin Infect DisReopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.18 Jan 2021IsraelAsiaEpidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab035/6103916
de Gier, BHahne, SEuro Surveill Occupation- and age-associated risk of SARS-CoV-2 test positivity, the Netherlands, June to October 202017 Dec 2020NetherlandsEurope000000000000000Epidemiology - Disease Burdenhttps://doi.org/10.2807/1560-7917.ES.2020.25.50.2001884

This is a comprehensive survey of all PCR tests for SARS-CoV-2 in all ages in the Netherlands, covering 5 months of the pandemic. Data gathering there is centralised, and unlike some other national surveys, they recorded information on occupations.

The situation in the Netherlands was very similar to the UK, both in terms of Covid-19 prevalence and preventative measures taken by government. Much of this survey concerns occupational groups in adults and is of limited interest to paediatricians. Also there are many missing data and possible biases. However some findings are worth noting.

As elsewhere, they found that the proportion of children tested who proved positive was much lower than that seen in adults. This changed later in the year, but only because national policy changed to deliberately not testing children under 13 years with only mild symptoms, to conserve testing resources for adults. Educators did not appear to be at especially high risk.

They observed that positivity rates were lower in healthcare workers and school staff, compared to other occupations involving close personal contact (e.g. hairdressers). They explain this by suggesting that they were better at using PPE, or that they were more likely to ask for a test even when they had symptoms not due to Covid-19; although not stated, it is also possible that they had enhanced immunity due to prior exposure to other corona viruses. This study could not address this question.

Vos E R Avan der Klis F R MJ Epidemiol Community HealthNationwide seroprevalence of SARS-CoV-2 and identification of risk factors in the general population of the Netherlands during the first epidemic wave10 Nov 2020NetherlandsEurope586Epidemiology - Disease Burdenhttps://jech.bmj.com/content/early/2020/11/28/jech-2020-215678

The authors motivated by lack of scope of Covid-2 prevalence in populations aimed to detect SARS-CoV-2 serum antibodies in the general population of the Netherlands and also identify risk factors for seropositivity amidst the first COVID-19 epidemic wave. The Netherlands first case had been confirmed on 27 February 2020 and interventions to suppress the virus were implemented on March 16 commenced to relax on 1st June 2020.

The authors employed a previously (2016-2017) created two stage cluster-designed nationwide sero-survey population sample (Pienter-3 created to gain insights into protection from vaccine preventable diseases by vaccination offered by the Netherlands National Immunisation Programme) and an adjuncted enhanced random sample among the Orthodox-Reformed Protestant populations described to live a socio-demographically clustered life-style to launch the Pienter-Corona or PICO study.

Subjects (n=6,100 of 7,600 Pienter-3 population sample) aged 2-90 years completed an online questionnaire in which they provided information including sociodemographic characteristics, COVID-19-related symptoms, comorbidities, medication use and behavioural factors and who in addition self-collected 0.3ml microtainer samples.

Half the subjects (n=3207, 53% of the 6100 invited from the 7,600 Pienter-3 candidate baseline) responded, 2,637 from the national survey (NS) and 570 from the low vaccination coverage (LVC) municipalities including the Orthodox -Reformed Protestants sociodemographic community. Using microtainers subjects aged 2 years to 90years self-collected 0.3ml size blood samples and sent them to the laboratory where sera was assayed for SARSCoV-2 spike S1-specific IgG antibodies on 3,100 subjects (less than 5% of subjects lost to follow through) and the titre cut-off concentration for seropositivity was set at 2.37 AU/mL applied.

Analyses were conducted in SAS v.9.4 (SAS Institute Inc., USA) and R v.3.6. The authors accepted P values of <0.05 to be statistically significant. Sociodemographic characteristics and COVID-19-related symptoms (general, respiratory, and gastrointestinal) that had developed since onset of the epidemic were stratified by sample (NS vs LVC), or sex, respectively, and described for seropositive and seronegative participants. Differences were tested via Pearson’s χ², or Fisher’s exact test. Differences in geometric mean concentration between reported symptoms in seropositive subjects were determined and tested by the Mann-Whitney U-test.

Adult (18-90 years) SARS-CoV-2 seropositivity was 2.8%. Seropositivity among the 586 (18.9%) children aged 2-17 years was 1.7%, ranging from <1% at 2y to 3% at 17y.This was considered low compared to seropositivity rate of 5.3% among 226 young adults aged 18-24 years and compared to the whole adult study cohort. Half (56%) the parents of participants were reported to have had daily contact with patients, clients and/or children in their normal profession or volunteer work. The children were not further separately stratified.

This study showed a low SARS-CoV-2 seropositivity in children aged 2-17 years despite the exposure of their parents in work including in the caring professions. However, this study has mostly described common risk factors for infection and so sero-positivity as it pertains to adults even in the low vaccination coverage communities notable the Orthodox Reformed Protestant communities. In addition the extent to which infection may occur but fail to stimulate and manifest antibody response in an individual including in children remains an unknown, and so one can ask if that factor could pull back Covid-2 infection prevalence estimates? That antibody production might be suppressed in an individual adult or child on immunosuppressant would be on the radar of most clinicians but immunosuppression although met with often is an exception not the norm.

It is likely the particularly high rates of seropositivity among young adults are due to contact patterns during this period. Lower rates in children may be a reflection of both reduced susceptibility and reduced contacts due to school closure. More seropositivity prevalence studies would be warranted in the child population while deployment of vaccine against Covid-2 is still to come.

Wang, MChen, WJ. Paediatr. Child HealthEpidemiological characteristics and transmission dynamics of paediatric cases with coronavirus disease 2019 in Hubei province, China08 12 2020ChinaAsia1386Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1111/jpc.15287

In this study, the epidemiological characteristics of children and adults with suspected and confirmed SARS-CoV-2 infection in Hubei province, China are compared. Cases from 8th December 2019 and 7th March 2020 were identified from the National Infectious Diseases Surveillance System. Due to limitation in PCR testing availability early in the pandemic, "clinically diagnosed" cases with consistent symptoms, imaging and an epidemiological link were included.

A total of 1369 paediatric cases were identified, including 384 clinically diagnosed cases and 985 laboratory confirmed cases. Median age was 9yo (IQR 3-14yo). Most cases were mild (50.1%) or moderate (30.9%). Compared with adults (total 68,541 cases), children were more likely to be asymptomatic (15.4% vs 2.9%) and less likely to have severe or critical illness (3.6% vs 18.6%).

The paediatric epidemiological curve peaked 19 days later than that of adults (11th February vs 23rd January). The reduction in transmission occurred concurrent with the isolation of Wuhan City from neighbouring regions (23rd January) and prior to the implementation of a province-wide stay-at-home order(16th February). Compared with adults, children were more likely to have a contact history with a confimred case (44.5% vs 22.4%) or a link with a known cluster (22.0% vs 12.5%).

This study has several limitations including the inclusion of non-laboratory confirmed cases, the likely incomplete case ascertainment given early testing limitations and missing data on some variables in a significant proportion of cases. Notwithstanding this, the milder clinical course and higher proportion of asymptomatic cases in children is consistent with data elsewhere, although the absolute proportion of asymptomatic cases here is likely an underestimate. The demonstrated lag in the paediatric epidemiological curve may not be immediately generalisable to other settings given the unique circumstances in Hubei with potential occupational exposure in adults at the very start of the pandemic together with the timing coinciding with the school holiday period. The findings here do highlight the importance of household exposure in paediatric SARS-CoV-2 infections, consistent with data from contact tracing studies elsewhere.

Maltezou, HTsolia, MPediatr Infect Dis JChildren and Adolescents With SARS-CoV-2 Infection: Epidemiology, Clinical Course and Viral Loads01 DEC 2020GreeceEurope203Epidemiology - Disease Burdenhttps://doi.org/10.1097/inf.0000000000002899

This is a retrospective study of data from a national registry of SARS-CoV-2 cases which analysed within-family transmission and examined the viral loads of affected children in Greece between February 26th and June 30th 2020.

Analysis; 203 SARS-CoV-2-infected children were identified (median age 11y, range 6 days - 18.4y). 111 (54.7%) had an asymptomatic infection. Of the 92 children with symptomatic disease 24 (26.1%) were hospitalised. One child with an underlying neuromuscular disorder had a severe illness. All the other children made full recoveries and there were no deaths.

Virologic investigation was by RT-PCR of respiratory samples. Viral loads were categorised using PCR amplification cycle threshold (Ct) values as high, moderate, low or negative (Ct <25, 25–30, >30, or >38 respectively).

Transmission from a household member accounted for 132 (74.2%) of the 178 paediatric cases with SARS-CoV-2 infection. The median attack rate was 40% (range 11.1%–100%) per family. An adult was the first case of infection in the families of 125 (66.8%) children with SARS-CoV-2 infection. 62 children (33.2%) were identified as the first case of infection in their families. Child-to-child infection occurred in only one case. In only one family was there evidence of transmission from a paediatric case (a 16-year-old) to an adult.

Of 164 children for whom Ct values were available, 46 (28.1%) had a high, 44 (26.8%) a moderate and 74 (45.1%) a low viral load. Viral load did not differ significantly between children of different ages, sex, underlying condition, fever and hospitalisation.

The authors concluded that adults played the key role in the introduction and spread of SARS-CoV-2 infection in families.

Szépfalusi, ZFrischer, TPediatr Allergy ImmunolLessons from low seroprevalence of SARS-CoV-2 antibodies in schoolchildren: a cross-sectional study 29 JAN 2021AustriaEurope2069Epidemiology - Disease Burdenhttps://doi.org/10.1111/pai.13459

This was a cross-sectional study of the prevalence of SARS-CoV-2 antibodies and virus RNA in children and young people (CYP), combined with contact tracing and symptom reporting from Austria between 18 May to 2 July 2020.

Analysis

The study enrolled 2069 children and young people (52.4% female) between the ages of 5 and 21 years (median 13, IQR 10-15) in Vienna. Oropharyngeal and nasopharyngeal samples were analysed for SARS-CoV-2 by real-time PCR. SARS-CoV-2-specific antibodies were identified in blood by ELISA testing. Questionnaires about gender, age, symptoms of SARS-CoV-2 infection and contact with infected individuals were administered on the day of screening.

SARS-CoV-2 RNA was detected in 2 CYP by RT-PCR (1 pair of siblings, 0.1%). 26 CYP (1.3%) tested positive for specific antibodies. Seroprevalence was higher in children older than 10 years and peaked at the age of 13. Seropositivity was associated with a history of mild clinical symptoms in 14 CYP (53.8%), while the remainder had no symptoms.

Contact tracing of seropositive individuals revealed 16 CYP had been in contact with confirmed COVID-19 cases: 7 from within their families and 9 from outside the family – all of these were intergenerational contacts.

A significantly larger probability of seropositivity (n=11, 42%, p<0.001) was found in CYP whose family members had been in contact with a suspected COVID-19-case. 6.3% of CYP who had been in contact with a suspected SARS-CoV-2 case showed a seropositive result as compared to 0.8% of children with no such contact.

The authors conclude that the rate of infection with SARS-CoV-2 was low in schoolchildren and was associated with mild or no symptoms. Spread of virus was far more likely to occur between intergenerational contacts than among siblings in the same household.

Kociolek, LPollock, NJ Clin MicrobiologyComparison of upper respiratory viral load distributions in asymptomatic and symptomatic children diagnosed with SARS-CoV-2 infection in pediatric hospital testing programs.22 Oct 2020USA, CanadaNorth America817Epidemiology - Disease Burdenhttps://jcm.asm.org/content/early/2020/10/22/JCM.02593-20

This study, published online on 22nd October 2020, analyses SARS-CoV-2 viral load data in asymptomatic and symptomatic infected children (aged 0-17 years) tested by 9 children’s hospitals in the USA and Canada from March to July 2020. The article contributes to what is known about upper respiratory viral burden and risk factors in SARS-CoV-2 infected children and to the search for clarification of the role of infected children with and without COVID-19 symptoms in the transmission of SARS-CoV-2.

Study population: Medical charts at 8 children’s hospitals across the USA (in Boston, Los Angeles, Wisconsin, Chicago, Washington, Colorado, Texas and Atlanta) and Canada (Toronto) were retrospectively reviewed for patients testing positive for SARS-CoV-2 by nasopharyngeal or oropharyngeal sampling, blinded to PCR cycle threshold (Ct) values (which are inversely related to viral loads). Clinical data collected for each patient at the time of testing included age, sex, race, ethnicity, presence or absence of immunocompromise and diabetes. Only the first positive test for each patient was included.

The primary reasons for testing asymptomatic (ASx) patients (n=339) were coded in 3 categories: surveillance (contact tracing or broad community surveillance), pre-operative/aerosol generating procedure or hospital admission screening. These patients had no symptoms nor clinical suspicion of COVID-19 at the time of testing (other than potential contact status). Data were collected on known contacts and their timing ( 2 wks/> 2 wks prior to testing or unknown) and whether any symptoms of COVID-19 developed within 5 days after the positive test.

Symptomatic (Sx) patients (n=478) were required to have 2 or more symptoms consistent with COVID-19 (cough, fever/chills, shortness of breath, sore throat, abdominal pain, diarrhoea, fatigue, myalgia, new loss of sense of taste or smell, headache, congestion/rhinorrhoea, nausea/vomiting, rash, conjunctivitis) at the time of testing and were tested due to clinical suspicion of COVID-19.

Within each institution, each asymptomatic patient was matched with up to 2 symptomatic patients by age bracket (0-4 yrs, 5-9 yrs, 10-13 yrs, 14-17 yrs) and date of testing (as close as possible, minimum within 30 days). They were required to have been tested with the same sample type (either nasopharyngeal or oropharyngeal).

The testing assay used (12 different assays were used across the 9 institutions) and Ct values obtained (averaged for assays with more than one target) were recorded for each positive test. Ct values are assay-dependent: to standardise Ct data across the multiple assays used in the different institutions adjusted Ct values were calculated using a centering technique, whereby each institution calculated the median/IQR for Ct values for all positive symptomatic patients (or a representative subset) tested with each assay over the study period, to obtain an institutional symptomatic median; the difference between individual Ct values and this calculated institutional median are reported as adjusted Ct values, which are aggregated in this study. Each institution also reported a viral load (VL) estimate (copies/mL sample) for each Ct value, based on data from internal validation studies, the manufacturer or package inserts.

Demographics of study population: ASx: male 178/339 (52.5%), female 161/339 (47.5%); Sx: male 248/478 (51.9%), female 230/478 (48.1%). Age of ASx patients: 0-4 yrs 118/339 (34.8%), 5-9 yrs 79/339 (23.3%), 10-13 yrs 69/339 (20.4%), 14-17 yrs 73/339 (21.5%); age of Sx patients: 0-4 yrs 197/478 (41.2%), 5-9 yrs 97/478 (20.3%), 10-13 yrs 75/478 (15.7%), 14-17 yrs 109/478 (22.8%).

Co-morbidities recorded in study population: ASx with immunocompromise 35/339 (10.3%); Sx with immunocompromise 16/478 (3.3%). ASx with diabetes 9/339 (2.7%); Sx with diabetes 10/478 (2.1%).

Adjusted Ct values/estimated VLs in ASx and Sx patients: ASx median adjusted Ct value 8.6 (IQR 2.5 to 12.2) versus Sx median adjusted Ct value -1.7 (IQR -6.0 to 4.8) (p<0.0001), i.e. 10.3 cycles higher in ASx children. ASx median estimated VL 2.0 x 103 copies/mL (IQR 162 to 1.7 x 105) versus Sx median estimated VL 1.3 x 107 copies/mL (IQR 5.6 x 104 to 3.8 x 108) (p<0.0001), i.e. viral load 3-4 logs lower in ASx children.

Adjusted Ct values/estimated VLs in ASx and Sx patients by age, sex, ethnicity and race: For each of the four age brackets, differences of similar magnitude with p<0.0001 were observed for both adjusted Ct and estimated VL; these differences narrowed with increasing age (ages 0-4 yrs 11.95 cycle difference; 5-9 yrs 10.32; 10-13 yrs 9.78; 14-17 yrs 8.49), correlating with progressively decreasing median estimated VL in the symptomatic group within each age bracket (ages 0-4 yrs ASx 1.28 x 103 vs Sx 5.33 x 107; 5-9 yrs ASx 1.74 x 103 vs Sx 1.36 x 107; ages 10-13 yrs ASx 4.26 x 103 vs Sx 5.58 x 106; 14-17 yrs ASx 2.43 x 103 vs Sx 2.52 x 106 copies/mL). These differences were consistent across all institutions and were not affected by sex, ethnicity or race.

Adjusted Ct values/estimated VLs in ASx patients by co-morbidities, reason for testing, timing of contacts, subsequent development of symptoms: Odds ratios were calculated to assess the estimated risk of having a Ct value in the lowest quartile (or viral load in the highest quartile) within the asymptomatic Ct value distribution. There was a higher estimated risk of having a Ct value in the lowest quartile for ASx children with diabetes (OR 6.5, p=0.01), recent contact with a COVID-19 case (OR 2.3, p=0.02) and testing for surveillance (OR 2.7, p=0.05) than for ASx children without these risk factors, while immunocompromise, sex, race and ethnicity had no effect. Similar results were obtained for these risk factors in ASx children using estimated VLs. Pre-symptomatic children (those who developed symptoms within 5 days after testing) trended towards higher median VLs (7.7 x 104 copies/mL) versus non-pre-symptomatic children (1.4 x 104), although this difference was not statistically significant.

Conclusions: In this study combining SARS-CoV-2 PCR test results from 9 North American paediatric institutions from March to July 2020, infected children across all ages from 0 to 17 years without symptoms had higher Ct values and lower estimated viral loads than children with symptoms matched by age bracket and test date range. Differences in viral burden were consistent across all 9 collaborating institutions, despite the fact that they used different SARS-CoV-2 test assays and were at different stages of the pandemic over the study period. There was overlap between viral load distributions in asymptomatic and symptomatic children in all age brackets, but asymptomatic children with diabetes, recent contact with a COVID-19 case and those tested for surveillance purposes (rather than pre-procedure or pre-admission) had a higher estimated risk of being in the highest viral load quartile. The authors note that in the pre-procedure and pre-admission screening groups, almost all viral loads were probably below the limits of detection of available rapid antigen tests. The question of interest is that of the potential for disease transmission by asymptomatic individuals; correlation of viral load with ability to recover virus in culture, often used as a surrogate for infectivity, is challenging, and inability to recover replicating virus in culture does not necessarily preclude transmissibility. Additional research is needed to determine the extent to which individuals of any age are able to transmit infection at low viral loads.

Limitations identified by authors: The symptomatic population in this study may have been slightly biased towards more severe disease by requiring that each patient have a minimum of 2 symptoms (this was to maximise the chances that symptoms were truly caused by SARS-CoV-2). The asymptomatic population in this study may not be representative of recently infected asymptomatic children; the asymptomatic children analysed here may be biased towards lower viral loads due to a higher frequency of infections remote in time picked up on screening testing. The pre-symptomatic children in this study had a slightly higher median viral load than those who did not develop symptoms, but their viral loads were still relatively low. Data about contacts or subsequent symptoms were not available for many asymptomatic children in the study. Further investigation to define the peak viral load in asymptomatic and pre-symptomatic children is needed. However, even in the asymptomatic surveillance sub-cohort with highest viral loads, median viral loads were still significantly lower than in the symptomatic cohort.

Buonsenso, DValentini, PmedRxivSARS-CoV-2 infections in Italian schools: preliminary findings after one month of school opening during the second wave of the pandemic11 Oct 2020ItalyEurope1059Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.10.10.20210328v1

This article is a pre-print and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

This study about SARS-CoV-2 cases in Italian schools from the opening of schools in September to 5th October 2020 was posted on medRxiv on 11th October 2020.

Methodology: The authors (who are based in Rome) used an open access, online dataset developed on 14th September 2020 by two PhD students. They monitor media news about SARS-CoV-2 infections in Italian schools on a daily basis, using internet searches, institutional websites and other news reports. For each relevant news report, the spreadsheet records date, region, province, city, school name, type of school, number of SARS-CoV-2 positive cases within the school, numbers of students/teachers/others, type of quarantine activated after notification of a positive case, whether the school was closed, number of secondary positive cases and reference to the news reports. The article includes a map of Italy showing the location of cases reported. The dataset is ongoing (the first entry is for 3rd September 2020, with data analysed for this article to 5th October 2020). Most Italian schools opened on 14th September 2020. The article states that more than 8 million students attend school in Italy (7,599,259 for national schools and 866,805 for peer schools (undefined) for 2019-20).

Results: As of 5th October 2020, the dataset records 1350 SARS-CoV-2 cases in Italian schools, comprising 1059/1350 (78.4%) students, 145/1350 (10.7%) teachers and 146/1350 (10.8%) other school members. The 146 other school members are divided in the tables supplied into 52/146 “others” and 94/146 “missing”. The cases involved 1212 Italian schools (1.9% out of a total 65,104 schools).

Cases by type of school: Nurseries/kindergardens 236/1350 (17.5%), elementary (primary) schools 300/1350 (22.2%), middle (lower secondary) schools 208/1350 (15.4%), high (upper secondary) schools 452/1350 (33.5%), peer schools 55/1350 (4.1%), school type unavailable 99/1350 (7.3%).

Students as proportion of cases in each type of school: Nurseries/kindergardens 171/236 (72.5%), elementary schools 230/300 (76.7%), middle schools 177/208 (85.1%), high schools 384/452 (85.0%), peer schools 28/55 (50.9%) (plus 69 student cases out of the 99 cases with school type unavailable).

Numbers of cases in each school: With the exception of peer schools, only 1 case of SARS-CoV-2 was reported in more than 90% of reports, and only in 1 high school was there a cluster of more than 10 cases. Breakdown by type of school for reports of numbers of cases in a school: nurseries/kindergardens with 1 case 218/236 (92.4%), 2-5 cases 10/236 (4.2%), 6-10 cases 0%, > 10 cases 0%, details missing 8/236 (3.3%); elementary schools with 1 case 280/300 (93.3%), 2-5 cases 17/300 (5.7%), 6-10 cases 2/300 (0.7%), > 10 cases 0%, details missing 1/300 (0.3%); middle schools with 1 case 198/208 (95.2%), 2-5 cases 5/208 (2.4%), 6-10 cases 1/208 (0.5%), > 10 cases 0%, details missing 4/208 (2.0%); high schools with 1 case 419/452 (92.7%), 2-5 cases 25/452 (5.5%), 6-10 cases 2/452 (0.4%), > 10 cases 1/452 (0.2%), details missing 5/452 (1.1%); peer schools with 1 case 47/55 (85.5%), 2-5 cases 3/55 (5.5%), 6-10 cases 0%, > 10 cases 0%, details missing 5/55 (9.1%) (plus 99/1350 cases with school type unavailable).

School closures after 1 or more positive cases identified: 192 schools were closed (14.2% of schools with 1 or more cases), by school type: nurseries/kindergardens 51/236 (21.6%), elementary schools 38/300 (12.7%), middle schools 23/208 (11.1%), high schools 49/452 (10.8%), peer schools 21/55 (21.6%).

Limitations of study: This dataset is based on news available on the internet with no further investigation to verify reliability of reports. The breakdown of cases between students, teachers and other school members includes 94 cases (7%) where it wasn’t possible to identify which category they belonged to. School type was unavailable for 99 cases (7%).

Leeb, RTLozier MCenters for Disease Control and Prevention Morbidity and Mortality Weekly Report (MMWR)COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 202002 Oct 2020USANorth America277285Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6939e2.htm

This paper describes the trends in COVID infection in school age children in the USA. There are about 56 million kids in school there (age 5-17). They all went back to school in Sept, but the analysis is only for the 277,285 cases in 5-17 years olds from March 1st to Sept 19 (so not really capturing the effect of going back to school).

Confirmed cases included in this report had a positive real-time reverse transcription–polymerase chain reaction (RT-PCR) test result for SARS-CoV-2. This means that may be underreporting the impact of the disease on children as children not tested not included. Weekly incidence in 12-17y roughly twice children age 5-11 (37.4 cases per 100,000 v 19.0). Of the 277,285, 101,503 (37%) in children aged 5–11 years and 175,782 (63%) in adolescents aged 12–17 years. Data is an aggregate of the cases and deaths reported. These data do not include cases where no sex or age was included in the reports aggregated – so may be an underestimate.

Underlying conditions were more common among school-aged children with severe outcomes related to COVID-19: among school-aged children who were hospitalized, admitted to an intensive care unit (ICU), or who died, 16%, 27%, and 28%, respectively, had at least one underlying medical condition. Among school-aged children with COVID-19, at least one underlying condition was reported for 7,738 (3%), including approximately 3% of adolescents and 2% of younger children.

Among those with an underlying condition, chronic lung disease, including asthma, was most commonly reported (55%), followed by disability*** (9%), immunosuppressive conditions (7%), diabetes (6%), psychological conditions (6%), cardiovascular disease (5%), and severe obesity (4%)

BUT Underlying conditions were based on pre-defined categories on the reporting form and were skewed to adult problems – hypertension, severe obesity based on a BMI >40, cardiovascular disease – there was an disability (including neurological) option, and “other” – but nothing for CF, or renal transplant, or DMD – so again I do wonder about underreporting of underlying conditions specific to childhood.

This report contains a lot of US national testing capacity data – showing oscillations in the amount of tests requested. Adolescents (12-17) had more tests than the younger children (5-11). Percentage positivity also reported for US nationally and regionally.

Other interesting facts from these data: Among school-aged children with laboratory-confirmed COVID-19, 58% reported at least one symptom, 5% reported no symptoms, and information on symptoms was missing or unknown for 37%. Overall, 3,240 (1.2%) school-aged children with COVID-19 were hospitalized, including 404 (0.1%) who required ICU admission. Fifty-one (<0.01%) school age children died of COVID-19

Among school-aged children with complete information on race/ethnicity who were hospitalized (2,473 [76%]) or admitted to an ICU (321 [80%]), Hispanic ethnicity was most commonly reported (45%and 43%, respectively), followed by Black (24% and 28%, respectively) and White (22% and 17%, respectively) races

Conclusion: these are high quality data that provide an idea of the minimum harm that COVID has caused for school age children in the USA. The table is especially The mortality is low, and I wonder how accurate the capturing of underlying conditions is based on the reported methodology. Provides a baseline for measuring national trends and comparing nations. And may help unravel the impact of return to school as these data are not included here.

Kuchar, EKubiak, JEur J Clin Microbiol Infect DisChildren were less frequently infected with SARS-CoV-2 than adults during 2020 COVID-19 pandemic in Warsaw, Poland28 Sep 2020PolandEurope904Epidemiology - Disease Burdenhttps://doi.org/10.1007/s10096-020-04038-9

Question: Were children in Warsaw, Poland affected less frequently and less severely than adults with COVID-19 during the 2020 pandemic?

Methods: Subjects were children, from 1 month to 18 years old, and adults, over 18 years old. Patients were enrolled from 2 hospitals in Warsaw during March and May 2020. The Adults and Children groups were each divided into asymptomatic and symptomatic subgroups.

Symptoms: fever, respiratory tract infection syndromes, gastrointestinal symptoms, dyspnoea, cough, chest pain, and seizures were included in the symptomatic groups.

Asymptomatic group: made up of two groups: (1) asymptomatic children who underwent screening for SARS-CoV-2 at the admission for planned hospitalization unrelated to COVID-19, (2) asymptomatic legal guardians of the asymptomatic children and medical staff involved in contact tracing.

All participants were tested by rtPCR for SARS-CoV-2 on NP/OP swabs. Some were also tested for additional respiratory viruses

Results: Symptomatic children (n = 459), Symptomatic adults (n = 1774), Asymptomatic children (n = 445), Asymptomatic adults (n = 239) Total number of children was 904 and adults = 2013

Symptomatic: SARS-CoV-2 in Symptomatic Children: 3.26% (15/459) ,SARS-CoV-2 in Symptomatic Adults: 5.58% (99/1774), p = 0.0448

Asymptomatic: SARS-CoV-2 in Asymptomatic Children 0% (0/445), SARS-CoV-2 in Asymptomatic Adults: 0.83% (2/239), p value = 0.0533

Other respiratory viruses in symptomatic children:, RSV positive: 17.14% (6/35) (p = 0.0002), Influenza A: 8.16% (4/49), Influenza B: 2.04% (1/49), No cases of co-infection with SARS-CoV-2

Authors’ conclusion on the analysis of their key outcome was that there was a difference between the proportions infected in children and adults. Children were more likely to be infected with RSV or influenza A/B than with SARS-CoV-2.

Commentary: There was only weak statistical evidence for a difference between adults and children in likelihood of COVID-19 infection given that a p value of 0.0448 approximates to 0.05, the threshold defined by the authors for “significance”. The secondary aim was a comparison of symptomatology between adults and children, but no data were supplied.

The sources of bias in this study are of concern: sampling bias may be likely in the population studied: are the children admitted to these hospitals, representative of the general population in Warsaw? Parents may have kept COVID-19 positive mildly symptomatic children at home. Were the infections acquired in hospital or in the community? Were all hospitals attendances screened for COVID-19 on admission? There was no information on the selection criteria of the subgroup of symptomatic paediatric patients who were tested for other respiratory viruses. The only reasonable conclusion of this study, assuming no bias in the selection of patients who were tested for other respiratory viruses is that: during the COVD-19 2020 epidemic in the months of March through to May, in symptomatic children admitted to 2 hospitals in Warsaw, RSV and Influenza A or B were more likely to be isolated than SARS-CoV-2, from throat or naso-pharyngeal swabs.

Ulyte, AKriemler, SmedRxivVariation in SARS-CoV-2 seroprevalence in school-children across districts, schools and classes18 Sep 2020SwitzerlandEurope2585Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.09.18.20191254v1

This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

This cross-sectional analysis of baseline measurements of a Swiss longitudinal cohort study of 2585 children aged 6-16 years in 55 randomly selected schools in the canton of Zurich (population 1.5 million) was posted on medRxiv on 18th September 2020. Schools in Switzerland were closed for 2 months (16th March to 10th May 2020) because of the COVID-19 pandemic; there was an initial partial re-opening for 4 weeks (e.g. teaching in half-classes, restricting larger group activities) and then on 7th June 2020 regular teaching resumed. This analysis presents SARS-CoV-2 seroprevalence measured in this cohort of school children between 16th June and 9th July 2020.

Study design: This large prospective school-based study (Ciao Corona, described in an article posted on medRxiv on 2nd September 2020) aims to follow SARS-CoV-2 seroprevalence and symptoms, in addition to sociodemographic and lifestyle factors, of a cohort of enrolled school children (and their parents and school staff) in the canton of Zurich (which includes both urban and rural settings and an ethically diverse population) from June 2020 to April 2021, to assess SARS-CoV-2 prevalence, transmission routes, clustering, temporal trends, asymptomatic cases, risk factors and duration of immunity. The study is part of a research programme across Switzerland (Corona Immunitas, www.corona-immunitas.ch) investigating SARS-CoV-2 immunity across the country.

Children aged 5 to 16 years attending primary and secondary schools in the canton of Zurich were enrolled from 16th June to 9th July 2020, with collection of venous blood samples for SARS-CoV-2 serological testing planned in 3 phases: June/July 2020 (baseline estimate of seroprevalence after lockdown and subsequent re-opening of schools, reported in this article), October/November 2020 (after summer break and 3 months of school) and March/April 2021 (after the winter season). Primary schools (public and private) were selected randomly and the nearest secondary school matched with each, with a predetermined target number of schools to enrol for each of the 12 districts of the canton, depending on district size (initial target was 29 primary and 29 secondary schools). Within the schools, children were invited to participate from randomly selected classes within lower (grades 1-2, ages 6 to 9 years), middle (grades 4-5, ages 9 to 13 years) and upper (grades 7-8, ages 12 to 16 years) levels of schools (grades 3, 6 and 9 were excluded as follow-up would be compromised for students changing school after the summer break). Exclusions included small school size and suspected or confirmed SARS-CoV-2 infection during testing. Serological testing of parents and school personnel will also take place during the course of the study. Questionnaires completed for enrolled children (by their parents) and by parents living in the same household and all school personnel of participating schools assess symptoms and tests, health, preventative behaviour, lifestyle and quality of life over the course of the study.

Study population: 55 out of 156 invited primary and secondary schools agreed to participate and 2585 children (1337/2585 (52%) girls, median age 11 yrs, range 6-16 yrs) were enrolled in randomly selected classes in the participating schools. Mean participation rate across classes was 45% (range 5% to 94%). Participation rate by school level: 754/2585 (29%) lower, 899/2585 (35%) middle, 932/2585 (36%) upper. [Participation bias is a factor to consider at the school and individual level.]M

SARS-CoV-2 seroprevalence findings: Venous blood samples were collected from 2484/2585 (96%) enrolled children (1276/2484 (51%) girls, median age 11 yrs, age range 6-16 yrs). At the University of Zurich an in-house binding assay based on the Luminex technology was used to analyse IgG, IgM and IgA antibodies against 4 SARS-CoV-2 targets (receptor binding domain, spike proteins S1 and S2 and the nucleocapsid protein), yielding 12 different measurements: samples were defined as SARS-CoV-2 seropositive if at least 2 of the 12 parameters were above cut-off values established against pre-pandemic plasma (sensitivity 93.3% and specificity 99.6%). Bayesian hierarchical modelling was used to estimate seroprevalence, accounting for the sensitivity and specificity of the antibody test, the hierarchical structure of the cohort and adjustment for population-level grade level and geographical district.

74 children had SARS-CoV-2 antibodies, resulting in an overall weighted seroprevalence of 2.8% (95% credible interval 1.6-4.1%) and a range from 1.0% to 4.5% in different districts, with 3.8% (1.9-6.1%) in grades 1-2 (6-9 yr olds), 2.5% (1.1-4.2%) in grades 4-5 (9-13 yr olds) and 1.5% (0.5-3.0%) in grades 7-8 (12-16 yr olds). Girls 2.8% (1.6-4.1%), boys 2.7% (1.5-4.0%). At least one seropositive child was found in 36/55 (65%) of tested schools: 24% of all classes (regardless of participation rate) had at least one seropositive child; 34% (43/128) of classes with 5 children and 50% of the class tested had at least one seropositive child (with a maximum of 3 cases per class in this participation rate bracket); 45% of classes with 15 children and 60% of the class tested had at least one case.

Comparison with adult seroprevalence: To compare seroprevalence estimates in children and adults, data from a random sample (in the same region in June-July 2020) of 577 adults taking part in the Corona Immunitas research programme was used: this uses the SenASTrIS test to detect IgG and IgA binding to the entire trimeric S protein of SARS-CoV-2 (98.3% sensitivity and 98.4% specificity for IgG and IgA combined). For comparability, 1717 children’s blood samples from the Ciao Corona study were also analysed with the SenASTrIS test.

Seroprevalence of children (measured using the Corona Immunitas test of IgG and IgA combined) was very similar to that of the adult sample (3.1%, 95% CI 1.4-5.4% versus 3.3%, 95% CI 1.4-5.5%).

Comparison with PCR-confirmed cases: Based on the cumulative incidence of SARS-CoV-2 RT-PCR-confirmed cases by the end of June (0.03% for children and 0.24% for adults, using official statistics for the canton of Zurich), the authors calculate “total infections” (using seropositivity) to be 89 times PCR-confirmed cases in children and 12 times PCR-confirmed cases in adults.

Symptom questionnaire: Baseline online questionnaires were completed for 2259/2585 (87%) children. 73% of children reported any SARS-CoV-2 compatible symptoms between January and June 2020 (from most frequently reported to least: runny nose, cough, headache, sore throat, fever, fatigue, muscle soreness, diarrhoea, nausea, loss of appetite, upset stomach, shortness of breath, anosmia): none of the symptoms were more frequent in seropositive than seronegative children.

Conclusion: The authors reported variation in SARS-CoV-2 seroprevalence in 6 to 16 year olds across districts, schools and classes in this study of randomly sampled schools and classes in the canton of Zurich, Switzerland in June/July 2020, reflecting SARS-CoV-2 infection in this cohort of school children in the 4 months to approximately end of May 2020 (allowing for an estimated time interval for production of antibodies), which included 2 months of school closure and a month of “mild” population lockdown. They reported no indication of clustering of SARS-CoV-2 seropositive cases within schools or major transmission within schools. Although no outbreaks were reported in schools in the region at the time of testing, seropositive cases were detected in more than half of tested schools and a third of tested classes (for classes with a participation rate of 5 children and 50% tested). The vast majority of classes with cases had only a single case. Overall estimated seroprevalence was the same in children and adults (approximately 3%), but only approximately 1 in 90 cases in children had been previously confirmed by PCR testing, compared to 1 in 12 cases in adults. The authors suggest that these differences might be explained by the non-specific nature of symptoms in children versus adults and differences in testing indications. Differences in asymptomatic case rates are presumably also relevant. When seroprevalence across school levels was compared, there was a trend of higher seroprevalence in younger children (3.8% for 6-9 year olds versus 1.5% for 12-16 year olds). The reporting of COVID-19-compatible symptoms during the 6 month period prior to enrolment was extremely common in the cohort and not specific to seropositive children.

Gabriel, MFernández-Cañadas Morillo, APediatr Infect Dis JMaternal, Perinatal and Neonatal Outcomes With COVID-19: A Multicenter Study of 242 Pregnancies and Their 248 Infant Newborns During Their First Month of Life11 Sep 2020SpainEurope235Epidemiology - Disease Burdenhttps://journals.lww.com/pidj/Abstract/9000/Maternal,_Perinatal_and_Neonatal_Outcomes_With.96042.aspx

Spain has been one of the worst-hit countries in Europe with regard to Coronavirus-19 infection, having recorded more than half a million cases and currently declaring a 10% test positivity rate – more than twice that of France and four times that of the UK. It is important, therefore, to have reliable data which help understand the impact the infection is having on pregnancy outcomes in that country.

This paper reports a multicentre observational study with the aim, first, of documenting the symptoms and perinatal outcomes for women who were diagnosed as having contracted Covid-19 infection during the third trimester of pregnancy and, second, of tracking the progress of their babies during the first month of life. The study was conducted in 16 Spanish university hospitals by the newly-formed Neo-COVID-19 Research Group. The hospitals involved are not listed but the majority of the members of the research group are based in Madrid with others in Barcelona, Girona, Santiago de Compostela and Valladolid, all in northern Spain. The study took place over an 11-week period from March 13 to May 31, 2020.

The study design is reported to be descriptive and prospective except for the first week of the study, for which data were collected retrospectively. Full details of case ascertainment are not given but all of the included women were positive either for SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR) testing of nasopharyngeal (NP) and/or oropharyngeal (OP) swab samples (92.1%), or had positive serological testing during labour for IgG using ELISA assays (7.8%) – 2.4% were also positive for IgM. Clinical data and information for the 242 mothers were collected from the medical records; perinatal data for the 248 babies were collected from the hospital medical records. Follow up information for 235 babies (94.7%) was acquired at one month, when the parents were contacted to determine details of hospitalisation or emergency medical consultations.

With regard to symptoms, 40.5% of the pregnant women were asymptomatic; it is not clear why these mothers were tested. The commonest recorded symptoms were coughing (33%) and fever (29.7%); anosmia occurred in 16.1%, ageusia in 9.1% and dyspnoea in 15.7%. 19% were admitted to hospital because of Covid-19-related illness and 2.7% deteriorated sufficiently to require admission to intensive care. One patient died as a result of a massive thromboembolic event.

Delivery was by caesarean section (CS) in 26%; clinical deterioration was the indication for the CS in 2.4%. This represented an increased risk of CS for all infected women; the calculated OR was 2.15 (95% CI: 1.09;4.25, p=0.027). The source of the comparator data for the OR is not given but the inference must be that standard caesarean section rates are much lower in Spain than those currently in the UK.

Thirty-six (14.5%) of the deliveries were preterm and 58.3% of these were late preterm; only 4 (1.6% of all babies) were born at less than 32 weeks gestation. The risk of preterm delivery was higher for infants whose mothers had been admitted because of their Covid-19 infection - OR 2.95 (95%CI: 1.37;6.41, p=0.006). The authors concluded that the prematurity rate was higher than for non-Covid pregnancies.

Of the 115 babies (46.3%) admitted to a neonatal unit the reason for admission for 87 (75.6%) was organisational in that that their mothers were being nursed in a Covid-19 area, rather than a maternity ward. 11.3% were admitted to a NICU - 10.4% required respiratory support and 1.2% were mechanically ventilated. One infant, who was test negative, developed hypoxic ischaemic encephalopathy (HIE). There were no deaths. At the time of discharge 40.4% were exclusively breast feeding and another 38.4% were having some breast feeds; the rates at one month were 40.4% and 35.7% respectively.

RT-PCR testing was performed on NP or OP samples in 230 (92.7%) of the babies at a median age of 3 hours (IQR 2-15) - it was not performed on the other 7.2% because their mothers were RT-PCR negative during labour. The tests were positive in 11 (4.4%), two of the babies having been delivered by CS; six of the eleven had been allowed skin-to-skin contact with their mothers and four had been born to mothers who were RT-PCR positive during delivery; all of these babies tested negative on re-testing. Two infants who tested negative on a first sample were found to have positive tests on a second; both were asymptomatic and these infants were considered to be false positives. Re-testing for RT-PCR in another 85 showed negative results. The authors concluded that no evidence of vertical transmission had been found.

At the one-month follow-up phone call five babies were reported to have been re-tested for Covid-19 because of either fever or primarily upper respiratory signs and all tested negative. The authors considered that, overall, there had been a slightly higher rate of visits to the emergency ward compared with published data.

Over the past few months there have been a number of studies, including systematic reviews, reporting perinatal outcomes for pregnancies in which the mother tested positive for SARS-CoV-2. For the mothers, there is general agreement among the studies that common symptoms include fever, cough, lethargy and dyspnoea while the frequency of others, such as myalgia, anosmia and ageusia, is more variable. The relevance of caesarean section to clinical deterioration in the mother is uncertain. For other perinatal outcomes, comparison between published studies is more complex. The table below shows the outcomes of the current study and those of a UK cohort review and two systematic reviews.

The disparity reflects not only differences in study design, methodology and timing of infection but also variations between units and between countries in clinical practice. There is also evidence of a risk of iatrogenic preterm birth and caesarean section in Covid-19 pregnancies which affects the inferences which can be drawn from the reported data.3 There seems to be agreement, however, that perinatal mortality rates are low in babies born to mothers who contract Covid-19 in pregnancy and the current paper adds to the evidence that in-utero transmission of SARS-CoV-2 is rare. Other important aspects of the management of Covid-19 pregnancies, such as skin-to-skin contact and breast feeding, will hopefully form the topics for future studies.

Kam, KYung, CmedRxivSARS-CoV-2 Viral RNA Load Dynamics in the Nasopharynx of Infected Children02 Sep 2020SingaporeAsia17Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.08.21.20178574v1

This observational study, posted on medRxiv on 2nd September 2020, measured the daily SARS-CoV-2 viral load in nasopharyngeal samples of 17 infected children at KK Women’s and Children’s Hospital (KKH) in Singapore, in order to analyse the temporal trend of viral load in symptomatic and asymptomatic infected children.

Methodology: KKH (an 830-bed teaching hospital for women and children) is the primary hospital for evaluation and isolation of paediatric COVID-19 cases in Singapore. Data was collected from hospital records of paediatric inpatients presenting to the hospital between 23rd March and 5th April 2020 who were diagnosed as confirmed COVID-19 cases by nasopharyngeal swabs positive for SARS-CoV-2 rRT-PCR E gene assay (using the Corman et al protocol). Most of these children were contacts of confirmed cases in their households. Nasopharyngeal swabs were taken daily from every confirmed case. Confirmed cases were discharged from hospital once they had 2 negative swab results on consecutive days. Age, gender and cycle threshold (Ct) values of all nasopharyngeal swabs for each confirmed case were recorded. Ct values are inversely correlated with viral load. A Ct of 45 was considered undetectable. All first-time positive results for each patient were confirmed by a second different PCR assay.

Measurement of viral load over time: Ct values were reported in relation to: 1. day of onset of illness for symptomatic patients and 2. day of diagnosis for asymptomatic patients. Average Ct values were calculated for each day of illness (symptomatic patients) or diagnosis (asymptomatic patients). These were plotted graphically to compare average Ct trends on each day of illness/diagnosis for the 2 groups. Since it is difficult to ascertain the exact day of infection in both symptomatic and asymptomatic children, a second analysis was performed in order to mitigate bias in timing of detection between the two groups, using an estimated day of infection for each case. This was during the early part of the pandemic in Singapore with detailed contact tracing and testing and most children in this study were likely to have been infected by a household confirmed case: the date of symptom onset for the index household COVID-19 case was used as the estimated day of infection (for cases where this information was unavailable, the average duration for cases where the information was available was used).

Clinical features of confirmed cases: 17 children with nasopharyngeal swabs positive for SARS-CoV-2 were cared for as inpatients at the hospital during this two week period. Median age was 7.7 years (range 0.3 to 15.8 years). Gender of cases is not stated. The cohort included Chinese, Malay, Indian and Eurasian ethnicities. 10/17 (58.8%) were symptomatic. All symptomatic children had a mild upper respiratory tract illness (no pneumonia or complications) with symptoms resolved by day 5 of illness. All asymptomatic children remained well with no symptoms until discharge.

Mean duration of viral shedding: Combined group 16 days (range 3-29 days) with symptomatic children 17 days and asymptomatic children 14 days (not statistically significant, p=0.48). In the second analysis, using estimated day of infection to adjust for bias in timing of detection, the durations of viral shedding for the two groups were similar. The longest duration of viral shedding was 30 days in a previously symptomatic child.

Viral loads in confirmed cases: Higher on day 7 of illness for symptomatic children (mean Ct 28.6) than asymptomatic children (mean Ct 36.7) (95% CI = 1.9 to 14.3, p=0.02). Peak viral loads occurred around days 2-3 of illness (symptomatic)/diagnosis (asymptomatic). In the second analysis, using estimated day of infection to adjust for bias in timing of detection, the viral loads remained higher in symptomatic versus asymptomatic children.

Conclusions: In this study (of a small sample of paediatric COVID-19 inpatients in a Singaporean hospital with mild illness or asymptomatic in isolation after a positive test) the symptomatic SARS-CoV-2-infected children had higher viral loads in the nasopharynx than the asymptomatic children. The authors suggest that this may indicate that symptomatic children may be more likely to transmit SARS-CoV-2 than asymptomatic children. They also suggest that pre-symptomatic transmission is probable, since peak SARS-CoV-2 viral loads occurred early at around 2-3 days post-symptom onset. Around 60% of infected children were symptomatic and around 40% asymptomatic. The majority of cases had detectable virus on day 7 of illness/diagnosis.

Sola, A MChan, D KJAMA PediatrPrevalence of SARS-CoV-2 Infection in Children Without Symptoms of Coronavirus Disease 201925 Aug 2020USNorth America33041Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2769878

An epidemiological study of asymptomatic Covid-19 in children across 28 centres in the US from 29/05/2020 to 09/07/2020. Asymptomatic children presenting to the ENT team (for surgery, clinic or planned admissions) were screened for Covid-19. It is noted that they may have had symptoms attributed to their underlying conditions that overlap with Covid-19 symptoms, but that there was not clinical suspicion of Covid-19.

Covid-19 weekly incidence data for the whole population was then obtained for the geographical areas of the hospitals from Johns Hopkins for the same time period and compared with the paediatric asymptomatic screening results.

Results: 250 of 33 041 children (age range, 0-18 years) without symptoms were positive for Covid-19 (on PCR testing). Prevalence varied from 0% to 2.2% between areas, with a pooled prevalence of 0.65% (95% CI, 0.47%-0.83%, with significant heterogeneity).

The whole population weekly Covid-19 incidence for each area was strongly correlated to the paediatric asymptomatic prevalence for that area.

Conclusions: Asymptomatic carriage of Covid-19 in children was found to be low but with significant heterogeneity of results according to centre. It was strongly correlated with the whole population incidence of Covid-19 in that area.

Wood, JJohn, CCureusPrevalence of Asymptomatic SARS-CoV-2 Infection in Children and Adults in Marion County, Indiana16 Aug 2020USANorth America119Epidemiology - Disease Burdenhttps://www.cureus.com/articles/35775-prevalence-of-asymptomatic-sars-cov-2-infection-in-children-and-adults-in-marion-county-indiana
Ladhani, SNRamsay, ME ADCCOVID-19 in children: analysis of the first pandemic peak in England12 Aug 2020UKEurope35200Epidemiology - Disease Burdenhttps://adc.bmj.com/content/early/2020/07/28/archdischild-2020-320042

Ladhani et al have provided epidemiological insight into COVID-19 between the dates of 16 January to 3 May 2020 in children compared to adults in England by reporting data from both Public Health England surveillance and Patient Demographic Service fatality data.

Their data adds to the growing evidence bank of the limited role played by children in the pandemic: only 1% of all cases of COVID-19 in England in the first four months of the pandemic were in the under 16 age group.

During the study period nearly half a million people in England were tested for SARS-CoV-2. Twenty-four percent of tests were positive but only 1.1% (1,408) of the positive cases were children.

35,200 children were swabbed, but only 4% were positive. The highest rates of SARS-CoV-2 were found in infants, particularly those under 3 months. This was a much lower percentage than adults who were swabbed, who tested positive in 19.1 – 34.9% of adults and older ages (the highest rates being in the over 80s).

When the data for people presenting in the community with an acute respiratory infection was analysed it demonstrated a very low percentage of children (only 2.8%) positive for SARS-CoV-2 contrasting with much higher rates in adults, reaching nearly 50% in the over 80s.

During the 3 and a half months of the study, 8 children with SARS-CoV-2 died (0.3%), 4 of whom had multiple comorbidities. The other 4 children died of other causes, with SARS-CoV-2 reported as an incidental or indirect contributor to death. Overall, despite fears that the national ‘Stay at Home’ message would lead to delayed presentations to emergency departments and potentially avoidable fatalities, there was no increase in excess deaths in children, even though excess deaths were reported in other age groups.

The findings from this study are consistent with data from other countries: children make up only a very small percentage of COVID-19, with a low case-fatality rate. Contrary to some assertions the data cannot inform us regarding children's involvement in transmission

Kim, LGarg, SMMWR Morb Mortal Wkly RepHospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-Confirmed COVID-19 - COVID-NET, 14 States, March 1-July 25, 202007 Aug 2020USANorth America576Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6932e3.htm

This report was posted as a Morbidity and Mortality Weekly Report Early Release on 7th August 2020 on the US Centers for Disease Control and Prevention (CDC) website (https://www.cdc.gov/mmwr). Most COVID-19 cases in children under 18 years of age are asymptomatic or mild; here data is presented about more severe cases in children hospitalised with COVID-19 between 1st March and 25th July 2020 in 14 US states.

Background: The COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) is a population-based surveillance system which collects data on laboratory-confirmed COVID-19 hospitalisations in 99 counties of 14 states in the USA (California, Connecticut, Colorado, Georgia, Iowa, Maryland, Michigan, Minnesota, New Mexico, New York, Ohio, Oregon, Tennessee, Utah) representing all 10 US Department of Health and Human Services Regions. COVID-NET surveillance includes COVID-19-associated hospitalisations among residents in a predefined surveillance catchment area who had a positive SARS-CoV-2 molecular test (ordered at the discretion of the treating health care provider) during hospitalisation or up to 14 days before admission. Trained surveillance officers perform medical chart abstractions for all identified cases.

Study design: 576 patients < 18 years of age hospitalised with COVID-19 were reported to COVID-NET from 1st March to 25th July 2020. 208/576 (36%) had complete medical chart reviews. This report is a descriptive analysis of the available data for these inpatients with a positive SARS-CoV-2 test up to 14 days before or during admission to hospital. Only those hospitalisations with complete medical chart review where patients were discharged alive or died during hospitalisation were included for clinical intervention, treatment and outcome figures. Weekly and cumulative COVID-19–associated hospitalisation rates were also calculated: numerator = number of catchment area residents hospitalised with COVID-19 / denominator = National Center for Health Statistics vintage 2019 bridged-race postcensal population estimates.

Age of children hospitalised with COVID-19: Median age was 8 years (IQR 9 months to 15 yrs). Breakdown: under 3 months: 108/576 (18.8%), 3-5 months 20/576 (3.5%), 6-11 months 29/576 (5.0%), 12-23 months 31/576 (5.4%), 2-4 yrs 50/576 (8.7%), 5-11 yrs 97/576 (16.8%), 12-17 yrs 241/597 (41.8%).

Gender of children hospitalised with COVID-19: Male 292/576 (50.7%), female 284/576 (49.3%). Breakdown by age: 0-2 yrs 56% male/44% female; 2-4 yrs 50% male/50% female; 5-17 yrs 48% male/52% female.

Race/ethnicity of children hospitalised with COVID-19: Information about race/ethnicity was reported for 526/576 (91.3%) patients. Hispanic/Latino 241/526 (45.8%), non-Hispanic black 156/526 (29.7%), non-Hispanic white 74/526 (14.1%), non-Hispanic Asian or Pacific Islander 24/526 (4.6%), non-Hispanic American Indian/Alaska Native 4/526 (0.8%), multiple races 3/526 (0.6%), unknown 24/526 (4.6%).

Underlying medical conditions in children hospitalised with COVID-19: Information about underlying medical conditions was available for 222/576 (38.5%) patients. One or more underlying medical conditions 94/222 (42.3%), obesity (defined as body mass index (kg/m2) 95th percentile for age and sex based on CDC growth charts among children aged 2 yrs; not evaluated for children < 2 yrs) 42/111 (37.8%), chronic lung disease 40/222 (18.0%) (including 30 asthma), prematurity (< 37 weeks, data collected only for children < 2 yrs) 10/65 (15.4%), neurologic disorder 31/222 (14.0%), immunocompromised 12/222 (5.4%), feeding tube dependent 12/222 (5.4%), chronic metabolic disease 10/222 (4.5%) (including 6 diabetes mellitus), blood disorders 8/222 (3.6%) (including 6 sickle cell disease), cardiovascular disease 7/222 (3.2%) (including 4 congenital heart disease).

Breakdown of underlying medical conditions by race/ethnicity: Hispanic/Latino 43/94 (45.7%), non-Hispanic Black 28/94 (29.8%), non-Hispanic White 14/94 (14.9%).

Signs and symptoms reported on admission to hospital: Fever/chills 121/224 (54.0%) (commonest in < 2 yrs 50/67 (74.6%)), inability to eat/poor feeding (data collected only in < 2 yrs) 22/67 (32.8%), nausea/vomiting 69/224 (30.8%), cough 66/224 (29.5%), nasal congestion/rhinorrhoea 53/224 (23.7%), shortness of breath/respiratory distress 50/224 (22.3%), abdominal pain 42/224 (18.8%), diarrhoea 27/224 (12.1%). Gastrointestinal symptoms were reported by 42% of hospitalised children overall.

Length of stay in hospital (N=208): Median duration of stay 2.5 days (IQR 1-5 days), similar for all age groups.

Chest radiograph findings (N=67): Infiltrate/consolidation 44/67 (65.7%), bronchopneumonia/pneumonia 14/67 (20.9%), pleural effusion 4/67 (6.0%).

Chest CT findings (N=14): Ground glass opacities 10/14 (71.4%), infiltrate/consolidation 7/14 (50.0%), bronchopneumonia/pneumonia 4/14 (28.6%), pleural effusion 3/14 (21.4%).

COVID-19 investigational treatments: Only 12/208 (5.8%) received these medications, all aged 5-17 yrs (treatment categories not mutually exclusive). Remdesivir 9/208 (4.3%), azithromycin 6/208 (2.9%), hydroxychloroquine 4/208 (1.9%), convalescent plasma 1/208 (0.5%), lopinavir-ritonavir 1/208 (0.5%).

Admission to ICU: 69/208 (33.2%) admitted to ICU. Median length of stay in ICU 2 days (IQR 1-5 days). Breakdown by age: 0-2 yrs 19/61 (31.1%)(median stay 1 day), 2-4 yrs 9/24 (37.5%) (median stay 2 days), 5-17 yrs 41/123 (33.3%) (median stay 3.5 days). The proportion of hospitalised children admitted to ICU (approx. 1 in 3) is similar to the proportion of hospitalised adults admitted to ICU (32.0%) reported to COVID-NET.

Interventions: The highest level of respiratory support needed for each case that required respiratory support were as follows: invasive mechanical ventilation 12/207 (5.8%), BIPAP/CPAP 8/207 (3.9%), high flow nasal cannula 5/207 (2.4%). Administered: systemic steroids 19/208 (9.1%), intravenous immunoglobulin 14/208 (6.7%), vasopressor 10/208 (4.8%). 2 hospitalised children received ECMO. None received renal replacement therapy. Invasive mechanical ventilation was more frequently required in adults (18.6%).

Multisystem inflammatory syndrome in children (MIS-C): From 18th June 2020 onwards, information enabling discharge diagnoses of MIS-C where relevant has been systematically collected by COVID-NET: 9/83 (10.8%) of children with completed medical chart reviews after this date received a diagnosis of MIS-C.

Outcomes in children hospitalised with COVID-19: 1/208 (0.5%) death in hospital (a child with multiple underlying conditions).

Cumulative rate of COVID-19-associated hospitalisation in children (< 18 yrs): 8.0 per 100,000 population from 1st March to 25th July 2020, with highest rate among children < 2 yrs (24.8 per 100,000). Breakdown by race/ethnicity: Hispanic/Latino 16.4 per 100,000; non-Hispanic black 10.5 per 100,000; non-Hispanic white 2.1 per 100,000 (compared to 164.5 per 100,000 among adults).

Limitations of report suggested by authors: Laboratory confirmation of COVID-19 is dependent on clinician-ordered SARS-CoV-2 testing and rates are likely to be underestimates. Hospitalisation rates are preliminary and may change as additional cases are identified during the surveillance period. Approximately 60% of paediatric hospitalisations reported to COVID-NET have not had a medical chart review and the sample may be biased. Data on MIS-C was not collected until 18th June. However, data from COVID-NET is more geographically and racially diverse than single-centre or state-based studies and this report provides useful information about children hospitalised with COVID-19 in the US. Obesity was the most prevalent underlying condition in children hospitalised with COVID-19 in this report and Hispanic/Latino and black children had higher rates of COVID-19-associated hospitalisation than white children.

Bellino, SPezzotti, PediatrCOVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy14 Jul 2020ITALYEurope3836Epidemiology - Disease Burdenhttps://pediatrics.aappublications.org/content/early/2020/07/16/peds.2020-009399

This study used an Italian national case based surveillance system of SARS-CoV-2 infections from February 27th until May 8th 2020. It focuses on the 3,836 paediatric cases (which accounts for 1.8% of the 216,305 total infections).

Cases were divided in severity into asymptomatic, paucisymptomatic, mild (uncomplicated URTI without dyspnoea or abnormal imaging), severe (pneumonia, hypoxia, dyspnoea, tachypnoea requiring hospitalisation) and critical (requiring intensive care).

Rates of infection among children were highest in teenagers and reduced with younger age groups. Adolescents 13-17 years accounted for 40.1% of childhood cases, followed by 7-12 year olds (28.9%), 2-6 year olds (17.2%) and 0-1 (13.8%). Just over half of all cases were male (51.5%)

Of all childhood cases, 13.3% required hospitalisation, however almost half the cases were children under 6 years of age (children <1 year accounted for 36.6%, 2-6 years 12.9%). This was followed by adolescents (13-17yo, 8.9%) and finally 7-12 years olds (8.8%). Children were more likely to have more severe disease if they had pre-existing medical conditions (OR 2.8, 95% CI [1.74-4.48]).

ICU admission occurred in 3.5% of childhood cases, and the highest proportion were children 2-6 years of age (9.5%).  There were four deaths (0.1% of all paediatric cases) - all children who had significant pre-existing underlying medical conditions as follows:

- 5 year old girl who developed SARS-CoV-2 pneumonia on a background of type 2 mucolipidosis with hypertrophic cardiomyopathy, thickened mitral and aortic valves and sleep apnoea- 2 month old boy with William's Syndrome who could not be weaned off ECMO following cardiac surgery for stenosis  and hypoplasia of pulmonary artery and supravalvular aortic stenosis.- 6 month old infant (gender not specified) with an extra renal malignant rhabdoid tumour who developed febrile neutropenia and pneumonia- 6yo girl with heart failure post-operative for a mitral annuloplasty for severe mitral insufficiency and left ventricular dysfunction.

Median time from symptom onset to diagnosis ranged from 3 days in infants to 6 days in adolescents. Symptom onset to hospitalisation also increased with age, from 1 day in infants to 4 days in adolescents. Due to ongoing data collection in the study, only 38.6% of childhood cases had completed recovery, but from available data, there was a median of 29 days from symptom onset to recovery (IQR, 23-37).

The study also looked at paediatric cases within the time frames of the first month of the epidemic, three weeks post peak epidemic and the last three weeks of the study dates. Cases detected in the last period  had lower risk of disease severity (3.5% vs 5.4% in the first month) and a longer time between symptom onset and diagnosis (9 days compared to 3 and 5 days in the prior periods). This may reflects change in testing practices, health care burden and management of cases over time.

When examining the larger data set of 216,305 total infections in the groups of paediatric (<18 years), adult (18-64 years) and elderly (>65 years), children had lower rates of infection, hospitalisation, ICU admission and much fewer deaths.

Over half of paediatric cases (63.4%) were asymptomatic or paucosymptomatic compared to 44% and 27.3% of adults and elderly respectively.  During the study period, 13.3% of children were hospitalised compared to 28.3% of adults and 49.9% of elderly. Severe or critical cases occurred in 4.2% in children, 17.2% adults and 41.1% elderly. Mortality rates were much higher in elderly (25.8%) and adults (5.8%) groups compared to the 4 deaths (0.1% in the paediatric population.

Overall, children had lower rates of SARS-CoV-2 infection and severity than adults and elderly. Within the paediatric population, adolescents were most likely to be infected (40.1% of cases), however the proportion of hospitalisation was higher in infants under 1 year of age (36.6% of cases) and ICU admission was more common in children from 2-6 years of age (9.5% of cases). All four deaths occurred in children 6 years and under who had significant pre-existing medical conditions.

Pollan, MYotti, RLancetPrevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study06 Jul 2020spain Europe6527Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31483-5/fulltext

Introduction; Spain was one of the countries in Europe hit hardest by the Covid 19 pandemic. These are the first wave results from the Seroepidemiological Survey of SARS-CoV-2 Virus Infection in Spain (Encuesta Seroepidemiológica de la Infección por el Virus SARS-CoV-2 en España; ENE-COVID). This is an epidemiological study with an aim to estimate the sero-prevalence of Sars Cov2 in Spain through symptom checking, point of care antibody testing, and serology.

Methods: 35 883 households across Spain were selected through stratified two stage sampling and invited to take part. This is the result of the first wave of sampling which was conducted from April 27 to May 11, 2020. Participants within selected households answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors. “Asymptomatic” was no symptoms, “paucisymptomatic” (1–2 symptoms without anosmia or ageusia), and symptomatic (anosmia or ageusia, or at least three symptoms among fever; chills; severe tiredness; sore throat; cough; shortness of breath; headache; or nausea, vomiting, or diarrhoea). Participants were contacted by phone and then invited to go to local primary care centre for testing or have a home visit. All participants were offered point-of-care antibody test (Orient Gene Biotech COVID-19 IgG/IgM Rapid Test Cassette; Zhejiang Orient GeneBiotech, Zhejiang, China, SARS-CoV-2 spike protein) and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay (SARS-CoV-2 IgG for use with ARCHITECT; Abbott Laboratories, Abbott Park, IL, USA, SARS-CoV-2 nucleoprotein). Sensitivity of the test was deemed any test positive (point of care/ serum), with specificity both tests positive. Of note Spain was under lockdown at the time of this study.

Results: Of 95 699 eligible individuals, 66 805 study participants took part, with 61 075 receiving point of care testing and 51 958 the immunoassay. Overall seroprevalence was 5.0% (CI 4.7–5.4) by the point-of-care test and 4.6% (CI 4.3–5.0) by immunoassay. In 7 provinces in the central part of Spain, including Madrid, seroprevalence was greater than 10% by both methods. Seroprevalence was similar for females and males. Seroprevalence was lower in the oldest age groups (≥85 years) compared with other adults. With regards occupation it was highest in health-care workers, 10.2% (7.9 - 13) than in other occupations these results were supported by the immunoassay.

In those who reported a contact with a confirmed case, seroprevalence was greater in those who had a confirmed case in their household (range 31.4% to 37.4% between the two tests), in their workplace 9.9–10.6%, among their non-cohabitating family members and friends 13.2–13.7%, or among their caregivers and cleaning staff 12.4–13.5%

Symptoms: For both tests seroprevalence was highest in those with a confirmed Sars CoV2 PCR more than 14 days before testing (88·6–90·1%). Among those with a positive test, the proportion of individuals who reported anosmia or three or more symptoms compatible with COVID-19 was 49.1% for the point-of-care test and 54. 2% for the immunoassay. In 32.7% (CI 30.2–35.4) of point-of-care test and 28.5% (CI 25.6–31.6) participants were asymptomatic.

Results in children: 11,422 children (<19 years) had a point of care test, with 6,527 also having an immunoassay. The proportion of paediatric participants having serology was lower than that of adults, though not unsurprising given the need for extra phlebotomy. Overall seroprevalence for those < 19 years was 3·4% (2·9–3·9) for point of care testing, and 6527 3·8% (3·2–4·6) for immunoassay.

Looking at specific age ranges for point-of-care test seroprevalence was < 1 year, 1.1% (0.3–3.5): 1- 4 years 2.1 %(1.3–3.4); 5 – 9 years 3.1% (2.2–4.2); 10-14 years 4.0% (3.1–5.0); and 15 – 19 years, 3.7% (2.9–4.8). The same pattern but slightly higher percentages were seen with immunoassay <1 year 0.0% (0.0–11.9); 1- 5 years 3.5% (1.7–6.8): 5 – 9 years 3.6% (2.3–5.7); 10 – 14 years 4.1% (3.1–5.5); and 15 – 19 years 3.8 (2.8–5.0). This paper did not give data on symptoms separately in age groups.

Conclusion: Population seroprevalence is lower than expected in areas of high endemic SARS-CoV-2, and is lowest in children. Close contact with people, particularly in the same household increases viral transmission. Over 30% of those with seroprevalence were asymptomatic. This highlights the importance of rapid identification and isolation with those with confirmed SARS-CoV-2, however isolation and separation for other household members may not be realistic in poorer or urban areas.

Ooldali, NDanis, KLancet Child Adolescent HealthEmergence of Kawasaki Disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic:a time-series analysis02 Jul 2020FranceEurope10Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30175-9/fulltext#seccestitle140

This study aimed to determine whether the COVID-19 epidemic was associated with an increase in Kawasaki Disease.

Between December 2005 and May 20th 2020, 230 children presenting to this tertiary Paediatric centre in Paris, France were diagnosed with Kawasaki Disease (KD), or incomplete KD, according to diagnostic criteria of American Heart Association. The quasi-Poisson model estimated the median number of KD cases as 1.2 per month but with 2 notable peaks of increased incidence: in December 2009 when there was Influenza A H1N1 epidemic and in April-May 2020. The latter increase in Kawasaki cases started 2 weeks after the peak of the COVID-19 epidemic in Paris.

During April-May 2020, 10 paediatric in-patients were diagnosed with Kawasaki Disease (6 complete) median age 11.8y, 6 males. Symptoms of SARS-CoV-2 are not reported. 8 had a positive SARS-CoV-2 Nasopharyngeal PCR and/or SARS-CoV-2 serology and/or contact with a case: 1 of the other 2, had exposure to a confirmed case. Median CRP 23.6 mg/dl, Lymphocytes 1042 x 109. Radiological findings are not given. 6 of these children were admitted to PICU but all survived.

This group of patients is compared with a cluster in Bergamo in March-April 2020 and to the cluster at this hospital in December 2009 and there were significant differences with the latter.

The authors comment that this study adds to the evidence that suggests viral respiratory infections, including SARS-CoV-2, could be triggers for Kawasaki Disease. It is not stated how many of the 10 children would also meet the criteria for diagnosis of Paediatric Multi-system Inflammatory Syndrome temporally associated with COVID-19 and so adds more to the literature on Kawasaki Disease than that on PIMS-TS.

Gampel, BRoberts, SSPediatr Blood CancerCOVID‐19 disease in New York City pediatric hematology and oncology patients26 Jun 2020USANorth America174Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1002/pbc.28420

This retrospective observational study provides some insight into the impact of COVID-19 on haematology/oncology patients. There were some limitations in the data collection process as testing was performed for different reasons at the two different sites that are considered. However, we see that between 10/03/2020 - 06/04/2020, 19 out of 174 tested children (each of whom had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation) tested positive for COVID-19. Of these, 11 required hospitalisation. Five required PICU and one sadly died.

Method of data collection: All patients 21 years old or younger who underwent clinical laboratory COVID‐19 testing at two New York haem/onc centres were included. All patients had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation. Informed consent was waived.

The two centres tested differently: “MSK tested all symptomatic patients and screened all patients prior to admission, procedures requiring sedation, and planned myelosuppressive chemotherapy. NYP tested only those patients for whom a positive test would alter management, including those who were symptomatic, likely COVID‐19 exposed, or with planned disposition to a chronic care facility.”

Features specific to children:19 out of 174 tested positive. Of these: 68% had fever, 47% had cough and 37% had dyspnea. 11 patients required hospitalisation and 4 patients required supplemental oxygen. 2 patients required mechanical ventilation and a further 3 were also admitted to PICU (all male). 3 patients received ‘COVID-19-directed therapy’ (with hydroxychloroquine and azithromycin) 1 patient died (“a child with sickle cell disease without a significant history of prior complications. Although this patient demonstrated pulmonary disease, his death may have been preceded by an acute cardiac event. Autopsy was refused…”). The authors make note that 64% of COVID+ oncology patients experienced treatment delays, showing the harms to these patients may not come primarily from COVID-19 disease itself

Pagani, GGalli, MmedRxivSeroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA)24 Jun 2020ItalyEurope000Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.06.24.20138875v1

In this brief report of a SARS-CoV-2 serosurvey from Castiglione D'Adda in Italy, the results of a logistic regression model based on the random sampling of 509 subjects from the region (total population 4550) following the peak of transmission in the region are detailed. Prior to this serosurvey testing was limited to severely symptomatic cases.

The exact number of children included is not provided but the age related prevalence was significantly lower in children - 9.1% (0-5yo), 10.1% (5-10yo), 11.2% (10-15yo), 12.5% (15-20yo) - compared with overall seroprevalence of 22.6%.

The methodological details are limited in this report but the data are consistent with serosurvey data from elsewehere in Europe suggesting that children are less susceptible to SARS-CoV-2 infection compared with adults. 

Rha, BLangley,GJ Pediatric Infect DisSARS-CoV-2 Infections in Children - Multi-Center Surveillance, United States, January-March 2020."18 Jun 2020USANorth America4Epidemiology - Disease Burdenhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa075/5859277?searchresult=1
Hua, CFu, JJ Med VirolEpidemiological features and viral shedding in children with SARS-CoV-2 infection15 Jun 2020ChinaAsia43Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26180
Stringhini, SGuessous, IThe LancetSeroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study11 Jun 2020SwitzerlandEurope455Epidemiology - Disease Burdenhttps://doi.org/10.1016/S0140-6736(20)31304-0

Methods: This study takes a representative population sample from Geneva, Switzerland (already identified by a pre-existing health study) and invites them to attend blood tests looking for antibodies against the SARS-CoV-2 virus over time. The purpose is to monitor what proportion of the population are infected and see how it changes during the course of the pandemic (5 weeks in this study). Participants could only attend once, and were invited by email with a telephone follow up. The only exclusion criteria was living in a prison or care home. Antibodies were measured using a commercial assay (ELISA for S1 domain of spike protein IgG). They performed in house validation of the assay using a couple of techniques (the results of the immunofluorescence validation were factored in to the sensitivity analysis of the model used later in the study)

Analysis: The statistical analysis performed was a Bayesian regression which had a random effect for households and factored in age/sex as well as the test performance to extrapolate the sample results on to population estimates of seropositivity. They calculated the relative risk (RR) of age groups having been infected with age 20 – 49yrs as the reference group.

Results: 5492 people were invited and the final analysis included 2766 people (3426 of the rest were non-responders or awaiting an appointment). 455 children participated. Seropositivity in the population increased between weeks 1 and 2 (4.8% to 8.5%), with no statistically significant difference thereafter (final estimate 10.8%).

The most significant result is that of the children<10yrs in the study, only 1/115 children tested positive (although a further 8 had an equivocal result). This made the RR of infection for children <10yrs 0.32 (0.11 – 0.63) compared to adults aged 20 – 49yrs. There was no statistically significant difference between children aged 10 – 19 yrs (OR 0.86, 0.57–1.22). Another important factor was strong association between household contacts (unsurprisingly). This is important, as there were also lower rates of infection seen in the elderly (>65 yrs OR 0.5, 0.28–0.78) but only 3% of these participants had a positive household contact. Of the 123 children aged 5-9yrs, 17% of them had a positive household contact.

This study adds to a growing body of evidence that younger children (particularly those under 10yrs) may be less susceptible to acquiring infection than adults. The RR of 0.3 despite a relatively high proportion having positive household contacts is in contrast to the elderly, whose low infectivity rate may be explained by reduces exposure (additionally, a relatively high number of elderly will have been hospitalised or passed away from infection during the study, meaning they will not be counted in these statistics).

Considerations: Schools were closed for the duration of this study period which will have reduced community exposure of young children. In addition, almost all validation of antibody assays has been in adults so far. There were a notable number of equivocal results in the young children, but the significance of this is unclear. The results are however consistent with the largest seroprevalence study to date, from Spain.

Alvarez-Roman, MTJimenez-Yuste, VHaemophiliaREGISTRY OF PATIENTS WITH CONGENITAL BLEEDING AND COVID-19 IN MADRID10 Jun 2020SpainEurope84Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/hae.14089
Belot, ALevy-Bruhl, DEurosurveillanceSARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 202004 Jun 2020FranceEurope156Epidemiology - Disease Burdenhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.22.2001010#t1

The first epidemiological surveillance study of SARS-CoV-2-related paediatric inflammatory multisystem syndrome (also known as PIMS-TS). Carried out in France (population: 67 million) this was a nationwide study through the French public health agency. 156 cases were reported between 1st March and 17th May 2020 through both prospective and retrospective case identification.

Case definition required one or more of the following symptoms: seritis (serositis), characteristics of macrophage activation syndrome (MAS), myocarditis and/or Kawasaki-like disease (KLD). Cases were divided according to associated Covid status into confirmed, probable or possible CoV and non-CoV. Comparison was undertaken between non-CoV PIMS and CoV PIMS.

Of note, this definition differs marginally from the UK RCPCH definition of PIMS-TS which is a child with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopaenia) and evidence of single or multi-organ dysfunction.

.Age distribution showed a median of 8 years and an interquartile range of 5–11 years. Peak incidence was week of 18th to 27th April, which was 4-5 weeks behind the peak of the Covid-19 epidemic in France.

95 of the 156 reported cases were confirmed or probable Covid, supporting a causal link between Covid-19 infection and PIMS.

CoV-PIMS cases (n=108) compared with non-CoV PIMS cases (n=48) had a higher median age (8 vs 3) and showed higher rates of myocarditis (70% vs 10%), macrophage-activation syndrome (23% vs 2%), seritis (22% vs 10%) and ITU admission (67% vs 8%). Rates of Kawasaki-like disease (KLD) were higher in the non-CoV group (81% vs 61%0) supporting the idea that these are ‘classic’ Kawasaki Disease presentations. In the CoV-PIMS groups 73% required vasopressors, 43% were ventilated and one child died.

This is the first epidemiological surveillance study of PIMS-TS indicating rates across a population. It supports a causal link with Covid following 4-5 weeks behind the clinical illness.

Jie QuanYuan LiClin Inect DisAge-dependent gender differences of COVID-19 in mainland China: comparative study30 May 2020ChinaAsia0Epidemiology - Disease Burdenhttps://doi.org/10.1093/cid/ciaa683
Choe, PKim, NKJIMSelecting coronavirus disease 2019 patients with negligible risk of progression: early experience from non-hospital isolation facility in Korea29 May 2020KoreaAsia0Epidemiology - Disease Burdenhttp://kjim.org/upload/kjim-2020-159.pdf
Bandi, SMahdavinia, MPediatr Allergy ImmunolAfrican American children are at higher risk for COVID-19 infection29 May 2020USANorth America474Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/abs/10.1111/pai.13298
Zheng, XChen, JJ. InfectionCo-infection of SARS-CoV-2 and Influenza virus in Early Stage of the COVID-19 Epidemic in Wuhan, China28 May 2020ChinaAsia1Epidemiology - Disease Burdenhttps://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.journalofinfection.com%2Farticle%2FS0163-4453(20)30319-4%2Fpdf&data=02%7C01%7Cdr98%40leicester.ac.uk%7C1a70a2a944e24723c11108d807052900%7Caebecd6a31d44b0195ce8274afe853d9%7C0%7C0%7C637267066036624572&sdata=sL1i5FVbIszDDJ6an2gzf9kXbJakQIakOv4kzeTtDSw%3D&reserved=0
Yang, LLei, YJ Clin VirolEpidemiological and clinical features of 200 hospitalized patients with corona virus disease 2019 outside Wuhan, China: A descriptive study26 May 2020ChinaAsia3Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250074/pdf/main.pdf
Tao, YMo, XmedRxivPreliminary analysis of scRNA sequencing of children's lung tissues excludes the expression of SARS-CoV-2 entry related genes as the key reason for the milder syndromes of COVID-19 in children25 May 2020ChinaAsia10Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.25.20110890v2

As a pre print, this study should be interpreted with caution whilst awaiting peer review.

Question: do different expression levels of viral-entry associated genes in infection with SARS-CoV-2 in children compared to adults explain milder COVID-19 symptoms seen in children?

What was analysed? RNA and immunohistochemistry of Angiotensin converting enzyme 2 (ACE2), Transmembrane Protease Serine 2 (TMPRSS2). ACE2 interacts with the spike (S) protein of the virus which is then cleaved by TMPRSS2. They also looked at FURIN because a FURIN cleavage site has been identified in the S protein which may act as another pathway for the virus to gain entry.

Comparison: expression level of ACE2, TMPRSS2 AND FURIN in normal lung tissue derived from children and adults.

Methods: For scRNA-seq analysis for gene level expression lung tissue from:

Adults: 8 adult lung transplant donors, age range 20 to 69 years, 2 males and 6 females (5 African American, 1 Asian and 2 White)

Children: areas of normal lung tissue from 4 children requiring lobectomies, aged less than 1 year, 1 male and 3 females with congenital heart abnormalities (Ebstein Anomaly (EA), Tetralogy of Fallot (ToF), AVSD and VSD). Children with EA and ToF also had pulmonary hypoplasia, child with AVSD had pulmonary emphysema and child with VSD had a pulmonary cyst.

Results of scRNA-seq analysis: ACE2 mainly expressed in Alveolar type 2 (AT2) cells in adults and children. TMPRSS2 mainly expressed in AT2, AT1 and club cells in adults and children, FURIN in Endothelial Cells and monocytes in adults; in AT2 and club cells in children. No significant changes were observed in expression levels of ACE2, TMPRSS2 and FURIN between adults and children

For immunohistochemistry analysis for protein level expression lung tissue from: Adults: 10 adults with lung adenocarcinoma, aged between 40 and 79.

Children: 10 children aged between 1 and 15 years with various forms of cancer with lung metastasis.

Results of Immuno-histochemistry analysis: Overall expression levels of ACE2 similar in adults and children. TMPRSS2 and FURIN expression higher in children than in adults (although differences in FURIN not statistically significant

Interpretation: ACE2 receptors found mainly in AT2 cells, confirming that primary target of SARS-CoV-2 is the AT2 cell.

Partial discrepancy between results from scRNA-seq and IHC might be due to: complicated processes downstream of transcription, or semi-quantitative IHC and its limitations in identifying cell types

Conclusion: Comparable levels of expression of ACE2 and other genes in both children and adults suggests that different expression of these viral entry genes is unlikely to be the key reason for the milder symptoms of COVID-19 found in children.

Phaksy, AGabbie, SEMAResponse to "SARS-CoV-2 Testing and Outcomes in the First 30 Days after the first case of COVID-19 at an Australian Children's Hospital23 May 2020UKEurope18Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/abs/10.1111/1742-6723.13560
Buonsenso, DValentini, PLancet Inf DisToward a clinically based classification of disease severity for paediatric COVID-1915 May 2020ItalyEurope0000Epidemiology - Disease Burdenhttps://doi.org/10.1016/S1473-3099(20)30396-0
de Lusignan, SHobs, FLancet Infect DisRisk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study15 May 2020UKEurope23Epidemiology - Disease Burdenhttps://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930371-6

This study examines the demographic and clinical risk factors for testing positive for SARS-CoV-2 amongst patients within a large primary care network in the UK. This included tests done through Public Health England and the UK National Health Service (NHS) between January 28th and April 4th 2020 with clinical and sociodemographic data extracted from patients' primary care medical records.

Overall 587 of 3802 patient tests returned a positive result for SARS-CoV-2. Of children 4.6% (23/499) tested positive compared with 17.1% (564/3303) of adults.

In multivariate logistic regression, adults had significantly higher odds of a positive test compared with children; those aged 40-64 (aOR 5.36, 95% CI 3.28-8.76) and >75 (aOR 5.23, 95% CI 3.00-9.09) were at highest risk.

Male sex (aOR 1.55, 95% CI 1.27-1.89), social deprivation (aOR 2.03, 95% CI 1.51-2.71) and black ethnicity (aOR 4.75, 95% CI 2.65-8.51) were also associated with an increased risk of a positive SARS-CoV -2 test. Of clinical factors, only chronic kidney disease (aOR 1.91, 95% CI 1.31-2.78) and obesity (aOR 1.41, 95% CI 1.04-1.91) were significantly associated with testing positive. Surprisingly active smoking was associated with lower odds of a positive test (aOR 0.49, 95% CI 0.34-0.71) possibly due to presentation confounding (i.e. presence of cough in chronic smokers prompting increased testing in this group).

This is the first study to utilise primary care data to assess risk factors for testing positive for SARS-CoV-2 in the community. The risk factors identified are similar to those associated with severe COVID-19 in hospitalised patients including increased age, male sex and obesity. The higher odds of a positive test in adults compared with children here are consistent with other studies suggesting children are at lower risk of SARS-CoV-2 infection compared with adults.

Deng, XYu, HClin Infect DisCase fatality risk of the first pandemic wave of novel coronavirus disease 2019 (COVID-19) in China15 May 2020ChinaAsia996Epidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa578/5837356
COVID-19 National Incident Room Surveillance TeamCommun Dis IntellCOVID-19, Australia: Epidemiology Report 1515 May 2020AustraliaAustralasia172Epidemiology - Disease Burdenhttps://doi.org/10.33321/cdi.2020.44.43
Yanover, C.Mizrahi, B.Med archivesWhat factors increase the risk of complications in SARS-CoV-2 positive patients? A cohort study in a nationwide Israeli health organization13 May 2020IsraelMiddle East647Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.07.20091652v2.full.pdf+html
Talarico, VRaiola, GActa Biomed .Preliminary Epidemiological Analysis on Children and Adolescents With Novel Coronavirus Disease (2019-nCoV) in a Central Area of Calabria Region11 May 2020ItalyEurope173Epidemiology - Disease Burdenhttps://www.mattioli1885journals.com/index.php/actabiomedica/article/view/9550/8798
Das, AGopalan, SMedrxivEpidemiology of CoVID-19 and predictors of recovery in the Republic of Korea11 May 2020Republic of KoreaAsia202Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.07.20094094v1.full.pdf+html
Garazzino, SItalian SITIP-SIP Paediatric Infection Study GroupEurosurveillanceMulticentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 202007 May 2020ItalyEurope168Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219028/

This rapid communication reports the preliminary results of an Italian multicentre study involving 11 of 13 exclusively paediatric hospitals and 51 of 390 paediatric units across Italy (mainly in central and northern Italy). Retrospective data collection began on 25 March 2020.

Study design: Data to 10 April 2020 collected by participating physicians and hospitals for all paediatric patients (aged 1 day to 17 years) with at least one RT-PCR SARS-CoV-2 positive nasal/pharyngeal swab AND adequate follow-up considered necessary by the clinician to define the final outcome (usually 2 wks).

Findings: Data collected for 168 children and adolescents with documented COVID-19:

Gender: 94/168 male (55.9%) & 74/168 female (44.1%)

Age: median 2.3 yrs (IQR 0.3-9.6 yrs, range 1 day-17.7 yrs, mean 5 yrs. <1 yr: 66/168 (39.3%), of which 15/168 neonates (6.9%). 1-5 yrs: 38/168 (22.6%). 6-10 yrs: 24/168 (14.3%). 11-17 yrs: 40/168 (23.8%)

Hospitalised: 110/168 (65.1%): <1 yr: 52/66 (78.8%). 1-5 yrs: 24/38 (63.2%). 6-10 yrs: 13/24 (54.2%). 11-17 yrs: 21/40 (52.5%)

Comorbidities: 33/168 (19.6%): chronic lung disease 7, congenital malformations or complex genetic syndromes 14, cancer 4, epilepsy 5, gastrointestinal disorders 2, metabolic disorders 1,immunosuppression 4, immunocompromise 3. The hospitalisation rate was similar between children with comorbidities (23/33, 70%) and those without (87/135, 64%).

Source of infection: Close contact with a COVID-19 infected person outside the family was rarely reported. 113/168 (67.3%) of children had at least one parent who tested positive for SARS-CoV-2 infection. Symptom onset in relatives preceded symptoms in the infected child by 1 to 14 days in 88/113 (77.8%).

Symptoms: 4/168 (2.4%) asymptomatic. Fever (37.5 to 39C) 138/168 (82.1%), cough 82/168 (48.8%), rhinitis 45/168 (26.8%), diarrhoea 22/168 (13.1%), dyspnoea 16/168 (9.5%), pharyngitis 9/168 (5.4%), vomiting 9/168 (5.4%), conjunctivitis 6/168 (3.6%), chest pain 4/168 (2.4%), fatigue 3/168 (1.8%), non-febrile seizures 3/168 (1.8%, all 3 had a known history of epilepsy), febrile seizures 2/168 (1.2%, 1 with a history of febrile seizures and 1 with first episode of febrile seizures as onset of COVID-19).

Blood results: Of the children who had blood tests, 47/121 (38.8%) had CRP > 0.5 mg/dl. Other abnormal findings were rare.

Complications: 33/168 (19.6%) developed complications: interstitial pneumonia 26/168 (15.5%), severe acute respiratory illness 14/168 (8.3%), peripheral vasculitis 1/168 (0.6%)

No child underwent a chest CT scan; pneumonia was assessed using X-ray or ultrasound in 75/168. Co-infection: Documented in 10/168 (5.9%), including 3 RSV, 3 rhinovirus, 2 EBV, 1 influenza A, 1 non-SARS coronavirus infection, 1 Strep pneumoniae.

Treatment: 16/168 (9.5%) required non-invasive oxygen treatment. 2 were admitted to ICU for mechanical ventilation (1 preterm neonate and a 2-month-old with congenital heart disease). 49/168 (29.2%) children (those with more severe illness) received experimental SARS-CoV-2 treatments, including lopinavir/ritonavir, hydroxychloroquine and/or azithromycin/clarithromycin, systemic steroids.All children, including those with comorbidities, recovered fully and there were no sequelae reported at the time of submission. This paediatric data is in contrast to the high number of cases and case-fatality rate seen in adults in Italy. Children comprised a marginal percentage of those hospitalised in Italy with SARS-CoV-2 infection.

Lounis, MElectron J Gen MedA Descriptive Study of the Current Situation of COVID-19 in Algeria06 May 2020AlgeriaAfrica79Epidemiology - Disease Burdenhttps://www.ejgm.co.uk/download/a-descriptive-study-of-the-current-situation-of-covid-19-in-algeria-8287.pdf
Lian, JYang, YWileyEpidemiological, clinical, and virological characteristics of 465 hospitalized cases of coronavirus disease 2019 (COVID‐19) from Zhejiang province in China04 May 2020ChinaAsia3Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1111/irv.12758
COVID-19 National Incident Room Surveillance TeamCommun Dis Intell COVID-19, Australia: Epidemiology Report 13 (Reporting Week to 23:59 AEST 26 April 2020)01 May 2020AustraliaInternationalEpidemiology - Disease Burdenhttps://www1.health.gov.au/internet/main/publishing.nsf/Content/1D03BCB527F40C8BCA258503000302EB/$File/epidemiology_report_13_reporting_week_ending_23_59_aest_26_april_2020.pdf
Li, HHe, YFront Med (Lausanne) 7: 190.Age-Dependent Risks of Incidence and Mortality of COVID-19 in Hubei Province and Other Parts of China30 Apr 2020ChinaAsia260Epidemiology - Disease Burdenhttps://www.frontiersin.org/articles/10.3389/fmed.2020.00190/full
Goldstein, ELipsitch, MEurosurveillanceTemporal rise in the proportion of younger adults and older adolescents among coronavirus disease (COVID-19) cases following the introduction of physical distancing measures, Germany, March to April 202030 Apr 2020GermanyEuropeEpidemiology - Disease Burdenhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.17.2000596
Chen, PXu, YJournal of Formosan Medical AssociationEpidemiological and clinical characteristics of 136 cases of COVID-19 in main district of Chongqing29 Apr 2020ChinaAsia4Epidemiology - Disease Burdenhttps://www.sciencedirect.com/science/article/pii/S0929664620301558
Sun, YWang, FJournal of Autoimmunity Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience24 Apr 2020China Asia3Epidemiology - Disease Burdenhttps://www.sciencedirect.com/science/article/pii/S0896841120300895
Nikpouraghdam, MBagheri, MJournal of Clinical VirologyEpidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in iran: A single center study21 Apr 2020IranMiddle East10Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172806/pdf/main.pdf
Wang, PChen, SInt. J. Infect. DisStatistical and network analysis of 1212 COVID-19 patients in Henan, China18 Apr 2020ChinaAsia31Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180361/pdf/main.pdf
Lavezzo, ECrisanti, AmedRXivSuppression of COVID-19 outbreak in the municipality of Vo, Italy 17 Apr 2020ItalyEurope468Epidemiology - Disease Burdenhttps://doi.org/10.1101/2020.04.17.20053157

This paper outlines the strategy of a small town in Italy which immediately shutdown for 14 days following their first death from COVID-19 on Feb 21st 2020. They subsequently screened 86% of the population for SARS-CoV-2 using nasopharyngeal swabs, then screened again 2 weeks later (71.5% of the population).

At the start of the lockdown 2.6% (95% CI 2.1 – 3.3%) of the population tested positive, but 0 of 217 children aged 0 – 10 tested positive (0%), and only 3/250 aged 11 – 20 (1.2%) tested positive. By the end of the lockdown, 0/157 (0%) children aged 0 – 10 tested positive, and 2/210 (1%) children aged 11- 20 tested positive. Many of the children aged 0 -10 lived with infected individuals. They also noted >40% of people who tested positive were asymptomatic. They note a significant number of infections appeared to have come from asymptomatic individuals during contact tracing. They also note these asymptomatic individuals never developed symptoms, and had similar viral loads to symptomatic patients (as determined by the cycle threshold from RT-PCR).

This study has relatively small numbers, but again appears to provide evidence for several important features of paediatric infection: primarily that children appear significantly less likely to become infected than adults. It presents evidence for asymptomatic transmission, and against the theory of viral load correlation with symptom burden.

Randhawa A KJerome K RJAMAChanges in SARS-CoV-2 Positivity Rate in Outpatients in Seattle and Washington State, March 1-April 16, 202015 Apr 2020USANorth America909Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2766035
Gujski, MPinkas, JMed Sci MonitEpidemiological Analysis of the First 1389 Cases of COVID-19 in Poland: A Preliminary Report15 Apr 2020PolandEurope231Epidemiology - Disease Burdenhttps://www.medscimonit.com/download/index/idArt/924702
Gudbjartsson, FStefansson, KNEJMSpread of SARS-CoV-2 in the Icelandic Population14 Apr 2020IcelandEurope1412Epidemiology - Disease Burdenhttps://www.nejm.org/doi/full/10.1056/NEJMoa2006100

This study describes the entry and spread of SARS-CoV-2 through Iceland. Importantly, this is the first epidemiological report to include SARS-CoV-2 screening of the general population and likely represents the most complete national epidemiological data published to date.

Study design: This report includes all confirmed SARS-CoV-2 infections in Iceland identified through either: targeted testing (January 31st to March 31st 2020) – 9199 predominantly symptomatic patients with travel to a high risk country or contact with a confirmed case; population screening (March 13th to April 1st 2020) – 13080 volunteers screened from the general population (without high-risk travel or contact with a confirmed case). Most patients in the population screening cohort were asymptomatic, with a minority with predominantly mild URTI symptoms. A subsequent period of random population screening from April 1st-4th excluded children.

SARS-CoV-2 real-time PCR was performed on combined oropharyngeal and nasopharyngeal samples. All confirmed cases were isolated and close contacts placed in quarantine for 14 days.

Key paediatric findings - there is comparative data provided on the 1412 children <10 years of age tested: of 564 children <10 years old tested in the targeted testing cohort, 6.7% (38) were positive – compared with 13.7% of persons >10 years old; of 848 children <10 years old tested in the population screening cohort, 0% (0) were positive – compared with 0.8% of persons >10 years old.

Details on severity of infection, hospitalisation rates and age specific symptom profiles are not included.

Discussion: The first SARS-CoV-2 infection in Iceland was confirmed on 28th February 2020. The dynamics of new cases has transitioned from imported infections initially to ongoing community spread. To date just over 0.5% of the population have had confirmed infection. Whilst physical distancing measures have been put into place including limiting gatherings to a maximum of 20 people, elementary schools have remained open. Iceland has amongst the highest national rates of SARS-CoV-2 testing per capita, with 6% of the population tested as described here. As a result this report provides the most accurate and complete national epidemiological data published to date.

The lower rate of positive tests in childen <10 year olds adds support the hypothesis that children are less susceptible to SARS-CoV-2 infection compared to adults. Similarly the lack of positive tests amongst >800 children screened goes against the theory that the low reported rates of COVID-19 in children are due to a large number of undocumented/asymptomatic paediatric cases. This finding, particularly, has important implications in decision-making around patient flow and isolation in general paediatric care, suggesting that routine testing and isolation of asymptomatic children may be of low yield in similar settings. Clearly a single PCR screening test at one time point has an insufficient negative predictive value to exclude infection. As such, serological studies will be important in providing a clearer picture of the extent of SARS-CoV-2 infection in children.

Conclusion: Children under 10 yo appear to be less likely to develop SARSCoV-2 infection compared with people >10 yo. In settings with moderate levels of SARS-CoV-2 infection (0.5% population with confirmed infection in this setting), screening of asymptomatic children without overseas travel or contact with a known case is of very low yield.

Amira, YWakita, TEmerg Infect DisSevere Acute Respiratory Syndrome Coronavirus 2 Infection among Returnees to Japan from Wuhan, China, 202010 Apr 2020JapanAsia10Epidemiology - Disease Burdenhttps://wwwnc.cdc.gov/eid/article/26/7/20-0994_article
Santacroce, LDel Prete, REJGMCOVID-19 in Italy: An Overview from the First Case to Date08 Apr 2020ItalyEurope1Epidemiology - Disease Burdenhttps://www.ejgm.co.uk/article/covid-19-in-italy-an-overview-from-the-first-case-to-date-7926
Tagarro, AJAMA PedScreening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain08 Apr 2020SpainEurope365Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2764394

This is a registry of confirmed COVID-19 cases in Madrid, Spain from March 2 to March 16 – the first 2 weeks of the epidemic in Spain. Children were screened according to recommendations at the time with PCR.

Of 365 children tested, 41 were positive (11.2%), out of the 4695 cases in the Madrid region (0.8%). 16 children (39%) with confirmed COVID had a known contact with a confirmed case. The median age of positive cases was 1 years. 60% required hospitalisation, 9.7% required PICU admission, and 9.7% required respiratory support beyond nasal prongs (including both non-invasive and invasive mechanical ventilation). Of those requiring ICU admission, only 1 (25%) had a comorbidity (recurrent wheeze). There were no deaths. Two patients (5%) had co-infection with influenza B, but it was not clear whether all patients were tested for co-infection.

CDCMMRWCoronavirus Disease 2019 in Children — United States, February 12–April 2, 202006 Apr 2020USANorth America2572Epidemiology - Disease Burdenhttp://dx.doi.org/10.15585/mmwr.mm6914e4

This is the first USA CDC report of COVID-19 looking specifically at children, examining confirmed cases nationally between FEbruary 12th and April 2nd. Due to the extremely disparate nature of public health reporting in the USA, the data quality and availability for this report is highly variable. There is no information as to the basis on which tests were performed, whether for presentation to hospital, symptomology or due to contact tracing. This cohort is therefore likely extremely heterogeneous. Of the nearly 150,000 confirmed cases in the US at this time, 2,572 (1.7%) were in children. New York City had 33% of paediatric cases. The median age was 11y and males account for 57%. Nearly 33% of cases were in children aged 15 – 17yrs, 15% in children <1y, 11% in children ages 1 – 4y and 15% in children 5 – 9y. 91% of cases had xposure to a known COVID-19 case.

Data on signs/symptoms was only available for 11% of cases. Fever, cough OR shortness of breath were present in 73% of cases, with fever in 56%, cough in 54%, shortness of breath in 13%, rhinorrhoea 7.2%, sore throat 24%, vomiting 11% and diarrhoea 13%. They have not reported on “asymptomatic” cases due to incomplete reporting on symptoms.CU admission was documented for 2% of cases. Hospitalisation was most common in infants (62%), with little difference between other age groups in regards to hospitalisation or ICU admission. From low numbers infants id not appear significantly more likely to be admitted to ICU. Underlying conditions were present in 23% of cases, most commonly respiratory (such as asthma), followed by cardiac conditions and immunosuppression. There are 3 deaths reported, but review is ongoing to determine whether COVID-19 was the cause. This patchy data from the US is useful as it closely resembles data from Chinese cohorts of children in regards to low frequency of severity and adverse outcomes. It confirms available data suggesting lower frequency of common symptoms in children as compared to adults.

Bialek, SSauber-Schatz, ECDC + Morb Mortal Wkly RepSevere Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 202018 Mar 2020USAAmerica123Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w

Epidemiologic study of reported COVID–19 cases, by age group published by the United States’s CDC for the period, February 12–March 16, 2020. Data includes hospitalization, intensive care unit (ICU) admission, and case–fatality percentages by age, for 2449 patients with confirmed COVID-19 PCR, including 123 cases aged <19 year old. Of which, 1.6-2.5% hospitalisation rate, no ICU admissions, no deaths.

LivingstonBucherLancetCoronavirus Disease 2019 (COVID-19) in Italy17 Mar 2020ItalyEurope250Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2763401

This is a helpful one page summary of data around COVID-19 numbers in Italy as of 15th March 2020.

Of note, there have been 22,512 cases of COVID-19 with 2026 (9%) being health care workers. There have been 1625 deaths (7.2%) of cases in Italy, which is a higher case fatality than rates from China and other countries so far. Below are two of the charts below which depict the age range and severity of COVID-19 infections. From a paediatric perspective, 1.2% of cases have been in patients <18 years old and remarkably there have been 0 deaths under 30yrs of age so far.

Choe, YMedRxIVCoronavirus disease-19: The First 7,755 Cases in the Republic of Korea15 Mar 2020South KoreaAsia480Epidemiology - Disease Burdenhttps://doi.org/10.1101/2020.03.15.20036368

This is a report of the first 7755 patients with confirmed COVID-19 in Korea as of March 13th. It is notable as Korea undertook one of the worlds most intensive strategies to community testing, which may give a better understanding of the proportions of different groups affected who may have had mild or subclinical infection and might otherwise not have been tested.

The finding of significance is that children made up a very small proportion of total cases, with only 75 (1%) under 9 years of age, and 405 (5.2%) aged 10–19 years. There were no deaths in patients under 30 years of age. This suggests not just low severity of infection in children, but a low attack rate with such low cases numbers.

Dong, YTong, SPediatricsEpidemiology of COVID-19 Among Children in China01 Mar 2020ChinaAsia2143Epidemiology - Disease Burdenhttps://pediatrics.aappublications.org/content/early/2020/03/16/peds.2020-0702

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.

This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Wu, ZMcGoogan, JJAMACharacteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China; Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention24 Feb 2020ChinaAsia1400Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2762130

A cornerstone paper outlining the initial epidemiological data from the outbreak (up to February 11th 2020). This paper gave us the first indication of the enormous impact of age on prognosis from the disease. It reports on 72,312 cases (44,672 confirmed and 16,186 suspected). Of these only 1% were aged <9 years (2% <19 years) with no deaths aged under 9 years.

Zimmerman, KBenjamin, DPediatricsIncidence and Secondary Transmission of SARS-CoV-2 Infections in Schools.8 Jan 2021USANorth AmericaEpidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/01/06/peds.2020-048090

This prepublication release, published online on 8th January 2021, reports a study in North Carolina, USA, which examined 11 school districts (with nearly 100,000 students and staff) open for 9 weeks (first quarter of the 2020-21 academic year) of hybrid in-person schooling, looking at within-school secondary transmission of SARS-CoV-2.

Background: North Carolina public schools (pre-kindergarten to grade 12, ages 4 to 18 years) were closed to in-person instruction on 14th March 2020 because of the COVID-19 pandemic. School districts were allowed to re-open for the start of the 2020-21 school year, choosing either remote learning or a “hybrid” model combining in-person and remote learning. The hybrid model generally involved students attending in-person school for 2 days each week (50% attending Monday/Tuesday, 50% attending Thursday/Friday, with Wednesday all-remote learning and cleaning of the school building). Families in school districts offering the hybrid model could choose between hybrid or all-remote learning. Schools in districts choosing the hybrid model were required to implement mitigation strategies (masks, distancing, hand hygiene, daily symptom and temperature monitoring). The ABC Science Collaborative, a programme developed by faculty at Duke University and the University of North Carolina at Chapel Hill to respond to the impact of COVID-19 on schooling, pairs scientists and physicians with school and community leaders to implement public health measures, share lessons learned to keep schools safe and engage in research.

Study population: Of the 115 school districts in North Carolina (100 per county plus 15 city districts), 56/115 participated in the ABC Science Collaborative. 35/56 of these participating districts offered hybrid in-person schooling for at least part of the 9 week study period (15th August to 23rd October 2020) and 21/56 remained all-remote. 17/35 of the districts offering hybrid in-person schooling did so for all 9 weeks (of the 18/35 remaining, about half did so for 4+ weeks). 11/17 of the districts offering hybrid in-person schooling for all 9 weeks were able to report both primary and secondary infections; these 11 were included in the study (9 country districts + 2 city districts). For most of the 9 weeks examined, the rate of SARS-CoV-2 infection was 1-2 cases per 1,000 residents per week across North Carolina; the 11 counties of the school districts studied had slightly higher community-acquired case rates. Around one third of the students opted to continue with remote schooling, even though their schools were offering hybrid in-person schooling (77,446 students in person reported in the 11 school districts versus 117,417 students in 2019, i.e. 66%).

Collection of data: During the first 9 weeks after re-opening, participating school districts provided data to the ABC School Collaborative about SARS-CoV-2 cases and secondary transmission in schools. Case adjudication of within-school transmission was performed via contact tracing by the local health department. Publicly available data was collected for number of staff, student enrolment and demographics. The number of children attending in person was confirmed with each school superintendent.

Primary cases and secondary transmission in schools: Across the 11 school districts over 9 weeks of schooling, 773 community-acquired SARS-CoV-2 cases were documented by molecular testing, but only 32 adjudicated cases of secondary transmission. 6/11 school districts had zero, 2/11 had one and 3/11 had multiple secondary infections. The 32 secondary cases were distributed across types of school as follows: 6/32 pre-kindergarten, 11/32 elementary schools, 6/32 middle schools, 5/32 high schools, 4/32 K-12 schools. There were no cases of child-to-adult within-school transmission (child-to-child and adult-to-child transmission were not reported).

Conclusions and limitations: This study aimed to address a key question for policy makers: is within-school spread of SARS-CoV-2 greater than, equal to, or less than that observed in the broader community? There was considerable community transmission during the 9 week study period in the 11 counties of the participating school districts, reflected in the 773 community-acquired cases seen in schools. Based on the fact that, on average, North Carolina residents with SARS-CoV-2 infected slightly more than one other individual during the study period, if secondary transmission were as common in schools as in the community, the authors anticipated 800-900 secondary infections in schools, but only 32 were documented. The authors note that participation by school districts in the ABC Science Collaborative is voluntary and that studying those school districts which participated and submitted data may select for school districts that are also better at enforcing mitigation measures. Close contacts of cases were quarantined for 14 days; testing was encouraged, but not enforced, so infections amongst these close contacts may have been missed. The incidence of child-to-child or adult-to-child transmission was not analysed because of confidentiality issues. The study setting doesn’t illustrate 100% in-person school attendance, because in-person schooling was combined with remote schooling in the hybrid model (with students attending 2 out of 5 days per week) and approximately one-third of students opted to remain all-remote even in the districts offering hybrid in-person schooling. The breakdown of case numbers between staff and students is not clear (some figures referred to in the text are not available currently online), nor whether cases in schools were identified by symptoms followed by testing, or whether there was any random testing which might pick up asymptomatic or pauci-symptomatic infections.

Zhu, YShort K RClin Infect DisA meta-analysis on the role of children in SARS-CoV-2 in household transmission clusters 6 Dec 2020AustraliaInternational102Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1825/6024998

The main finding in this meta-analysis of household cluster SARS-Cov-2 infection appears to be that children are less likely to be index cases and are may be resilient to infection from a family member. This meta-analysis sought to bring out evidence if it exists of the extent to which children are an important source of transmission for SARS-Cov-2 in households by examining data of prevalence of child index cases of SARS-Cov-2 and appearing child and adult secondary infections.

Between December 1, 2019 and August 24, 2020 the authors captured data on household SARS-Cov-2 clusters from 12 countries around the globe: China, Japan, France, Germany, Italy, USA, Vietnam, Malaysia, Singapore, Morocco, Greece and South Korea. They identified 57 articles out of 1207 as having sufficient and appropriate data: individuals who first developed symptoms in the household and were positive for SARS-Cov-2 (43 articles) and secondary cases who were confirmed SARS-CoV-2 positive household contacts (14 articles).

There were found 213 pooled index case household clusters comprising only 8/213 (3.8%) clusters involving a child index case (n= 8 ages 42days to 17 years, paediatric index cases of which 5 were in clusters from China). There was a total of 611 individuals in the 213 clusters of whom only 102(16. 7%) were children. Resulting secondary cases were 398 of which only 16 (4%) arose from child transmission suggesting two secondary cases per child index case.

Possible confounders were revealed to include if asymptomatic child contacts but SARSCoV-2 positive were index cases when the index case prevalence went up to 39 (18.5%) children; if only clusters in which there had been no travel by the index case were used in the analysis (152 clusters), then a little more, 32 (21%) child index cases were found; and finally if only clusters outside of lockdown period were analysed, only 3% of clusters had a child as an index case.

Cluster numbers were too few for the authors to define the difference in secondary attack rates (SAR) between child index cases and adult index cases. Too few studies in this meta-analysis had provided information on how many SARS-CoV-2 positive cluster members there were and how many negative (5 clusters containing a child index case yielding an SAR of 46.7% with a large SD ( 28.2%) and 22 clusters containing adult index cases, SAR of 65.8% with an equally large SD of 23.3%).

Comparing the SAR from symptomatic index cases to asymptomatic found significantly less transmission from asymptomatic index cases (RR 0.17).

Meta-analysis of SAR to children from adult index cases found a significantly lower SAR than to other adults (RR 0.62)

Although the meta-analysis has shown in the few clusters where there was sufficient information to make the analysis that SAR was lower in child index case clusters compared to adult index SARS-CoV-2 positive clusters, larger cluster samples in which there are more child SARS-CoV-2 positive index cases may be warranted during this period prior to the Covid-19 vaccinations being rolled out population-wide.

Pray, IWestergaard, RMMWR Morb Mortal Wkly RepCOVID-19 Outbreak at an Overnight Summer School Retreat ― Wisconsin, July–August 202030 OCT 2020USANorth America127Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6943a4

This is a study of an outbreak of COVID-19 which occurred at a boys’ faith based overnight summer school retreat in Wisconsin, USA between July 2 and August 11, 2020.

The retreat was attended by 152 people: 127 male students aged 14-17 years; 21 counsellors aged 17-24 years; and 4 staff aged 21-45 years.

A single student, who received a negative SARS-CoV-2 RT-PCR test result <1 week before the retreat and experienced symptoms 1 day after arriving, was the likely source of introduction, resulting in infection of 76% of attendees.

At the retreat, students and counsellors were not required to wear masks or social distance, and students mixed freely. Classes were outdoors with students seated <2 m apart. Teachers wore masks. The sleeping residences for the 127 students were tightly spaced, with shared bathrooms and common areas. Counsellors and staff members resided separately.

Extensive and rapid transmission of SARS-CoV-2 occurred, especially amongst the students, of whom 100 were affected; 15 counsellors and 1 staff member were also affected. 24 attendees had previous positive serologic results. The attack rate in the susceptible attendees who were not positive was 91%.

Confirmed COVID-19 cases were defined by a positive SARS-CoV-2 RT-PCR test result and occurred in 64 of the 127 students (52%); in 14 of the 21 counsellors (67%); and in none of the staff members. Probable cases were defined by an illness meeting clinical criteria for COVID-19 with symptom onset during the retreat and occurred in 36 students (28%), 1 counsellor (5%) and 1 staff member (25%).

Only one person was asymptomatic. The remainder had mild to moderate symptoms. None required admission to hospital and no deaths occurred.

Conclusions

The authors conclude that SARS-CoV-2 can spread rapidly among adolescents and young adults in a setting with inadequate COVID-19 mitigation measures. They observed that of 24 attendees who had documented evidence of antibodies to SARS-CoV-2 before arrival, none tested positive for SARS-CoV-2 RT-PCR at the retreat, suggesting a possible protective effect. The authors recommend that a robust COVID-19 mitigation plan developed in collaboration with public health authorities is important for preventing and containing similar outbreaks at overnight camps and residential schools.

Peaper, DMurray, TPediatr Infect Dis J Severe Acute Respiratory Syndrome Coronavirus 2 Testing in Children in a Large Regional US Health System During the Coronavirus Disease 2019 Pandemic30 Nov 2020 preprintUnited StatesNorth America688Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.95926.aspx

A cross sectional survey undertaken between 1st March 2020 and 26th September 2020 in North Eastern United States of clinical virology results in children. Nearly ¼ million COVID test were done at the testing laboratories during the period of the study of which 6.8% were positive. 23,137 (9.8%) of the tests were done on children (≤18 years of age). Of these 688 children had 734 positive tests (3.2%). The age of the children with a positive test were significantly older 12.0 years (IQR 5.0-16.0) compared to those who were negative 10.0 (IQR 4.0-16.0). This age difference occurred throughout the study period regardless of community prevalence.

After the first positive child case, the positivity rate increased by 3.7% per week, a significantly slower rate than adults 4.3%. The rate of positivity peaked in children at 18% at the end of March, the rate of decline was 1.6% per week slower in children than adults and plateaued at < 1% at the end of June. There was then another much smaller peak towards the end of July.

The increased number of positive children in the later part of the study was because of increased testing rather than an increased positivity rate. After the reopening of schools there was no increase in positivity.

129 children had repeated tests and of these 31 had at least one positive test. For patients with more than 1 positive test the longest interval between initial and last positive test was 104 days, with 64.5% having a repeat positive test ≥ 10 days.

The authors conclude “An increase in pediatric cases documented in the late summer was predominately due to increased access to testing for children. The percent positivity in children did not change in the first 3 weeks after school opened. A subset of children has detectable severe acute respiratory syndrome coronavirus 2 RNA in the upper respiratory tract for weeks after the initial infection.”

Although an interesting paper, as it is based on laboratory data, is not possible to ascertain why the children were being tested nor how the study population reflects the whole paediatric population of the study area.

Hommes F, van Loon W, Thielecke M, et al. SARS-CoV-2 infection, risk perception, behaviour, and preventive measures at schools in Berlin, Germany, during the early post-lockdown phase: A cross-sectional study. medRxiv. December 18th 2020, https://doi.org/10.1101/2020.12.18.20248398

This is a cross-sectional study from Germany between 11th to 19th of June 2020 comprising questionnaires, clinical and laboratory data obtained from 535 students and teachers attending 24 different schools in Berlin. The article is a preprint which has not yet been peer-reviewed.

The investigators selected schools in areas of Berlin with different socio-economic profiles and studied 193 primary school students, 192 secondary school students and 150 school staff. Median ages were 10 years (range 8-13) for primary and 15 (13-18) for secondary students; sex ratio was 1:1. Of the staff, 98 (71%) were female.

Staff and students completed a questionnaire and had their body temperatures measured. SARS-CoV-2 infection was determined by real-time-PCR from oro- and naso-pharyngeal swabs. Anti-SARS-CoV-2-IgG was measured in blood samples.

Only one SARS-CoV-2 infection was detected in the 532 subjects (0.2%): a 16-year-old, afebrile female student who had headache and rhinorrhoea as her sole symptoms. Seven students (1.3%) (median age 14 years, range 9-17), had IgG antibodies to SARS-CoV-2 – three of these were in the same secondary school class. One of them reported loss of smell and taste in the preceding two weeks.

Symptoms of infection (headache, rhinorrhoea, cough and sore throat) on the day of examination were reported by 19% of primary students, 16% of secondary students and 12% of staff. A temperature of ≥37.5oC was detected in 2.3%.

More than 50% of students and staff reported seeing friends less frequently outside of school than before the pandemic. 72.9% of primary and 60.5 % of secondary students reported a low perception of risk of infection, whereas 59.1% of staff reported a high perception of risk. 81% of primary students, 54.7% of secondary students and 76.9% of staff reported that they frequently to always physically distanced at school. 50% of primary students, 35.3% of secondary students and 39.9% of staff reported that they frequently to always wore a facemask at school.

The majority of schools had reduced class sizes at the time of the study. Sports activities were suspended in all primary and the majority of secondary schools. The time spent in online learning varied between different schools: on average 15% (range 0-50%) of teaching was online in primary schools and 50% (range 0-90%) in secondary schools.

The authors conclude that infection prevention and control measures can be successfully implemented in schools (in the region under study).

Yoon, YYae-Jin, KJ Korean Med SciStepwise School Opening and an Impact on the Epidemiology of COVID-19 in the Children30 NOV 2020South KoreaAsia13100Epidemiology - Transmissionhttps://doi.org/10.3346/jkms.2020.35.e414

This is a retrospective study of data derived from a national registry of SARS-CoV-2 cases which examined whether school re-opening led to an increase in the number of paediatric COVID-19 cases in South Korea, conducted between 18 February to 31 July 2020

The first paediatric case of SARS-CoV-2 infection in a child in South Korea occurred on 18 February 2020. In that country, there are two weeks of school in February, and then a two-week-break before the new academic year starts in March. Because of the pandemic, it was decided to delay school re-opening, which eventually took place at one-weekly intervals between 20 May and 8 June 2020, beginning with high school senior students. Online classes had been held from 9 April.

The authors analysed data derived from press-releases given by the Korea Centers for Disease Control and Prevention.

13,000 students and school staff were tested for COVID-19 infection (by SARS-CoV-2 PCR) during the study period. 44 children were found to be positive after schools re-opened. The authors state that there was not an obvious sudden increase in the number of paediatric cases, or in the proportion of paediatric cases amongst all confirmed cases, before and after school re-opening. They do not provide a statistical analysis of these comparisons.

Out of 800 tests at kindergartens (5- to 7-year-olds), six children were positive for SARS-CoV-2 by PCR. There were no cases of transmission between kindergarten children. Out of 3,000 tests at elementary schools (7- to 12-year-olds), 17 children were positive. There was only one case of transmission, between a pupil who infected two fellow pupils. Out of 7,500 tests at middle schools (13- to 15-year-olds) and high schools (16- to 18-year-olds), 21 students were positive. There were no cases of transmission between students at middle school or high schools.

The authors conclude that school re-opening in South Korea did not cause a significant school-related outbreak of COVID-19 infection in children.

Lee, EJHan, MSEmerg Infect Dis 27(1)Absence of SARS-CoV-2 Transmission from Children in Isolation to Guardians, South Korea30 Nov 2020South KoreaAsia12Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/27/1/20-3450_article

Early online release of a research letter from a small study in S Korea between 18/02–07/06/20. There was no transmission of SARS-CoV-2 from child to adult in 12 cases where all care was given by a unique carer whilst a child was in hospital isolation. Seven children were asymptomatic, 4 had fever or respiratory symptoms and 1 had pneumonia. Median age of children was 6 years (range 2months – 1years). Median length of isolation was 17days (range 7-37days). All adults wore PPE of various types and combinations. Ten of 12 had frequent close contacts. The authors report that appropriate use of PPE may protection adult carers of infected children, and may also support the hypothesis that onward transmission from young children to adults is less likely than from infected adults to other adults.

Laxminarayan, RLewnard, JScienceEpidemiology and transmission dynamics of COVID-19 in two Indian states30 09 2020IndiaAsia20000Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/09/29/science.abd7672/tab-article-info

In this large study from India, surveillance, and contact tracing data from two large states (Tamil Nadu and Andhra Pradesh; population 127.8 million) from between 4th March and 1st August 2020 are analysed. Both states implemented rigorous contact tracing from early in the pandemic response with an attempt to follow up all contacts of laboratory confirmed cases, including testing of contacts between 5-14 days after contact with primary case, irrespective of symptoms. The authors aim to describe transmission dynamics and clinical outcomes.

Just over 435,000 cases were identified with over 3 million exposed contacts reached by contact tracers. Age specific incidence was lower in the 0-4y.o. (6.3 per 10,000) and 5-17y.o. (12.7 per 10,000) compared with adults (35.0-45.3 per 10,000). Case fatality rate was lowest in the 5-17 yo age group (0.05%), increasing with advancing age, and was highest in the >85y.o. group (16.6%).

Individual-level epidemiological data was available for 575,071 contacts of 84,965 cases. A mean of 7.3 contacts were tested for each case (IQR 2-9) and 70% of index cases had no positive contacts. The overall secondary attack rate was 7.5%, higher within households (9.0%) compared with in the community (2.6%) and healthcare settings (1.2%); the highest attack rate (79.3%) was among those with high-risk travel exposures (close proximity in shared conveyance for >6 hours).

Assuming test-positive contacts were infected by the index case, the highest probability of transmission was within contact pairs of the same age. This pattern was strongest among children 0-14 years and adults >65 years. Notably children represented a small proportion of index cases (0-4y.o.=1%, 5-17y.o.=6%) and the greatest proportion of contacts who tested positive were exposed to an index case aged 20-44y.o (~50% of index cases).

This represents the largest dataset to date examining the epidemiology of SARS-CoV-2 transmission and clinical outcomes in a low / middle income setting. The under-representation of children amongst detected cases and the low mortality rate in younger individuals is consistent with previous data. Similarly, the high number of index cases with no positive contacts is in keeping with evidence of substantial variation in likelihood of transmission between individuals and the potential important of super-spread. The apparent increased probability of transmission between child case contact pairs should be interpreted with caution given the small proportion of paediatric index cases. Importantly, the lack of temporal data limits the ability to establish directionality of transmission; meaning children classified as case contact pairs may have rather shared a common exposure to another index case. Moreover, the majority of test-positive contacts overall were traced to young adult index cases.

Considered in totality, this study is consistent with data from some high-income settings implicating young adults, rather than children, as major drivers of transmission of SARS-CoV-2.

Pitman-Hunt, CKannikeswaran, NJ Pediatric Infect Dis SocSARS-CoV-2 Transmission in an Urban Community: The Role of Children and Household Contacts27 Nov 2020USANorth America71Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa158/6007439

This was a retrospective study of SARS-CoV-2 household transmissions patterns in an urban US community, and found no evidence of within-household child to adult transmission.

Study design; This study recruited children testing positive for SARS-CoV-2 (via nasal swab) between 12 March and 15 June at the Michigan Children’s Hospital in Detroit. Patient notes were reviewed retrospectively for the existence of a sick household contact, defined as someone living in the same house and who either tested positive for SARS-CoV-2 or who had symptoms (listed as fever, cough, congestion, sore throat or diarrhoea). Participants were followed up by telephone 6 weeks after discharge to identify any subsequently developing sick household contacts.

Cohort; The study included 71 children ranging from less than 1 year to 17 years of age. Median age was 6 years (IQR 0.8-13 years). 58% were female and 85% were African American (where race was recorded). Severity of illness in the studied children varied from asymptomatic to critical, with 55% being asymptomatic or having mild disease, 23% having moderate disease and 23% having severe or critical disease. Interestingly, 83% of participants were hospitalised, which , based on the figures provided, must have included some mild as well as asymptomatic infection (perhaps with incidental SARS-CoV-2 diagnosis).

Results; In 30 of the 71 cases (42%), a sick household contact with earlier illness onset than the index child was identified. In almost all of these households, the contact had a positive test (the contact was diagnosed symptomatically in 5 households). 76% of these sick contacts were parents and 20% were grandparents. In just 2 cases, the sick contact was a sibling, but one of these was an adult sibling. The timing of the child’s illness onset relative to the sick contact ranged from less than a week after to more than 4 weeks after. No further sick contacts were identified at follow up, suggesting that there were no cases of child to adult within-household transmission in this cohort, or at minimum none who developed symptoms.

Summary; This study supports the findings of previous studies that levels of child to adult transmission of SARS-CoV-2 are low. The authors note that less than half of participants had an identified sick household contact, which is at odds with other studies which have found children predominately infected within the household. This may reflect particular factors in what is a deprived urban community, and difficulties adhering to measures designed to limit community transmission. There may also be a degree of under-reporting of sick household contacts, who may have been asymptomatic.

Although a small study looking at a specific population, this is a useful addition to the body of evidence that children are not primary vectors for SARS-CoV-2.

Kriemler, SRadtke, TmedRxivSurveillance of acute SARS-CoV-2 infections in school children and point-prevalence during a time of high community transmission in Switzerland26 Dec 2020SwitzerlandEurope641Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.24.20248558v1

This is a surveillance pilot study conducted in Zurich Switzerland between 01/12/20 – 11/12/20. The aim was to identify the impact and prevalence of asymptomatic and oligosymptomatic children and teachers in the school setting. Participants underwent buccal swabs for a PCR and rapid diagnostic test (RDT) at two separate time points 1 week apart. 641 children and 66 teachers from 14 different primary and secondary schools took part in the surveillance study and underwent testing at least once. 198 children and 5 teachers reported symptoms in the 5 days prior to the testing. There was one child who had a positive PCR test (negative RDT test) at the 1st collection time point. This child had a runny nose and at the second time point reported anosmia but had a negative PCR and RDT swab test at this time point. This gave a point prevalence of 0.2% (CI 0.0%-1.1%). No teacher had a positive PCR test. There were 7 positive RDTs in children (point prevalence 1.1%) and 2 in the teachers (point prevalence 3%). These were repeated at a time interval ranging from 2 hours to 2 days and they were all negative and as were the PCR swabs. These were therefore classified as false positives. The specificity of the RDT was 99.4% in children and 99.5% in teachers.

This study shows that there is a very low point prevalence in school setting where there was widespread testing as part of the surveillance. It was felt therefore that surveillance testing in schools was not efficient and instead testing should be limited to those with symptoms with effective preventative measures in place and a policy of test, track, isolate and quarantine. The false positives of the RDT lead the authors to conclude that further evaluation was required on this method before more widespread use. The study reports that the buccal route of testing was validated on acutely ill adult patients. Given the low point prevalence, beyond what was expected at a time of high community transmission, the validity of the buccal route of testing in children needs to be questioned. It would have been helpful to have had a nasopharyngeal swab alongside the buccal swab to authenticate the results obtained from the buccal swabs. The study does not specify the strain of SARS CoV2 in circulation at the time of the study. Minimal information is given regarding the participant’s background characteristics/ demographics.

In conclusion, the study shows a lower-than-expected prevalence in the school setting from asymptomatic or oligosymptomatic children and teachers. However, the use of buccal swab testing calls into question the internal validity of the results and the unspecified strain of SARS CoV2 reduces the external validity.

Davies, NEdmunds, JmedRxivEstimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England26 12 2020UKEurope0000000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.24.20248822v1

The SARS-CoV-2 variant - VOC 202012/01 - has recently emerged and rapidly outcompeted pre-existing variants in the UK. This variant is defined by 17 mutations, three of which are of particular concern:

• N501Y which has been shown to increase affinity for the ACE2 receptor

• P681H located near the important furin cleavage site in the spike protein and

• a deletion of 2 amino acids at positions 69-70 which has been associated with immune escape in immunocompromised patients and enhanced infectivity in vitro.

The incidence of VOC 202012/01 increased through the November national lockdown and continued to increase through ongoing Tier 3 restrictions. There has been concern that this variant may be more transmissible, and separately that children may be more susceptible to VOC 202012/01 compared with pre-existing strains.

In this study, a two-strain mathematical model of SARS-CoV-2 transmission fitted COVID-19 admissions, bed occupancy, deaths, and SARS-CoV-2 PCR prevalence to the relative frequency of VOC 202012/01 in the three most heavily affected NHS regions (South East, East of England and London).

Four alternative hypotheses were considered to explain the increased spread of VOC 202012/01: increased infectiousness, immune escape, increased susceptibility among children and shorter generation time (time between exposure and infectiousness). The model for increased infectiousness best matched the observed data suggesting transmissibility of the variant was 56% higher than pre-existing variants (95% CI 50-74%). There was no evidence of a higher risk of severe disease or death based on this model.The other models, including modelling increased susceptibility in children to VOC 202012/01 underestimated the relative growth rate of the new variant.

Projection of future transmission using the increased infectiousness model suggested that even with ongoing Tier 4 restrictions from December until the end of January, COVID-19 cases and deaths would continue to rise, peaking in spring 2021. Schools closures in addition to Tier 4 restrictions were modelled by removing all school related contacts and assuming a reduction in transmissibility across age groups following closure. In this model, closing schools and universities until the end of January 2021 did not reduce the overall burden of disease, but did delay the peak of cases potentially allowing time for more widespread population vaccination in the interim. Finally, only an accelerated uptake of vaccination (2 million vaccination per week vs 200,000 per week) in combination with Tier 4 restrictions and school closures was modelled to reduce peak ICU burden below levels seen during the first wave in the UK.

Based on this mathematical modelling, the observed increase in SARS-CoV-2 burden and relative frequency of the VOC 202012/01 variant, is best accounted for by general increased transmissibility of the new variant by an order of around 50%, rather than increased susceptibility of children alone. With the rapid acceleration of SARS-CoV-2 cases in the UK, the addition of school closures to general restrictions (noting the limitations of the model's assumptions) may serve to delay the peak of cases. A concomitant effort to accelerate vaccine delivery will be vital to reduce ongoing transmission and limit the impact on health care systems.

Falk, AHoeg, TMMWR Morb Mortal Wkly RepCOVID-19 Cases and Transmission in 17 K–12 Schools — Wood County, Wisconsin, August 31–November 29, 202026 01 2021USANorth America133Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7004e3.htm#suggestedcitation

This study from the US assessed the transmission of SARS-CoV-2 infection within 17 selected schools in Wood County, Wisconsin between August 31st to November 29th 2020. During the study period, the majority of students attended in-person learning (estimated 12.4% attending virtually) and infection mitigation measures were employed at all schools including mask wearing for all students and teachers, limitations on mixing between classes and between staff. Community transmission of SARS-CoV-2 in Wood County during the study period was high with test positivity ranging from 7% up to 40% from community samples.

All cases occurring in students or staff during the study period were reported. For each case, infection source was determined though case investigation conducted by the public health department or school administration. Contact tracing was carried out with close contacts required to quarantine at home with further investigation undertaken for contacts who experienced symptoms during quarantine. Surveillance testing and routine testing of contacts was not undertaken.

A total of 4,876 students attending in-person (1,529 primary and 3,347 secondary) and 654 staff were included. A total of 191 of cases were reported within schools; 133 student and 58 adults. Incidence in schools was 37% lower than in the surrounding community (3,454 vs 5,466 cases per 100,000 persons). Of 191 cases, only 7 (3.7%) were associated with in-school transmission, all occurring between students; no staff infections were linked to in-school transmission. No transmission between students and staff or between students in separate classrooms was documented. Compliance with mask wearing in classrooms ranged from 92.1% to 97.4% according to teacher survey responses.

This study adds to a growing body of data demonstrating limited transmission of SARS-CoV-2 in schools with a variety of infection mitigation measures. In contrast to a number of these recent papers, the low number of cases of in-school transmission here was observed despite high levels of transmission in the surrounding community. The authors acknowledge that the study did not include surveillance testing of children, and therefore asymptomatic transmission was not assessed, but highlight recent epidemiological data suggesting asymptomatic cases are much less likely to transmit SARS-CoV-2. Notwithstanding this limitation, the results here suggest that keeping schools open, even in the setting of moderate to high community transmission may be possible with minimal in-school SARS-CoV-2 transmission, provided appropriate mitigation strategies are employed.

Sun, KYu, HScienceTransmission heterogeneities, kinetics, and controllability of SARS-CoV-224 11 2020ChinaAsia0000000Epidemiology - Transmissionhttps://doi.org/10.1126/science.abe2424

In this detailed contact tracing study from Hunan, China, granular epidemiological data was collected from laboratory confirmed SARS-CoV-2 infected individuals and their close contacts between January 16th and April 3rd, 2020.

All cases were admitted to dedicated hospitals for isolation regardless of clinical severity. Contacts were quarantined in medical observation facilities and followed up for a minimum of 2 weeks. Prior to February 7th, contacts were tested if they developed symptoms. After February 7th, all contacts were tested (PCR) at least once during quarantine, regardless of symptoms.

Transmission chains were reconstructed, and timing of infection was estimated based on each patient's exposure history. The impact of factors including type and duration of exposure, age of contact, and timing of exposure relative to symptom onset was measured using a mixed effects multiple logistic regression model. The data was further analysed to determine transmission kinetics, infectiousness profile of a typical case and the expected impact of individual and population-based interventions on control of SARS-CoV-2 transmission.

A total of 1178 SARS-CoV-2 infected individuals and their 15,648 close contacts were included. In 210 epidemiological clusters, between 0 and 4 generations of transmission were observed with 80% of secondary infections traced back to 15% of SARS-CoV-2 infected individuals.

In a subset of 14622 contacts of 870 SARS-CoV-2 patients (excluding those with contacts reporting travel history of Wuhan) transmission was higher for household contacts compared with social or community contacts. Transmission in households increased during the lockdown period whilst community contacts decreased concurrently. Longer exposure increased risk by 10% for each additional day of exposure.

Susceptibility in children 0-12y.o. was lower than in adults 26-64y.o. (OR 0.41, 95% CI 0.26 - 0.63) and higher in those >65 y.o. (OR 1.39, 95% CI 1.02 - 1.91). No statistically significant difference was found between index cases 0-25 y.o. compared with adults 26-64 y.o. In a sensitivity analysis of the regression model infectiousness of children 0-12y.o. was lower compared with adults 26-64 y.o. (OR 0.11) but confidence intervals for this estimate were very wide (crossing 1), likely owing to the low number of child index cases.

Using probabilistic reconstruction of infector-infectee pairs, a median serial interval of 5.3 days was determined (time from symptom onset in an infector to symptom onset in the infectee). Serial interval was prolonged for those isolated > 6 days after symptom onset compared to those isolated <2 days from symptoms (median serial interval 1.7 days vs 7.3 days) indicating prompt case isolation restricts transmission to earlier stages of infection. Peak infectiousness was found to occur at time of symptom onset and half of transmission was estimated to occur in the pre-symptomatic period. Modelling of intervention scenarios suggested case isolation and quarantine of contacts alone would be insufficient to interrupt transmission of SARS-CoV-2, highlighting the need for layered interventions including population level measures such as physical distancing and broad adoption of face masks.

This study is amongst the most detailed contact tracing studies of SARS-CoV-2 infection to date, including temporal data on symptom onset and timing of exposure as well as universal testing of contacts for the majority of the study period. The finding of transmission heterogeneity from index cases is consistent with data elsewhere highlighting the importance of super-spreading in SARS-CoV-2 transmission. The lower susceptibility in child contacts is also consistent with other large epidemiological studies, together with the low number of child index cases. The sensitivity analysis hints at reduced infectiousness of children <12y, but with a high degree of uncertainty. With peak infectiousness occurring near the time of symptom onset, this data underlines the need for a combined approach of case isolation and quarantine of contacts together with broader population measures to control SARS-CoV-2 transmission.

Hallal, PVictora, C LancetSARS-CoV-2 antibody prevalence in Brazil : results from two successive nationwide serological household surveys23 Sept 2020BrazilSouth America56190Epidemiology - Transmissionhttps://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30387-9/fulltext

This is a nationwide repeated cross-sectional study with 2 seroprevalence surveys in 133 sentinel cities in Brazil.1st survey was carried out during 14-21 May 2020 (n=25025) and 2nd survey 4-7June (n=31165).

Methods: They randomly selected households and then randomly selected one individual from all household members. Presence of Ab against SARS-CoV-2 was assessed using lateral flow point-of-care test (WONDFO SARS-Cov-2 Antibody Test) using two drops of blood from finger prick samples.

Results: There were 3400 individuals in 1st survey and 4412 in 2nd survey were aged 1-19 yrs. 2/3 were 10-19 yrs; under1 yr age were excluded. 45/3400 (1.3%) in 1st survey and 79/4412 (1.8% ) in 2nd survey were found positive for SARS-CoV-2 antibodies

Prevalence in children in the 1st survey was similar to that of older age groups. In the 2nd survey prevalence was higher in 20 to 59-year olds (around 3%). There was no significant difference between 1-4, 5-9, and 10-19year olds.

Data on children was not provided separately, but for the whole population groups there were geographical differences in prevalence and it was higher in those living in crowded conditions and households with 6 or more people, and indigenous people (6.4%) compared with white people (1.4%). Prevalence in poorer socio-economic quintile was 3.7% compared with 1.7% in the wealthiest quintile.

The authors conclusion are as follows: antibody prevalence was highly heterogeneous by country region with rapid initial escalation in Brazil’s north and north east. Prevalence is strongly associated with indigenous ancestry and low socio-economic status. These population subgroups are unlikely to be protected if the policy responds to the pandemic by the national government continues to downplay scientific evidence.

This is an impressive well carried out population based nationwide study involving over 56,000 individuals who as part of the study had their SARS-CoV -2 antibodies tested as well as information collected on a range of issues including age, gender, ethnicity, socio-economic status and number of people living in a household. This is probably the largest population-based study in geographical scope. It found high prevalence in 11 cities along the Amazon river, with levels that were among the highest ever reported in population-based studies. This finding of high prevalence in tropical region contradicts the view that continents such as Africa might be protected against COVID-19 because of high ambient temperature. Consistent with other large, well conducted sero-prevalence studies, fewer children were found to have SARS-CoV-2 antibodies than adults.

Tönshoff BKräusslich, H-GJAMA PediatrPrevalence of SARS-CoV-2 Infection in Children and Their Parents in Southwest Germany22 Jan 2021GermanyEurope2482Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2775656

Methods: cross-sectional study carried out during lockdown in Baden-Württemberg, a region with the second highest number of cases of COVID-19 (337 cases per 100,000) in Germany. This study aimed to describe the rates of SARS-Cov-2 infections and the seroprevalence of SARS-CoV-2 antibodies in child-parent pairs, using a population-based sample. Children aged 1 to 10 years old and their corresponding parent (no age limit) living in the same household were eligible for this study. Previous laboratory-confirmed SARS-Cov-2 infection diagnosed before enrolment in either, the child or their parent and/or a child history of severe congenital disease or severe congenital malformations were specified as exclusion criteria. Data collection commenced on the 22nd April 2020 and finalised on 15th May 2020. RTC-PCR testing in naso and oropharyngeal swabs was used to detect the SARS-CoV-2 infections. SARS-Cov-2 IgG antibodies were measured using both, a commercial ELISA for the virus S1 protein and an immunofluorescence test. Where negative in both assays, no further testing was undertaken; if results were discordant, confirmation was carried out with a second ELISA, an in-house-Luminex based assay or electrochemiluminescense assay. Study participation was voluntary.

Analysis: Mixed-effect logistic regression models using seropositivity as response were fitted to account with the paired child-parent structure.

Results: 2250-child-parent pairs were enrolled and 2482 were included in the final analysis (2482 children aged between 1 and 10 years, and 2482 corresponding parents aged between 23 and 66 years old).

70/4964 participants were classified as IgG-positive (9/1129 children aged 1 to 5 years [0.8%]; 13/1353 children aged 6 to 10 years [1.0%] and 48/2482 parents [1.9%]), 60 in both assays and 10 were confirmed through a third test. SARS-Cov-2 neutralising antibodies were detected in 66/70 samples.

56 families with at least one parent or child seropositive for SARS-Cov-2 were reported. The most common combination was seropositive parent and seronegative child (34/56), followed by seropositive child-parent pairs (14/56) and seropositive child with seronegative parent (8/56). The estimated seroprevalence in parents was 1.8% (95% CI, 1.2-2.4), 3.6-fold lower in children aged 1 to 5 years old (0.5%[95% CI 0.2-0.9]) and 2.6-fold lower in children aged 6 to 10 years old (0.7% [95% CI 0.4-1.4])

Only 2 participants(0.04%) tested positive for SARS-Cov-2 RT-PCR (1 child and the corresponding parent). They reported mild-symptoms suggestive of COVID-19 several weeks before enrolment and had detectable neutralising antibodies.

No statistically significant differences in seropositivity were found among children attending exceptional child day-care during lockdown compared to those not attending. A history of symptoms suggestive of SARS-Cov-2 coupled with seropositivity was more common in parents than in children.

Considerations: this is a point-seroprevalence study of SARS-Cov-2 antibodies estimated in a large sample size of child-parent pairs, combining at least 2 serological assays to maximise diagnostic accuracy in a setting with low prevalence. An exciting finding of this study lies on the rates of seropositivity in children attending exceptional childcare. While these were not higher than the observed in children not attending exceptional childcare, the result suggests that contact restrictions may not explain the difference in seropositivity between children and adults. It is important to state that this study was carried out during lockdown and the impact of reduced exposure on the seroprevelance of SARS-Cov-2 IgG in children cannot be excluded.

Leidman, ESauber-Schatz, EMMWR Morb Mortal Wkly Rep 70(3): 88-94COVID-19 Trends Among Persons Aged 0–24 Years — United States, March 1–December 12, 2020 22 Jan 2021United States of AmericaNorth America1222033Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7003e1-H.pdf

The study took place between 1st March 2020 and 12th December 2020 across 44 states in the United States of America with 2,871,828 test results in children and young adults analysed. 1,222,033 (42.6%). of the total were in children aged 0-17; 7.4% were age 0-4, 10.9% age 5-10, 7.9% age 11-13 and 16.3% age 14-17. There was no gender difference in the children aged 0-17. For analysis the children were divided into different age groups reflecting their type of education.

Weekly incidence was higher in each successively increasing age group; and was highest during the final week of the review period (the week of 6th December) in all age groups: 99.9 per 100,000 (0–4 years), 131.4 (5–10 years), 180.6 (11–13 years), 255.6 (14–17 years), and 379.3 (18–24 years). Trends in weekly incidence for all age groups aged 0–17 years paralleled those observed among adults since June. The trend in incidence among young adults aged 18–24 years had a distinct and more prominent peak during the week of 6th September.

Weekly SARS-CoV-2 laboratory testing among children, adolescents, and young adults increased 423.3% from 435,434 tests during the week beginning 31st May to 2,278,688 tests during the week beginning 6th December. At their peak during the week of 15th November, tests conducted among children and adolescents aged 0–17 years represented 9.5% of all tests performed, and tests among young adults aged 18–24 years represented 15.3%.

Case data do not indicate that increases in incidence among adults were preceded by increases among preschool- and school-aged children and adolescents. In contrast, incidence among young adults (aged 18–24 years) was higher than that in other age groups throughout the summer and autumn, with peaks in mid-July and early September that preceded increases among other age groups, suggesting that young adults (age 18-24) might contribute more to community transmission than do younger children.

The authors highlight four limitations of their study, testing was often prioritised amongst symptomatic patients, the data for ethnicity and underlying conditions was incomplete, the reporting of laboratory data differed by jurisdiction and might underrepresent the actual volume of laboratory tests performed, and finally, the presented analysis explored case surveillance data for children, adolescents, and young adults; trends in cases among teachers and school staff members were not available because cases are not reported nationally by occupations other than health care workers.

This is an important paper whose conclusion for children are highly significant. In the last paragraph of the papers the authors are very clear saying “CDC recommends that K–12 (Kindergarten to year 12) schools be the last settings to close after all other mitigation measures have been employed and the first to reopen when they can do so safely”

Ulyte, A Kriemler, SmedRxivClustering and longitudinal change in SARS-1 CoV-2 seroprevalence in 2 school-children: prospective cohort study of 55 schools in Switzerland22 dec 2020switzerlandEurope2603Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.19.20248513v1.full.pdf

This article is a pre-print and has not been peer-reviewed.

Introduction: This study was a longitudinal cohort study of school going children in Switzerland across two time measuring SARS-CoV-2 antibodies and symptoms across two time points, June-July (T1) and October-November (T2). Schools were open with preventative measures during both time points. In Autumn 2020, Switzerland experienced one of the highest second waves of Sars-Cov-2 infection in the world at the time.

Methods: Primary schools in Zurich were randomly selected, stratified by region, and matched with the geographically closest secondary school. Of 156 invited schools 55 took part. Classes within participating schools were selected randomly stratified by school level; lower school grade 1-2 attended by 6 to 9-year-olds; middle school grades 4-5 attended by 9 to 13/14 year-olds and upper school grades 7-8 attended by 12 to 16-year-olds. Children were excluded who had active symptoms of SARS-COV2 as this precluded their attendance at school. Clusters within classes were defined as three or more cases of newly seropositive children within a class in autumn (T2) testing. Clustering was compared against stimulated models where independent chance of seropositive testing was assumed. Semi structured interviews with school principals where clustering occurred to further investigate clusters

Infection control measures: Preventative measures were by August varying degrees of; masks for teachers and students over 12 years, tapering of school breaks, distancing rules in class and teacher rooms, no parents on premises. Mandatory masks for adults in schools from October. Mandatory masks for children over 12 years from November. Once an index case was identified in a school children and school personnel were quarantined based on contact-tracing of close contacts. Full classes were quarantined only when two or more infected students were identified within a class.

Results: Estimated SARS-CoV-2 seroprevalence in T1 in children was 2.4%. Seroprevalence in autumn (newly seropositive in T2) in children was 4.5%. T1+T2 seroprevalence (ever positive to covid) per age was lower school 8.5% , middle school 8.0% , and upper school 6.4%. At least one ever seropositive child was detected in 52 out of 55 schools and in 125 out of 275 classes. Clusters of 3 or more newly seropositive children were observed only in 7 classes out of 55 schools. Symptoms between the summer break and November 2020 were reported in 21.8% of seronegative and in 28.7% newly seropositive children (T2).

In T2 SARS-CoV-2 antibodies were not detected after four months for 40% previously seropositive children.

Conclusion: This study demonstrated only minimal clustering of seropositive children between July and November 2020 despite a clear increase in seroprevalence among children during a time of very high community transmission. Clustering occurred within classes rather than across schools. In contrast to some other studies, a higher seroprevalence or clustering of cases in children of older age in the secondary schools was not observed. Authors felt this may be related to mandatory mask wearing in these older children. Authors suggested this study would support keeping schools open even in times of high community prevalence, once preventative measures are in place within schools and communities.

Villaverde, STagarro, AJ Pediatr.Diagnostic Accuracy of the Panbio SARS-CoV-2 Antigen Rapid Test Compared with Rt-Pcr Testing of Nasopharyngeal Samples in the Pediatric Population20 JAN 2020SpainEurope1620Epidemiology - Transmissionhttps://www.jpeds.com/article/S0022-3476(21)00034-2/fulltext

Background: There is currently a gap between the increasing number of patients and the testing capacity of RT-PCR laboratories; rapid antigen tests have emerged as a possible solution. The Panbio Rapid Antigen Test (Panbio Test) is a simple and rapid test that can detect the SARS-COV-2 virus in nasopharyngeal samples (NPS) and is based on lateral immunochromatography. According to the manufacturer’s information, the test has a sensitivity of 93.9% (95%CI: 86.5-97.4%) in the adult population with <7 days of symptoms. Further studies in the adult population have shown a sensitivity closer to 85% in adults with <5 days of symptoms. However, there is a lack of data assessing the accuracy of these rapid antigen tests in the paediatric population.

Method: This retrospective, multicentre study, which was nested in a prospective, observational multicentre study assessed the diagnostic accuracy of the Panbio test against the more globally used RT-PCR in the paediatric population. Paediatric patients aged between 0-16 years who presented to one of seven Spanish Emergency Departments with symptoms compatible with SARS-COV-2 infection of ≤5 days of evolution were included in the study. Patients who had close contact with confirmed COVID-19 patients and were asymptomatic were excluded.

The collection of two nasopharyngeal samples from each patient occurred concurrently by trained nurses. The Panbio test was performed on site with guidance from the manufacturer’s instructions and interpreted by attending clinicians. Whereas the RT-PCR tests were analysed by microbiology specialists from the laboratories in the participating centres. The study achieved the minimum sample size of 1200 patients, calculated with the use of 80% power, for a 5% prevalence of COVID-19 and a 90% sensitivity of the Panbio test. RT-PCR was also used as the gold standard reference. A total of 1620 paediatric patients were recruited between September and October 2020.

Results: Of the 1620 patients tested, 77 tested positive by RT-PCR (4.8%), 38 tested positive by the Panbio Rapid Antigen Test (2.3%) and 35 patients tested positive by both tests (2.1%). Discordant results occurred in 45 antigen test results compared with RT-PCR (2.7%): 3/1543 (0.2%) false-positive antigen tests and 42/77 (54.5%) false-negative test results. There was a significant difference between the two diagnostic results (P value = 1.47 x 10-08). The sensitivity of the Panbio test was 45.5% (95%CI, 34.1-57.2) and the specificity was 99.8% (95%CI, 99.4-99.9). The test also had a positive predictive value (PPV) of 92.5% (95CI, 78.6-97.4) and a negative predictive value (NPV) of 97.3% (95CI, 96.8-97.8). The positive likelihood ratio (PLR) was 233.8 (95%CI, 73.5-743.3) and the negative likelihood ratios (NLR) was 0.54 (95%CI, 0.44-0.67).

Conclusions and Limitations: The aim of this study was to assess whether the Panbio test is effective in identifying SARS-COV-2 in the paediatric population; and whether it can be used as an alternative to the expensive and slow RT-PCR test. Although the manufacturers state a high sensitivity of the Panbio test in the adult population, this study found that the Panbio test had a relatively low sensitivity in the paediatric population (45.5%, 95%CI, 34.1-57.2). The low sensitivity meant a high proportion of false-negative results (54.5%) which would result in the spread of the infection increasing if contagious patients are not accurately identified and isolated. Regardless of the low sensitivity and NLR, the use of the Panbio test as a primary screening tool may be viable due to the low cost, speed of results and high PLR. However, clinicians should be made aware of the actual accuracy of the test and whether other methods of diagnosis are required.

Without further assessment, the large number of false negative results may seem to be an issue with the antigen test itself but there are multiple explanations which could lead to the invalidity of the results. This study used RT-PCR as the gold standard diagnostic method however, a study by Rhee et al. (2020) found that RT-PCR positivity can persist for weeks to months after infection of SARS-COV-2. However, concordance between contagiousness and RT-PCR or antigen positivity is not clearly known and therefore, the use of RT-PCR as the gold standard may not be appropriate when assessing the accuracy of the Panbio test.

The study also failed to note the time between onset of symptoms and testing or the cycle-threshold values of RT-PCR, and therefore it was not possible to assess whether a high cycle threshold could be attributed to the low sensitivity of the antigen test. The inclusion criteria of symptoms were also not listed. Without this data, it is not possible assess whether the Panbio test would be suitable for inter-country use as the guidance of COVID-19 symptoms may differ between countries. In addition to the above, epidemiological data on the participants of this study were not given. As noted in some studies, NPS viral loads may differ between adult and paediatric populations and the exclusion of data relating to the age and gender of the participants makes it difficult to exclude data collection bias. The authors do note however that as a pre proof, the ongoing research of the study team will include some of the missing information.

Hommes, FMockenhaupt, FmedRxivSARS-CoV-2 infection, risk perception, behaviour, and preventive measures at schools in Berlin, Germany, during the early post-lockdown phase: A cross-sectional study18 Dec 2020GermanyEurope385Epidemiology - Transmissionhttps://doi.org/10.1101/2020.12.18.20248398
Larosa, EBedeschi, EmedRxivSecondary transmission of COVID-19 in preschool and school settings after their reopening in northern Italy: a population-based study18 11 2020ItalyEurope43Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.17.20229583v1

This study is a pre-print and so should be interpreted with caution whilst awaiting peer review.

This is a prospective study looking at transmission of COVID-19 in schools in the Reggio Emilio province of northern Italy (population 530,000). Schools re-opened in Italy from the beginning of September.

Methods: All SARS-Cov-2 positive tests are reported to the local authority and contact tracing is done. This study analyses consecutive cases that investigation showed attended or worked in a school or nursery between 01.09.20 and 15.10.20. For each of these index cases, everyone in the class was immediately tested. If this was less than 6 days from the last contact with the index case, a 2nd swab was collected at 10-14 days. Only close contacts of the case were isolated unless social distancing was not observed, or a secondary case was identified.

Results

• 43 index cases were found (5 teachers and 38 students)

• 994 students and 204 teachers were identified as possible contacts and tested

• 39 secondary cases were found among the students, an attack rate of 3.9% overall but 0% in pre-school children, 0.44% in primary and 6.64% in secondary children

• No secondary cases amongst the teachers

• The authors were satisfied that all the positive cases were most probably secondary to the identified index case

More details of the contact tracing are given but no indication as to its completeness though it was clearly done on the ground with assessment of the risk of secondary infection in each individual class so that whole classes were not necessarily sent to isolate.

Importantly, infection prevention measures are listed including:

- Masks worn unless at desks and not speaking (exception is primary school where they are never mandatory

- Single desks 1m apart

- Avoiding crowding at school entrance/exists by staggered start/stop times

- Suspension of extracurricular activities

- If class sizes too small for social distancing, class sized halved and a rota system adopted

This study was done as case numbers were rising during the second wave in Italy but concluded 4 weeks before the peak. The authors explain why they do not think this affects their results.

Conclusion: A low secondary attack rate was observed in educational settings in Italy during the start of the second surge of cases, increasing dependant on age with no secondary cases in pre school and 6.6% in secondary children. The low SAR is particularly notable in the youngest children given modest infection prevention measures and no mandatory mask use.

Li, FWong, GLancet Infect DisHousehold transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study18 01 2021ChinaAsia327Epidemiology - Transmissionhttps://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30981-6/fulltext

In this large retrospective from Wuhan, China, household transmissibility of SARS-CoV-2 and risk factors for transmission were assessed based on the epidemiological investigation conducted by the Wuhan Center for Disease Control and Prevention.

Methods: All clinically or laboratory confirmed cases diagnosed in Wuhan between December 2nd, 2019 and April 18th, 2020 and their household contacts were included. A household contact was defined as a close family member or relative with unprotected contact with a case within 2 days before symptom onset or positive PCR test. For each household, the date of first symptoms onset or first positive test of a household member was defined as day 1; primary cases were defined as cases with symptom onset or positive test on day 1 or 2 (allowing for co-primary cases within a household). Later cases were classified as secondary. Notable changes in case identification during the study period included a requirement to report asymptomatic infections from February 1st and testing of all household contacts regardless of presence of symptoms from February 23rd.

Observed secondary attack rate was calculated as the proportion of secondary infections amongst household contacts. Further analysis was conducted using two models. Firstly, a generalised estimating equation (GEE) regression model was used to assess individual and household level risk factors for infection of household contacts. This analysis included only household with a single primary case. Secondly, a binomial transmission model was used to evaluate infectivity and susceptibility to infection accounting for exposure history by comparing the daily probability of transmission from cases to their household contacts between groups. This model also accounted for relative susceptibility of household contacts in assessing infectivity of a primary case.

Results: A total of 27,101 households with 29,578 primary cases with 57,581 household contacts were included. Median household size was 3 (IQR 2-4); median age amongst cases was 56 years (IQR 43-66). Secondary attack rate in houses with a single primary case was 16.0% (95% CI 15.7-16.3%).

Household contacts <20y.o. were 66-86% less susceptible to infection compared to adults >60y.o. in the transmission model (and 68-85% less susceptible in the GEE model). Infants <1y.o. were relatively more susceptible to infection compared with older children aged 2-5y.o. (OR 2.20 (95% CI 1.40-3.44)) and 6-12y.o. (OR 1.53 (95% CI 1.01-2.34)), but less susceptible compared with adults >60y.o. (OR 0.32 (95% CI 0.21-0.50)). Of secondary cases <20y.o. a similar proportion remained asymptomatic (15.3%) compared to the asymptomatic proportion overall (16.0%). Severe or critical COVID was significantly less common in secondary cases <20y.o. (2.4%) compared with those >60y.o. (18.8%)

For primary cases <20y.o. household transmission was 34% less likely to occur compared to primary cases aged 60-79y.o. (OR 0.66 (95% CI 0.48-0.90)) according to the GEE model. In contrast, the transmission model identified primary cases <20y.o. to be more infectious than compared to those aged >60y.o. (OR 1.58 (95% CI 1.28-1.95). Notably only 1.4% of primary cases were <20y.o.(413 / 29,578) and analysis of more refined age groups amongst primary cases was not attempted "due to the limited number of cases among young children".

Both models found that primary cases who remained asymptomatic were less likely to infect household contacts; OR 0.21 (95% CI 0.14-0.31) in the transmission model (for cases after February 1st).

Discussion: The findings of this large contact tracing study are largely in keeping with data from similar studies previously published, including the lower susceptibility of children to SARS-CoV-2 infection and the milder course of COVID-19 in children compared with adults. Similarly, the reduced infectivity of asymptomatic primary cases is in keeping with emerging data from epidemiological studies elsewhere.

The conflicting findings regarding infectivity of primary cases <20y.o. is likely related to the differences between the two models with the GEE model indicating lower infectivity and the transmission model higher infectivity in this age group. The transmission model attempted to adjust for duration of exposure by calculating daily transmission probability (which was inversely proportional to exposure person-days (denominator)). In post-hoc exploratory analysis, the authors attribute the higher infectivity in primary cases <20y.o. indicated by the transmission model to a shorter exposure period from onset of illness to isolation compared with adults (5 days vs 10-11 days). The validity of the adjustment in this model for exposure time may not be entirely sound considering the period of highest infectivity of SARS-CoV-2 occurs just prior to or soon after symptom onset. In addition, children were grossly underrepresented as index cases, with a surprisingly small fraction of asymptomatic cases documented. Oversampling of symptomatic children is likely to overestimate the infectiousness of children more generally, due to the noted disparity between the infectiousness of symptomatic vs asymptomatic cases. Considering the limitations of the model used together with the lack of more detailed age banded analysis due to the limited number of primary cases among young children, the results regarding infectiousness should be interpreted with caution.

Lewis, NKirking, HClin Inf DisHousehold Transmission of SARS-CoV-2 in the United States.16 Aug 2020USANorth America69Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1166/5893024

This study, published on 16th August 2020, recruited COVID-19 patients and their household contacts in two US states, Utah and Wisconsin, from 22nd March to 25th April 2020, to examine SARS-CoV-2 transmission, estimate the household secondary infection rate (SIR) and evaluate potential risk factors for secondary infection within US households.

Background: The Centre for Disease Control and Prevention (CDC) collaborated with state and local health departments in the Milwaukee, Wisconsin, and Salt Lake City, Utah, metropolitan areas to identify laboratory-confirmed SARS-CoV-2 infections in “index patients”. These two areas were chosen based on the presence of interested public health partners and the relatively low COVID-19 prevalence in both regions (thereby reducing the risk of additional community exposure to household contacts). March to May 2020 was a period of shelter-in-place orders and social distancing recommendations across the United States; stay at home orders/recommendations came into effect in both states in late March.

Study population: Local health department staff completed their own investigations of reported cases captured by public health surveillance during the period 22nd March to 25th April 2020 and then informed potential eligible index cases about CDC’s study: index cases were considered eligible if not hospitalised at the time, living with 1 additional person and tested positive for SARS-CoV-2 rRT-PCR from a nasopharyngeal swab collected  10 days prior to enrolment. Households where >1 household contact declined to participate were excluded; households with separate entrances were prioritised (to facilitate patient confidentiality and CDC team infection control). At the time SARS-CoV-2 outpatient testing was limited to individuals meeting CDC criteria for influenza testing in Wisconsin (excluding asymptomatic or mildly symptomatic cases who were not health care workers) and required clinical features (fever, cough or shortness of breath) and an epidemiologic risk factor in Utah. Once enrolled by the CDC investigation team, all household members were classified as either “primary patients” (positive PCR test with symptom onset >1 day prior to symptom onset of others in the household with laboratory-confirmed SARS-CoV-2 infection; this person could differ from the index case if during the investigation infection was confirmed in a person with an earlier symptom onset date than the index case) or “household contacts” (everyone living in the same household as the primary patient). For asymptomatic cases, onset was defined as collection date of first positive PCR test. Secondary infections were defined as household contacts with either respiratory swabs positive for SARS-CoV-2 rRT-PCR or sera positive for SARS-CoV-2 antibodies tested by enzyme-linked immunosorbent assay (ELISA).

Collection of data: Phone questionnaires covering demographics, medical histories and recent symptoms for index patients and all household contacts were administered prior to the first household visit. A household-level questionnaire detailed physical characteristics of the residence. There were 2 in-person visits by the investigation team to each household on day 0 and day 14, collecting a nasopharyngeal swab, a self-collected anterior nasal swab and a blood sample for all household members, including the index patient. Each person completed a daily symptom diary from day 0 to day 14. If a household member became newly symptomatic there was an interim visit at which repeat swabs were obtained for all household contacts.

Characteristics of households: 62 households were enrolled (36 in Utah and 26 in Wisconsin); 4 were excluded where the primary patient could not be identified. The remaining 58 households (34 in Utah and 24 in Wisconsin) comprised 58 primary patients and 188/197 (95%) household contacts (9 household contacts declined participation after initial household enrolment). Median number of persons per household: 4 (range 2-16). Median house size: 2,200 square feet (range 600-8,000). 55/58 (95%) households reported precautionary practices (such as ill persons sleeping in a separate bedroom and using face coverings) at some point following symptom onset of the first confirmed case in the household.

Characteristics of 58 primary patients: Median age: 40 years (range 16-90). <18 yrs 1/58 (2%, aged 16 yrs), 18-49 yrs 39/58 (67%), 50-64 yrs 16/58 (28%), 65 yrs 2/58 (3%). Female 26/58 (45%). Co-morbidities: 21/58 (36%) (lung disease 16%, cardiovascular disease 12%, diabetes mellitus 5%, renal disease 3%, immunopromising condition or medication 3%). Symptoms: respiratory 56/58 (97%), neurological 51/58 (88%), constitutional (chills, fever, myalgia) 50/58 (86%), gastrointestinal 41/58 (71%). 1 primary patient asymptomatic (tested based on a known non-household exposure). Median interval from symptom onset to day 0 household visit: 11 days (IQR 8-16). Median interval from collection of first positive specimen to day 0 household visit: 6 days (IQR 4-8). 3/58 (5%) hospitalised; 1/58 (2%) died.

Characteristics of 188 household contacts: Median age: 22 years (range <1-76). <1 yr 1/188 (0.5%), 1-9 yrs 28/188 (15%), 10-17 yrs 39/188 (21%), 18-49 yrs 88/188 (47%), 50-64 yrs 26/188 (14%), 65 yrs 6/188 (3%). Female 96/188 (51%). Co-morbidities: 60/188 (32%) (lung disease 18%, cardiovascular disease 9%, diabetes mellitus 3%, renal disease 1%, immunocompromising condition or medication 1%, liver disease 1%). 3 pregnant (out of 37 females aged 15-44 yrs, 8%).

Secondary infections among household contacts: Secondary transmission in 31/58 (53%, 95% CI: 41-66%) households. Secondary infections in 52/188 (SIR 28%, 95% CI 22-34%) household contacts: 44/52 (85%) with positive PCR and 46/50 (92%) with SARS-CoV-2 antibodies. Median interval between symptom onset of primary patient and infected household contact 5 days (IQR 4-9). At day 0 initial visit 43/52 (83%) had already acquired secondary infection; 9/52 (17%) acquired secondary infection during the 14 day investigation period. 8/52 (15%) had SARS-CoV-2 antibodies but no positive PCR during the investigation (all 8 symptomatic with symptom onset 2 days after primary patient: 4 seropositive on day 0, 3 seroconverted between days 0 and 14, 1 didn’t have serology test on day 0 but seropositive and PCR negative on day 14).

Repeat analysis excluding contacts with evidence of secondary infection by serology only (to address potential misclassification of secondary infections) and using positive PCR results only: 44/188 (SIR 23%, 95% CI 18-3-%).

Secondary infections by age and family relationships: SIRs were highest among children (<18 yrs old) of the primary patient (18/43, 42%), adult children (18 yrs old) of the primary patient (6/17, 35%) and spouses/partners of the primary patient (11/33, 33%).

However, the SIR in children hides important differences. Of the children <10 years the SIR was significantly lower for both children of the index case (3/17, 18%) and not of the index case (0/12, 0%) compared to children aged 10 – 18 years (child of primary = 15/26, 58%, non-child of primary = 1/13, 8%).

There was only one primary patient aged <18 yrs: their 3 household contacts remained uninfected.

Risk factors for secondary infection in household contacts: Household contacts with diabetes mellitus had higher odds of secondary infection compared with those without (SIR 80% vs 26%, OR 7.8, 95% CI 1.3-47.3). The authors note that collinearity between diabetes mellitus and obesity may have confounded the association. Household contacts of a male primary patient were more likely to acquire secondary infection than those of a female primary patient (SIR 36% vs 18%, OR 2.4, 95% CI 1.1-5.3). Household contacts of a primary patient with an immunocompromising condition had higher odds of secondary infection compared with contacts of a primary patient without an immunocompromising condition (SIR 88% vs 25%, OR 18.1, 95% CI 2.6-125.1). The authors suggested that this could be due to more severe or prolonged illness in these primary patients, resulting in greater viral shedding, or closer caregiving needs required by these patients, resulting in higher risk to contacts. There was only one asymptomatic primary patient: their 2 household contacts remained uninfected. Households with <6 persons had a median of 1 secondary infection (IQR 1-2) and households with 6 persons had a median of 3 secondary infections (IQR 2-4). The risk of transmission within a household was not different based on square footage per person or number of persons per bedroom or bathroom.

Limitations identified by authors: This study assumed that household transmission was responsible for infections in household contacts: while stay-at-home orders should have limited community exposures at the time, this may overestimate household SIR. Potential misclassification of primary patients would affect the analysis. The study population may not be representative of all US households (both states have relatively larger average household sizes and apartment buildings were excluded). Delays in testing and reporting at the time meant that transmission had already occurred by enrolment in many households, which made transmission dynamics more difficult to assess. Additional transmission chains may have occurred after the investigation period.

Conclusions: There was only one primary patient in this study aged <18 years (who didn’t transmit infection to their 3 household contacts), so conclusions cannot be drawn about transmission from SARS-CoV-2-infected children to their household contacts. The study showed a relatively high rate of secondary infection amongst household contacts of SARS-CoV-2-infected adults, with 31/58 (53%) of households having evidence of at least 1 household contact who acquired secondary infection from the primary patient. The SIR was 29% (55/188 household contacts acquiring secondary infection from the primary patient). Children aged <10 years had a lower SIR, where-as children aged 10 – 18years had a higher than average SIR. This highlights the importance of age disaggregated data when analysing infection properties amongst children.

Brotons, PMunoz-Almargo, CClinical infectious diseases SUSCEPTIBILITY TO SARS-COV-2 INFECTION AMONG CHILDREN AND ADULTS: A SEROPREVALENCE STUDY OF FAMILY HOUSEHOLDS IN THE BARCELONA METROPOLITAN REGION, SPAIN12 Nov 2020SpainEurope672Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1721/5979490

A cross sectional survey of 381 quarantined households undertaken between 28 April 2020 and 3 June 2020 in Barcelona, Northern Spain. The households were identified by at least one parent being Real Time PCR positive for SARS-CoV-2. Family members, 672 children (defined as <15 years of age) 357 boys and 412 adults (defined as ≥ 15 years age) 235 male, were tested at home by a rapid SARS-CoV-2 antibody assay using finger-prick capillary blood.

The number of children who were seropositive was 118 of 672 (17.6%, 95% CI 14.8-20.7%) and was not different to the number of adults 77 of 335 (18.7%, 95% CI 15.0-22.8%) who were positive. Very few children had symptoms except one child who developed multi-system inflammatory syndrome (Kawasaki like).

The authors concluded “Children appear to have similar probability as adults to become infected by SARS-CoV-2 in quarantined family households but remain largely asymptomatic once infected”

Limitations to the study include that although similar prevalence of seropositivity was observed between the 2 groups, it cannot be confirmed whether the exposure was in the household given the study period was after the most intense period of community transmission in Spain. In addition, evidence is emerging which suggests children can seroconvert following exposure to the virus without developing clinical or virological infection.

Tosif, SCrawford, NNat CommunImmune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-1911 NOV 2020AustraliaAustralasia3Epidemiology - Transmissionhttps://doi.org/10.1038/s41467-020-19545-8

This is a retrospective case study of three children, of parents with symptomatic COVID-19 disease, who developed immunologic evidence of infection whilst exhibiting only mild or no symptoms. The study was conducted in Melbourne, Australia during March 2020.

Analysis: The two parents, age 38 and 47 years, developed symptomatic COVID-19 infection, comprising cough, coryza, fever and headache. They were SARS-CoV-2 PCR positive on nasopharyngeal (NP) swabs. Seven days later one child (male, age 9 years) developed cough, coryza, sore throat, abdominal pain and loose stools and a second child (female, age 7 years) developed cough and coryza. A third child (female, age 5 years) was asymptomatic. Repeated NP swabs from the children were negative for SARS-CoV-2 by PCR, as were saliva and stool samples.

All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA. Plasma from both parents and one child had IgG antibody against the S1 protein and virus-neutralizing activity detected. All family members, including the children, exhibited SARS-CoV-2-specific antibody features that differed from pre-pandemic controls. Cellular immune profiles and cytokine responses of all three children were similar to the parents at all timepoints.

Conclusions: The authors conclude that despite having no virological evidence of infection, all three children developed antibody responses against various SARS-CoV-2 epitopes. They suggest that the children were infected with SARS-CoV-2 but, unlike the adults, mounted an immune response that was highly effective in restricting virus replication. They speculate whether this will confer protection against re-infection.

Finally, the authors note that the discordance between the virological PCR results and clinical serological testing, despite an evident immune response. This highlights an important difference in studies which aim to either assess for evidence of clinical infection (rt-PCR) or combined evidence of infection or exposure (serology). Testing for rt-PCR only may miss children who have had exposure to the virus. However, testing via serology may detect children who have seroconverted without ever developing clinical or virological infection.

Depending on the purpose of testing or screening programmes, this raises the possibility of false negatives for rt-PCR and false positives for serology. This studies would suggest rt-PCR is superior for understanding the risk of transmission to or from children, as those who seroconvert in the absence of any virological evidence of disease are extremely unlikely to pose a risk of passing infection on to others

Oster, AMBoehmer TKMMWRTransmission dynamics by age group in COVID-19 hotspot counties - United States, April–September 202009 OCT 2020USANorth AmericaEpidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6941e1.htm

This retrospective observational review reports the temporal progress of SARS-CoV-2 infections in ‘hotspots’ across the entire USA, between April and September 2020, with regard to the peaks for distinct age cohorts. Case numbers are not given but children (0-17yrs) are included. Of interest is the trend for young adults (18-24yrs) to lead the outbreak, followed by children, before spreading, in age order, to older cohorts. This was seen in all the regional breakdowns analysed, as well as the overall picture for the US.

The reason for this is not addressed (perhaps due to increased rates of mixing in high risk situations), but the authors highlight the need for policy measures focussed on reducing transmission among young adults, as well as preparation for the likely rise in cases, hospitalisations and fatalities in older age groups which follows from these surges.

Gandini, SScorrano, LmedRxivNo evidence of association between schools and SARS-CoV-2 second wave in Italy08 Jan 2021ItalyEurope112000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.16.20248134v2

This is a prospective cross sectional cohort study of school children (6-18yrs), teachers and school staff in Italy. Data was derived from those schools who were reporting their cases to the national database from the ministry of education. A variety of different epidemiological parameters were determined at different times between 20/09/2020 – 05/12/2020. The children were split into 4 groups (Kindergarten 3-5yr olds, elementary 6-10yr olds, middle school 11-13yr olds and high school 14-18yr olds) based on their educational setting. The incidence of positive cases (determined in the time period 20/09/20 – 8/11/2020) was lower in school children (66/10 000 in elementary and middle school and 98/10 000 in high school) than in the population (108/10 000). However, the incidence in teachers and staff members was two-fold higher (220/10 000) than the population. Incidence of new positive cases in elementary and middle school was on average 38.9% lower and in high school (except in 3 regions where it was higher) 9% lower than in the population. The new positive cases were higher in teachers (1.52% of teachers) and staff members (1.96% of staff members) than students (0.32% of students).

Setting New positive cases (% of students) New positive cases (% of teachers) P value

Kindergarten 0.21 2.35 <0.001

Elementary 0.35 1.83 <0.001

Middle school 0.45 1.6 <0.001

High school

Contract tracing information (collected between 23/11/20-5/12/20) gave a least square estimation of secondary cases of 1% per school per week for teachers and students in kindergarten, elementary and middle school. This rate was not statistically different in situations where the index case was teacher or student. Clusters (>2 positive cases in the one week following contact tracing of index case) occurred in 5-7% of schools.

Temporal investigations to determine whether schools were a driver in the second wave, looked at the timings school opening and the increase in the reproduction number (Rt) in different regional pairs. The increase in Rt occurred after school re-opening but time delayed increasing in Rt was shorter in regions that opened later with 5.7 days delay where schools re-opened 22-24 of September compared to 12.4 days where reopening was 14-16 September. A heatmap of Covid 19 cases in the region of Veneto was created for the period of August-early September which showed that the earliest increases in the incidence of new cases occurred in the 20-49yr olds for this 8 week period. Comparison of incidence of cases amongst teachers and the general population aged 25-65 in Veneto between19/09-18/10 shows that the incidence in teachers increases after the increase in the general population with no statistical difference in incidence at the end of this period (12/10 000 teachers and 11.1/10 000 gen population p=0.36). Secondary case analysis for the region of Veneto between 25/11/20-21/12/20 showed 380 student, 30 staff and 114 teachers’ index cases in 339 schools for which contact tracing was performed. 76 secondary cases were found with 71% of these being students. A secondary case among teacher is more frequent when the index case is a teacher than a student (38% vs. 11%, P=0.007). In the regions of Lombardy and Campania the Rt decline started occurring before the school closures were mandated on the 26/10 and 16/10 respectively(other restrictions were placed in the lead up to school closures). In Campania the incidence dropped in amongst students after school closure but continued to increase in the general population accounting for the Rt being >1 until 5-11 of November.

Not all schools nationally were contributing to the database and therefore the incidence may be higher than the figures stated in this paper. The data is also subject to delay in reporting as well as difference in criteria for reporting in different regions. Across all settings students seem to be less effected in terms of being infected and being the index case. Teachers however are more affected than the general population and the study suggests that the school setting confers a greater risk of acquiring the infection. The data from one region in Italy shows that the rate of incidence in teachers is the same as that of The temporal investigations suggests that the school re-opening coincided with a number of other drivers (unknown) occurring before or around the same time which was already poised to start increasing the Rt. You cannot rule out that the school re-opening did not contribute to the increase as all increases occurred after school re-opening. The data presented for the region of Veneto regarding index and secondar cases suggests that index and secondar cases are commonly students with teachers more likely to be secondary case if the index case was a teacher. These results are in a small sample and should be investigated further. The study states that the school closure did not affect the rate of Rt decline but this based on the figures from two regions only provide analysis on the rate of change in Rt in the days after school closure and not more long term and the rates themselves are not stated very clearly. The lag time in Campania between school closure and the Rt dropping below 1 was about a month and it would be interesting to know whether there was a similar time lag in other regions. The study states that the school closures in Campania did not curtail the rising incidence of cases in the population but fail to take into account the drop in incidence they mention amongst students or that the Rt only remained >1 until the 5-11th of November.

Brandal, LWinje, BEuro SurveillMinimal transmission of SARS-CoV-2 from paediatric COVID-19 cases in primary schools, Norway, August-November 202007 01 2021NorwayEurope13Epidemiology - Transmissionhttps://doi.org/10.2807/1560-7917.ES.2020.26.1.2002011

This is a prospective study designed to give a better understanding of the transmission of SARS-CoV-2 in school settings by systematic testing. This was done in the Oslo/Viken areas of Norway.

Since re-opening after the 1st wave, all schools implemented strengthened hygiene measure, physical distancing and had a strong message that children should stay at home with even mild symptoms.

Methods: 13 school contact tracing groups were identified. These had 14 index cases – children aged 5-13 with PCR-confirmed SARS-CoV-2 infection from nasopharyngeal swab, who had attended school within 48h before symptom onset or date of sampling. (8 of these 5-10y, 5 11-13y). 2 index cases were in the same class so treated as 1 contact tracing group.

292 school contacts of these children consented and were included (234 children, 58 adults)

2 Saliva samples were taken from index children and all contacts, the 1st as soon as possible after identification (for index cases this was 2-6 days after the NP sample, and for the contacts the morning after identification), the 2nd at the end of their 10-day quarantine. These were analysed by PCR.

Results: 3 of the contacts (2 children and 1 adult) tested positive on their 1st saliva test and are referred to as primary cases.

2 of these were children (2/234 0.9%) and 1 adult (1/58 1.7%).

No other contacts tested positive on their 2nd saliva test (these would have been secondary cases).

Other: The authors found self-collection of saliva samples to be acceptable, efficient and sensitive: the 1st saliva samples of 11/13 (85%) index cases were positive.

All except 1 index case had initial NP PCR done because of a positive household contact. Only 4 of the index cases were symptomatic at any point.

The authors note that the results are only valid for primary schools.

Caveats

• The incidence of SARS-CoV-2 infection was relatively low though rising during the study period (14-day incidence < 150 cases/100,000 inhabitants by November)

• Unclear how the 13/14 index cases were chosen from much larger group

• Article is not consistent re number of index cases (13 or 14)/contact tracing groups (13)

• 393 contacts were identified with 292 (c75%) consenting to participate in the study

Woolworth, KRTong, VTMMWR Morb Mortal Wkly Rep 2020Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 202006 Nov 2020USANorth America4527Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6944e2

This is a large cohort study of pregnant women with SARS-CoV-2 in the USA gathered through the SET-NET notifiable disease network covering multiple jurisdictions across the country. 5,252 pregnant women testing positive for SARS-CoV-2 were reported on.

Among the 3,912 infants with known gestational age born to women with SARS-CoV-2 infection, 12.9% were preterm (<37 weeks), higher than a US national estimate of 10.2%. The authors state that the data is preliminary and describe primarily women with second and third trimester infection, and their findings are subject to change pending completion of pregnancy for all women in the cohort and enhanced efforts to improve reporting of gestational age. This finding is consistent with other CDC reports describing higher proportions of preterm births among women hospitalized at the time of SARS-CoV-2 infection and includes outcomes for women hospitalized as well as those not hospitalized at the time of infection (representing a population including persons with less severe illness). Studies comparing pregnant women with and without COVID-19 are needed to assess the actual risk of preterm birth.

Non-Hispanic Black and Hispanic women were disproportionally represented in this surveillance cohort. Racial and ethnic disparities exist for maternal morbidity, mortality, and adverse birth outcomes and the higher incidence and increased severity of COVID-19 among women. This means national rates of preterm birth might not be directly comparable.

Further surveillance efforts, including reporting by additional jurisdictions to improve representativeness, and careful analysis of outcomes by race and ethnicity, will permit more direct and targeted public health action.

Information regarding the frequency and severity of perinatal (potentially including in utero, peripartum, and postnatal) infection is lacking. The American Academy of Paediatrics and CDC recommend testing all infants born to mothers with suspected or confirmed COVID-19 however, testing results were infrequently reported in this cohort.

Perinatal infection was uncommon, affecting only 16/610 (2.6%) infants known to have been tested for SARS-CoV-2 and occurred primarily among infants born to women with infection within 1 week of delivery.

Among the infants with positive test results, one half were born preterm, which might reflect higher rates of screening in the ICU. These findings also support the growing evidence that although severe COVID-19 does occur in neonates the majority of term neonates experience asymptomatic infection or mild disease, however, information on long term outcomes among exposed infants is unknown

Sisk, BOlson, LPediatricsNational Trends of Cases of COVID-19 in Children Based on US State Health Department Data06 Dec 2020United States of AmericaNorth America549432Epidemiology - Transmissionhttps://doi.org/10.1542/peds.2020-027425

Background: There has been a discrepancy in the data from the US on the proportion of cases of COVID-19 affecting children when comparing reports from the beginning of the pandemic with more recent reports. This report was from the American Association of Paediatrics and the Children’s Hospital Association in the US.

Methods: Data were collected extracted from state health departments publicly available reports on COVID-19 in children: COVID-19 incidence, trends by region, proportion of cases of COVID-19 occurring in children, hospitalization and mortality rate of COVID-19 in children.

The data came from 49 states, 2 urban centres (New York City (NYC) and Washington DC and 2 territory (Puerto Rico and Guam). Geographic regions were based on census categories: Northeast, Midwest, South and West.

Data was gathered from 16th April 2020 to 10th September 2020, pooled to derive national and regional information.

There were inter states differences in the use and reporting of viral tests.

Results: There was variation in the type of data provided among the states. Age distribution was provided by all states with the exception of 1 state which provided it based on 8% of its cases. Hospitalization rates were provided by 24 states and NYC and mortality rates were provided by 42 states and NYC. There were differences in child age range definitions: 0 to 17 years in 14 states and NYC, 0 to 19 years in 29 states and Washington DC, 0 to 14 years in 2 states and 0 to 20 years in 2 states with 1 state changing the definition on the 13th August from 0 to 24 to 0 to 17. Data from this state were not included on the trend analysis.

From 16th April 2020 to 10th September 2020 there were 549432 child COVID_19 cases, 729 per 100000 children.

Trends in overall number of cases reported per week in each of the 4 regions. There was marked variation in case growth per region:

Midwest: cases grew progressively during this period, peaking in September.

Northeast: although in April this region reported more cases than others, numbers decreased, and number of cases remained the lowest of the 4 regions.

South: Cases increases exponentially, reaching the highest number of cases per week of all 4 regions, peaking at the end of July but remaining high during the subsequent months.

West: Similar pattern of increase as in the South but with a smaller peek in late July, gradually dropping thereafter.

Trend in percentage of overall cases occurring in children:

The percentage of new cases per week occurring in children: this increased from 2.6% in April to 15.9% by the end of data collection in September. By mid-June, it had increased to 12.7%. There was a slight decrease during early July to around 10%, steadying at around 12% till mid-August when the percentage started increasing more rapidly again reaching 15.9% by September 10th.

The cumulative percentage of cases of COVID-19 occurring in children: this increased steadily from 2.2% in the latter part of April to 10% by September 10th. This is below the children’s share of the US population which is 22.6%.

Hospitalization: children made up a cumulative total of 1.7% of the total number of hospitalizations because of COVID-19. Approximately 2% of child cases resulted in hospital admission.

Mortality: Children made up 0.07% if total death because of COVID-19. 0.01% if child cases resulted in death.

The rate of hospitalizations and of mortality have remained stable across the study period.

Authors’ conclusions:

The data confirms that although children can contract COVID-19, severe disease is uncommon. The geographical profile of growth in cases, moving from the North East in April to the South and West in June and to the Midwest in July follow the pattern of the general population.

Comments: The strength of this report lies in its large data base derived from almost the whole of the US. However, there are a number of observations that are necessary:

Trends of cases in the 4 regions: the cases per week are not related to a population denominator and therefore it is not possible to comment on the overall burden of disease in each region. Nor are any adult data given for comparison. However, the most striking feature when comparing the epidemic curves in each of the 4 regions is that there were markedly fewer cases in the Northeast throughout the period of observation, with new cases remaining under 3000/week, whereas in the other 3 regions the cases increased exponentially to approximately 13,000/week in the Midwest, 15,000/week in the West and 22,0000/week in the South. The cases peaked in July in the South and West but were still increasing in September in the Midwest. There is no further information nor discussion as to possible explanations behind the very different pattern seen in the Northeast: is it due to lack of testing or to the implementation of social distancing and other non-pharmacological measures in this region to slow transmission? It is difficult to know how much of the epidemic curves are explained by increasing testing rates.

Percentage of children affected: the increase in the percentage of children affected might be due to either a true increase in transmissibility among children but is more likely to be due to either increasing testing in children relative to testing in adults as the months went on or that the infection rate in older adults was brought under control but community transmission among younger people and children continued.

There were variations between states as to age definitions and unfortunately there was no breakdown of the data into age groups, for example pre-school and school age children which might have yielded important information on transmission.

Grijalva, CTalbot, HMorb Mortal Wkly Rep.Transmission of SARS-COV-2 Infections in Households — Tennessee and Wisconsin, April–September 2020. 06 11 2020USANorth America14Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6944e1

In this prospective study of SARS-CoV-2 transmission, patients with laboratory SARS-CoV-2 infection and their household members were enrolled and followed for 14-days with a symptom diary and daily RT-PCR testing of self-collected nasal and saliva swabs. Households were recruited from Nashville, Tennessee and Marshfield, Wisconsin from April-September 2020. The index case was defined as the first household member to develop COVID-19 compatible symptoms with a positive RT-PCR result. Specimens collected in the first 7 days from enrolment were analysed for this report.

Results: A total of 101 households were enrolled and completed at least 7 days follow up: 101 index cases and 191 household members. The majority of index cases were young adults (65% aged 18-49yo) with a small number of child (5% aged <12yo) and adolescent (9% aged 12-17yo) index cases. Enrolment occurred a median of 4 days (IQR 2-4 days) after illness onset in the index case.

Among household members 102/191 had SARS-CoV-2 detected from a nasal or saliva specimen giving a secondary attack rate of 53% (95% CI = 46%-60%). For the small number of index cases <18yo, secondary attack rate was 53% (95% CI = 31%-74%) for children <12yo and 38% (95% CI 23%-56%) for those aged 12-17yo. One third (33%) of secondary cases remained asymptomatic through 7 days of follow up. Excluding 54 household members who were SARS-CoV-2 positive at enrolment (and therefore may have been infected at the same time as the index case from a shared exposure) the secondary attack rate was 35% (95% CI 23-56%).

Interpretation: The secondary attack rate reported here is higher than in a number of previous reports, possibly owing to the regular testing of household contacts detecting a higher proportion of asymptomatic secondary infections. In addition, many previous reports are from studies conducted in Asia, were prompt quarantine of all household members of an index cases are implemented, often in dedicated facilities or hospitals. Prolonged exposure would be expected to increase the SAR, as would the potential for 3rd generation infections (becoming infected from a different household member who became infected from the index case).

Similar to previous contact tracing studies, the small number of paediatric index cases limits the ability to draw conclusions about the overall contribution of children to SARS-CoV-2 transmission from this data. Furthermore, in the large proportion of household members who had detectable infection at the time of enrolment, determining direction of transmission is not possible as the potential for shared exposure of the index and secondary cases remains.

Notwithstanding limitations, the high secondary attack rate, and the proportion of asymptomatic cases reported here highlight the importance of mitigation measures within households as well as the isolation of all patients with SARS-CoV-2 and prompt quarantine and testing of close contacts to limit onward transmission.

Ng, KKassiotis, GSciencePreexisting and de novo humoral immunity to SARS-CoV-2 in humans06 11 2020UKEurope48Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/11/05/science.abe1107

It has been hypothesised that pre-existing immunity from previous seasonal "common cold" human coronavirus (HCoV) infection may provide individuals with some protection from SARS-CoV-2. In theory, cross-reactive antibodies may account for some of the variation in clinical severity within populations, including the relatively mild course of disease amongst children. In this paper from the UK, serum samples from uninfected adults and children were examined for cross-reactive antibodies to SARS-CoV-2 using a flow-cytometry-based assay. The presence, level, and target(s) of cross-reactive antibodies were assessed along with the ability of the antibodies to neutralise the virus in the laboratory.

Of initial samples from 302 uninfected adults, 5.3% (n=16) had detectable IgG to SARS-CoV-2. These antibodies cross-reacted with the S2 subunit SARS-CoV-2 spike protein (S2 is relatively conserved among coronaviruses compared with the S1 subunit) but not the receptor-binding domain (RBD) which is key in allowing binding to cells to facilitate infection. The level of SARS-CoV-2 cross-reactive antibodies correlated with the level of HCoV IgG and IgA in uninfected individuals, supporting a link between previous HCoV infection and cross-protection. Notably, cross-reactive antibodies were found in individuals both with and without evidence of recent HCoV infection, suggesting that other factors such as frequency of HCoV infection may be important for SARS-CoV-2 cross-protection.

Remarkably, 43.8% (21/48) of SARS-CoV-2 uninfected children (1-16yo) had SARS-CoV-2 cross reactive antibodies (IgG), compared with 2.3% (1/43) of young adults (17-25yo). Amongst children 6-16yo, almost two thirds (62%) had detectable cross-reactive antibodies. This observation is in keeping with the known age distribution of HCoV infection frequency which peaks in children and adolescents. Importantly, sera containing cross-reactive antibodies from uninfected patients demonstrated the ability to neutralise the virus in vitro, preventing viral entry into cells.

This interesting data support the hypothesis that pre-existing cross-reactive antibodies from previous HCoV infection are present in some individuals and may protect against COVID-19. The degree and duration of individual protection conferred by pre-existing cross-reactive antibodies along with any impact on onward transmission of SARS-CoV-2 remain uncertain. The higher prevalence of these pre-existing antibodies in children and adolescents may be an important factor in explaining the milder course of SARS-CoV-2 infection in this age group.

Ludvigsson, JNordenhall, CN Engl J MedOpen Schools, Covid-19, and Child and Teacher Morbidity in Sweden06 01 2021SwedenEurope15Epidemiology - Transmissionhttps://www.nejm.org/doi/full/10.1056/NEJMc2026670

This research letter presents Swedish data on severe COVID-19 in children and schoolteachers from March 1st and June 30th, 2020. Preschools (for children aged 1 to 6 years old) and schools (children 7 to 16 years old) in Sweden remained open throughout the study period; social distancing was encouraged, but wearing facemasks was not. Patients with severe COVID-19, defined as laboratory or clinically confirmed SARS-CoV-2 infection requiring ICU admission, were identified from a national intensive care registry and the Public Health Agency of Sweden.

A total of 15 children were admitted to ICU with COVID-19 during the study period (0.77 per 100,000 children); no child with COVID-19 died. For teachers, the relative risk of requiring ICU care with COVID-19 was not higher compared with the general population (excluding health care workers): sex- and age-adjusted relative risk 1.10 (95% C.I. 0.49-2.49) for pre-school teachers (total 10 admitted to ICU) and 0.43 (95% C.I. 0.28-0.68) for schoolteachers (total 20 admitted to ICU).

This report is consistent with data from other countries indicating children are at very low risk of severe COVID-19. The observation of low incidence of severe paediatric COVID-19, despite schools remaining open aligns with a growing body of evidence that transmission between children in schools is not a major driver of SARS-CoV-2 spread. The lack of an increased risk of severe COVID-19 in schoolteachers is reassuring, again consistent with data elsewhere that risk of in-school transmission of SARS-CoV-2 from children to teachers is low when age (the predominant risk factor) and sex are adjusted for. A notable caveat is that during most of the study period, testing criteria were restricted to the most severe cases only. Therefore it is highly likely that a significant number of non-severe infections went undocumented.

Jiehao CaiMei ZengVirologica Sinica Comparison of Clinical and Epidemiological Characteristics of Asymptomatic and Symptomatic SARS-CoV-2 Infection in Children04 Nov 2020ChinaAsia49Epidemiology - Transmissionhttps://doi.org/10.1007/s12250-020-00312-4

Chinese researchers are ahead of the rest of the world in Covid-19 research, not just because the pandemic struck them first, but also because they immediately set about detailed and systematic investigation of their cases. This important paper gives extensive data on all 49 children with SARS-CoV-2 infection confirmed by RT-PCR in Shanghai between 19th January and 30th April 2020. Of these 21 (43%) were asymptomatic. 38 (78%) were imported from outside China (mostly from Europe and the US), and their policy of screening all new arrivals might explain this high proportion. There will have been many more domestic asymptomatic cases that were never detected, so this is not an estimate of population prevalence. None of the asymptomatic cases subsequently became symptomatic. 43% had had contact with confirmed or suspected Covid-19 cases, mostly household.

All these children (mean age 11.5 +/-5.1 years) were admitted to hospital, even if asymptomatic, until two nasopharyngeal PCR swabs were negative 24 hours apart. They were then followed up for 2 weeks. None became seriously ill. The most common symptoms, as expected, were cough (43%) and fever (33%), which was mostly < 39˚C and lasted a mean 2.5 days; but significant numbers had sore throat (16%) and rhinorrhoea (14%). 40/49 underwent chest CT scanning and/or chest X-ray, including, controversially, some of the asymptomatic children. Lung lesions – ground-glass opacities and patchy infiltrates - were found in 20 of these, including 5 who had no symptoms. Only 1 progressed to clinical pneumonia, treated with Azithromycin. Blood tests were largely unremarkable: most had normal cell counts and CRP levels.

They also did sequential IgG and IgM SARS-CoV-2 specific antibody tests: 28% of the symptomatic children had positive antibodies at diagnosis, rising to 36% after 14 days. By contrast, 67% of the asymptomatic group were antibody positive at diagnosis, perhaps because they had unknowingly had the infection for longer.

An important epidemiological observation was viral shedding: nasopharyngeal swabs remained PCR positive for around 14 days, with little difference between the symptomatic and asymptomatic groups. They also tested stool sequentially for viral RNA: surprisingly, this remained PCR positive for much longer: mean 31 (+/- 19) days in those with symptoms, and 28 (+/-13) days in those without. None had diarrhoea at any stage.

The public health implications of this are significant: asymptomatic children remain PCR- positive just as long as those with symptoms. Also, we do not yet know to what extent faecal-oral transmission might occur. In the meantime we should be encouraging good toilet hygiene for all.

Bi, QAzman, AmedrxivHousehold Transmission of SARS-COV-2: Insights from a Population-based Serological Survey04 11 2020SwitzerlandEurope626Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.04.20225573v1

This study is a pre-print and so should be interpreted with caution whilst awaiting peer review.

In this household-based population study from Geneva, Switzerland, serosurvey, symptom and contact data were applied to transmission models to determine risk of transmission of SARS-CoV-2 within and from outside of households as well as risk factors for transmission. Participants were recruited as part of the SEROCoV-POP study between April 3rd and June 30th 2020.

Serological testing for anti-SARS-CoV-2 IgG antibodies was performed in each participant. Self-reported data on demographics, household composition, symptoms consistent with SARS-CoV-2 and frequency of extra-household contacts was collected. Chain binomial transmission models were used to determine the probability of extra-household infection and the probability of being infected from a single infected household member.

Of 10,587 invited participants, 4543 members of 2627 households were able to provide complete data for all household members including a blood sample. Median house size was 2 (IQR 1-2), median age was 53 (IQR 34-65). Overall seroprevalence was 6.6%; seroprevalence was lower in young children 5-9y.o. (4.8%), and children 10-19y.o. (6.8%) compared with young adults 20-49y.o. (9.1%).

The probability of being infected by a single infected household member was 17.2% overall. Risk was lowest among young children 5-9y.o. at 7.5% (95% CI 1.3%-20.3%) and highest amongst those >65y.o. at 30.2% (95% CI 14.3-48.2%). Risk of being infected by a household member was similar in those aged 10-19y.o. (16%) compared with those aged 20-49y.o. and 50-64y.o. respectively (17%) Risk of infection from extra-household exposures was 5.1% overall, highest in adults 20-49y.o. (7.4%). Notably, schools were closed locally throughout the study period.

Symptoms consistent with COVID-19 (fever, cough, shortness of breath, or loss of smell or taste) were reported in 70.6% of seropositive participants overall; only 37.5% of seropositive young children (3/8) reported symptoms. Asymptomatic seropositive individuals had significantly lower odds of infecting another household member compared with symptomatic individuals (OR 0.25, 95% CI 0.10-0.56).

The household attack rate reported here falls within the range reported in previous household contact tracing studies. The lower susceptibility of young children is also consistent with previous data from epidemiological studies. Of note those in the broad age bracket 10-19y.o. had similar susceptibility to adults. Importantly, these data suggest asymptomatic individuals are significantly less likely to transmit SARS-CoV-2 within households. Whilst age of the index case did not appear to impact infectivity in this model, the relative lack of symptoms in children could possibly translate to a lower risk of onward transmission from paediatric cases. Limitations include direction of transmission being inferred from modelling rather than detailed case ascertainment and contact tracing.

Forbes, HTomlinson, LmedRxivAssociation between living with children and outcomes from COVID-19: an OpenSAFELY cohort study of 12 million adults in England02 Nov 2020EnglandEurope5738498Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.01.20222315v1

Study Question: Does living with children alter the risk in adults of SARS-CoV-2 infection and its outcome compared to not living with children?

Background: this study addresses the issue of the role of children in the transmission of SARS-CoV-2.

Methods: This was a large, population-based cohort study involving 40% of the population in England. The exposure was children in the household, classified into 3 subgroups: no children under 18 years in household, any child aged 0 to 11 years in the household and no children in the 0 – 11 age group in the household but at least one or more children aged 12 to 18 years in the household.

There were 5 Outcomes:

1. Evidence of SARS-CoV-2 infection recorded in primary care defined as a code indicating either a clinical diagnosis a positive swab test or sequelae from COVID-19

2. Hospital admission with ICD-10 code indicating COVID-19 in primary diagnosis field

3. ICU admission with COVID-19

4. COVID-19 related death

5. Post hoc non-COVID-19 death from death certificate

This study was done through OpenSAFELY, a data analytics platform created on behalf of NHS England to address urgent COVID-19 research questions. It links the Primary Care records of 24 million people (40% of England’s population) currently registered with GP surgeries which use The Phoenix Partnership (TPP) SystmOne software. The records are linked to Secondary Uses Service (SUS) hospital admissions, to Intensive Care National Audit & Research Centre (ICNARC) COVID-19-related Intensive Care Unit (ICU) admissions and to the Office for National Statistics (ONS) mortality records. The study population included all adults aged ≥18 years, registered and active for three months, in an English TPP general practice on 1st February 2020.

Multivariate Cox regression Hazard Ratios (HRs) were obtained from data from 1st Feb to 3rd Aug 2020 for each of the 5 outcomes, comparing adults living with and without children in the household, allowing for clustering, stratifying by geographic area to allow for regional variation in infection rates. HRs were adjusted for: age, sex, ethnicity, number adults in household, IMD, BMI, smoking, hypertension or high blood pressure, chronic respiratory disease, asthma, cancer, chronic liver disease, stroke or dementia, other neurological disease, reduced kidney function, end-stage renal disease, solid organ transplant, asplenia, rheumatoid, lupus or psoriasis, other immunosuppressive condition.

Results: there were 9,157,814 adults aged ≤65 years and 2,567,671 aged >65y (after exclusions of households with less than 3 months at the GP practice, households without ID, households with more than 10 people and care homes, households missing basic demographics (age, sex, ethnicity)).

Number of children under 18 years: 5738498

28% of ≤65s lived with children under 11y and 9% lived with children aged 12-18 years.

2.3% of >65s lived with children under 11y and 1.1% lived with children aged 12-18 years

Risk in adults aged ≤65 years:

a) who live with children aged 0 to 11 years:

There was no association with increased risk of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission. There was a reduction in the risk of dying from COVID-19 (HR 0.75, 95%CI 0.62 – 0.92).

b) who live with children aged 12 to 18 years:

There was a small increase in recorded infection (HR 1.08, 95%CI 1.03-1.13), but no association with hospital, ICU admission or death from COVID-19.Risk in adults aged >65 years:

a) who live with children aged 0 to 11 years:

There was no evidence of association with any outcome.

b) who live with children aged 12 to 18 years:

There was no evidence of association with any outcome.

Living with children of any age was associated with a lower risk of dying from non-COVID-19 causes in the ≤65 years but no association was seen in the >65 group.

Extensive sensitivity analyses which included for example, assumptions on the distribution of high- risk occupations, didn’t materially altered the results from the comorbidity adjusted models, although there were higher recorded infections in the period three weeks after school closures. However, there was no increased risk for any of the other outcomes. There was no evidence of a “dose-response” related to the number of children in the household.

Interpretation: the data shows that at a population level, transmission from school age children does not result in an increased risk of serious outcomes from COVID-19 among the adults they live with. Crucially, this study found no evidence of severe outcomes of COVID-19 comparing periods before and after school closures.

Comments: this is a carefully conducted, large scale population-based study. It is powered enough to look at several outcomes and has taken into account many potential confounders as well as looking for important interactions.

Hurst, JKelly, MJPIDSSARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study03 Nov 2020USANorth America382Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1693/5952826

In this prospective clinical and epidemiological study from Duke University Health System (DUHS), USA, risk factors, clinical manifestations and nasopharyngeal viral loads of a cohort of non-hospitalised children (<21 years old) with confirmed SARS-CoV-2 infection were documented. Cases were identified between April 7th and July 16th either through clinical presentation to DUHS or contact tracing of children with close contact with a confirmed case.

A total of 382 children were included; median age 9.7 years (IQR 4.8-15.9; 81% were of hispanic ethnicity. The majority (286/382 - 75%) received clinical testing for SARS-CoV-2 infection, whilst the remainder were tested specifically as part of the study. Overall 57% had a parent with SARS-CoV-2, 25% a sibling and 27% an "other" contact. 

In total 293 (77%) had confirmed SARS-CoV-2 infection. Infected children were more likely to be of Hispanic ethnicity (88% vs 57%) and have a co-infected sibling (49% vs 29%) than non-infected children. Asthma was less common amongst SARS-CoV-2 infected children (6% vs 17%). Of children with an infected sibling 46/145 (32%) did not have an identified adult close contact with SARS-CoV-2; median age amongst these 46 children was 12 (IQR 8.2-16.2).

The most common symptoms were fever (42%), cough (34%) and headache (26%). Asymptomatic cases accounted for 30% of confirmed infections; with a higher proportion asymptomatic amongst those 6-13 y.o. (39%), compared to 0-5 y.o. (25%) and 14-20 y.o. (24%). Children 0-5 y.o. and those 6-13 y.o. had significantly shorter duration of illness compared to adolescents (median 4 vs 7 days). Only one infant required hospitalisation. SARS-CoV-2 virals loads did not vary between age groups and there was no association between viral load and presence of symptoms. Viral loads were highest in the 3 days prior to symptom onset and declined thereafter.

This study represents one of the largest clinical and epidemiological studies of non-hospitalised children with SARS-CoV-2 infection. The findings of mild illness children with SARS-CoV-2 infection here is similar to previous reports. In addition this data suggest a shorter duration of illness in children 0-13 y.o. compared with older children. Secondary attack rates could not be calculated as case identification was not exclusively by prospective contact tracing. Furthermore, it was not possible to determine direction of transmission within households, although some cases of sibling to sibling transmission amongst the 46 cases without a close adult contact is plausible; notably these children were older compared to the overall study population. Similar to adult data, viral load was found to peak in the pre-symptomatic phase

Dugas MSchmidt HIJIDAssociation of contact to small children with a mild course of COVID-1901 Nov 2020GermanyEurope00000Epidemiology - Transmissionhttps://doi.org/10.1016/j.ijid.2020.09.003

We don’t yet know why children appear to suffer Covid-19 less severely than adults. One interesting theory is that they have transient cross-reactive immunity from prior frequent exposure to non-Covid coronaviruses, which cause only minor respiratory infections. If so, one would expect adults who have close contact with young children and hence exposure to similar viruses to likewise have enhanced immunity to Covid-19.

This small study from Germany investigated this by questioning about 4000 adults who had recovered from confirmed Covid-19. Some were recruits from a plasma-donation trial, others were ICU survivors. Of the 1186 who responded, about 7% had jobs that involved daily close child contact (e.g. nursery and primary teachers and paediatricians), and 23% had their own children under 10 years. Most of the cohort had had only mild Covid symptoms, and the authors considered that those with child contact in this group were over-represented compared to the German population, suggesting that child contact was protective against severe symptoms. By contrast those who had no child contact were more likely to have received intensive care than those who had (40% of in-patients vs 16%, p=0.056).

This study should not be over-interpreted: it could be biased because of low response rate, lack of objective confirmation and small numbers. However it might prompt future prospective studies, with full immunology data and adequate numbers, possibly using vaccine trial volunteers.

Okarska-Napierała, MKuchar, EEmerg Infect Dis SARS-CoV-2 Cluster in Nursery, Poland01 Oct 2020PolandEurope8Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/27/1/20-3849_article

This research letter from Poland describes an outbreak of Covid-19 in a nursery in June 2020. The presumed index case was a 52 year old symptomatic worker who contracted Covid-19 from a symptomatic family member. Subsequently 4 other workers at the nursery tested positive one of whom was symptomatic. 8 children at the nursery tested positive though none had symptoms and a total of 11 relatives of nursery children tested positive all of whom were asymptomatic. During the time of the outbreak a mean of 25 children attended daily. At the time, the national prevalence rate of Covid-19 was 1% compared to 27% in the nursery cluster. The authors felt the national rate was too low to account for the nursery outbreak and that children were effective mediators of transmission to adults. This episode confirms the potential for transmission to adults via young children, and is consistent with other outbreaks in childcare/educational facilities which have predominantly been sparked by an adult index case.

Gilliam, WOmer, SPediatricsCOVID-19 Transmission in US Child Care Programs01 Oct 2020United statesNorth America0Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/pediatrics/early/2020/10/16/peds.2020-031971.full.pdf

This is a study from the US to compare Covid 19 outcomes in child care providers who continued to provide childcare during the first three months of the pandemic versus those who did not, to assess levels of transmission of Covid 19 in childcare facilities.

Methods : A multi-state canvas of US child care workers was conducted from May 22 to June 8 2020 via a Qualtrix online survey. Participants were canvassed mainly through two large national child care organisations as well as child care workforce registries. Three rounds of reminders were sent and offer of entry into a raffle on completion of survey was given to incentivise responses.

Inclusion criteria, was those who self-identified as a childcare worker, who was working in direct contact with children pre pandemic, and could provide data on Covid 19 outcome and childcare exposure. Covid 19 outcome was determined by i. a positive Covid 19 test, or ii. hospitalisation with covid 19. Information on confounders, such as geographical location, and Covid mitigation measures used were also recorded.

Results : The link was accessed by 94,390 individual’s self-identifying as a child care worker across 28 states in the US. 82,741 individuals consented to take part in the study and 57,335 (69.3%) chose to participate by providing enough detail on childcare exposure and COvid 19 outcome.

51.4% of respondents reported that their facility had closed and was still closed at time of survey.

Respondents reported that child care facilities that remained open had smaller group sizes, considerable infection mitigation efforts were in place, and the 81.1% of children served were <6 years old.

Results indicated no association between COVID-19 outcome and exposure to child care (odds ratio [OR], 1.06; 95% CI, 0.82 to 1.38; P = 0.66). in further analysis Covid 19 was associated with high level of community infection, with race and ethnicity, and with being a home based child care provider rather than at a facility.

Conclusions : Overall, this study did not provide evidence that child care was a significant contributor to COVID-19 transmission to adults. Rates were higher among those who identified as American Indian/Alaskan Native, African American/Black, or Latinx, as well as those working in counties with high COVID-19 death rate.

Authors caution that these results should be interpreted within the context of community transmission rates, mitigation practices within child care programs, and that this was primarily in children under 6 years of age.

Wada, KShobugawa, YBMJ Paed OpenInfection and transmission of COVID-19 among students and teachers in schools in Japan after the reopening in June 2020.29 Sep 2020JapanAsia168Epidemiology - Transmissionhttps://bmjpaedsopen.bmj.com/content/4/1/e000854

This article (published on 29th September 2020) reports confirmed COVID-19 cases among students and teachers in elementary schools (ages 6-12 years) and junior high schools (ages 13-15 years) in Japan from 1st June to 31st July 2020.

Background: Elementary and junior high schools in Japan began closing on 2nd March 2020 as a result of the COVID-19 pandemic and remained closed until the end of May 2020. They reopened on 1st June 2020 with infection control guidelines in place, including physical distancing, face masks and hand washing. There were restrictions on attending school if a household member had symptoms of COVID-19 and for positive cases until non-infectious. Where judged necessary depending on numbers of positive cases in particular schools, affected classes, year groups or schools were closed for a few days to disinfect classrooms and monitor symptoms in students and teachers. Additionally, teachers were asked to avoid high-risk settings outside school. These guidelines were developed by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), which also requested all schools and governing boards of education to report cases of COVID-19 in students and teachers to local public health centres, which conducted active surveillance to identify and trace close contacts and to assess routes of transmission. This study reports on confirmed COVID-19 cases in all elementary and junior high schools for a two month period from 1st June 2020, when schools reopened, to 31st July 2020, when the summer holidays began. During the study period the Japanese government reported 19,115 confirmed cases of COVID-19 in Japan.

Numbers of schools, students and teachers involved in this study: 2019 data for the schools covered in this study: 19,738 elementary schools in Japan (ages 6-12 years) with 6,368,550 students and 421,935 teachers; 10,222 junior high schools in Japan (ages 13-15 years) with 3,218,137 students and 246,825 teachers.

Cases of COVID-19 reported in schools from 1st June to 31st July 2020: Elementary schools: 105 student cases, 29 teacher cases. Junior high schools: 63 student cases, 10 teacher cases. Combined: 168 student cases, 39 teacher cases. Total 207 confirmed cases in both students and teachers in both types of school covering ages 6-15 years during this 2 month period. There were no reported deaths in students or teachers. [NB Data supplied from table in article, rather than text.]

Routes of possible transmission for student cases as assessed by local public health centres: Positive cases in elementary schools resulting from transmission in households 75/105 (71%), transmission in schools 1/105 (1%), transmission outside households or schools 9/105 (9%), returning from other countries 3/105 (3%), unknown 17/105 (16%). Positive cases in junior high schools resulting from transmission in households 38/63 (60%), transmission in schools 6/63 (10%), transmission outside households or schools 3/63 (5%), returning from other countries 2/63 (3%), unknown 14/63 (22%).

Routes of possible transmission for teacher cases as assessed by local public health centres: Positive cases in elementary schools resulting from transmission in households 5/29 (17%), transmission in schools 0/29, transmission outside households or schools 3/29 (10%), returning from other countries 0/29, unknown 21/29 (72%). Positive cases in junior high schools resulting from transmission in households 1/10 (10%), transmission in schools 0/10, transmission outside households or schools 0/10, returning from other countries 0/10, unknown 9/10 (90%).

Conclusions: During this two month period after schools reopened at the beginning of June 2020 in Japan, the number of reported confirmed cases of COVID-19 in elementary and junior high schools was relatively low in both students and teachers (168 cases in students and 39 cases in teachers). Household transmission was identified by local public health centres as the source of infection for most cases in students (71% of elementary school student cases and 60% of junior high school student cases), with only 1 student case (1%) in elementary schools and 6 student cases (10%) in junior high schools identified as transmitted in schools. The route of transmission was unknown for 16% of elementary school student cases and 22% of junior high school student cases. However, for teacher cases in both types of school the route of transmission was unknown in the majority of cases (72% of elementary school teacher cases and 90% of junior high school teacher cases). The authors speculate that this may be a consequence of teachers being asked to avoid high-risk behaviours such as attendance at social gatherings, which may result in unsuccessful contact tracing if there are negative consequences to disclosure of activities. No teacher cases were identified as having been transmitted in school settings. The authors conclude that efforts to reopen schools safely will continue in order to protect children’s rights to learn and socialise.

Wang, MPang, JFront. Med.Effectiveness of surgical masks in reducing acute respiratory infections in non-lealth care settings: a systematic review and meta-analysis25 Sep 2020SingaporeInternational7448Epidemiology - Transmissionhttps://doi.org/10.3389/fmed.2020.564280
Viner, REggo, RJAMA PediatrSusceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis.25 Sep 2020WorldwideInternational41640Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2771181

This systematic review and meta-analysis (published on 25th September 2020) of 32 studies from 21 countries examines the evidence in published and unpublished literature on susceptibility to and transmission of SARS-CoV-2 among children and adolescents compared to adults. How easily do children and adolescents become infected by SARS-CoV-2 and how infectious are they once infected? Factors influencing the transmission of SARS-CoV-2 in different age groups include the risk of exposure to the virus, probability of being infected on exposure (susceptibility), extent to which symptoms develop once infected, viral load becoming high enough to transmit and then the likelihood of making infectious contact with others (dependent on social contact patterns and behaviour).

Study selection: The authors of this review, who are based in the UK, the Netherlands and Australia, undertook a rapid systematic review of published and preprint literature as well as data from a national public health website reporting government statistics and studies. Included studies were limited to: 1. contact-tracing studies (with systematic follow-up of all contacts to establish secondary attack rates in different age groups) to assess differential susceptibility and 2. population screening studies (identifying infection or prior infection through detection of viral RNA or antibodies) to assess prevalence. These two types of study are likely to be the most informative and least subject to bias when investigating the role of children and adolescents compared to adults in the chain of infection of SARS-CoV-2. Symptom-based studies underestimate SARS-CoV-2 infection in children, because children experience milder illness and have more asymptomatic infection than adults, so studies were required to include data on proven SARS-CoV-2 infection (by PCR or serology) and report in children/adolescents compared with adults either the rate of secondary infections or infection prevalence/seroprevalence. Exclusions included studies of single household/institution outbreaks and hospitalised patients, clinical studies, symptom-based cohorts, modelling studies, clinical contact prevalence studies, residual sera seroprevalence studies, studies of overlapping populations where time periods also overlapped and seroprevalence studies only in children with no adult comparison group.

Data sources: A search of two electronic databases on 16th May 2020, with an update on 28th July 2020, yielded 3,465 studies on PubMed (of which 113 were examined in full and 9 included) and 10,461 studies on the medical preprint server medRxiv (90 examined in full and 7 included). Reference checking and professional contacts identified a further 6 and 10 studies respectively, totalling 32 studies comprising 41,640 children and adolescents and 268,945 adults included in the review.

Total 32 included studies: contact-tracing studies 18/32 (3/32 based in schools), population screening studies 14/32.

Assessment of included studies: Data were extracted (using PRISMA guidelines) on country, study type, study context (social distancing measures/school closures in place), case definition, testing and sampling methods and infection rates in children and adults. The methodological quality of each included study was assessed as high, medium, low or uncertain, using a critical appraisal checklist for prevalence studies plus 2 additional criteria assessing risk of bias (whether symptomatic contacts/individuals were more likely to participate than asymptomatic ones and whether the obtained sample was more than 75% of the intended sample).

Quality of included studies: high 2/32, medium 22/32, low 7/32, uncertain 1/32.

Results from contact-tracing studies (evidence of differential susceptibility): 18 studies from: mainland China (6/18), USA (2/18), Taiwan, Japan, South Korea, Israel, Netherlands, Brunei, India (each 1/18) plus 3/18 based in schools from Australia, Ireland and Singapore.

Secondary attack rates reported in children/adolescents vs adults:

Lower in 11 studies (China, Taiwan, Japan, USA, Israel, Netherlands)

No significant difference in 3 studies (China, Brunei, India)

Higher in those < 19 yrs in 1 study (South Korea)

Lower in younger children but as high/higher in teenagers than adults in 3 studies (South Korea, India, Brunei)

Random-effects meta-analysis of secondary attack rates in children/adolescents vs adults: Data included from 14 studies from China, South Korea, Taiwan, Japan, Israel, India, USA, Brunei, Netherlands; data were combined on children and adolescents < 20 yrs and compared with an adult group  20 yrs.

Pooled odds ratio estimate of secondary infection for children vs adults 0.56 (95% CI, 0.37-0.85) with high heterogeneity (I2 = 94.6%)

Meta-analysis of a subgroup of 7 studies from China, USA, Israel, South Korea using only household contacts (assumed to have a similar exposure to infection from index cases so more likely to reflect relative susceptibility):

Pooled odd ratio estimate of secondary infection for children vs adults 0.41 (household contacts only) (95% CI, 0.22-0.76) (I2 = 91.4%)

Meta-analysis of a subgroup of 8 studies from China, South Korea, Israel, India, USA, Brunei, Netherlands grouped by age of child; ages differed across studies, so children defined < 10-14 yrs, adolescents > 10-12 yrs & < 20 yrs, adults  20 yrs:

Pooled odds ratio estimate of secondary infection (being an infected contact) for:

Children < 10-14 yrs vs adults 0.52 (95% CI, 0.33-0.82), significant difference

Adolescents vs adults 1.23 (95% CI, 0.64-2.36), non-significant difference

3 school-based contact-tracing studies found minimal transmission from child or teacher index cases.

Results from population screening studies (evidence of prevalence): 14 studies from Iceland, Italy, Sweden, England, Spain, Netherlands, Brazil, Iran, Georgia, Switzerland, Japan, Germany. Data from these studies were heterogenous and not suitable for meta-analysis.

4/14 virus prevalence studies (oro/nasopharyngeal PCR testing): 3 national prevalence studies (Iceland and Sweden, undertaken while primary schools open, and Italy undertaken just before lockdown while schools open) showed lower prevalence among children/adolescents than adults. 1 nationally representative survey (England, covering lockdown and subsequent month) showed no significant differences by age.

10/14 seroprevalence studies (antibodies): 3/10 nationally representative, 4/10 regional/municipal, 3/10 post-outbreak. A lower seroprevalence was found in children and in some adolescents compared with adults in studies from Spain, Netherlands, Iran, USA, Switzerland and Japan, but no difference by age in a study from Brazil. 2 post-outbreak studies from Italy and Germany found lower seroprevalence among children/adolescents than adults, the third post-outbreak study (from Germany) found no difference by age.

Separating children < 10 yrs from adolescents 10-19 yrs suggested that seroprevalence of children < 10 yrs was lower than adults, but that seroprevalance of adolescents 10-19 yrs was similar to adults (not formally tested in this review).

Limitations identified by authors: Prevalence of SARS-CoV-2 in a particular age group within a population depends on exposure, susceptibility, proportion of that age group within the population, mixing rates and mitigating interventions, therefore isn’t a direct indicator of susceptibility or transmission. Many study types are underpowered to identify age differences. Studies and study types open to very significant bias were excluded from this review, but only 2 out of 32 studies were identified as high quality and nearly all studies were open to bias. Most studies were from high and middle income countries in Europe and East Asia. The age bands of the studies were not aligned, making direct comparisons challenging. The sensitivity of tests (both PCR and serology) may differ by age and confound findings. Strict control and social distancing measures (eg school/workplace closures, travel restrictions) will affect results of both types of study included in this review; lockdowns decrease contacts outside households, but increase contacts within households, so extrapolating results from these studies to unmitigated environments is problematic. Numbers of nominated and traced children appeared low in some contact-tracing studies. The number of children tested in most of the included population screening studies was low (usually less than the 15-25% of the population under 18 yrs in most countries) and probably reflects lower recruitment of children.

Conclusions: Contact-tracing studies in this review indicated that children have lower susceptibility to SARS-CoV-2 infection than adults, with only one study finding higher odds of infection in those younger than 20 years versus adults, but this was only in 10-19 year olds. Children and adolescents had 44% lower odds of secondary infection compared with adults 20 years and older. Lower susceptibility appeared to be confined to those younger than 10-14 years. Population screening studies mostly indicated lower prevalence and seroprevalence in those younger than 20 years versus adults, with no studies reporting higher prevalence in children and adolescents. Seroprevalence in adolescents appeared similar to adults in all studies. Overall, the preliminary findings indicate that children younger than 10-14 years are less susceptible to SARS-CoV-2 infection than those older than 20 years, while adolescents seem to have similar susceptibility and prevalence rates to adults. The transmission of SARS-CoV-2 is not directly addressed in this review, although there is some weak evidence that children and adolescents play a limited role. Further studies of this type are urgently needed, sufficiently powered across different age groups and including repeated testing over time, in different locations and settings (particularly low income settings) and under different mitigating circumstances.

Otte im Kampe, EHaas, WEuro SurveillSurveillance of COVID-19 school outbreaks, Germany, March to August 202024 Sep 2020GermanyEurope114Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.38.2001645

In this study from Germany, national surveillance data on COVID-19 school outbreaks from 28th January to 31st August 2020 are reported. All primary and secondary schools were closed in Germany from 16th March with gradual re-opening from 20th April for secondary schools and 4th May for primary schools. A range of non-pharmaceutical interventions to limit transmission in schools were employed with decisions on specific interventions made by individual states. Laboratory confirmed cases were identified from the national surveillance system and all school outbreaks with two or more cases were analysed.

Of 8,841 total COVID-19 outbreaks during the period, comprising 61,540 cases, only 48 (0.5%) outbreaks occurred in schools with a total of 216 cases. Almost half of these cases (47.2%) occurred in adults >21 years; 10 of 48 school outbreaks involved only adult cases. There were 114 paediatric cases; 39 in 15-20 year olds, 45 in 11-14 year olds and 30 in 6-10 year olds. Following re-opening of schools an average of 2.2 outbreaks with 4 cases per outbreak were reported nationally. The largest outbreak (20 cases in students aged 13-14) occurred prior to non-pharmaceutical mitigation measures. Notably, at the time of schools re-opening in Germany the incidence of COVID-19 in the general population was low.

These data are reassuring regarding risk of transmission within schools. The number of COVID-19 outbreaks occurring in schools represented a small proportion of the total number of outbreaks and the number of cases per outbreak in schools was small; consistent with limited onward transmission within school classes. Importantly, adults within schools represent a significant proportion of cases linked to outbreaks. Whilst transmission in schools is possible, with non-pharmaceutical measures to mitigate risk of transmission within schools and, importantly, adequate public health capacity to rapidly identify, test and isolate suspected cases and contacts, the impact of school outbreaks of COVID-19 in Germany has been minimal.

This study adds further evidence that schools can be re-opened safely in the setting of low community COVID transmission with appropriate mitigation measures within schools and adequate public health capacity to test, trace and isolate in a timely manner.

Fong, MWWu, PEuro survCOVID-19 cases among school-aged children and school-based measures in Hong Kong, July 2020. 16 Sep 2020Hong KongAsia000000000Epidemiology - Transmission https://doi.org/10.2807/1560-7917.ES.2020.25.37.2001671

This brief report from Hong Kong adds to the evidence of low transmission rates of SARS-CoV-2 in schools. All schools in Hong Kong closed in January 2020 and did not re-open until the end of May. No cases occurred in school-age children until early July, and the schools then closed early for summer on 13 July. By that time twenty COVID-19 cases had been identified, and they studied these in detail. Fifteen were linked to household or community clusters, not school. For the 5 school-acquired cases (all secondary school), and 7 of the 15 non-school-acquired cases, all children in their schools were tested. No other cases were detected. None are known to have acquired the virus since.

They speculate that the reasons for low transmission in their schools compared to elsewhere (e.g. Israel;

www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.29.2001352) may have been their rigorous infection control measures; e.g. daily temperature checks, face-masks at all times, spacing of desks, half-day schooling and staggered arrival and departure times.

Milani, GConstantino, GJAMA Pediatr.Frequency of Children vs Adults Carrying Severe Acute Respiratory Syndrome Coronavirus 2 Asymptomatically14 Sep 2020ItalyEurope83Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2770117

In this retrospective study, frequency of asymptomatic infection with SARS-CoV-2 was compared between adults and children admitted to a hospital in Milan between March 1st to April 30th, 2020. A nasopharyngeal swab was taken from all patients on admission during this period, with repeat sampling at 12-48 hours if initial test was negative. Individuals with any symptoms compatible with SARS-CoV-2 infection or history of recent exposure to SARS-CoV-2 were excluded.

Amongst 83 children and 131 adults included , the most common reasons for admissions were surgical intervention, neurological disease and trauma. 

Asymptomatic children were significantly less likely to test positive for SARS-CoV-2 compared with asymptomatic adults (1.2% vs 9.2%; OR 0.12 (95% CI, 0.02-0.95))

No patients who tested positive progressed to develop symptoms in the subsequent 48 hours.

Although limited by the single-centre retrospective design, the inherent differences between hospitalised adults and children as well as the timing of the study (during school closures), these data go against the hypothesis that children are at higher risk of asymptomatic carriage of SARS-CoV-2 compared with adults, but are limited by the bias of non-random sampling and an unknown wider community prevalence of infection among both children and adults; most serological surveys have demonstrated lower rates of infection in children generally during the first wave of the pandemic.

Lopez, ASTran, CHMMWR Morb Mortal Wkly Rep 69(37): 1319-1323Transmission Dynamics of COVID-19 Outbreaks Associated with Child Care Facilities - Salt Lake City, Utah, April - July 202011 Sep 2020USANorth America110Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6937e3.htm

Outbreaks/transmission occurred in 17 childcare facilities in Salt Lake City, USA, between 01/04-10/07/20, and detailed information is given for 3. 110 children were involved (43 male, 58 male, 9 gender not specified), aged 0.2-16yrs (median 7yrs). 12 paediatric and 10 adult cases occurred in the facilities or in household contacts of confirmed/suspected cases. The index cases in all 3 facilities was an adult staff member. There was evidence of adult-to-adult, adult-to-child, child-to-adult, and child-to-child transmission. The greatest number of cases acquired directly from the adult index case occurred in a facility where adult staff were not required to wear masks.

Ehrhardt, JBrockmann, SEuro SurveillTransmission of SARS-CoV-2 in children aged 0 to 19 years in childcare facilities and schools after their reopening in May 2020, Baden-Württemberg, Germany10 Sep 2020GermanyEurope557Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.36.2001587

Schools and childcare facilities were closed in Germany on 17th March. There was initially very limited reopening for children of emergency workers until between 4th May and 15th June when all school children went back and final full opening of childcare facilities on 29th June. During March there were over 1000 cases/day locally, and this had reduced to <100 when the reopening began.

To try to prevent transmission in schools, all sites reduced capacity by 50%, excluded sick children, cleaned surfaces, ventilated rooms and encouraged hand hygiene and cough etiquette. Some schools asked for mask use outside classrooms and secondary schools asked children to physically distance from each other.

Method: All lab-confirmed cases of SARS-CoV-2 in children 0-19 years between 25th May and 5th August 2020 (I week after school re-opening to 1 week after closure for school summer holidays) in the state of  Baden-Württemberg (population 10.8m). As each case was found, local health officials initiated "thorough contact investigations".

For this study, data on school or childcare attendance whilst presumed infectious (from 2 days before onset of symptoms or, if asymptomatic, from 48hrs before positive test) was collected.

Main Findings: 557 cases of SARS-CoV-2 infection in children aged 0-19 (17.9% of the 3,104 cases of all ages in the state during this time period). Information on school attendance was found for 453 (81.3%) of these. 137 of these children attended school/childcare setting for at least 1 day whilst presumed infectious. Nasopharangeal swabs were taken, 3-5 days after index case identified, from 2,300 close contacts of the index cases and from close contacts of secondary cases. 6 index cases were found to have infected 11 additional pupils (3 in childcare settings, 1 in a primary school, 7 in secondary age education)

Conclusions: This study shows a low rate of transmission: 1 new case per approximately 25 infectious school days (137 infected children in school for, say, 2 days when infectious) which may be even less as the 104 index cases for whom no school attendance data was obtained may have been in school while infectious and contributed to the 11 infections [I'm not sure this latter conclusion is justified] An Irish study had similar findings although a study from Israel reports a large outbreak from an over-crowded school where mask usage had been abandoned due to a heat wave.

The authors note that group sizes will increase as all return to full-time school and advocate strict ventilation of classrooms and wearing of masks in and out of classrooms

Link-Gelles, RBandy, UMMWRSecondary Transmission of SARS-CoV-2 in Child Care Programs — Rhode Island, June 1–July 31, 202028 Aug 2020USANorth America18945Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6934e2.htm

Following the reopening of state childcare programs with enhanced hygiene regulations in Rhode Island, USA, cases were examined for evidence of any transmission in the childcare setting, between 01/06/20-31/07/20. Of the 52 cases who were positive on testing or judged to be ‘probable’ in the absence of a test, 30 were children (median age 5 years) and 22 were adults (20 staff and 2 parents). Cases were found in 29/666 of the reopened programs. 20 had a single case with no evidence of any onward transmission. 5 programs had between 2-5 cases but without evidence of onward transmission. In the remaining 4 programs, onward transmission could not be ruled out. 10 cases occurred in one program which was found not to have been adhering to the enhanced state hygiene regulations.

This review highlights that in an area with relatively low levels of community transmission, basic infection prevention measures were effective and no significant transmission events were observed in childcare settings.

Hao LeiYuelong ShuJ InfectionHousehold transmission of COVID-19-a systematic review and meta-analysis25 Aug 2020chinaEverywhere2500Epidemiology - Transmissionhttps://doi.org/10.1016/j.jinf.2020.08.033

Normally systematic reviews and meta-analyses are done only after research studies have accumulated over a long period of time. However with COVID-19, as in so many ways, the whole process has been accelerated. This brief review attempts to summarise the published evidence around rates of household transmission of the SARS-CoV2 virus from studies conducted in January-March 2020. Their search came up with 24 papers reporting 18 studies from China, 2 from South Korea, 2 from USA and 1 each from Taiwan and Germany. Only one study was prospective: the others were case ascertainment (13), or retrospective cohort studies (10).

The key outcome meta-analysed was the household secondary attack rate (SAR), i.e. the number of identified cases divided by the number of household contacts. They found huge variations in SAR, ranging from 4.6% to 90%. This did not seem to depend on location. This degree of heterogeneity would suggest that the studies were very different in their methods and outcome measures. The pooled SAR was estimated at 27% (95% CI 21-32).

Some studies compared at-home and outside-home contacts, and found consistently, but not surprisingly, that home contacts were much more likely to transmit the virus: about 10 times the risk (OR 10.7; 95% CI 5.7-20.2).

More relevant to paediatricians, from the 8 studies where ages were reported, they found that adults were about 4 times more likely to become infected from household contacts than children (OR 3.7; 95% CI 2.8-4.9).

There is so much data missing from this meta-analysis that any conclusions must be guarded. Case definitions, testing accuracy, confidence that infection was acquired within the home rather than externally, and population demographics, will all have varied. There is also no distinction made between family households, and adult house-sharers: this may be particularly relevant as students return to universities.

Ismail, SLadhani, SmedRxivSARS-CoV-2 infection and transmission in educational settings: cross-sectional analysis of clusters and outbreaks in England24 Aug 2020EnglandEurope70Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.08.21.20178574v1

This article is a preprint so should be interpreted with caution pending peer review This study, posted on medRxiv on 24th August 2020, uses Public Health England national surveillance data about COVID-19-related situations in educational settings across England gathered during the month of June, following the partial re-opening of schools in England from 1st June 2020, with follow-up until 31st July 2020.

Background: Schools across England were closed from 20th March 2020 because of rising COVID-19 cases. Vulnerable children and those with keyworker parents were able to continue attending school throughout the remainder of the spring term and the summer term. As part of gradual easing of lockdown measures, there was a partial re-opening of early years settings and primary schools from 1st June 2020, with children attending early years settings (nurseries and preschools for < 5 yr olds) and selected years in primary schools (reception (age 4-5 yrs), year 1 (age 5-6 yrs) and year 6 (age 10-11yrs)) allowed to return to school with strict infection control measures (including smaller classes separated into social bubbles (groups of staff and pupils who perform all activities together and don’t mix with other bubbles), social distancing and hand hygiene). This was followed on 15th June by the partial return to school of year 10 (age 14-15 yrs) and year 12 (age 16-17 yrs) in secondary schools, sixth forms and further education colleges. Attendance was not mandatory, not all schools re-opened and many eligible children did not return to school during the remainder of the summer term (June to mid-July 2020). In particular, attendance of older children in years 10 and 12 was much lower than in early years settings and primary schools.

Data collection: Public Health England (PHE) is responsible for the surveillance and public health management of COVID-19 in the community in England, including within educational settings. Suspected or confirmed cases of COVID-19 must be reported by institutions to their local PHE Health Protection Team (HPT), which performs a risk assessment for each event and decides on necessary investigations and measures. All events are recorded on HPZone, a national online database used to record health protection-related events requiring public health management, and reviewed daily at a national level. Missing information is obtained from outbreak reports or directly from the local HPT or educational setting. All COVID-19 situations reported to HPTs during the month of June 2020 were followed up for at least 14 days after the educational settings closed for the summer term. Educational settings include nurseries, preschools, infant schools, junior schools, primary schools, secondary schools, further education colleges, and settings catering to children of mixed age groups, or those of any age with special educational needs and/or disabilities (SEND).

Definitions: A case of COVID-19 was confirmed by a verifiable positive SARS-CoV-2 PCR from an upper respiratory tract sample. Cases were classified into 3 types:single confirmed cases, co-primary cases (2 or more confirmed cases with a common epidemiological link who were diagnosed at the same time – often asymptomatic siblings diagnosed during contract tracing after a positive result in a parent), outbreaks (2 or more epidemiologically linked cases where sequential cases were diagnosed within a 14 day period)

Educational settings were categorised into 3 groups: early years, primary schools (reception, year 1 and year 6 only) and secondary schools (years 10 and 12 only).

SARS-CoV-2 infections in educational settings in England: PHE received 170 reports of COVID-19-related events in educational settings in England from 1st to 30th June 2020. Public health investigations identified SARS-CoV-2 infections in only 101/170 (59%) of these events.

Breakdown of these 101 confirmed events:

Single confirmed cases: 67 events/101 (66%) involving 30/67 (45%) children and 37/67 (55%) staff members

Co-primary cases: 4 events/101 (4%) involving 10 children (0 staff)

Confirmed outbreaks: 30 events/101 (30%) involving 121 cases with 30/121 (25%) in children and 91/121 (75%) in staff

Total 198 confirmed cases: 70/198 (35%) in children, 128 (65%) in staff

Single confirmed cases: Occurred mainly in primary schools with 45/67 events (67%) (21 cases in children, 24 cases in staff) and early years settings with 10/67 (15%) (5 cases in children, 5 cases in staff). Secondary schools had 4/67 events (6%) (2 cases in children, 2 cases in staff). Other settings (mixed age groups, SEND, colleges) had 8/67 events (12%) (2 cases in children, 6 cases in staff).

Co-primary cases: In the 4 co-primary events involving 10 children, the co-primary cases lived in the same household. All 10 children were asymptomatic and had been tested because they were household contacts of an index case (a parent in 4/5 households).

Confirmed outbreaks: Primary schools 18/30 events (60%), early years 7/30 (23%), secondary schools 2/30 (7%), SEND schools 3/30 (10%). Affected contact bubbles were excluded in all 30 outbreaks and 13 settings also decided to close on an interim basis or for the rest of term.

Primary school outbreaks: 9/18 (50%) outbreaks involved staff only (affecting 32 people), of which 5/9 events had only 2 confirmed cases. The other 4/9 events had 4, 5, 6 and 7 confirmed cases. In 3 of these latter events the source was not identified, but the outbreak was propagated through contact between administrative and teaching staff in the school. Contact tracing in the final latter event was unusual in that 3/4 positive staff had probably acquired their infections separately from household members with confirmed COVID-19. 7/18 (39%) outbreaks involved staff and students, with a student the most likely index case in 6/7. In 5/7 of these the child index case was identified through testing of the whole household when parents (healthcare workers in 3 cases) had tested positive for SARS-CoV-2. The 7th outbreak involving staff and students was likely staff to pupil. The final 2/18 primary school outbreaks involved possible transmission between 2 children only, although acquisition in the household or community could not be ruled out.

Early years settings outbreaks: A staff member was the index case in all 7/7 (100%) outbreaks. 2/7 outbreaks involved only staff (2 and 12 confirmed cases, the latter following community exposure linked to a religious festival), 5/7 outbreaks involved staff transmission to small groups of children (maximum 4).

Secondary school outbreaks: Only 2 events involving only staff, with 2 confirmed staff cases each.

SEND settings outbreaks: 3 events with 2/3 involving staff only (6 and 2 confirmed staff cases), 1/3 with staff to child transmission (7 staff members positive with 1 child infected, at which point wider testing was carried out).

Source of infection: Single confirmed cases: not systematically collected.

Co-primary events: 10 children acquired infection from a household member.

Confirmed outbreaks: staff-to-staff 15/30 (50%), staff-to-student 7/30 (23%), student-to-staff 6/30 (20%), student-to-student 2/30 (7%). The likely source of infection identified in 27/30 children involved in an outbreak was a household contact in 8/27 (30%), school staff member in 17/27 (63%) and another student in 2/27 (7%). The likely source of infection identified in 61/91 staff members involved in an outbreak was a household contact in 9/61 (15%, these staff members were all likely index cases in the educational setting), 46/61 (75%) from another staff member and 6/61 (10%) from a student.

Number of secondary cases per index case in 30 confirmed outbreaks: For staff members as index case: only 1 secondary case in 11 outbreaks, between 2 and 9 secondary cases in 11 other outbreaks. For child as index case: only 1 secondary case in 5 outbreaks, 2 secondary cases in 3 outbreaks.

Correlation with regional COVID-19 incidence: There was a strong correlation between number of outbreaks in educational settings in June 2020 and regional COVID-19 incidence (0.51 outbreaks for each SARS-CoV-2 infection per 100,000 in the community, p=0.001). There was no correlation between single cases and regional incidence, nor between single cases or outbreaks and regional population size. National daily reports of positive SARS-CoV-2 PCR results collated by PHE for COVID-19 surveillance were used to calculate average weekly regional prevalence of infection.

Limitations identified by authors: Generalisation of these findings need to take into account the fact that educational settings started opening in England when SARS-CoV-2 incidence was low and only in regions with low community transmission. Stringent infection control measures were in place and only 1.6 million of 8.9 million students nationally attended any educational setting during this period. In particular, attendance by secondary school students was very low and these findings are unlikely to be generalisable to the full opening of secondary schools. Only a few settings were selected for wider testing.

Conclusion: SARS-CoV-2 infections and outbreaks were uncommon across all educational settings in England during June 2020. Outbreaks were usually small in size and 53% involved only one secondary case linked to the index case. Where the index case was a child, the maximum number of secondary cases was 2 (compared with 9 for staff members). Staff members had an increased risk of infection compared to students in any educational setting and the majority of cases linked to outbreaks were in staff.

Buonsenso, DSali, MmedRxiv preprintSeroprevalence of anti-SARS-CoV-2 IgG antibodies in children with household exposition to adults with COVID-19: preliminary findings12 Aug 2020ItalyEurope53Epidemiology - Transmissionhttps://doi.org/10.1101/2020.08.10.20169912

This article is a preprint so should be interpreted with caution pending peer review

This is a study of the prevalence of anti-SARS-CoV-2 IgG in children with household exposure to SARS-CoV-2, compared to adults exposed to the same index cases. It is a pre-print of a short report, containing only a summary of the data from an on-going study. The authors state that all data are available upon request.

Analysis; From a cohort of 405 adults diagnosed with COVID-19 as outpatients, 33 were identified as living with children younger than 18 years of age; 30 of these agreed to participate in the study. They had a total of 80 same-household contacts of whom 53 were children and 27 adults.

A total of 44 of the 80 same-household contacts (55%) had anti SARS-CoV-2 IgG. 16/27 (59%) adults and 28/53 (53%) children were seropositive (P > 0.05). Similar relative frequencies of seropositivity where present in children more than 5 years of age (21/39, 54%) and those less than 5 years (7/14, 50%) (P > 0.05).

10/28 children (35.7%) and 5/16 adults (33.3%) adults with anti SARS-CoV-2 IgG had previously been diagnosed with COVID-19.

Conclusions; The authors conclude that household transmission of SARS-CoV-2 is high in both adults and children, with similar rates of SARS-CoV-2 IgG in all age groups, including younger children. They claim that the real burden of the SARS-CoV-2 pandemic in children is underestimated.

Teherani, MJaggi, PJ PEDIAT INF DIS SOCBurden of illness in households with SARS-CoV-2 infected children11 Aug 2020USANorth America32Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa097/5891283?rss=1

In this study from Atlanta, USA, household transmission was assessed in symptomatic children with laboratory-confirmed SARS-CoV-2 infection diagnosed from March 16th to June 14th 2020. 

Household contacts were identified by interviewing the patient's parents including:- the presence, absence and timing of symptoms consistent with COVID-19 in all household members, 

- any other household members with laboratory-confirmed SARS-CoV-2 infection and the likely household index case (the first household member to develop symptoms or test positive)

Of 138 children diagnosed, 32 (23%) families who were contactable and consented to interview were included.

Of the 32 cases:

- median age was 12.7 (IQR 8.3-15.7) - 15 were hospitalised for a median of 3 days (IQR 2-13); 17 were discharged from ED

Of the 144 identified household contacts:- 58 were children, 86 were adults- only 29 (20%) were reported to have had SARS-CoV-2 testing- 67 (46.5%) developed symptoms consistent with COVID-19 including:31 (21.5%) after the identified paediatric case36 (25%) before the identified paediatric case

In 7/32 (22%) the identified paediatric case was determined to be the household index case (the first to develop symptoms) with suspected transmission to one or more adult household contacts. 

This study has several notable limitations including:- the small cohort size and the low response rate to interview. - the reliance on parental recall of symptoms to determine transmission direction- the lack of systemic measurement or reporting of proportion of contacts with laboratory-confirmed SARS-CoV-2 infection - the possibility of exposures outside of the household - over half of adult household contacts identified were essential workers, including 14 households with potential occupational exposure to SARS-CoV-2 identified.

As a result of these limitations it is difficult to draw broad conclusions from this study. It is clear that transmission from children infected with SARS-CoV-2 to others can occur, the frequency of this transmission and the relative contribution to disease transmission overall remains poorly defined. 

Maltezou, HPape, AJ. Med. VirolTransmission dynamics of SARS‐CoV‐2 within families with children in Greece: a study of 23 clusters07 Aug 2020GreeceEurope43Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/10.1002/jmv.26394

A study of Covid-19 transmission dynamics among 23 household clusters in Greece, identified through a national registry. Diagnosis of Covid-19 was made by PCR testing of respiratory samples with viral load classified as low, medium or high.

Study period: 26/02/2020 to 03/05/2020

Participants: 109 household members (66 adults and 43 children).

Results: The median attack rate per cluster was 60% (range: 33.4%‐100%). An adult member with COVID‐19 was the first case in 21 (91.3%) clusters. Transmission of infection occurred from an adult to a child in 19 clusters and/or from an adult to another adult in 12 clusters.

There was no evidence of child‐to‐adult or child‐to‐child transmission.Children were more likely to have an asymptomatic infection compared to adults (40% versus 10.5%, p‐value=0.021). In addition, infected children were significantly more likely than adults to have a low viral load (40.7% versus 18.5%, p‐value=0.016). It is noted in the discussion that five clusters came to attention because an infant was hospitalised, but no children required intensive care.

Limitations: it was unclear how clusters were selected and what the exclusion or inclusion criteria were.

This study adds evidence that children are much lower risk than adults for transmission of Covid-19, consistent with them having a low viral load.

Szablewski, CStewart, RMMWRSARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp — Georgia, June 202007 Aug 2020USANorth America409Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6931e1

Question: The question addressed by this report is the transmissibility of SARS-CoV-2 among children and young people in a group setting. The background is to what extent opening schools after the summer holidays might contribute to community transmission of COVID-19.

Setting: investigation of an outbreak of COVID-19 at a camp for children and young people in Georgia, USA between 17/06/202 to 27/06/2020

Methodology: Department of Public Health outbreak investigation

Results: From 17th – 20th June staff and trainees held orientation course at camp. On 21st June trainees left, staff stayed, and 3 senior staff and 363 campers arrived at camp. Median age campers = 12 years (range 6 – 19), median age of staff = 17 years (range 14 – 59).

Variety of indoor and outdoor activities including daily vigorous singing and cheering

Risk mitigation measures at the camp: -evidence of negative viral SARS-CoV-2 within 12 days of arriving in staff, trainees and campers.-Cloth masks for staff (but not campers), cabin cohorts of <26 people, staggering cohorts for use of outdoors, physical distancing, cleaning and disinfection.-Not implemented: opening windows and doors for increased ventilation.

Index case: a teenage member of staff who developed COVID symptoms on the evening of 22nd June who left the camp on 23rd June.

Case definition: positive viral SARS-CoV-2 test in any camp attendee (staff, trainee or camper) up to 14 days after leaving the camp.

Measure of transmission: attack rates (numbers with positive test/total number of attendees)

Attack rates: -per age group were: 6 – 10 year = 51/100 = 51%, 11 – 17 = 180/409 = 44%, 18 – 21 = 27/81 = 33%, 22 – 59 = 2/7 = 29%.

-per type of attendee: trainee (17th – 21st June) = 26/134 = 19%, staff (17th – 27th June) = 66/117, camper (21st – 27th June) = 168/346 = 49%

Analysis: Transmission from staff is possible and probable, more so than from children:Having a negative COVID test with 12 days of arriving still allows infection and transmission subsequently, after negative test and date of arrival to the camp.This could have happened to member(s) of staff or campers.

Information was not provided on age composition of cabins but likely mixed.

It is estimated that the earliest transmission can occur is after 48 hours after infection. Index case developed symptoms on the evening of the 22nd, less than 48 hours after campers arrived.

On the 21st June, trainees were leaving as campers were arriving. The attack rate among trainees was 19%. It is unlikely that there was an opportunity for transmission from campers to trainees on that day. There infections are more likely to have arisen from contact with an infected fellow trainee or member of staff sometime between 17th and 20th June before the campers arrived.

The likelihood of transmission depends on the amount of contact and susceptibility. The campers were at the camp between 3 and 6 days. Had a camper brought in COVID with them, he/she would have had to have an extremely high rate of contact with many staff, trainees and campers to explain the high attack rates seen in all groups. In addition, the 6 days window (from the 21st June when the campers arrived to the 27th, is a short time and doesn’t allow for a long chain of transmission to explain the high attack rates seen in all groups. A more likely explanation is that the attack rates are the result of multiple chains of transmission arising from an infected staff or trainee early on.

It is possible that cases may have arisen before camp attendance or acquired after campt attendance, up to 14 days after leaving the camp.

Sources of measurement error: In the calculation of attack rates, the denominator was made up of attendees whose viral test result was not available to DPH on the assumption that not all negative results were consistently reported by the laboratory. It is not known how many people were not tested. The specificity of PCR SARS-CoV-2 averages about 70% allowing for false negatives.

Impression: this is a very interesting report, but the data do not support any definitive statement about the ability of children to transmit SARS-CoV-2. The report shows that children can be infected in large outbreaks given the high attack rates, but it doesn’t answer the question on transmissibility by children.

Kim, JChoi, EArchives of disease in childhoodRole of children in household transmission of COVID-1907 Aug 2020South KoreaAsia107Epidemiology - Transmissionhttps://adc.bmj.com/content/early/2020/08/06/archdischild-2020-319910
MacCartney, KWood, NLancet Child Adolesc Health Transmission of SARS-CoV-2 in Australian educational settings: a prospective cohort study03 Aug 2020AustraliaAsia22Epidemiology - Transmissionhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30251-0/fulltext

In this epidemiological study from New South Wales (NSW), Australia (state population 8.1 million), the transmission of SARS-CoV-2 in schools and early childhood education centres (ECECs) was examined during the first wave of infections between January 25th to April 9th 2020.  Schools and ECECs remained open throughout the study period with distance learning at schools implemented on March 23rd, and physical attendance limited to children children without other care options - leading to a decrease in attendance from 90% to 10% for the last 2 weeks of the study period.

All adult and paediatric laboratory-confirmed cases of SARS-CoV-2 infection in NSW who attended a school or ECEC whilst infectious were identified. Schools were closed temporarily on initial case notification to allow for contact tracing and generally re-opened after 24-48 hours. Close contacts underwent home quarantine for 14 days after last exposure and were instructed to undergo PCR testing if they developed symptoms of infection. Selected educational settings were offered enhanced investigation of contacts which included upper respiratory tract swab for PCR at day 5-10 and serology testing at day 21 regardless of symptoms. 

In total, 27 index cases were identified including 15 adults and 12 children (median age 15 years (IQR 14-16)) - 8 of whom were in high school. A total of 1448 close contacts were identified, including 633 (44%) who underwent PCR or serology testing. Of 18 secondary cases identified, 10 were children and only 2 were due to child to child transmission. Only 1 case of child to adult transmission was identified; 8 cases of adult to child and 7 cases of adult to adult staff transmission occurred. The overall attack rate was 1.2% - 0.3% for child to child contacts, 1.5% for adult staff to child contacts and 4.4% for adult to adult staff contacts. One large cluster occurred in an ECEC facility with a single adult index case in which 6/12 (50%) adult staff and 7/25 (28%) children were infected. 

This data is in keeping with other school contact tracing studies from Ireland and France demonstrating low attack secondary attack rates in children exposed in educational settings. The higher rate of staff to student and staff to staff transmission relative to transmission from a child index case to others is in keeping with other data suggesting "children are unlikely to initiate or propagate outbreaks". Importantly, the authors point out the intensive tracking and contact tracing in this study was only possible in the context of low numbers of case introductions to schools, underpinned by effective control and suppression of community transmission at a statewide level.

This study highlights that schools are able to be kept open safely with effective case identification and contact tracing in the context of an effective epidemic response in the general population. 

Hecht, JRoberts, DMod PatholSARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers 02 Aug 2020USANorth America0Epidemiology - Transmissionhttps://doi.org/10.1038/s41379-020-0639-4

Although SARS-CoV-2 infection in pregnant women has been widely documented in a variety of settings, only a handful of cases of probable vertical transmission from mother to fetus have been reported and in only two of these cases was evidence of infection of the placenta provided. The authors of the study reviewed here have sought to determine whether the apparent low frequency of vertical transmission of SARS-CoV-2 is due to a low rate of placental infection and/or a low rate of viral transmission across the placenta.

In this retrospective study the placentas of nineteen women with evidence of Covid-19 infection were examined. All of the women had tested positive to SARS-CoV-2 using commercial assay RNA testing performed of nasopharyngeal swabs. The swabs were taken at an average of three days prior to delivery and the median gestational ages of the pregnancies was 36 weeks and 4 days (range 22- 41 weeks). An additional “negative test” was also included as a “negative control”; this case seems to have been included in the results of the test-positives. The placentas were subjected to the following investigations: gross and histologic examination; evidence of direct placental SARSCoV-2 expression shown by the presence of viral nucleocapsid, using in situ hybridisation (ISH), or of viral RNA, using immunohistochemistry (IHC); evidence of the expression of the receptor protein, ACE2, and the priming protein, TMPRSS2, using IHC; expression of these proteins is required for SARS-CoV-2 to infect the placenta.

For comparison, there were three control groups of placentas: 10 placentas of mothers who had histories and histopathological evidence of RNA viral infections other than SARS-CoV-2; 130 placentas from pregnancies in which the baby suffered hypoxic ischaemic encephalopathy; 120 “normal” controls.

The main findings were that, although there was evidence of ACE2 expression in the syncitiotrophoblast (ST) and extra-villous trophoblast (EVT) of all test-positive placentas, and in the cytotrophoblast of 14, there was SARS-CoV-2 nucleocapsid in only two placentas and SARS-CoV-2 RNA in two. TMPRSS2 expression was only present weakly in the villous endothelium of ten placentas and rarely in the ST. Of note, there was a polarised pattern of ACE2 expression, highest on the stromal side of the ST; this is relatively distant from the maternal circulation. There were no characteristic findings on gross and histologic examination.

The authors conclude that, although the placenta is capable of being infected by SARS-CoV-2, this is a rare event. They speculate that the explanation for placental infection being infrequent may be a combination of the polarised pattern of ACE2 expression “away from the maternal blood” and the “pronounced paucity” of TMPRSS2 expression in the trophoblast.

Madewell, ZDean, NmedRxi (preprint)Household transmission of SARS-CoV-2: a systematic review and meta-analysis of secondary attack rate01 Aug 2020USA InternationalInternationalEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.07.29.20164590v1

This systematic review examined 40 published studies of household secondary transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The investigators were from the United States. Nineteen of the 40 identified published studies were from China, 5 from South Korea, 4 from the USA, 2 from Spain and one each from Australia, Brazil, Brunei, Germany, India, Israel, Italy, Singapore, Taiwan and the UK. The meta-analysis included all identified publications prior to 29 July 2020.

The secondary attack rate (SAR) for each household or family was calculated as follows: The denominator was the number of exposed contacts, and the numerator was the number who became infected with SARS-CoV-2 or developed COVID- 19. Following meta-analyses, the secondary attack rate (SAR) estimate from all 40 publications was 0.188.

The subgroup secondary attack rate (SAR) estimate from symptomatic index cases to household and family contacts (16 studies) was 0.199 (range 0.039 to 0.446); whereas the subgroup SAR estimate from asymptomatic index cases to household and family contacts (3 studies) was 0.07 (range 0 to 0.054). The analysis also found that household secondary attack rates (SARs) were higher to spouses than other family contacts, and in households with one contact than households with three or more contacts.

The secondary attack rate (SAR) estimate for adult (≥18 years) household and family contacts was 0.310 (range 0.089 to 0.696). The secondary attack rate (SAR) estimate for children (<18 years) household and family contacts was 0.157 (range 0.040 to 0.269) (9 studies).

Stein-Zamir, CMiskin, IEurosurveillanceA large COVID-19 outbreak in a high school 10 days after schools' reopening, Israel, May 202023 Jul 2020IsraelMiddle East1161Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.29.2001352#html_fulltext

This rapid communication (published 23rd July 2020) describes an outbreak of COVID-19 in May 2020 in a public high school in Jerusalem, Israel, shortly after the re-opening of schools after 2 months of mandatory closure.

Background: Israel’s schools were closed by the government on 13th March because of the COVID-19 pandemic and were fully re-opened on 17th May (with a partial re-opening prior to that on 3rd May for kindergartens, grades 1-3 and grades 11-12). Requirements for school re-opening included daily health reports, hygiene, facemasks, social distancing and minimal interaction between classes. The population of Israel is 9.1 million (median age 30 years); the Jerusalem health office serves 1.25 million residents (median age 23.5 years) characterised by moderate to low socioeconomic status and large households.

Outbreak: The school subject to the outbreak was a regional public school with 1,190 students aged 12-18 years (grades 7-12), who travel from suburbs and neighbourhoods by public or school bus, and 162 staff members. The school schedule is 6 days per week for 38-40 hours weekly. The school re-opened after 2 months closure on 18th May: a student case of COVID-19 was notified on 26th May (the source of infection was unknown; at this point close contacts (4 household, 50 students and 14 teachers) were instructed to self-isolate) and then a second student case (in a different grade and epidemiologically unlinked to the first case) was notified on 27th May, at which point the whole school was closed and most of the remaining school community was tested between 28th and 30th May by nasopharyngeal swab PCR for SARS-CoV-2 (26 students and 10 teachers had not attended school since re-opening and were therefore excluded; 1,161/1,164 students and 151/152 teachers were tested) The two initial positive cases attended school 19th to 21st May and reported mild symptoms.

Results of testing: 153/1,161 (13.2%) students (median age 15 yrs for positive cases) and 25/151 (16.6%) staff (median age 40 yrs for positive cases) tested SARS-CoV-2 positive, with males slightly overrepresented in grades 7 to 10 and amongst staff. Gender: 597/1,161 (51%) male of all students tested and 86/597 (14%) of male students positive; 564/1,161 (49%) female and 67/564 (12%) of female students positive; 51/151 (34%) male of all staff tested and 9/25 (36%) of male staff positive; 100/151 (66%) female of all staff tested and 16/100 (16%) of female staff positive. Grades 7-9 (median ages 13-15 yrs) had higher positive rates than grades 10-12 (median ages 16-18 yrs). The age/grade and gender of the two initial cases are not given.

Symptoms reported: The two initial student cases reported mild symptoms (anosmia, ageusia, fever and headache). Questioning of those in the school community with subsequent positive SARS-CoV-2 tests revealed symptoms in 66/153 (43%) of students and 19/25 (76%) of staff. Commonest symptoms reported were cough, headache, fever, sore throat and myalgia. There was one emergency room visit recorded (age of patient not given) and no hospitalisations.

Factors suggested which may have facilitated outbreak: An environmental school inspection reported crowded classes: 35-38 students per class in class areas of 39-49 m2, allowing 1.1-1.3 m2 per student, where distancing between students and between students and teachers was not possible. There was an extreme heatwave from 19th to 21st May during which schoolchildren were exempted from wearing facemasks for 3 days and the school air-conditioning functioned continuously (separate systems for each class). Daily travel time to school approximates to 20-45 minutes on public or school buses. Most students also participate in extracurricular activities such as sports or dance for an average of 2-4 hrs per week. The authors cite the “three C’s” to be avoided to minimise risks of outbreaks: closed spaces with poor ventilation, crowded places and close-contact settings. They reference the European Centre for Disease Prevention and Control’s June 2020 report on air-conditioning and ventilation systems and COVID-19, which recommends increasing air exchange rate and outdoor air use and decreasing air recirculation to reduce spread in indoor spaces.

This study demonstrates the potential for widespread infection with education settings. The chain of transmissions cannot be eludicated from this study. Given the concurrent relaxation of multiple lockdown measures, it is unclear how much transmission occurred within the school and how many cases were imported in following community transmission.

Park, YJeong, KEmerg Infect DisContact tracing during coronavirus disease outbreak, South Korea, 202016 Jul 2020South KoreaAsia153Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-1315_article

And Kim, Choe et al 2020. These papers will be reviewed as a pair, as they analyse the same data but use differing methods, which have altered the conclusions in each.

Both studies utilise data from South Koreas national public health database of COVID-19 cases and contact tracing. They aim to assess the infectiousness of different cohorts, but assessing how many secondary infections result from each “index case” – defined as those who are first determined within a household (or according to symptom chronology). Park et al looks at several different age categories, and compares SAR according to age. Kim at al only looks at children <18yrs

There is one important difference between the two papers. Park et al just analyses the raw numbers to produce a SAR. Park et al take into account that many of the index cases actually shared the same initial exposure as some of their secondary cases, meaning that they most likely both became infected at the same time by the same 3rd party, but as one of them developed symptoms before the other, they were misclassified as an index case. They removed these cases from the analysis.

Park et al found the following household SAR per age brackets; 0-9y 5.3%, 10–19y 18.6%, 20y + between 7% (20-29y) and 18% (70-79y). There was a marked difference in the number of index cases in each age group, with only 29 aged 0-9, and 124 aged 10 – 19 (compared to 1695 aged 20 -29). These results suggest that young children appear to be significantly less infectious than adults, but that children aged 10 – 19 were just as infectious as adults.

Kim et al corrected for shared exposure. Of the 41 secondary infections from the 248 contacts, only 1 did not share the same exposure, giving an SAR of 0.5% for children <18years in this cohort. Using the same methodology, a different paper found an SAR in adults of 7%.

These papers make 2 important points: firstly, they present some evidence that children may be less infectious than adults. The absolute SAR being so extraordinarily low (0.5%) cannot be extrapolated out of this setting, as South Korea uses intensive infection prevention measures in households, including isolating every individual member from each other, and children are cared for by parents wearing full airborne precaution PPE. In addition, correcting for shared exposure will bias the SAR downwards as some of these cases are likely to be true secondary cases. It is however interesting that this appears lower than the SAR for adults using similar methods of analysis.

The next important point is how much care must be taken interpreting these data. When Park et al was published, it made media headlines about older children being just as infectious as adults, and many schools changed their policies on that data. When Kim et al was published a few weeks later, it became clear that this conclusion was not tenable based on the original data, due to the confounding of shared exposures. When so many potential confounders exist, it is very important to take each study with a pinch of salt and interpret it in the context of the evidence which has preceded it.

In conclusions, these studies together provide some evidence towards the theory that children with COVID-19 may be less infectious than adults. More direct data is needed to gain clarification on the infectiousness of children.

Torres, JPO'Ryan, MClin Infect DisSARS-CoV-2 antibody prevalence in blood in a large school community subject to a Covid-19 outbreak: a cross-sectional study10 Jul 2020ChileS America1000Epidemiology - Transmissionhttps://academic.oup.com/cid/article/doi/10.1093/cid/ciaa955/5869860

This cross-sectional study describes in detail the effects of an outbreak of Covid-19 at a school in Santiago, Chile, probably arising from a single adult index case. As well as PCR nasopharyngeal antigen swabs, they followed up with home-administered blood antibody tests in a stratified sample, and asked staff, students and parents about symptoms and contacts. This presented an opportunity to examine the relationship between symptoms, antigen and antibody positivity across the age range, and the role of asymptomatic transmission, in a previously unexposed population.

The private school has 2600 students across all school years, and 318 staff. The outbreak started on March 13th 2020, only 9 days after Chile’s first case, and spread rapidly, possibly because of a series of parents’ evenings. The school was immediately closed, before the general lockdown in Chile.

Symptomatic, antigen-positive Covid-19 occurred in 7 students, 18 staff and 27 parents. There was one death.

A stratified sample of 1009 students and 235 had home IgG/IgM antibody-testing from 4th-19th May. Of the students, 9.9% were positive; of the staff, 17% were positive. Antibody positivity was associated with younger age (possibly because the index adult dealt with early years children), previous antigen positivity on PCR, and contact with a confirmed case, as expected.

More interestingly, they asked about symptoms through questionnaires: the antibody-positive children reported a range, with the most common being abdominal pain (21%) and fever (17%), but 40% reported no symptoms at all. Of the antibody-positive staff, weakness, myalgia and hyposmia were more prevalent, and 18% had no symptoms. Many of those with symptoms and positive antibodies had had negative antigen tests. Covid-type symptoms occurred in some who were both antigen and antibody negative.

An interesting side-issue is that they found home-testing kits for blood antigens to be effective and acceptable to their population: these could be widely used in seroprevalence studies.

This study cannot answer perhaps the most important question: to what extent can asymptomatic children spread the virus? However, they could conclude that adults (parents and staff) were disproportionately affected in terms of both symptoms and antibody-positivity compared to children, and that control of spread in schools should concentrate on preventing adult-to-adult transmission.

Yung CFThoon KCJ PediatrHousehold Transmission of SARS-CoV-2 from Adults to Children02 Jul 2020SingaporeAsia213Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334921/

This paper from Singapore considers the transmission of SARS-CoV-2 from known infected adults to paediatric household contacts. Data collection was between 5 March 2020 to 30 April 2020 (8 week period). All paediatric household contacts (whether symptomatic or not) of people with confirmed COVID-19 were screened using nasopharyngeal swabs/RT-PCR. 223 adults (from 137 households) had laboratory-confirmed COVID-19. Their paediatric household contacts equated to 213 children (less than 17 years old) who were all tested, and of these, 13 cases were detected (from 7 households). This demonstrates a 6.1% rate of infection among children who were part of households with an individual with laboratory confirmed COVID-19.

Of the 13 cases in children, two children displayed symptoms: one child had a sore throat and one child had an isolated episode of pyrexia.

Looking at age distribution of paediatric household contacts, they found that:- of all those <5 years, 1.3% were infected- of all those 5-9 years, 8.1% were infected- of all those 10-16 years, 9.8% were infected

If the mother was the household index case, the rate of infection in children was highest (11.1%).

It is unclear why the 223 adults who had laboratory-confirmed COVID-19 were initially tested. However, the paper states that patients identified to have COVID-19 were isolated in hospital, so it is also unclear how much exposure the children would have had to the confirmed ‘household’ case of COVID-19.

L'Huillier, AEckerle, IEmerg Infect Dis. Culture-Competent SARS-CoV-2 in Nasopharynx of Symptomatic Neonates, Children, and Adolescents30 Jun 2020SwitzerlandEurope23Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-2403_article#suggestedcitation

In this study from Switzerland, nasopharyngeal samples of 23 children with PCR confirmed SARS-CoV-2 infection were inoculated into a cell culture to determine the presence or absence of of viable virus. All children aged <16 years, daignsosed at the Geneva University Hospital laboratory between January 25th

 

Of the 23 children with SARS-CoV-2 +ve PCR, median age was 12 years (range 7 days to 15.9 years), the majority (13/23 - 57%) had symptoms of upper respiratory tract infection and 7/23 (30.4%) were admitted to hospital. All samples were taken within 5 days of symptom onset (20/20 where reported), median 2 days (IQR 1-3 days). Median viral load was 3.0 x 10^6 copies / mL (IQR 6.9 x 10^3 - 4.4 x 10^8).

Viable SARS-CoV-2 virus was isolated in half (12/23 - 52%) of children including an infant diagnosed at 7 days of age. Virus isolation was associated with higher viral load (median 1.7 x 10^8 vs 6.9 x 10^3 in culture negative patients).

The results here demonstrate that children with symptomatic SARS-CoV-2 infection have similar viral loads to those seen in adults. Similar to adults, children, particularly those with high viral loads, can also shed viable virus particles early in the course of illness. These findings confirm that transmission of SARS-CoV-2 by children is plausible. It remains however that children appear less susceptible to infection compared with adults in the first instance and when infected tend to experience milder symptoms and therefore as a whole are unlikely to be major drivers of transmission. Indeed, this study identified only 23 paediatric cases of SARS-CoV-2 infection in a region severely affected by the pandemic.

Whilst children with symptomatic SARS-CoV-2 infection can shed viable virus, the small proportion of paediatric cases observed globally indicate a limited role of symptomatic children in disease transmission. 

Fontanet, AHoen, BmedRxivSARS-CoV-2 infection in primary schools in northern France: A retrospective cohort study in an area of high transmission29 Jun 2020FranceEurope510Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.06.25.20140178v2
Yung, CNg, KClincal infectious diseasesNovel coronavirus 2019 transmission risk in educational settings25 Jun 2020SingaporeAsia119Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciaa794

A study of contact tracing of 3 clusters of confirmed COVID-19 within schools in Singapore. Only close contacts of the affected students were placed into quarantine for 14 days, not complete year groups/schools/or classes. Target health measures implemented included terminal cleaning and interventions to reduce mixing (examples were cancelling of extra-curricular activities and staggered break times). For 3rd incident in day care, the school was closed due to increasing cases amongst staff, and all students were tested regardless of exposure/symptoms.

Case 1: 12yr male in secondary school infected at home (sibling of case 2). Attended on day 1 of symptom and subsequently quarantined. 8 classmates developed compatible symptoms, all tested negative.

Case 2: 5yr male in primary school. Attended on day 1 of symptoms and quarantined. 34 classmates developed compatible symptoms, all tested negative.

Case 3: Multiple adult staff members in pre-school involved in cluster. 70% of all students tested, all negative.

These findings are consistent with the small number of other studies of transmission within a school setting so far, which have demonstrated infrequent transmission from children.

Wongsawat, JDisthakumpa, AJ Paediatr Child HealthRisk of novel coronavirus 2019 transmission from children to caregivers: A case series22 Jun 2020ThailandAsia3Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1111/jpc.14965
Ferraiolo AArioni CMedicinaReport of Positive Placental Swabs for SARS-CoV-2 in an Asymptomatic Pregnant Woman with COVID-1922 Jun 2020ItalyEurope1Epidemiology - Transmissionhttps://doi.org/10.3390/medicina56060306
Tomb, RGunson, RJ InfectRetrospective screening for SARS-CoV-2 in Greater Glasgow and Clyde ICUs between December 2019 and February 202015 Jun 2020ScotlandEurope23Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295493/
Rovida, F.Cereda, D.Clin Microbiol InfectLow risk for SARS-CoV2 symptomatic infection and early complications in paediatric patients during the ongoing CoVID19 epidemics in Lombardy12 Jun 2020ItalyEurope27Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289743/
Kayem, G.Winer, N.J Gynecol Obstet Hum ReprodA snapshot of the Covid-19 pandemic among pregnant women in France04 Jun 2020FranceEurope181Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270811
Han, MChoi, EEmerg Infect Dis Viral RNA Load in Mildly Symptomatic and Asymptomatic Children with COVID-19, Seoul04 Jun 2020South Korea Asia12Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-2449_article
Gao, Y.Xu, R.Indian J Pediatr. Clinical Features and Treatment Protocol in Eleven Chinese Children with Mild COVID-1904 Jun 2020ChinaAsia11Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269701/
Nassih, HSab, IIndian J PediarAbsence of Evidence of Transmission of Coronavirus Disease 2019 from a Young Child to Mother Despite Prolonged Contact01 Jun 2020MoroccoNorth Africa1Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292798/pdf/12098_2020_Article_3382.pdf
Somekh, EStein, MPaediatric infectious disease journalThe Role of Children in the Dynamics of Intra Family Coronavirus 2019 Spread in Densely Populated Area01 Jun 2020IsraelMiddle East58Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/The_Role_of_Children_in_the_Dynamics_of_Intra.96128.aspx

This is a brief study of the transmission dynamics within households in Bnei Brak, an area of Isreal with high population density and high proportion of young people (almost 50% of its population are <18yrs). They assessed 13 family clusters and tested every member of their households by PCR, regardless of the presence or absence of symptoms. The index case was identified by date of onset of symptoms (this is standard practice but does leave open the possibility of mis-classifying the index case if they were truly asymptomatic).

The results were as follows; Excluding index cases, 58.3% of adults tested positive, 32.5% of children aged 5 – 17 tested positive, and 11.8% of children aged <5yrs tested positive. In 12/13 families the index case was an adult. The other case was a 14yr old male.

This evidence is consistent with almost all other household contact tracing studies which have demonstrated a significantly lower secondary attack rate in children compared to adults. A strength is the clear documentation that all household members were tested regardless of symptoms, and for clarity the index case was not included in the rates of infection making secondary AR better defined.

Behera, P.Parameswaran, G.F1000Research 9 (no pagination)(315)SARS-CoV-2 epidemic in India: epidemiological features and in silico analysis of the effect of interventions30 May 2020IndiaAsia109Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262570/
Wong, JChaw, L Influenza Other Respir VirusesAsymptomatic transmission of SARS‐CoV‐2 and implications for mass gatherings30 May 2020MalaysiaAsia2Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1111/irv.12767
Yang, MSu, WPublic HealthA three-generation family cluster with COVID-19 infection: should quarantine be prolonged?30 May 2020TaiwanAsia1Epidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S0033350620302055
Heavy, LMcDarby, GEuro Surveill No evidence of secondary transmission of COVID-19 from children attending school in Ireland, 202028 May 2020Ireland Europe3Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.21.2000903

This is an epidemiological study describing cases of Covid-19 in Irish school setting in March 2020. Cases were identified by screening all cases of SARS-CoV-2 notified to public health departments in the Republic of Ireland, to identify children under the age of 18 years, and adults who had attended the school setting.

Six cases were identified, 3 school going children, and 3 adults (1 a teacher, and 2 who conducted educational session in a school). 5 out of 6 cases presented symptomatically with fever or cough, the final case was asymptomatic and screened due to a household cluster. Contact-tracing records were reviewed to identify cases of secondary transmission.

A total of 1155 contact of these six cases were identified. In the school setting, among 924 child contacts and 101 adult contacts identified, there were no confirmed cases of COVID-19. The only documented transmission that occurred from this cohort was from an adult case to other adults working environment outside school.

In conclusion no case of onward transmission to other children or adults within the school occurred. In the case of children, no onward transmission was detected at all. Furthermore, no onward transmission from the three identified adult cases to children was identified.

Limitations of the study, was only symptomatic contacts were tested, and so asymptomatic secondary cases were not captured. Also, in Ireland, when a case was identified, all children and staff within the school were excluded thus limiting the potential for further transmission within the school setting once a case was identified. All Irish schools closed on March 12th 2020 and remain closed.

Chen, MZhao, DJournal of Infection and Public HealthA SARS-CoV-2 familial cluster infection reveals asymptomatic transmission to children27 May 2020ChinaAsia2Epidemiology - Transmissionhttps://doi.org/10.1016/j.jiph.2020.05.018
Posfay-Barbe, KL'Huillier, APediatrCOVID-19 in Children and the Dynamics of Infection in Families26 May 2020SwitzerlandEurope40Epidemiology - Transmissionhttps://doi.org/10.1542/peds.2020-1576

This is a report of the first 40 paediatric patients presenting to Geneva University Hospital’s surveillance network (Switzerland). The aim of the study was to describe the clinical presentation of the patients and the dynamics of their familial clusters. Out of a total of 4310 SARS-CoV-2 cases, 40 (0.9%) were in children <16 years.

Clinical Presentation: Patients presented to medical care, and were confirmed via RT-PCR. Median age, years (IQR) 11.1 (5.7-14.5), 22/40 (56%) were female. The most common presentation was cough 32 (82%), Fever 26 (67%), nasal discharge 25 (64%). Most were previously healthy; with comorbidities reported in only 26% of patients; asthma (10%), diabetes (8%), obesity (5%), premature birth (5%) and hypertension (3%). Seven patients were admitted, none needed ICU care or Sars Cov2 specific therapy

Family Clusters: Family cluster evaluation was conducted by phone. 111 household contacts (HHC) were identified; 39 mothers, 32 fathers, 23 pediatric siblings, 8 adult siblings and 7 grandparents.

Family member was suspect if they had fever of acute respiratory symptoms. 61/111 had RT-PCR conducted. 77% (85/111) of household contacts (HHC) were symptomatic. Adult HHC were suspected or confirmed to have covid symptoms before the child 79% (31/39) of cases. In only 8% (3/39) of households did the study child develop symptoms first. 85% (75/88) of adult HHC developed symptoms at some point, compared to 43% (10/23) of pediatric HHC, which was statistically significant (p<0.001). Mothers were statistically more likely to develop symptoms than fathers (36/39 v 24/32, p=0.04). Due to the need for symptoms to qualify for testing, there is the possibility of undercounting paediatric infections due to their being more likely to have asymptomatic or oligosymptomatic infection.

The authors conclude that children are uncommonly the index case in family clusters of Sars CoV2. Household contacts who are children are less likely to be symptomatic than adult contacts. Children are most likely to be infected inside of family clusters, albeit at a time in Switzerland when creches and schools were closed.

De Ioris, MRaponi, MJ Pediatric Infect Dis SocDynamic viral SARS-CoV-2 RNA shedding in children: preliminary data and clinical consideration of Italian regional center23 May 2020ItalyEurope22Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa065/5842265?searchresult=1

This study at a paediatric hospital in Rome tracked SARS-CoV-2 shedding (nasopharyngeal, faecal, urinary and conjunctival) by following a cohort of 22 children during their hospital stay, collecting clinical and microbiological data.

Study design: The study ran from 16th March to 12th April in the COVID centre at Bambino Gesu Pediatric Hospital and collected data on 22 inpatients with an initial positive nasopharyngeal swab (either prior to admission or on admission). RT-PCR for SARS-CoV-2 RNA on nasopharyngeal and conjunctival swabs and stool and urine samples were repeated every 2-3 days for each child while they were inpatients until they had two consecutive negative results in the absence of new symptoms. Kaplan-Meier analysis was used to estimate the duration of symptoms and viral shedding for symptomatic patients: patients whose last swab/sample was still positive were censored at the date of the last swab.

Study population: 15/22 (68%) male, 7/22 (32%) female. Median age 7 years (range 8 days to 17.5 years). 4/22 neonates (1/4 tested because mother positive and 3/4 tested because midwife positive). 2/22 comorbidity (Angelman syndrome, suspected genetic syndrome and autism). 13/22 patients were discharged before the end of the study period (median inpatient stay 7 days, range 3-15 days).Symptoms: 4/22 (18%) asymptomatic (including 2/4 neonates, the other 2/4 had low grade fever and poor feeding). 18 symptomatic patients: 15/18 (83%) fever, 10/18 (55%) respiratory symptoms, 7/18 (39%) diarrhoea and vomiting, 3/18 (17%) seizure. Symptoms had resolved in all 18 before discharge from hospital. Median duration of symptoms was 8 days (range 2-21 days). 15/22 had a positive stool sample at admission: of these 7/15 (47%) had respiratory symptoms and 3/15 (20%) had diarrhoea and vomiting.

Viral shedding: At diagnosis: 22/22 (100%) had positive nasopharyngeal swab (by definition), 15/22 (68%) had positive stool sample, 1/22 (5%) had positive urine sample (re-test 2 and 5 days later was negative; another patient had initial negative urine test but repeat 3 days later was positive) and 2/22 (9%) had positive conjunctival swab (both were negative 2-3 days later). A detailed table charting the dates of inpatient stay, onset and end of symptoms and positive/negative swabs/samples for each patient is supplied: the full screen of faecal, urinary and conjunctival sampling was performed at variable intervals after the initial positive nasopharyngeal swab (up to 5 days later in several cases). For symptomatic patients: (1) from date of symptom onset to negative nasopharyngeal swab: median 8 days (range 2-17 days) and (2) from date of symptom onset to negative stool sample: median 14 days (range 10-15 days). Estimate of persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab 52% and for stool sample 31%.

The authors note the need to confirm the clinical relevance of faecal SARS-CoV-2 shedding in terms of the risk of transmission via the faeco-oral route.

Wolf, GProtzer, UJ Paed Inf Dis SocClinical and Epidemiological Features of a Family Cluster of Symptomatic and Asymptomatic SARS-CoV-2 Infection22 May 2020GermanyEurope3Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa060/5842074
Yuan, CXiao, HEmerging microbes & infectionsViral loads in throat and anal swabs in children infected with SARS-CoV-218 May 2020ChinaAsia2138Epidemiology - Transmissionhttps://www.tandfonline.com/doi/pdf/10.1080/22221751.2020.1771219?needAccess=true

This is a retrospective review of RT-PCR testing results of 2138 paediatric patients with suspected SARS-CoV-2 infection at Wuhan Children’s Hospital in Hubei, China, from 1 January to 18 March 2020. All children were tested using throat swabs (TS); a subset of 212 were also tested using anal swabs (AS). Changes in viral load in both throat and anal swabs were monitored in 13 patients.

Findings: 217/2138 (10%) confirmed cases on EITHER throat or anal swab.78/217 confirmed cases had both types of swab: 24/78 (31%) positive for both TS & AS, 37/78 (47%) TS pos/AS neg, 17/78 (22%) TS neg/AS pos. For those cases where the TS and AS results didn’t match (i.e. TS pos/AS neg or TS neg/AS pos):

Asymptomatic: 12/37 (32%) TS pos & 10/17 (59%) AS posGI symptoms: 7/37 (19%) TS pos & 6/17 (35%) AS posCough: 16/37 (43%) TS pos & 4/17 (24%) AS posFever: 20/37 (54%) TS pos & 5/17 (29%) AS posCT evidence of pneumonia: 25/37 (68%) TS pos & 10/17 (59%) AS posTime from positive to negative for PCR assay: 7 days for TS pos & 6 days for AS posThe viral loads detected on throat swabs and anal swabs showed no difference.

Zhao FLiu YJ GastroThe Time Sequences of Oral and Fecal Viral Shedding of Coronavirus Disease 2019 (COVID-19) Patients16 May 2020ChinaAsia30Epidemiology - Transmission https://www.gastrojournal.org/article/S0016-5085(20)30663-6/pdf
Schwartz, NStewart, RMMWRAdolescent with COVID-19 as the Source of an Outbreak at 3-week Family Gathering - 4 States, June-July 2020010 May 2020USANorth America8Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6940e2.htm

This is a case report of a cluster associated with a paucisymptomatic child index case in the USA.

A 13y old girl, had a known exposure to COVID-19 but 4 days after exposure she had a negative rapid antigen test. 2 days later she had nasal congestion but travelled with her immediate family to a large gathering of the wider family. 14 people stayed in the same house for between 8 and 21 days and practiced no social distancing.

12 of these 14 people experienced symptoms and were classed as confirmed/probable/suspected COVID-19 cases.

Another 6 family members visited on 2 occasions (10 hours and 3 hours) but remained outdoors and socially distanced. None experienced any symptoms and 4 had negative RT-PCR tests 4 days after the last exposure.

Details of the days at which various members showed symptoms and the testing that was done are shown in the paper.

The index case had a 9y old brother and 10 y old cousin but all the others at the gathering were teenagers or older, the oldest being the grandparents who were 72.

This paper illustrates

• The high transmission rate of SARS-Cov-2 within households

• The necessity for 14 days self-isolation after exposure

• That outdoors, with social distancing, transmission is much less

Rosenberg, ENew York State Coronavirus 2019 Response TeamClinical Infectious DiseasesCOVID-19 Testing, Epidemic Features, Hospital Outcomes and Household Prevalence, New York State - March 202008 May 2020USANorth America50Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa549/5831986

This epidemiological study examined the first 229 positive cases diagnosed in New York State outside of the city of New York from 2nd March to 12th March 2020 and described their outcomes. In addition, from the 5th March to the 17th March, they screened any household contacts of the positive patient. There was one ‘source’ patient under 5 years of age and 7 ‘source’ patients from 5 to <18 years of age. Household screening identified a further 42 children with COVID-19. No children <18 years of age required hospitalisation but it appears they only had complete data on 18/50 positive children.

Household contact with positive patients of any age found that likelihood of the contact being positive for SARS-CoV-2 increased with the contact’s age. Of the 25 children screened <5 years of age, 5 (20%) were positive and of the 131 screened age 5 to <18 years 37 (28.2%) were positive, compared to 16/29 (55%) of contacts aged 65+ years (p 0.002). This supports previous studies which shows a lower prevalence of SARS-CoV-2 infection in children <18 years. Unfortunately it does not described whether the household contacts of the 50 source children were positive for the infection too which could contribute to the discussion about whether children spread SARS-CoV-2 as effectively as adults and would require completion of the missing data and more in-depth analysis of the findings.

Mao, LYuan, ZBMJ Infect DisA child with household transmitted COVID-1907 May 2020ChinaAsia1Epidemiology - Transmissionhttps://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05056-w
Zhang, JYu, HScienceChanges in contact patterns shape the dynamics of the COVID-19 outbreak in China29 Apr 2020ChinaAsia756Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/04/28/science.abb8001

This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghia) using 3 arms:

Surveys conducted within cities studying contacts between individuals, finding that during lockdown all contact except for those within households ceased – backing up evidence that about 90% of infections during this period occurred by household transmission

Most importantly for us – an age stratified model of susceptibility to acquiring infection was produced by assessing the data from the Hunan CDC, whereby every positive case found in Hunan had recent contacts placed under quarantine for 14 days and was tested for COVID-19. They estimated odds ratios for age groups to become infected, and performed statistical adjustment for clustering and correlation structures of contacts exposed t the same index case (generalized linear mixed model regression). Their finding was that susceptibility to infection increased with age, lowest in children 0-14 years (OR 0.34, 95% CI 0.24 – 0.49 – reference participants aged 15 – 64yrs).

Finally using the above data they estimated the effects of non-pharmceutical interventions on reducing spread of COVID-19. They found that closing schools was likely to significantly impact the R0 but not enoght to be a useful measure on its own. They describe social distancing as implemented in China, to be a sufficient measure to control COVID-19

This is the latest, and one of the most comprehensive of a number of studies to demonstrate significantly lower attack rate in children to adults, suggesting decreased susceptibility to infection.

Jiang XQiu JJ Med VirolAsymptomatic SARS‐CoV‐2 infected case with viral detection positive in stool but negative in nasopharyngeal samples lasts for 42 days24 Apr 2020ChinaAsia1Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25941
Luo, YXiao, WEmerg Infect DisAsymptomatic SARS-CoV-2 infection in household contacts of a healthcare provider, Wuhan, China.24 Apr 2020ChinaAsia2Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/8/20-1016_article
Song, RLi, XJ. Infect.Clinical and epidemiological features of COVID-19 family clusters in Beijing, China23 Apr 2020ChinaAsia7Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(20)30229-2/pdf

This early epidemiological study from Beijing describes four family clusters identified from January 16th through to January 29th 2020. All 4 index cases were adults. SARS-CoV-2 infection was confirmed in 18 of 20 contacts, including 7 of 8 children. The clinical course in these children ranged from asymptomatic infection to mild disease. PCR positivity was shorter in paediatric cases (range 5-17 days) compared with adults (7-37 days).

The transmission from adults index cases to children in this study is consistent with other studies of transmission dynamics in family clusters. Similarly the mild clinical course in children is in keeping with larger studies. The high household attack rate in this report may be due to the delay in diagnosis of the index cases, possibly owing to the timing of the study early in the pandemic.

Liu, SKuo, HJ Med VirolThree Taiwan's domestic family cluster infectionsof coronavirus disease 201923 Apr 2020TaiwanAsia1Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25949
Jiang, XMa, MJ. Infect.Transmission Potential of Asymptomatic and Paucisymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections: A 3-Family Cluster Study in China 22 Apr 2020ChinaAsia1Epidemiology - Transmissionhttps://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa206/5823691
Li, WChen, JClinical Infectious DiseasesThe characteristics of household transmission of COVID-1917 Apr 2020ChinaAsia100Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa450/5821281

This retrospective study calculated secondary attack rates of COVID-19 amongst 392 household contacts of 105 SARS-CoV-2 RT-PCR positive index cases hospitalised at Zaoyang First People’s Hospital (250 km from Wuhan) and Chibi People’s Hospital (150 km from Wuhan) between 1st January and 20th February 2020.

Study design: Households were eligible for the study if the index case was the only member of the household with a clear history of exposure to Wuhan, its residents or high-risk sites in the 14 days before onset of illness (the assumption then being that the only exposure of household contacts to SARS-CoV-2 was via the index case). Once index cases were confirmed, household contacts were quarantined for 14 days in local government sites and monitored daily, with at least 2 nasopharyngeal swabs (taken at the beginning and mid-point of quarantine). Variables analysed retrospectively in this study (using medical notes and telephone interviews) included household size, age/gender/symptoms of index cases and household contacts, time between onset of illness of the index case and hospitalisation (range 0-11 days) and spouse/non-spouse relationships.

Key paediatric findings: 100 of the 392 household contacts were under 18 years of age (median 6.5 yrs, IQR 4-11 yrs); of these, only 4 children became infected (all male, 1 aged 0-5 yrs, 3 aged 6-17 yrs). This secondary attack rate of 4% for children compares with 21% for the adult household contacts (60 out of 292 infected) and 16% overall (64 out of 392).

Of interest: 14 of the 105 index cases self-quarantined within the home immediately after onset of symptoms before hospitalisation (wearing masks, eating and residing separately from the rest of the household); in these households there was a 0% secondary attack rate, versus 18% in those households where the index case didn’t self-quarantine before hospitalisation. In households where the index case was afebrile, 13% of household contacts became infected, versus 19% where the index case had fever. In households where the index case had no cough, approximately the same proportion of household contacts became infected as in households where the index case had a cough (17% vs 16%). 9 of the infected household contacts were asymptomatic (14%), but this figure isn’t broken down by age in the article. [Note: there are some discrepancies between calculations in the text and data tables; data from tables used here.

This article provides further reassurance to the growing body of evidence of lower attack rates of COVID-19 in children as compared to adults, as well as a signal that symptomatic patients are higher risk of transmitting the virus than those who do not develop symptoms.

Pathak, EHambleton, IJPHMPCOVID-19 in Children in the United States: Intensive Care Admissions, Estimated Total Infected, and Projected Numbers of Severe Pediatric Cases in 202016 Apr 2020USANorth AmericaEpidemiology - Transmissionhttps://pubmed.ncbi.nlm.nih.gov/32282440/

This study uses data from modelling studies of the COVID-19 outbreak China in January and February 2020 (in particular, adjusted pediatric severity proportions and adjusted pediatric criticality proportions) plus data from US PICU cases (and therefore estimates of total SARS-CoV2 cases in children derived from this) to model and project potential PICU bed occupancy from COVID-19 under a variety of “cumulative pediatric infection proportion” scenarios (how many children in total get infected).

Essentially – a modelling study to try and predict how many children in the US might need PICU from COVID-19.

The headline is if 5% of children in the US get infected with SARS-Cov2, 1086 children would be predicted to need PICU. If 50% of children get infected with SARS-CoV2, 10865 children would be predicted to need PICU, which is a lot.

There are 2 major issues with this study. One which is addressed (albeit, perhaps not sufficiently) is the denominator issue. To determine what proportion of cases need PICU, you need to know how many children in total were infected in the population the data in the model was derived from. To put it bluntly, we have absolutely no idea what-so-ever how many children this is. We will not know the answer to this until we have comprehensive sero-surveillence data from children (testing antibodies), which is unlikely to be available for some time. This makes this type of projection an interesting thought experiment, but nothing more.

The second, glaring issue, is the evidence from around the world that nothing close to anything they have projected has come to fruition in any other developed country which is several weeks ahead of the US in regards to COVID-19. Italy, Spain, France, UK, have all had handfuls of children needing intensive care from COVID-19. The US has the benefit of looking into its future, and fortunately it doesn’t look anything like the projections in this study.

Jing, QYang, YmedRxiv (preprint)Household secondary attack rate of COVID-19, and associated determinants15 Apr 2020ChinaAsia254Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.04.11.20056010v1

A pre-print, this article should be interpreted with caution until it has undergone peer review.

This is study from Guangzhou, China documenting the attack rate amongst 2075 close contacts of 212 confirmed COVID-19 cases from January 7th to February 17th 2020.

There were 97 non-primary cases amongst 770 household contacts giving an attack rate of 12.6% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.3%.

In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.27 for close contacts and OR 0.23 for household contacts)

Only 10/217 (5%) of primary cases were children.

Although the criteria for testing contacts in this study are not entirely clear, the results suggests that children are less susceptible to SARS-CoV-2 infection compared with adults with similar exposure. This is in contrast to earlier data from Shenzhen, China suggesting similar attack rates in children, but is in keeping with more recent epidemiological data from Iceland and Italy.

Danis, KSaura, CClinical Infectious DiseasesCluster of coronavirus disease 2019 (Covid-19) in the French Alps, 202011 Apr 2020FranceEurope1Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciaa424

This is a study of a cluster of COVID-19 cases in the French alps liked to a single index case. A child became infected and was symptomatic, but despite attending 3 schools during this time with exposure to 112 different school contacts the child did not transmit the infection to any other contacts.

Whilst a single case study, this evidence suggests different transmission dynamics from children, supporting other data which consistently demonstrates reduced infection and infectivity of children in the transmission chain.

Pan, AWang, CJAMAAssociation of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China10 Apr 2020ChinaAsia536Epidemiology - Transmissionhttps://jamanetwork.com/journals/jama/fullarticle/2764658
Xiao, ZZheng, TJ Infect Dev CountrExamining the incubation period distributions of COVID-19 on Chinese patients with different travel histories08 Apr 2020ChinaAsiaEpidemiology - Transmissionhttps://jidc.org/index.php/journal/article/view/32379707/2227

Although all ages are affected by COVID-19, this paper makes it clear that the number of infected children is tiny compared to those in adults. The authors analyse incubation periods by age, finding that this increases in length in adults from aged 20 to 70+. The findings regarding children are more difficult to interpret due to small case numbers and therefore large confidence intervals, but it appears that 6 to 20 year olds may have a longer incubation period than young adults aged 20 to 60. The results for 0-5 year olds are fairly inconclusive. The authors then examine incubation in relation to travel history, finding that those who were affected by local community spread had longer incubation periods than those who had contracted the virus directly in Wuhan. They conclude that the virulence of the virus may decrease with intergenerational transmission, but that more work is needed.

Chen, DLei, CJMVFour cases from a family cluster were diagnosed as COVID-19 after 14-day of quarantine period08 Apr 2020ChinaAsia4Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25849

This paper was a case study of a family who was seen at First Affiliated Hospital of Guangzhao Medical  University. The family had four of six family members positive for SARS-CoV-2, all more than 14 days after the time of suspected exposure in Wuhan. The family had left Wuhan on 22nd January, and completed quarantine for two weeks, however subsequently developed symptoms. At the time of their diagnosis there were no known cases in their local area. They were managed  at the First Affiliated Hospital of Guangzhao Medical  University. The average length of time from leaving Wuhan until symptoms was 25 days. Diagnosis was made for patients by nasopharyngeal swabs via qRT_PCR (twice positive).

Within the family there was one paediatric patient who was diagnosed with SARS-CoV-2 (Patient 3), a 7 year old boy who became unwell on February 21st. His grandparents were the first in the family to be determined positive. His father was also positive but asymptomatic. HIs sister and mother were negative, although it was noted the sister did have radiological findings on chest imaging, but that these were not stereotypical for cover and she also tested negative for SARS-CoV-2.

Patient 3's symptoms were a low grade temperature of 37.3.  There are no details provided regarding his blood tests. He had CT chest showing right lobular and sub segmental ground-glass opacities. There were no further details given regarding the child's other symptoms or management.

Of the adult patients - all patients had normal WCC, but the grandparents both had reduced lymphocyte count.

Zhu, YShort, KMedRxivChildren are unlikely to have been the primary source of household SARS-CoV-2 infections30 Mar 2020InternationalInternational19Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.26.20044826

A pre-print, the information should be treated with caution until it has undergone peer review.

This study includes a review of symptom frequency in children, but most interestingly examines available case series in the literature of family clusters of COVID-19 to determine what contribution is made of children to the chain of transmission. Clusters were taken from China, Singapore, the USA, South Korea and Vietnam, totalling 31 household transmission clusters. Of these cases, only 3 (9.7%) had a child as the index case. Considering a worst case scenario (whereby ALL infected children were the index case in their family and had been mislabelled as a secondary in some studies), still children would only account for 6/28 (21%) infection clusters. They compare this to the H5N1 epidemic where children were the index case in 54% of household clusters. This provides further evidence that children appear to have a fairly limited role in the transmission of COVID-19, which has implications for non-pharmaceutical interventions such as school closures.

Davies, NJit, MMedRxivAge-dependent effects in the transmission and control of COVID-19 epidemics24 Mar 2020UKEuropeEpidemiology - Transmissionhttps://doi.org/10.1101/2020.03.24.20043018

A pre-print, the information should be treated with caution until it has undergone peer review. This is a mathematical modelling study from the London School of Hygiene and Tropical medicine, examining the explanation for the relatively low numbers of childhood cases of COVID-19. They assess three plausible explanations, including:

-Assortative mixing patterns or school closures decreasing mixing and spread between children.

-Children exhibiting lower susceptibility to infection.

-Children having a lower propensity to show clinical symptoms.

They tested these hypotheses by fitting an age structured model to epidemic data from six countries (China, Japan, Singapore, South Korea, Italy and Canada). The details of the modelling and simulations are highly specialist, but essentially they found that there was a strong age dependence in the probability of developing clinical symptoms. There are many implications to this, including limited efficacy of school closures in halting the spread of the pandemic, and that regions with older populations may see disproportionate more cases, in particular during the latter stages of the pandemic. They note that understanding the role of subclinical infection remains vital to informing policy to stem the spread of disease. We should remember this is based on mathematical modelling, and further clinical and epidemiological information will be necessary to confirm or refute their hypothesis.

Wang, ZZhang, RJournal of infectionHousehold transmission of SARS-CoV-221 Mar 2020chinaAsia18Epidemiology - Transmission https://www.journalofinfection.com/article/S0163-4453(20)30169-9/pdf

This is a retrospective case series of 85 patients admitted to Union Hospital in Wuhan City, Hubei Province, China and their households, one household per index case. The aim was to attempt to determine the transmission rate of SARS-CoV-2 among household members.

All patients were confirmed infected with SARS-CoV-2 with real-time reverse transcription polymerase chain reaction (RT-PCR) assays on throat swabs. The admission dates were February 13 and February 14, 2020. The city had been under lockdown measures since the 23rd of January.

The composition of these 85 households was 107 (45%) male adults, 115 (48%) female adults and 18 (7%) children.

64 (60%) of 107 male adults and 66 (58%) of 115 female adults were confirmed infected with SARS-CoV-2, only 2 (11%) of 18 children became positive. As a whole, there were totally 240 cases in these 85 households, with 132 (55%) of them were confirmed with SARS-CoV-2 infection and 57 (24%) cases were negative in RT-PCR assays.

The researchers found there was a secondary transmission rate of 30% and this increased to 50% for households with 2 contacts, they compared this to previous studies on other two coronavirus pneumonia epidemics which reported secondary transmission rates among household contacts of 5% for Middle East respiratory syndrome coronavirus (MERS-CoV) and 10.2% for severe acute respiratory syndrome coronavirus (SARS-CoV). The researchers concluded this demonstrated the need for stringent quarantining of household contacts.

This research did have some limitations. The researchers did not clarify what criteria they were using to guide testing nor did they quantify exactly how long they followed up household contacts for. It reproduces similar studies which have found significantly lower attack rates in children.

Jeong, EOsong Public Health Res PerspectCoronavirus Disease-19: Summary of 2,370 Contact Investigations of the First 30 Cases in the Republic of Korea20 Mar 2020South KoreaAsia155Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104686/pdf/ophrp-11-81.pdf

This paper from the Republic of Korea reports findings from the contact tracing of the first 30 positive COVID-19 cases in that country. 2,370 individuals were traced based on being in "close contact" with a case (being within 2 metres of a case) or "daily contact" (proximity without close contact). Of these, 155 were aged 0-19 years. Of these, one 10-19 year old tested positive giving a secondary attack rate of 1.49 (0.08 - 9.13). The mode of contact giving the greatest overall attack rate was being 'household contact' but these details are not presented specifically in relation to children.

Mizumoto, KNishiura, HMedRxIVAge specificity of cases and attack rate of novel coronavirus disease (COVID-19)13 Mar 2020JapanAsia176Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.09.20033142

A pre-print, the information should be treated with caution until it has undergone peer review.

This is a series of the 313 domestically acquired cases of COVID-19, in Japan, up until March 7th 2020. It looks at the ages of patients who acquired the disease and compares this to those exposed (n=2496) to estimate attack rates.Of note, there was a significantly lower attack rate in children (7.2% in males and 3.8% in females) than in the older populations (up to 22% in 50–59 year olds). This attack rate in children is similar to that observed in Shenzen, but much lower than observed in older adults in Japan. This suggests children are much less likely to acquire the disease than adults if exposed. This is at odds with the findings from Shenzen, and the reason for this disparity is unclear.

Bi, QFeng, TMedRxIVEpidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts24 Feb 2020ChinaAsia20Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.03.20028423
Pan, XLiu, JLancet: Infectious DiseasesAsymptomatic cases in a family cluster with SARS-CoV-2 infection19 Feb 2020ChinaAsia1Epidemiology - Transmissionhttps://doi.org/10.1016/S1473-3099(20)30114-6

This case study looks at another family cluster of COVID-19 involving asymptomatic patients. It involved a 3yr old boy who was positive for SARS-CoV-2 despite having no symptoms, normal bloods and a normal CT.

Fuk-Woo Chan, JYuen, KYLancetA familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster24 Jan 2020ChinaAsia1Epidemiology - Transmissionhttps://doi.org/10.1016/S0140-6736(20)30154-9

This case study looks at a family cluster, including a patient who had not traveled to Wuhan. There was one child, aged 10 in the cluster. They were asymptomatic but had bilateral ground-glass opacities on x-ray with essentially normal bloods.

Breslin, NGoffman,DNCBICoronavirus Disease 2019 among asymptomatic and symptomatic pregnant women9th April 2020USANorth America43Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144599/

This is a retrospective case-controlled study of 43 women who had presented to 2 affiliated hospitals in New York City between 13/03/20 and 27/03/20 and had positive nasopharyngeal swabs for SARS CoV 2 PCR. The average BMI of these women was 30.9 (60.5% had a BMI ≥30) and 18 women had co-morbidities (mild asthma being the most common). 29 women had COVID-19 related symptoms and underwent testing at presentation. 3 of these women were admitted for management of COVID-19 symptoms and 4 were admitted (unclear when in the two-week study period) for obstetric indications. 14 women were asymptomatic and had presented for obstetric reasons. 2 of these women were tested due to COVID-19 symptom onset during admission and went onto require ITU level care. The other 12 asymptomatic women were tested as part of the universal testing on admission to the delivery unit. Of the 18 women admitted for obstetric indications, 10 were planned admissions (9 inductions and 1 elective section). 4 COVID-19 symptomatic women (incl.1 preterm labour) and all asymptomatic women gave birth to a total of 18 babies (10 vaginal deliveries and 8 c-sections for obstetric reasons) with good APGAR scores. All babies had nasopharyngeal swabs on day 0; 15 babies were negative, 2 babies had initial unclear and then negative on repeat swab on day 1-2 and 1 baby had an indeterminate result and was clinically managed as ‘presumptive negative’. There were 3 admissions to NICU (n=1 preterm 34+6 n=1 antenatal diagnosis of multicystic dysplasic kidney and n=1 Resp distress with suspected sepsis – COVID-19 swab -ve). Babies not requiring NICU were kept with mothers and breast feeding encouraged with advice on strict hand hygiene and mask wearing. All babies have been discharged home.

There are two clear inconsistencies noted in this paper. Firstly, there is a different mean age of pregnant women stated in the table to that which is stated in the body of the text. Secondly, there is a mention of ‘3 of the 28 babies’ being admitted to NICU whereas elsewhere in the paper it consistently quotes 18 babies; this maybe a mis-print. There is also ambiguity in the way that results are presented for the symptomatic women for whom treatment was not required for their COVID-19 symptoms on initial presentation; the flowchart figure shows 26 patients with mild disease with 4 admissions for obstetric reasons, but the text reports 25 patients were stable for discharge. The most striking finding in this paper is the number of women who present with obstetric reasons and with no COVID-19 symptoms, who tested positive for COVID-19. This is even more poignant given that the 2 women requiring ITU level care were asymptomatic at presentation and were the only ones to require this level of support in this report. It is also important to note that 5 of the inductions of labour were in asymptomatic women for worsening pathologies such as cholestasis, reduced fetal movement and chronic and gestational hypertension and that one of symptomatic women went into preterm labour. It is reassuring that all neonates born, regardless of COVID-19 symptom status at presentation, did well clinically with most babies being kept with mothers post partum. The neonates were not assessed for IgG and IgM status.

Egerup, PNielsen, HObstet Gynecol.Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns27 Oct 2020DenmarkEurope1206Neonatal https://journals.lww.com/greenjournal/Fulltext/9900/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.29.aspx

This is a prospective cohort study conducted at a single centre in Denmark between 4th of April 2020 and 27th of April 2020. They recruited 1313 women (72% of all admissions), their partners (n=1188) and newborns (n=1206). The women and partners were tested for antibodies in the blood and a nasopharyngeal swab taken for PCR. Umbilical cord blood was taken to look for antibodies in the neonate. The iFlash 1800 kit was used for detecting antibodies and a positive IgM and IgG was defined as a level ≥8 arbitrary units/ml and ≥10 arbitrary units/ml.

With antibodies Without antibodies

Mothers 28 1285

Mothers with +ve swab at admission 0 1 (and 2 inconclusive)

Mothers with prev. +ve swab 3 2

Mothers reporting prior symptoms 14 (50%) 383 (31%)

Partners 32 1156

Partners with +ve swab at admission 1 (and 1 inconclusive) 0 (and 1 inconclusive

Partners with prev. +ve swab 2 1

Partners reporting prior symptoms 20 (65%) 329 (30%)

Newborn 17 (3/17 born to mothers negative for Ab) 1189

The only statistically significant baseline characteristic difference was that 61% of women in the antibody positive group were Blood group A compared to 41% in the Ab -ve group (p=0.034). There was no difference in the rate obstetric or neonatal complications between the two groups. 82% of neonates with antibodies were born to mothers who were also positive for antibodies (67% of antibody positive women had neonates with antibodies). The 3 neonates who born to mothers who were negative to antibody had levels which were close to the cutoff and therefore this result was determined to be concordant. All neonates were IgM negative. The study reports an adjusted prevalence of 2.6% in the women and 3.5% in the partners based on the serological results. They also report 37% increase in absolute risk of mother being Ab+ve if living with a partner who is Ab+ve and a 39% absolute risk of infection if the partners tested +ve.

This study has a small number of antibody positive participants and case control study would have been a better design to see if there was an association with antibody positivity and obstetric and neonatal outcomes. With regards to the frequency of the antibody it would have been better to choose a population who had already been determined to have had COVID infection or be asymptomatic carriers. Furthermore, the small numbers mean that risk have wide confidence intervals and they assume that mothers were living with their partners and that the partners contracted the infection first. The study is conducted in a young (mean age 31) population with normal BMI and a largely asymptomatic or mild COVID infection profile. The study does not provide details of ethnic background. The study does not provide a break down of IgM positivity in the mothers and partners. The high percentage of neonates with antibodies born to mothers with antibodies is reassuring but further study of this cohort of positive women is needed to determine what characteristics may hinder the transfer of these antibodies. It is also reassuring that all neonates were IgM negative, but we must keep in mind that the mothers were largely asymptomatic or had mild disease.

In conclusion, the results from this study are unreliable. They had two aims, to determine the frequency of antibody (wrong cohort) and to see if they had an association with obstetric and neonatal outcomes (wrong design).

Colomer, BMatías del Pozo, VFront PediatrNeonatal Infection Due to SARS-CoV-2: An Epidemiological Study in Spain23 Oct 2020SpainEurope40Neonatalhttps://www.frontiersin.org/articles/10.3389/fped.2020.580584/full

This is a national prospective observational study looking at postnatally acquired COVID 19 infection in neonates between the study period of 3/04/20 to 18/05/20. Of the 79 hospitals who were entering information into the national registry, 21 hospitals recorded 40 cases of postnatally acquired infection. These cases were split into community acquired and nosocomial and the clinical course, treatment, investigations and follow-up were analysed. Of the baseline characteristics analysed between the two group, statistically significant difference was noticed with the Noscomial group having smaller anthropometric measurements, greater number of preterms and lower rates of breast feeding. In both groups there was a greater prevalence of male infants.

This study provides the largest cohort assessment of babies and their clinical course following postnatally acquired COVID infection. The study describes a predominantly mild course of illness with respiratory infection being the most common clinical manifestation. Prematurity seems to be a possible risk factor for severe disease manifestation, along with other underlying background conditions and co-infections. In a minority of cases, it also reports white cell count abnormalities. The CXR abnormalities, when present, are similar to finding from other age group populations. In the majority of cases in both groups there was a source of infection identified(most commonly mother), indicating that the baby is unlikely to be the index case and that strict infection-control measures should be implemented to minimise horizontal transmission. They also report the use of hydroxychloroquine, the efficacy and appropriateness of which cannot be determined based on the information provided in this study. This study has had problems with missing data and they also do not look at the perinatal history of these babies. Overall, the descriptions provided by this study are helpful bear in mind in our own clinical practice.

Gale, CKurinczuk, JThe Lancet Child & Adolescent HealthCharacteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance 09 Nov 2020UKEurope66Neonatalhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30342-4/fulltext

The aim of this prospective study, reported by an eminent group of perinatal epidemiologists and academic clinicians, was to measure the population-level incidence, characteristics, transmission and outcomes of SARS-CoV-2 infection in neonates in the UK who received inpatient treatment for the infection in hospital. The data collection period was two months (1st March 2020 – 30th April 2020).

The data sources for identification of infected babies were the British Paediatric Surveillance Unit linked to national testing, the obstetrics surveillance database and paediatric intensive care (PIC) audit data. The defined outcomes included the UK incidence of (hospital-based) neonatal SARS-CoV-2, the incidence of severe neonatal SARS-CoV-2 disease, the proportion of these babies who acquired the infection by “vertical” transmission, the proportion who acquired the infection nosocomially and the clinical outcomes for infected babies.

A total of 66 infected babies met the inclusion criteria, giving an incidence of 5·6 [95% CI 4·3–7·1] per 10,000 livebirths during those two months. Of these, 28 (42%) had severe neonatal SARS-CoV-2 infection (incidence 2·4 [1·6–3·4] per10000 livebirths) and 16 (24%) were preterm. The criteria for “severe” follow the initial Dong et al paper, with any 2 of: Temperature >37.5, apnoea, cough, tachypnoea, respiratory distress, oxygen requirement, poor feeding, vomiting or diarrhoea, plus one of: low WCC, low lymphocytes, or CRP >5mg/L and: abnormal chest x-ray.

The most common signs at presentation were hyperthermia and poor feeding or vomiting but respiratory signs were also reported to be common. Of those tested, 55% had a raised serum lactate (>2mmol/L), 29% had a CRP >5mg/L and 9% had a low lymphocyte count.

With regard to ethnicity:

- 36 (55%) babies were from white ethnic groups (incidence 4·6 [3·2–6·4] per 10,000 livebirths)

- 14 (21%) were from Asian ethnic groups (incidence 15·2 [8·3–25·5] per 10000 livebirths)

- 8 (12%) were from Black ethnic groups (incidence 18·0 [7·8–35·5] per 10000 livebirths)

- 7 (11%) were from mixed/other ethnic groups (incidence 5·6 [2·2–11·5] per 10000 livebirths).

With regard to route of transmission

- 17 (26%) babies were born to mothers with known perinatal SARS-CoV-2 infection

- 2 (3%) were considered to have possible vertically acquired infection (SARS-CoV-2-positive sample within 12 hours of birth where the mother was also positive)

- 8 (12%) babies had suspected nosocomially acquired infection.

With regard to outcome:

- median length of stay was 7 days (IQR* 2-55) for babies admitted to a neonatal unit and 2 days (IQR* 0-4) for those admitted to a PIC unit

- 58 (88%) babies had been discharged home by July 28, 2020

- 7 (11%) were still admitted on July 28th

- 1 (2%) had died of a cause unrelated to SARS-CoV-2 infection

- 42% of neonates met the criteria for severe disease compared with 6% of older children, indicating that disease severity is greater in infected neonates.

A number of limitations of this study are acknowledged by the authors, including: the limited range of data available from the surveillance sources; the cross-sectional nature of the data; the low frequency of testing of neonates at 12 hours which compromises the estimation of vertical transmission; the absence of longitudinal data relating to the relationship between breastfeeding and SARS-CoV-2; the inability to estimate overall infection rates in the population as the study was confined to hospital patients.

Key messages from this study are: the high proportion of babies from Black, Asian, or minority ethnic groups requires further investigation; separation of newborn babies from their SARS-CoV-2 positive mothers is not justified; disease severity appears to be greater in neonates than older children.

Dong, LYin, MmedRxivEvaluation of vertical transmission of SARS-CoV-2 in utero: nine pregnant women and their newborns08 Jan 2021ChinaAsia9Neonatal https://www.medrxiv.org/content/10.1101/2020.12.28.20248874v1

The primary aim of this study was to characterise, first, the distribution of SARS-CoV-2 viral proteins (spike proteins and nucleoproteins) within the placentas of pregnant women diagnosed as having contracted Covid-19 infection and, second, to determine whether specific receptor proteins (ACE2, CD147 and GRP78), which are required for the virus to enter human cells, are present in the placenta.

The maternal subjects for the study were seven women who had tested positive using a “throat swab virus nucleic acid test” within 15 days of delivery at term. The controls were two uninfected women who delivered at term. The median gestational age of the nine pregnancies was 40 weeks (range 38-42 weeks). Amniotic fluid, colostrum and throat swabs taken from the neonates at 0, 24 and 48 hours after delivery, were tested for SARS-CoV-2 using RT-PCR testing.

The study found that the viral proteins were present in the syncytiotrophoblast (maternal side) of the placenta and that the ACE2, CD147 and GRP78 receptors were also present on the cell membranes. However, the viral proteins were not found in those parts of the placenta which were in direct contact with the fetus – the villous stroma and the interstitial blood vessels. There were fewer receptors in the membranes of the syncytiotrophoblasts of uninfected women. There was no evidence of the virus in amniotic fluid, colostrum or neonatal throat swabs.

The inference is that the SARS-CoV-2 virus can gain access to the maternal side of the placenta and then increase the expression of the receptors required to enable its entry into placental cells. However, breaching the “placental barrier” appears to be more of a challenge for the virus, possibly because of a lack of, or inaccessibility to, the requisite cell membrane receptors on the fetal side of the barrier. These findings are in accord with reports from previous placental studies and may help explain the finding of a growing number of clinical studies that in-utero transmission of SARS-CoV-2 from mother to fetus rarely occurs.

Patberg EKhullar PAJOGCOVID-19 Infection and Placental Histopathology in Women Delivering at Term20 Oct 2020USANorth AmericaNeonatal https://www.sciencedirect.com/science/article/pii/S0002937820311947

The evidence to date indicates that transmission of SARS-CoV-2 from mother to foetus during pregnancy (“vertical transmission”) is rare. It has been suggested that one reason for this is that co-expression of two receptors (ACE-2 and TMPRSS2), both of which are required for entry of the virus into host cells, rarely occurs in third trimester placentas. Does this mean, then, that we need have no concerns about babies born to mothers who acquired SARS-CoV-2 during pregnancy if the babies are born at term and appear well at birth? The authors of this study of placentas speculate that such an assumption is not yet justified and that their findings raise the question of whether these babies should receive long-term follow-up.

In a retrospective study of placentas they found that, in comparison with a control group of 56 term singleton placentas from SARS-CoV-2 negative pregnancies, signs of fetal vascular malperfusion - the presence of avascular villi and/or mural fibrin deposition – were more common in 77 singleton term placentas from mothers who were SARS-CoV-2 positive during pregnancy. The changes were seen in 32.5% of these placentas. After adjustment for maternal age, race/ethnicity, mode of delivery, preeclampsia, fetal growth restriction and oligohydramnios the frequency of fetal placental vascular malperfusion abnormalities was significantly higher in the SARS-CoV-2 positive group (OR= 12.63, 95% CI [2.40, 66.40]). The changes were present in placentas from both symptomatic and asymptomatic Covid-19 mothers. The distribution of the abnormalities was global in pattern, involved endothelial damage and was suggestive of altered flow rather than the thrombotic phenomena which have been associated with Covid-19. There was no association of findings of maternal placental vascular malperfusion with SARS-CoV-2 positivity. Neonatal outcomes including birthweight, Apgar scores and NICU admissions were similar between the groups and all babies of the Covid-19 mothers tested negative for SARS-CoV-2 using PCR.

Similar findings have been reported in some, but not all, previous studies. The authors acknowledge the limitations of this retrospective study, including the selective nature of the controls (most were from caesarean section deliveries pregnancies while the SARS-CoV-2 positive group were mainly vaginal deliveries) and the lack of information concerning the stage of pregnancy at which the virus was acquired. They emphasise that their study was confined to full term pregnancies.

The study also looked at “villitis of unknown etiology” and a similar trend was found but this did not reach statistical significance using a multivariate model.

This report raises some important questions for paediatricians. Do these vascular abnormalities on the fetal side of the placenta, if confirmed in prospective studies, have implications for the future health and development of the baby, child and adult? What do we know about long term outcomes for babies born to mothers who contracted SARS-CoV-2 during pregnancy? Have we been too complacent? It is important that long term prospective observational studies are carried out to answer these questions.

Kalamdani, PMondkar, JIndian PediatricsClinical Profile of SARS-CoV-2 Infected Neonates12 Oct 2020IndiaAsia12Neonatalhttps://www.indianpediatrics.net/epub102020/RP-00250.pdf

This is a retrospective case record review of infants with SARS-CoV-2 infection, born in hospital to infected mothers in Mumbai, India between 1 April 2020 to 31 May 2020

Of 1229 women admitted to the hospital in labour during the study period, 185 (15.05%) tested positive for SARS-CoV-2 infection, as ascertained by real time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs. Three (1.7%) mothers had fever and two of these three also had mild breathlessness.

The infants of these infected mothers were then tested and 12 (6.48%) were found to be positive for SARS-CoV-2 infection - 50% were tested at 48 hours, 25% at 72 hours

The median gestational age of the infected group was 38 weeks and the ratio of males to females was 2:1. No infected neonate had respiratory symptoms, lethargy or neurological symptoms. Three had fever and two had feeding difficulty. None required NICU admission and all remained with their mothers in the postnatal wards. All were breastfed. All infants in this group remained healthy at 2 months of age as ascertained by telephone follow-up.

Liver function tests were carried out in 9 infected infants and the authors state that “marked elevation of LDH levels and mild transaminitis were observed”. The actual results in the accompanying Table are: mean AST 75 IU/L, mean ALT 29 IU/L and mean LDH 1462 IU/L.

The authors conclude that SARS-COV-2 infection in neonates is mainly mild or asymptomatic and that infected neonates can be successfully roomed-in with their mothers and be breastfed.

Fenizia, CSavasi, VNat CommunAnalysis of SARS-CoV-2 vertical transmission during pregnancy12 Oct 2020ItalyEurope31Neonatalhttps://www.nature.com/articles/s41467-020-18933-4

This is a prospective multicentre cohort study conducted in Italy. Pregnant women who tested positive for SARS CoV 2 were recruited between March and April 2020. 31 women were included in the study and these women and their newborns were investigated for evidence of congenital infection. They analysed maternal plasma (viral RNA, IgG and IgM), vaginal swab, placenta, umbilical cord plasma (viral RNA, IgG and IgM), amniotic fluid, newborn nasopharyngeal (NP) swab and breast milk (viral RNA, IgG and IgM). According to the Shah et al classification, one newborn was confirmed to have congenital infection (case no 17) and another (case no 25) was a possible congenital infection.

Patient No 17 Patient No 25

Gestation at delivery Preterm (34/40) Term

Mode of delivery Vaginal Vaginal

Maternal illness severity Severe Mild

Maternal plasma viral genome Positive Negative

Maternal plasma antibody IgG and IgM positive IgG and IgM positive

Placental Viral RNA Positive Positive

Vaginal Viral RNA Positive Negative

Umbilical cord plasma viral genome Positive Negative

Umbilical cord plasma antibody IgG positive IgM negative IgG and IgM positive

Newborn NP swab Positive Positive then Negative at 48hrs

Neonatal clinical condition Asymptomatic at birth Asymptomatic at birth

Along with patient 17, patient no 4 (Severe maternal infection) was the only other maternal serum that was positive for the viral genome. IgM was positive in 32.1% of maternal serum and 3.3% (1 out of 30) umbilical cord and IgG was positive in 63.3% of maternal serum and 40.0% of umbilical cord sample. Of the 10 breastmilk sample tested, viral RNA and IgM was positive in only case no 1 (10%). They also conducted proinflammatory 84 gene pannel analysis on placental specimens from case no 17, 25 and 31 and compared it to an uninfected control placenta. There was a generalised immune activation profile in the cases (even in case 31 who had recovered 4 weeks before delivery) compared to the control. The hyeractivation profile was most evident in case no 17 and 25 compared to case 31. A 27 cytokine assay was carried out on maternal plasma from the 4 cases and these reflected the profiles seen at the level of the mRNA in the placenta.

This study shows that congenital infection with SARS CoV 2 may be possible. Maternal illness severity may be an influential factor in the vertical transmission as there is greater proinflammatory activation both at the placental and systemic levels in the severe manifestation of the infection. Also the only two cases in which viral genome was isolated in maternal serum had severe COVID infection As patient 17 was the only one to deliver prematurely it is also important to ask whether severe infection with SARS CoV2 triggers premature labour. However, patient 25 had a mild infection but their umbilical cord bood was IgM positive and therefore confer the possibility of vertical transmission. The study is too small and therefore further research is needed to draw conclusions.

Dumitriu, DGyamfi-Bannerman, CJAMA PediatricsOutcomes of Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection at a Large Medical Center in New York City12 Oct 2020USANorth America101Neonatalhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2771636

This is a retrospective cohort study conducted on women who either tested positive to SARS CoV 2 on swab (n=99) or were symptomatic with radiological findings consistent with SARS Cov2 (n=1). The women were admitted to two centres in New York City between 13th March 2020 to 24th April 2020. They were tested either because they were symptomatic (n=22) or as part of the universal screening which introduced later in the study period. The women were categorised into asymptomatic/mild disease (n=90) or severe/critical (n=10) based on the Wu and McGoogan classification. The women in the severe/critical group were older (34 vs 28 p=0.04), had more pregestational diabetes (2 vs1 p=0.03) and a lower gestation at delivery (37.9 vs 39.1 p=0.02). 50% of the severe critical had c-sections compared to 40.7% of asymptomatic/mild (not a statistically significant). All obstetric and neonatal care was carried out as per usual with vaginal deliveries, delayed cord clamping, skin to skin, rooming in for well-baby nursery (WBN) infants and encouragement of breast feeding (with appropriate infection control measures of hand and breast hygiene and mask wearing). There were 101 infants born to these mothers, with 19 infants being admitted to NICU (8 preterms, 8 congenital malformations, 2 respiratory distress syndrome and 1 suspected sepsis) and 82 to WBN. Of the babies in WBN, those born to mothers with severe/critical illness were at higher risk for requiring phototherapy (30% vs 7% p=0.04).The study defines vertical transmission as a positive swab on the initial swab and a postnatal transmission as a positive on subsequent swabs. Initial swabs were done on D0 of life (n=15), D1 of life (n=79) and D3 of life (n=7). Of the 141 neonatal swab tests performed (101 initial and 40 subsequent), 135 were negative, 4 were invalid and negative on repeat and 2 were indeterminate. Indeterminate indicated detection of low viral load and was taken to be a positive result in this study. These results were from swabs taken as the initial swab and therefore the study reports a transmission rate of 2%. The particulars of these two cases are outlined below.

Neonate 1 Neonate 2

Maternal illness Asymptomatic/Mild Asymptomatic/Mild

Mode of delivery Vaginal Nonemergent c-section for pathological fetal heart rate

Initial test Day 3 of life after maternal symptom development D0 of life as mother had intrapartum symptoms

Breast feeding Breast fed once Breast fed during hospital stay

Clinical course Uncomplicated Uncomplicated

Repeat test Not done On D2 was negative

Follow-up Well at assessment in clinic on D6 of life Well at assessment in clinic on D6 of life

55 infants were seen in follow-up clinics at time points ranging from D3 to D10 of life who were all well at assessment. 20 of these infants plus 3 other infants had 32 nonroutine encounters (up to D25 of life) but did not have SARS CoV 2 infection at each of these events.

The important aspect of the results from this study is that usual obstetric (vaginal delivery, delayed cord clamping) and immediate postnatal care (skin to skin, breastfeeding, rooming-in, delayed bathing) does not seem to affect the rate of postnatal/peripartum transmission. It is interesting that there is a significant difference is in the gestation at delivery between the asymptomatic/mild and severe/critical groups of women. However, there was no preterm rupture of membranes or preterm labour in the severe/critical group and only 1 preterm birth. Therefore, could the earlier birth have been down to c-sections for maternal reasons. Maternal age and pregestational diabetes seem to be risk factors in development of severe illness in the mother. The study claims a 2% transmission rate, but this is based on indeterminate swab results. Neonate 1 was tested on D3 (mother was not following infection control measures prior to developing symptoms and testing positive) and therefore could have been horizontally acquired. There is no antibody test performed/reported. Though the study does not offer an explanation for the increased phototherapy need in the WBN severe/critical maternal illness babies, it is likely that feeding (especially breast feeding) would have been affected due to the maternal illness. The follow-up assessments findings are reassuring, but longer-term follow-up is required.

Flannery, DPuopolo, KmedRxivTransplacental Transfer of SARS-CoV-2 Antibodies 11 Oct 2020USANorth America72Neonatalhttps://www.medrxiv.org/content/10.1101/2020.10.07.20207480v1

This single-centre cohort study was conducted in Pennsylvania, USA between 09/04/20-08/08/20 and it looks for SARS CoV 2 antibodies in the maternal/newborn dyads. They used cord blood samples and maternal serum (all discarded specimens) to determine the presence and levels of antibodies. They also looked at the results of maternal and neonatal napsopharyngeal PCR tests for SARS CoV 2. They used ELISA to detect IgG and IgM to SARS CoV 2 spike protein receptor binding domain with a cut off at 0.48 arbitary units to define seropositivity.

During the study period, there were 83 seropositive (IgG and/or IgM) mothers and 72/83 newborns who were IgG positive (all were IgM negative). Of the 11 seronegative babies were born to seropositive women, 5 were born to mothers who were only IgM positive and 6 other seronegative newborns had mothers who’s IgG was significantly lower (1.27 vs 5.22 arbitrary units, P=0.005) than the levels of the 72 mothers who’s newborns were positive for IgG. All babies born to the 1388 seronegative women, also tested negative for the antibodies. 50/83 of the seropositive women were asymptomatic. All but one of the 83 women underwent a nasopharyngeal swab and 44/82 of these were positive. 20 out of the 83 babies underwent nasophargngeal swab testing and they were all negative. There was a positive correlation with the level of SARS-CoV-2 IgG in maternal serum and cord (Pearson’s r2=0.7852, P<0.001). Moderate and critical illness (n=8) severity was associated with higher maternal serum IgG and IgM and their infants had higher cord IgG level (not statistically significant). Transplacental transfer ratio (infant IgG level divided by maternal IgG level) was used as a marker of transfer efficiency. Transfer ratio did not differ across illness severity. In symptomatic women (n=26), there was a positive correlation (Pearson’s r2=0.3845, P<0.001) with the time between the symptom-prompted viral PCR testing (used as a surrogate marker for viral exposure) and delivery, and the transfer ratio. There was no association between maternal demographics and pregnancy health characteristics and cord blood seropositivity. There was no difference in the transfer ratio between term and preterm infants.

Despite the small sample size of this study, it is the largest published cohort to show the presence of IgG antibodies in the cord blood, thus showing transplacental transfer of SARS CoV 2 antibodies. The absence of IgM in the cord blood adds weight to the notion that in-utero fetal infection with SARS CoV2 is rare. The study also shows that the higher the antibody level in the mother the higher the cord blood antibody (what might this mean for immunodeficient mothers?) level and the greater the length of time between onset of symptom and delivery the greater the transfer efficiency. Both associations have not been shown before. However, it is important to point out that the longest time period between testing and delivery was in those with moderate to critical illness and this could have caused the higher levels and acted as a confounding variable. Though this study shows no relationship between illness severity and transfer ratio, this may have been because of the small sample size in the moderate to critical illness category. The other positive correlations which were not statistically significant may have been because of the small sample size in this study. The clinical use of this study is limited as it does not show whether infants with the IgG against SARS CoV 2 have a better outcome when exposed to the virus. Further studies are required.

Flaherman, VGaw, LClin. Infect. DisInfant Outcomes Following Maternal Infection with SARS-CoV-2: First Report from the PRIORITY Study18 Sep 2020USANorth America263Neonatalhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1411/5908705

The Pregnancy CoronavIrus Outcome ReIsTrY (PRIORITY) study is based in the USA and collects data on US women aged ≥13 years of age, who were suspected or confirmed to have SARS-CoV-2 during their pregnancy. The data presented in this first report was collected between 22/03-22/06. The demographics were collected at the time of enrolment and the outcome data was collected at time of infant birth and 6-8 weeks postnatally. All data was as presented by mothers and infant electronic medical records were used to confirm specifically reported disease or occurrence of events. The infant outcome measures were: birth defects, NICU admission, abnormal newborn examination, positive test for SARS-CoV-2, respiratory complications, gestational age at birth, preterm birth, birthweight, gender, fast or difficulty breathing, upper respiratory infection, apnoea, rooming-in with mother and breastfeeding at 6-8 weeks. The outcome rates were compared between those infants born to mothers who tested positive with those born to mothers who tested negative for SARS-CoV-2.

The study reports on outcomes for 179 women who tested positive and 84 who tested negative for SARS-CoV-2 (a total of 263 infants). Due to the staggered nature of outcome measures being introduced in this study, not all measures were collected in all infants. There was no significant difference in the occurrence of outcome measures between the two groups. The study then reports on comparison on the rate of outcome occurrence in those babies born to mothers who tested positive at differing times prior to delivery.

Those babies who were born to mother who tested positive 0-14d prior to delivery were also less likely to room-in.

This is a weak study with many limitations. Firstly, the comparison group of who acted as the control included asymptomatic and symptomatic women who tested negative. This creates bias created by false negative results from swab tests in whom the clinical symptoms may typify a coronavirus infection. Though this study is nationwide, most women participating were white (58% of positive and 59% of negative), thus making generalisability difficult. The data on outcome measure is not available for all 263 infants in this study, in part due to the late introduction of certain outcome measures once the study period had commenced (in May 2020). Therefore, the small sample size is made even smaller, thus creating type 2 error. Though the study shows significant higher in NICU admission and lower gestation at birth for women who tested positive within 14 days of delivery, the reason and timing for testing is not standardised across provider centres. Therefore, it is difficult to say that the difference observed in these groups were related to timing of virus exposure in-utero.

Diriba, KGetu, EEur J Med ResThe effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal–fetal transmission: a systematic review and meta-analysis04 Sep 2020EthiopiaAfrica1316Neonatalhttps://eurjmedres.biomedcentral.com/articles/10.1186/s40001-020-00439-w

Although the broader aims of this ambitious study are outlined in the title, a primary objective appears to have been to provide point estimates of a range of outcome prevalences, in both mothers and babies, associated with infection in pregnancy caused by SARS-CoV-2, MERS-CoV, and SARS-CoV.

The stated process for literature selection and appraisal was that of a systematic review, using primarily the standard critical appraisal instruments of the Joanna Briggs Institute. However, the authors report that the methodological framework for the study was one which was described for scoping studies, and it may be that the outcomes of this study might be seen to be in line with those of a scoping study rather than providing the precision of useful point estimates, given the heterogeneity of the meta-analysis data.

The robustness of the processes of the systematic review is difficult to evaluate, given the limited description in the text, no doubt in part attributable to word count restrictions. I did not identify a defined PICO, or equivalent, although the inference would be that the “population” and “intervention” were combined as pregnant women who had contracted infection caused by one of the three viruses; no “comparator” was referred to. The stated primary outcome was “the pregnancy outcomes observed” which were listed as: preterm birth (PTB; either before 37 or 34  weeks of gestation); preeclampsia; preterm prelabor rupture of membranes (pPROM); fetal growth restriction (FGR); miscarriage; maternal death; mode of delivery; other clinical features; laboratory findings; coexisting disease. The keywords used for the literature search were: coronavirus; novel coronavirus-2019 infection; pregnancy; Middle East respiratory syndrome; severe acute respiratory syndrome; severe acute respiratory syndrome coronavirus-2, and vertical transmission. It is difficult to be confident that these terms would identify all reports of the outcomes of stated interest, such as maternal symptoms, laboratory findings and neonatal mortality. Although it is stated that Boolean operators were employed, there is no description of how they were used. Only studies reported in English during the period 2003 – 2020 were included and all study designs, including case reports and at least one placental study, were eligible. A more detailed critique of the methodology of the systematic review is outside the scope of this review.

Of the papers selected for the review, 25 related to SARS-CoV-2, 7 to MERS-CoV, and 7 to SARS-CoV. However, in terms of patient numbers the SARS-Co-V-2 group predominated, with 1271 identified pregnancies, compared with 12 and 33 respectively in the other two groups; the outcomes were reported separately for each of the three viruses. The following outcomes from this study focus on babies born to mothers who were infected with SARS-CoV-2 - the reported findings relating to the mothers is beyond the scope of this report.

Some of the reported outcome numbers and statistics would benefit from clarification but the findings relating to selected outcomes for the babies are shown in the table, compared with those of a UK-based prospective cohort study of pregnant women hospitalised with confirmed SARS-CoV-2, which was also included in this systematic review; the UK study included a historical non-infected comparator group, for which outcome data are also shown in the table.

None of the studies in this systematic review were found to have provided evidence of proven in-utero (“vertical”) transmission of Sars-CoV-2 from the mother to the fetus in utero.

The heterogeneity of the selected studies, and of the resulting outcome data, included in this systematic review is high, with an I2 value of 98% in a meta-analysis of one of the maternal outcomes. The risk of selection bias is, therefore, also high and the reported pooled prevalence outcomes must be viewed with caution. However, the broader findings of the review concur with previous studies that the risks of preterm delivery, caesarean section and NICU admission are increased for babies born to mothers infected with Sars-CoV-2; the data concerning perinatal mortality perhaps require further scrutiny. This systemic review has also identified a large number of studies relating to Sars-CoV-2 infection in pregnancy and possibly provides direction to more focused studies of relevant outcomes. The findings also support the evidence from previous studies that in-utero transmission of Sars-CoV-2, if it occurs, is uncommon.

Demers-Mathieu, VMedo, EJ. PerinatolDifference in levels of SARS-CoV-2 S1 and S2 subunits- and nucleocapsid protein-reactive SIgM/IgM, IgG and SIgA/IgA antibodies in human milk01 Sep 2020USANorth AmericaNeonatalhttps://www.nature.com/articles/s41372-020-00805-w

This is a case-control study making multiple comparison between different groups of human milk samples to determine the difference in the levels of SARS-CoV-2 antibodies. The study collected two groups of human breast milk samples; 2020 HM (n=41) was collected between 30/02/20 - 03/04/20 and 2018 HM (n=16) was collected between 06/09/18 – 29/11/18. Both groups were further subdivided into those who were vaccinated (2020 HM n=26) to influenza and/or tetanus, diptheria and polio during pregnancy and those who were unvaccinated (2020 HM n=15). The mothers from the 2020 HM were not asked about their COVID 19 infection/exposure but were asked about viral respiratory symptoms in the preceding year. Mothers did not have an infection of any kind at the time of milk collection. All donor mothers resided in the USA, had negative HIV, HTLV, Hep B, Hep C and syphilis status, completed a health questionnaire and were not using specific medications. The presence and levels of secretory IgM (SIgM)/IgM, IgG and SIgA/IgA antibodies to SARS-CoV-2 S1 and S2 subunits and nucleocapsid were determined using ELISA. The S1 and S2 subunits are integral to the virus binding to host cell and the subsequent release of the viral RNA into the cell, respectively. Nuclocapsid protein binds to viral RNA to form the capsid, as well as interacting with the viral membrane proteins during assembly. The paper clearly describes the experiment protocol used to quantify the levels of antibodies in different samples.

This study demonstrates the presence of antibodies to SARS CoV2 S1+S2 subunits and nucleocapsid in human breast milk, with SARS CoV2 S1+S2 reactive IgA and SARS CoV2 nucleocapsid reactive IgM being the highest levels of the antibody isotype to the antigens. The detection of these antibodies in the 2018 HM suggests that there may be cross reactivity from exposure to other coronavirus or other virus families. The authors also note that the human milk antibodies are polyreactive and have the ability recognise a variety of antigens. This may suggest that breastfeeding babies may allow transferring of SARS CoV2 related immunity to the infant whether mother was specifically exposed to COVID 19 or not. It is interesting that there is a higher level of SARS CoV2 S1+S2 IgG in the vaccinated and the influenza vaccinated group. This adds weight to the importance of driving home the public health aspect of getting vaccinated during pregnancy. There is no information available on whether the mothers were diagnosed with or had exposure to COVID 19. However, the self-reported viral symptoms group having higher levels of SARS CoV2 S1+S2 IgG suggests that clinical manifestation of viral infection increases the production of antibodies. The detection of these antibodies in human milk does not translate into avoidance of clinical manifestation of infection in infant. Further studies are required to assess the outcome of babies who are fed with breastmilk containing the antibodies against SARS CoV2 antigens, when exposed to COVID-19.

Kotlyar, ATal, RAm J Obstet Gynecol.Vertical Transmission of COVID-19: A Systematic Review and Meta-analysis29 Jul 2020Multiple countriesInternational979Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820308231

This is a systematic review and meta-analysis of case reports (n=30) and cohort/case series (n=39) published up until 28th of May 2020. Authors identified the articles in Pubmed, Embase, MedRXiv and BioRXiv databases using the free text terms for SARS-CoV-2, COVID-19,coronavirus, coronaviridae, pregnancy, fetus, infant, mother-to-child, mother-to-infant, maternal fetal, virus transmission, disease transmission, and vertical transmission. The articles met the inclusion criteria of containing a population of SARS COV 2 positive pregnant women with data available on the results of COVID testing on the neonates born to these women. The testing on the neonates need to have been carried out within 48 hours of birth for the study to be eligible for inclusion.

The 30 case reports contained 44 women who were SARS CoV2 +ve and 43 neonatal results were gleaned from these studies. Majority of these women were in their 3rd trimester (29/30 of the case reports) and of the 44 women, 32 delivered via c-sections. Within these case reports, 4 out of 20 placentas were positive for SARS CoV2. Special mention is made of the case report by Vivanti et al who showed SARS CoV2 RNA positivity at multiple sites ,including neonatal blood sample.

Quantitative analysis of transmission rates was analysed only on the cohort/case series findings to minimise selection bias. The rate of transmission as determined by positive nasopharygeal swabs on the neonate was the primary outcome. However other samples were also pooled for analysis of transmission rates. The heterogeneity of the cohort/case series for rates of transmission as assessed by the nasopharyngeal swabs (n=38), was assessed using the Random effects model which was to provide a more conservative estimate. The heterogeneity was shown not to be statistically significant with an I2 of 0% (95% CI 0.0-35.6%). Quality of the 39 cohort/case series articles were assessed using the Newcastle-Ottawa scale, with 13 being assessed as good, 16 moderate and 10 low quality. The authors make a distinction between the studies reported from China and those reported by the rest of the world as they site two different forms of the virus, D614 and G614 respectively.

This systematic review shows that there is evidence for vertical transmission of COVID 19 in a minority of pregnant women in their 3rd trimester. The rates described in this paper are not applicable to women in the first trimester and this is an area that needs further research. There is variation in the quality of the cohort/case series included in this meta-analysis with only 13 of the 39 being assessed to be of good quality. The samples were collected within 48 hours of birth thus minimising, but not eliminating the chances of horizontal acquisition of the virus. The best indicator of in-utero infection is the detection of IgM in neonatal serology which showed a similar transmission rate as that demonstrated by the nasopharyngeal swab results. The rates of transmission calculated for all but the nasopharyngeal swabs are based on a small sample size and thus open to a wide margin of error. The authors comment that the variation in the transmission rates produced by testing different samples warrants the need for multiple sites to be tested to minimise false negative rates. Placental histology has shown evidence of abnormalities especially of the vasculature, thus raising the possibility that the damaged placenta may hinder intrauterine growth and development (e.g. through pre-eclampsia or placental abruption). Therefore, long-term follow is required before conclusions can be drawn about the effects of maternal infection on the neonate. These studies do not consider asymptomatic women, although as the inclusion criteria is based on lab confirmation rather than clinical symptom diagnosis, and therefore some may still have been included. Further questions regarding the role of maternal disease severity in affecting the transmission rate needs research. The studies included are those written in English or have been translated into English, therefore missing out on others who may greatly influence the outcomes reported in this paper.

Overall, this paper is noteworthy when it comes to counselling women regarding the risks of vertical transmission of COVID infection (quoting the pooled rate or ‘rest of world’ rate form nasopharyngeal swabs) in the later stages of pregnancy, all the while bearing in mind that the severity of maternal infection is likely to play a role in influencing the rates mentioned in this paper.

Gao, JChen, LEmerg Infect DisDisappearance of SARS-CoV-2 Antibodies in Infants Born to Women with COVID-19, Wuhan, China03 Jul 2020ChinaAsia24Neonatal https://wwwnc.cdc.gov/eid/article/26/10/20-2328_article

This letter reports on SARS-Co-V-2 antibody concentrations in 24 infants born to mothers with PCR-confirmed COVID-19 who had developed symptoms of Covid-19 infection prior to delivery, the symptom-onset to delivery interval ranging from 0-60 days. They were compared with 40 infants born to mothers without Covid-19.

All babies were admitted to the neonatal section of Tongji Hospital (Wuhan, China) between January 19–April 12, 2020. The 40 infants born to the Covid-19 negative mothers are reported to have had throat and anal swabs which all tested negative for SARS-CoV-2 nucleic acid, using a qualitative SARS-CoV-2 RT-PCR test. The 24 infants born to Covid-19 positive mothers are also reported to have had negative nucleic acid PCR tests but there are no details concerning the swabs which were taken. It is reported that none of these infants had complications related to pneumonia but there are no other clinical details concerning the babies.

Antibody testing was implemented in early March. Quantitative measurement of IgG and IgM was performed using the IFlash3000 Chemiluminescence Immunoassay Analyzer (YHLO Biotech). IgM or IgG titres >10 AU/mL were considered to be positive. For the 40 babies born to Covid-19 negative mothers it is reported that antibody assays were negative but there is no information concerning the timing or number of tests performed.

Each of the 24 infants born to Covid-19 positive mothers had at least one test for both IgG and IgM from 0-75 days following delivery (median number of tests 3, range 1-6 – my calculations from data in the table). Of these, 15 (62.5%) had detectable IgG on at least one occasion between 0 and 75 days following delivery and 6 (25.0%) had detectable IgM. The paper provides graphs of IgG and IgM titres plotted against time over the 75–day period following birth which the authors interpret as showing a slower rate of decline of IgG in the babies in whom both IgG and IgM were detectable compared with those in whom only IgG was detected.

The placenta of the infant with the highest IgG and IgM titres at birth showed slight inflammation with slight fibrin deposition and lymphocyte infiltrates; a photograph of the histology is included in the paper. The significance of these findings is not clear.

The authors comment that, although the presence of IgM antibodies, which do not cross the placenta, suggests vertical transmission of SARS-Co-V-2 from mother to fetus, the negative PCR tests do not support this conclusion.

The authors acknowledge that interpretation of the data in this study is limited by the small sample size for each data point with regard to antibody concentrations, but it seems reasonable to conclude that:there was a rapid decline in both IgG and IgM serum concentrations over the first two months of life in babies born to mothers who developed Covid-19 in the last two months of pregnancythere was a trend for the decline in IgG concentrations to be slower in babies in whom both IgG and IgM was present at birth compared with those with IgG only, but the numbers were too small for statistical interpretation both passive and active antibody protection against SARS-CoV-2 infection in newborn infants born to Covid-19 positive mothers may last only a few weeks

Hantoushzadeh, S.Aagaard, K.American Journal of Obstetrics and GynecologyMaternal death due to COVID-1901 Jul 2020IranMiddle East9Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305160
Chhabra, A. Subramaniam, RIndian Journal of Anaesthesia Anaesthetic management of a COVID-19 parturient for caesarean section - Case report and lessons learnt.23 Jun 2020IndiaAsia1Neonatalhttp://www.ijaweb.org/article.asp?issn=0019-5049;year=2020;volume=64;issue=14;spage=141;epage=143;aulast=Chhabra
NawsherwanWang, SIndian J PediatrImpact of COVID-19 Pneumonia on Neonatal Birth Outcomes22 Jun 2020ChinaAsia7Neonatalhttps://link.springer.com/content/pdf/10.1007/s12098-020-03372-2.pdf
Nyholm, SDiderholm, BActa PaediatricaInvasive mechanical ventilation in a former preterm infant with COVID‐1922 Jun 2020SwedenEurope2Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15437
Deng, G.Yin, M. J HepatolCharacteristics of pregnant COVID-19 patients with liver injury.20 Jun 2020China Asia6Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305728/
McDevitt, K Pathak, S. J InfectOutcome of universal screening of neonates for COVID-19 from asymptomatic mothers 19 Jun 2020UKEurope9Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303651/

This study is reported as a letter to the Editor.

The North West Anglia NHS Foundation Trust based in Peterborough, UK, introduced universal screening for SARS-CoV-2 of all in-patients, including asymptomatic newborn infants, on 27th April 2020. The testing method was naso-pharyngeal RT-PCR of nasopharyngeal swabs.

Between 27th April and 21st May 2020 481 infants were delivered, of whom 418 were screened. Nine infants (2.2%) tested positive within the first 24 hours of life, three within three hours. The gestational ages ranged from 364 to 422 weeks and birthweights from 2815 to 4420 g. Only one infant developed signs of illness – an oxygen requirement for 2 hours and high flow humidified nasal cannulae for 22 hours, a chest X-ray showing streaky hila and hazy consolidation in both lower lobes. Seven babies were re-tested at one to seven days of age and all were negative.

With regard to mode of delivery, three babies were born by ELCS elective caesarean section, three by EMCS and three by SVD. No details concerning membrane rupture-delivery interval are provided. All mothers were asymptomatic and only one tested positive to SARS-CoV-2. Five mothers who tested negative were re-tested at un-specified times and all were again negative.

The authors considered the following explanations for the positive tests:

Contamination of the specimens – this was considered to be unlikely as the specimens were taken on different days by different members of staff, all of whom were wearing PPE.

False positive results – this was also considered unlikely as the CT values of the RT-PCR were 29-31 and the specificity was 100% at a CT of 35, with a positive predictive value of 100%.

Maternal false negative results – these could not be rules out but were unlikely as all mothers were asymptomatic and three of the positive swabs were taken within three hours.

The mothers might have been positive previously and, although they were no longer shedding viral RNA in the nasopharynx, they had shed RNA or RNA fragments into the amniotic fluid and these were still within the newborns’ nasopharynx on the first day of life but cleared by the second test. Possible confirmation of this by maternal/infant serology was not available at the time.

This paper is published as the first report of the outcome of universal screening of newborn infants for SARS-CoV-2. The explanation for the finding of 2.2% positive naso-pharyngeal swab RT-PCR tests in the babies of asymptomatic mothers is currently not certain.

Dong, YChen, WEmerging Microbes & Infections Antibodies in the breast milk of a maternal woman with COVID-19 18 Jun 2020ChinaAsia1Neonatalhttps://www.tandfonline.com/doi/full/10.1080/22221751.2020.1780952

This paper relates to a single mother-baby dyad and reports on SARS-2-CoV antibodies in the breast milk and blood of the mother, who was suffering from Covid-19 at the time of delivery, and in the blood of her baby.

The mother was 33 years old at presentation and had developed clinical symptoms consistent with SARS-CoV-2 infection two weeks before the spontaneous onset of labour at 382 weeks gestation. She was admitted to a hospital maternity unit where RT-PCR testing of a throat swab was positive for SARS-CoV-2 and a chest X-ray showed patchy ground-glass opacities in the periphery of left lung. Laboratory blood testing showed a mild elevation of hepatic enzymes, a reduction on the proportion of lymphocytes (15.6%) and an increase in the proportion of neutrophils (80%).

The woman gave birth in a negative-pressure operating room and PPE was worn by all attendants. A female infant, weighing 2950 g, was delivered; the route of delivery is not stated but it appears to have been vaginal. Apgar scores were 9 at 1 minute and 10 at 5 minutes. Mother and baby were nursed in separate ICU isolation facilities following the birth. The mother initially received antibacterial treatment with azithromycin and ornidazole in an ICU ward and, 10 days following the birth, was transferred to a designated hospital for Covid-19 treatment in a different city; she was discharged home, well, 25 days after delivery. It appears that mother and baby had no contact with each other during this time and it is not stated whether the baby received maternal expressed breast milk at any time.

For the mother, RT-PCR testing of throat swabs showed positive results, with low CT values for SARS-Co-V-2, tested positive 11, 15 and 18 days following delivery, becoming negative at 21 days. All body fluids, including breast milk, and faeces tested negative for SARS-Co-V-2 throughout.

For the baby, naso-pharyngeal swabs were taken at birth and at 25 days of age, both testing negative to RT-PCR for SARS-Co-V-2. No other clinical details are provided concerning the baby.

ELISA assay immunoglobulin testing of maternal and infant serum, and of breast milk, was performed using SARS-CoV-2 spike protein as antigen. The results are shown in the table.

* Breast milk from SARS-CoV-2 negative mothers had a mean titre of 0.98 * Breast milk from SARS-CoV-2 negative mothers had a mean titre of 0.90This is possibly the first published report of: - the detection of SARS-Co-V-2 IgG and IgA antibodies in breast milk - the apparent disappearance of SARS-Co-V-2 IgG antibodies, presumed to have been acquired by a neonate via placental transmission, after six weeks. The implications of these observations for the health of babies born to mothers with a recent history of Covid-19 infection remains to be determined.

Khoury, RDolan, SObstet GynecolCharacteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers16 Jun 2020USANorth America245Neonatal https://journals.lww.com/greenjournal/Abstract/9000/Characteristics_and_Outcomes_of_241_Births_to.97310.aspx
Chambers, CAldrovandi, GmedRxivEvaluation of SARS COV-2 in breastmilk from 18 infected women16 Jun 2020USANorth America64Neonatal https://doi.org/10.1101/2020.06.12.20127944

This is a letter to the editor of the journal in which the authors report their finding on detection of SARS COV-2 in the breast milk of 18 infected mothers in the USA. A total of 64 breastmilk samples were collected between 27/03 and 06/05, pre and post the mothers testing positive for COVID. All samples were tested with quantitative RT-PCR for SARS Cov-2. 26 of these samples (from 9 mothers) also underwent tissue culture for the replication component of SARS Cov-2. The researchers also tested the Holder Pasteurization technique in eliminating the virus. They spiked 2 donor breast milk samples with the virus and then testing the samples with RT-PCR and the tissue culture method after the spiked samples had been subjected to the pasteurisation.

Of the 64 samples of breastmilk which were tested for viral RNA, only one sample tested positive and this was noted to have been on the day of symptom onset in that mother. All 26 samples which underwent tissue culture for the replication component of the virus, including the sample which tested positive for the viral RNA, were negative. Both donor milk samples were negative on RT-PCR and tissue culture following pasteurisation.

It is a very small sample and there is no standardisation of when the milk was collected from each woman and how frequently it was collected (varying between only one sample contributed to 12 samples from the same mother). It would have also been useful to know the COVID swab and/or antibody status of the infants. The merits of this study lie in the use of the tissue culture for replication components of the SARS CoV 2 which has not been used by the previous case studies which only looked for viral RNA in breast milk. The tissue culture is likely to be a more clinically meaningful way of analysing the breastmilk to determine infection risk to infant. It is reassuring that Holder pasteurisation method (also commonly used by milk banks in the UK) in donor breast milk can neutralise the virus. Further large-scale study is required to draw firm conclusions.

Blitz, MNimaroff, MAm J Obstet GynecolMaternal mortality among women with coronavirus disease 2019 admitted to the intensive care unit15 Jun 2020USANorth America7Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294262/pdf/main.pdf
Sentiles, LDeruelle, PAm J Obstet GynecolCOVID-19 in pregnancy was associated with maternal morbidity and preterm birth15 Jun 2020FranceEurope21Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294260/pdf/main.pdf
Griffin, ISchenkman, AAm J PerinatolThe Impact of COVID-19 Infection on Labor and Delivery, Newborn Nursery, and Neonatal Intensive Care Unit: Prospective Observational Data from a Single Hospital System13 Jun 2020USANorth America62Neonatal https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1713416
Bani Hani, D. A.Aleshawi, A. J. Am J Case Reports Successful Anesthetic Management in Cesarean Section for Pregnant Woman with COVID-19.12 Jun 2020JordonMiddle East1Neonatalhttps://www.amjcaserep.com/download/index/idArt/925512
Li, YLu, XIJIDComparison of Hospitalized Patients with pneumonia caused by COVID-19 and influenza A in children under 5 years11 Jun 2020ChinaAsia57Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30462-8/fulltext

This Case Series of three infants with SARS-CoV-2 infection paper is published as a Brief Report.

The paper is a report of three full-term babies (39-41 weeks) who were admitted from home to the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital Colorado (CHCO) after presentation to the hospital’s Emergency Department (ED) between March 28, 2020, and April 1, 2020. Ages at onset of “symptoms” were 16, 25 and 31 days and ages at admission were 17, 27 and 33 days respectively. Two were exclusively receiving breast milk at the time of admission; there are no details regarding feeding for the third infant. The mothers of two infants had a recent history of upper respiratory symptoms but there was no history of ill contacts for the third.

All of the babies had fever, rhinorrhea, and mild hypoxia with oxygen saturations in room air of 80–90%; the youngest infant also had tachycardia, systemic vasodilation, and bilateral conjunctivitis and received 20 mL/kg normal saline fluid resuscitation in the ED. There is no description of other abnormal respiratory signs such as cough or work of breathing. Blood gases for all three infants were reported to be normal. All were treated with supplemental oxygen of 0.25 -1.0 l/min via nasal cannulae and with systemic antibiotics. Chest X-rays of all three showed low lung volumes with hazy opacities but no focal consolidation. Diagnosis

The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs for SARSCoV-2 which were taken in the ED; there was no repeat testing and no mention of antibody testing.

The youngest infant had initial lymphopenia, which resolved before discharge, subsequent neutropenia which ws ongoing at the time of discharge and a mildly elevated CRP (1.5mg/dL). CRPs in the other two infants were 1.1 and 1.2mg/dL and blood procalcitonin levels were within the normal range; liver function tests and other haematological tests were normal in all three and microbiology tests, including virology, were negative. The babies were discharged home when they had been afebrile for at least 24 hours, after stays of 77-81 hours. Details of follow-up are not given but two infants showed decreased absolute neutrophils at some point after discharge.

The paper provides details of three of the youngest patients reported to have developed community-acquired SARS-CoV-2. The authors state that the three infants (one was just outside the neonatal age range) met the diagnostic requirements proposed by Chinese researchers: (1) clinical symptoms including fever and the need for respiratory support, (2) abnormal chest radiographs, and (3) being at high risk for SARS-CoV-2 infection due to close contact with a person with symptoms consistent with SARS-CoV-2 or living in an area with widespread CA-SARS-CoV-2. All three had mild to moderate courses with short hospital stays, which is consistent with previous reports in the paediatric literature. The authors advise that caregivers of neonates should wear face masks and wash their hands before handling neonates in the community and that isolation from positive family members would be prudent.

Preßler, JWellmann, SPediatric Allergy & ImmunologyPostnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study09 Jun 2020GermanyEurope61Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pai.13302

This letter to the editor in Pediatric Allergy and Immunology presents data on 61 deliveries where there had been varying degrees of unprotected parental contact with SARS-CoV-2-infected midwives, nurses and doctors during the first week (precontainment) of a COVID-19 outbreak affecting 36 staff members in a large maternity and perinatal centre in Bavaria, Germany. Two previous papers in the same journal, published 22 April 2020 and 15 May 2020, have reported on containment strategies, symptoms, SARS-CoV-2 RT-PCR tests and antibody responses (IgG and IgA) in hospital staff during the outbreak. The index case was a midwife returning from holiday in Ischgl, Austria on 8 March 2020, who became unwell during a nightshift on 9 March at Regensburg University Hospital obstetric clinic; the first positive SARS-CoV-2 RT-PCR test result was received on 15 March and at that point contact tracing, testing and containment measures were introduced.

Study design: 66 families were identified with an infant born at the clinic during the week of 9 to 15 March where parents had had unprotected contact with SARS-CoV-2-infected medical staff; of these, 61 families consented to a prospective cohort study involving serial symptom interview, serial SARS-CoV-2 RT-PCR screening in throat rinsing fluid (parents) and faeces (infants) and serum IgA and IgG antibody studies (parents and infants) 4-5 weeks post-partum. Serum and breast milk were also tested using a different antibody assay to verify antibody responses. The authors note in their paper of 15 May 2020 that IgM antibody testing would have been useful, but that validated and certified IgM tests were not available to them at that time.

Key neonatal findings: The median gestational age at delivery was 39.3 weeks. Infants in the study received skin-to-skin care, rooming-in and breastfeeding in line with the hospital’s usual practice. The authors state that antepartum infections can be excluded and that any neonatal infections probably occurred via postnatal horizontal transmission in the family setting. 16/61 families reported parental symptoms consistent with COVID-19 within 2 weeks postpartum (one or both parents), although only 5/16 symptomatic families had COVID-19 confirmed based on RT-PCR and antibody evidence. 3 infants of these 5 symptomatic PCR-positive families developed non-specific signs of infection, including fever, dyspnoea and compromised circulation, at 5, 10 and 26 days old, and were admitted to NICU. Details of treatment are not supplied, but symptoms resolved for all 3 within a few days. Blood cultures and tests for non-SARS-CoV-2 viruses were negative. 2/3 symptomatic neonates had PCR positive faeces (one of these still had PCR positive faeces at 4-5 weeks) and 1 asymptomatic neonate also had PCR positive faeces at 4-5 weeks. None of the 3 SARS-CoV-2 PCR positive neonates nor the uninfected neonates had elevated or even borderline antibodies [note that there is some minor disparity between results summarised in the text and the detailed figure showing results in individual families]. Only one mother had IgG-positive breast milk (serum IgG also positive at 4-5 weeks, serum IgA negative, PCR positive at 1 week but not at 4-5 weeks, infant symptomatic at day 5 with negative faecal PCR at 1 week/4-5 weeks and negative serum IgG/IgA at 4-5 weeks).

This paper describes the clinical presentation and course of the 27 children and young people with COVID who required paediatric intensive care in and around Paris at the height of the corona virus peak in France. The total population of all ages of the Ile de France , the region for which this centre is responsible for tertiary paediatric referrals, is around 12 million. During the time covered by the study, there were around 5000 COVID deaths in France, with the Ile de France region being the hardest hit.

Knight, MKurinczuk, JBMJCharacteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study08 Jun 2020UKEurope12Neonatalhttps://doi.org/10.1136/bmj.m2107
Martínez-Perez, OBaud, DJAMAAssociation Between Mode of Delivery Among Pregnant Women With COVID-19 and Maternal and Neonatal Outcomes in Spain08 Jun 2020SpainEurope78Neonatal https://jamanetwork.com/journals/jama/fullarticle/2767206

This paper reports an observational study from 96 level 2 or 3 maternity hospitals in Spain. The study, which appears to have been prospective, looked at outcomes related to mode of delivery for mothers and their neonates, where the mother was RT-PCR test positive for SARS-CoV-2 infection within 14 days of delivery. Only singleton pregnancies and mothers with no or “mild”* COVID-19 symptoms, and their neonates, were included in the comparison. Multivariable logistic regression was performed assessing the association between mode of delivery and maternal and neonatal outcomes. The regression model included adjustments for maternal age, body mass index, comorbidities, need for oxygen supplementation at admission, abnormal chest x-ray findings at admission, nulliparity, smoking, and prematurity.

Seventy-eight mothers and babies were included, 11 of the mothers receiving oxygen supplementation, at a point not stated. Forty-one (53%) delivered vaginally, 8 at < 37 weeks gestation, and 37 (47%) by caesarean section (CS), 29 for obstetrical indications and 8 for COVID-19 symptoms without other obstetrical indications; 18 of the CS deliveries were at <37 weeks gestation.

For the mothers, the outcomes reported were: no “severe adverse outcomes**” for those who delivered vaginally compared with 5 (13.5%) Intensive Care Unit (ICU) admissions among those who delivered by CS; 2 (4.9%) mothers who delivered vaginally had “clinical deterioration***” after birth compared with 8 (21.6%) among the CS group. After adjustment for potential confounding factors, birth by CS was significantly associated with clinical deterioration (adjusted odds ratio, 13.4; 95% CI, 1.5-121.9; P = .02).

For the babies, 8 (19.5%) who delivered vaginally and 11 (29.7%) born by CS were admitted to the Neonatal Intensive Care Unit (NICU). After adjustment for confounding factors, birth by CS was significantly associated with an increased risk of NICU admission (adjusted odds ratio, 6.9; 95% CI, 1.3-37.1; P = .02). Three (4.2%) of the 72 babies who were tested within 6 hours after birth had a positive SARS-CoV-2 RT-PCR result. Repeat testing at 48 hours was negative. None of these developed COVID-19 symptoms within 10 days. In addition, 2 babies born by CS at term, who were test negative at birth and who had contact with their parents following delivery, developed COVID-19 “symptoms” within 10 days, becoming test positive. Their “symptoms” resolved within 48 hours.

In their discussion, with regard to adverse outcomes, the authors observe that all patients (presumed meaning mothers) with vaginal delivery had excellent outcomes while 13.5% of mothers undergoing CS had severe outcomes. There is no indication that there was a statistical difference for adverse outcomes. For clinical deterioration, after adjusting for confounding factors, the authors concluded that CS remained independently associated with an increased risk of clinical deterioration for the mother and an increased risk of NICU admission for the baby.

This paper is the first to report that CS is associated with a possible increased risk of clinical deterioration for mothers, and NICU admission for babies, in pregnancies where the mother is RT-PCR test positive for SARS-CoV-2 infection at or near the time of delivery. The authors acknowledge that the confidence intervals were wide and estimates “fragile”. The raw data show that there was excess of some risk factors in the pregnancies delivered by CS, including prematurity and maternal BMI >30, oxygen requirement at admission and abnormal chest X-ray. Interpretation of the outcome data is, therefore, heavily dependent on the robustness of the multiple regression analysis.

Gregorio-Hernandez, RMartinez-Gimeno, AEur J PediatrPoint-of-care lung ultrasound in three neonates with Covid-1905 Jun 2020SpainEurope3Neonatalhttps://link.springer.com/article/10.1007/s00431-020-03706-4
Silverstein, J. S.Penfield, C. A AJPAcute Respiratory Decompensation Requiring Intubation in Pregnant Women with SARS-CoV-2 (COVID-19)04 Jun 2020USANorth America2Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272216/
White, ADietz, RNeonatologyNeonates Hospitalized with Community-Acquired SARS-CoV-2 in a Colorado Neonatal Intensive Care Unit 04 Jun 2020USANorth America3Neonatalhttps://doi.org/10.1159/000508962

This Case Series of three infants with SARS-CoV-2 infection paper is published as a Brief Report.

The paper is a report of three full-term babies (39-41 weeks) who were admitted from home to the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital Colorado (CHCO) after presentation to the hospital’s Emergency Department (ED) between March 28, 2020, and April 1, 2020. Ages at onset of “symptoms” were 16, 25 and 31 days and ages at admission were 17, 27 and 33 days respectively. Two were exclusively receiving breast milk at the time of admission; there are no details regarding feeding for the third infant. The mothers of two infants had a recent history of upper respiratory symptoms but there was no history of ill contacts for the third.

All of the babies had fever, rhinorrhea, and mild hypoxia with oxygen saturations in room air of 80–90%; the youngest infant also had tachycardia, systemic vasodilation, and bilateral conjunctivitis and received 20 mL/kg normal saline fluid resuscitation in the ED. There is no description of other abnormal respiratory signs such as cough or work of breathing. Blood gases for all three infants were reported to be normal. All were treated with supplemental oxygen of 0.25 -1.0 l/min via nasal cannulae and with systemic antibiotics. Chest X-rays of all three showed low lung volumes with hazy opacities but no focal consolidation. Diagnosis

The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs for SARSCoV-2 which were taken in the ED; there was no repeat testing and no mention of antibody testing.

The youngest infant had initial lymphopenia, which resolved before discharge, subsequent neutropenia which ws ongoing at the time of discharge and a mildly elevated CRP (1.5mg/dL). CRPs in the other two infants were 1.1 and 1.2mg/dL and blood procalcitonin levels were within the normal range; liver function tests and other haematological tests were normal in all three and microbiology tests, including virology, were negative. The babies were discharged home when they had been afebrile for at least 24 hours, after stays of 77-81 hours. Details of follow-up are not given but two infants showed decreased absolute neutrophils at some point after discharge.

The paper provides details of three of the youngest patients reported to have developed community-acquired SARS-CoV-2. The authors state that the three infants (one was just outside the neonatal age range) met the diagnostic requirements proposed by Chinese researchers: (1) clinical symptoms including fever and the need for respiratory support, (2) abnormal chest radiographs, and (3) being at high risk for SARS-CoV-2 infection due to close contact with a person with symptoms consistent with SARS-CoV-2 or living in an area with widespread CA-SARS-CoV-2. All three had mild to moderate courses with short hospital stays, which is consistent with previous reports in the paediatric literature. The authors advise that caregivers of neonates should wear face masks and wash their hands before handling neonates in the community and that isolation from positive family members would be prudent.

Costa, SCattani, PCMIExcretion of SARS-CoV-2 in human breast milk02 Jun 2020ItalyEurope2Neonatalhttps://doi.org/10.1016/j.cmi.2020.05.027

This is a letter to the editor in which the authors describe the protocol used for testing for SARS COV 2 in human breast milk from 2 mothers who delivered in March 2020 at their hospital in Rome, Italy. They used the Seegene Allplex 2019-nCOV assay with special precautions taken with breast milk sample collections including dedicated electric pumps and aseptic technique for sample collection. A positive sample was identified if the cycle threshold vale was <40. Both patients were symptomatic (patient 1 requiring oxygen) at the time of delivery with positive nasopharyngeal swabs for SARS COV 2. Patient 1 delivered via emergency c-section due to fetal distress at 35+5 weeks. Patient 2 delivered via elective section due to previous section at term. Both infants had negative nasopharyngeal swabs, were clinically well and did not receive breast milk. Neonate of patient 1 had positive PCR on placental tissue, cord blood and 3 (D4, D5, D7) out of 6 (D4-D8 and D10) of the breast milk samples collected. All samples were negative for neonate of patient 2.

This letter raises the possibility of mother to infant viral transmission (albeit intermittent) directly through breast milk, rather than the previously thought of likely route which was through maternal respiratory droplets whilst breast feeding. The standardised method of breastmilk collection under aseptic technique minimises the risk of cross contamination. The letter calls for prohibiting breastfeeding until mother’s isolation period has ended and viral clearance is assessed. As neonates were not given the breastmilk, we cannot be sure whether the passing of viral RNA through breastmilk might have resulted in clinical infection in the neonate. Further large population-based studies are required to change current policies regarding breastfeeding in active cases of maternal COVID infection.

San-Juan, RAguado, JLancetIncidence and clinical profiles of COVID-19 pneumonia in pregnant women: A single-centre cohort study from Spain01 Jun 2020SpainEurope6Neonatalhttps://www.thelancet.com/action/showPdf?pii=S2589-5370%2820%2930151-6
Luo, QChen, HPre printSafety of Breastfeeding in Mothers with SARS-CoV-2 Infection01 Jun 2020ChinaAsia23Neonatalhttps://www.medrxiv.org/content/10.1101/2020.05.30.20033407v1
Piersigilli, FDanhaive, OThe Lancet, Child & Adolescent HealthCOVID-19 in a 26-week preterm neonate01 Jun 2020BelgiumEurope1Neonatalhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30140-1/fulltext
Zhu, CXia, YJ InfectRisk from Detectable Severe Acute Respiratory Syndrome Coronavirus 2 in Breastmilk01 Jun 2020ChinaAsia5Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270809/
Breslin, ND'Alton, MGynecology MFMCoronavirus disease 2019 in pregnancy: early lessons27 May 2020USANorth America2Neonatalhttps://reader.elsevier.com/reader/sd/pii/S2589933320300410?token=4C959DDF7EB12D7B76B1E63FA1F96A0989263A0BB2CECE20E5FCBFB628A46B1701A439F7D08AD5DEFCC46CCEBD5E24F0
Yilmaz, RUzun, STJ Clin AnesthAnesthetic management for cesarean birth in pregnancy with the novel coronavirus (COVID-19)27 May 2020TurkeyEurope1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250746/pdf/main.pdf
Fontanella, F.t Baalman, J. H. Eur J Obstet Gynecol Reprod Biol. COVID-19 infection during the third trimester of pregnancy: Current clinical dilemmas.26 May 2020Netherlands and Ireland, UKEurope2Neonatalhttps://www.ejog.org/article/S0301-2115(20)30337-7/fulltext
Campbell, KPettker, CMJAMAPrevalence of SARS-CoV-2 Among Patients Admitted for Childbirth in Southern Connecticut26 May 2020USANorth America30Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2766650
Salik, IMehta, BJournal of Clinical AnesthesiaTetralogy of Fallot palliation in a COVID-19 positive neonate25 May 2020USANorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0952818020308540?via%3Dihub
Carvalho, WJohnston, CClinicsNeonatal SARS-CoV-2 infection25 May 2020BrazilSouth America1Neonatalhttps://www.clinicsjournal.com/wp-content/uploads/articles_xml/1807-5932-clin-75-e1996/1807-5932-clin-75-e1996.pdf
Tang, MWBiermond, BJAm J HematolImmune Thrombocytopenia during Pregnancy due to COVID-19 23 May 2020Netherlands Europe1Neonatalhttps://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.25877

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2.

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

.Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

McLaren, RAMinkoff, HLAJOGDelivery for respiratory compromise among pregnant women with coronavirus disease 201923 May 2020USANorth America9Neonatalhttps://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930567-6
Precit, MBard, JJ Paediatric Infect Dis SocA Case Report of Neonatal Acute Respiratory Failure Due to SARS-CoV-222 May 2020USANorth America1Neonatalhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa064/5842097
Pereira, APerez-Medina, TActa Obstetricia et Gynecologica Scandinava Clinical course of coronavirus disease‐2019 in pregnancy22 May 2020Spain Europe23Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/aogs.13921
Alsharaydeh, IObeidat, NInt J Gynaecol ObstetChallenges and solutions for maternity and gynecology services during the COVID-19 crisis in Jordan22 May 2020JordanMiddle East2Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13240
Groß, RMünch, JLancetDetection of SARS-CoV-2 in human breastmilk21 May 2020GermanyEurope2Neonatal https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31181-8.pdf

The study primarily relates to the SARS­CoV­2 content of the breast milk of two “nursing mothers” who shared a room postnatally, with their babies, and who developed swab-positive mild Covid-19 infection after birth - three days and six days respectively. The gestation and birthweights of the babies are not reported but they seem to have been full term, well at birth and initially well for the first few days following delivery.

The babies developed abnormal respiratory signs, one with jaundice, at 8 days and 11 days respectively, both becoming swab positive for SARS­CoV­2 at about the same ages and both being admitted to a Neonatal Unit. One infant, who also tested positive for RSV, subsequently required mechanical ventilation. It is stated that one infant recovered but the outcome for the ventilated infant is not given.

The patient identification and recruitment processes are not described.

Breast milk was collected, after feeds and after nipple disinfection, from each mother starting at eight days and four days respectively after development of Covid-19 symptoms. Samples were collected on postnatal days 12-15 for the first mother and 10, 12, 13, 14 and 25 for the second. Testing for SARS­CoV­2 RNA was performed using RT­qPCR. Information on the method of nipple disinfection is not provided.

A separate laboratory-based study investigated the effect of breast milk on viral recovery rates by “spiking” breast milk with serial dilutions of a SARS­CoV­2 stock.

The main findings of potential importance are:1. The breast milk of one of the mothers tested positive for SARS­CoV­2 RNA at 10-13 days after birth. Testing of breast milk from the other mother was negative.2. Quantification using Ct values corresponded to 1∙32 × 10⁵ copies per mL in whole milk and 9∙48 × 10⁴ copies per mL in skimmed milk.3. An 89∙2% reduction in recovery rate in whole milk and 51∙5% in skimmed milk, suggesting that the actual viral loads in whole milk of the mother could be even higher than detected.

This study provides the first report of the detection of viral RNA in human breast milk collected from a mother who had clinical signs of Covid-19 confirmed by PCR testing of swabs. This does not provide evidence that the RNA was indicative of infectious virus or that transmission of the virus to the baby occurred via breastmilk.

Perrone, SEsposito, SJ Med VirolLack of viral transmission to preterm newborn from a COVID‐19 positive breastfeeding mother at 11 days postpartum21 May 2020ItalyEurope1Neonatalhttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26037
Zeng, YChen, DObstetrics & GynaecologyUpdate on clinical outcomes of women with COVID‐19 during pregnancy21 May 2020ChinaAsia16Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13236
Qadri, FMariona, FJ Matern Fetal Neonatal MedPregnancy affected by SARS-CoV-2 infection: a flash report from Michigan20 May 2020USANorth America16Neonatalhttps://www.tandfonline.com/doi/full/10.1080/14767058.2020.1765334
Joudi, NLyell, DAmerican Journal of Obstetrics & Gynecology MFMPreeclampsia treatment in severe acute respiratory syndrome coronavirus 220 May 2020AmericaNorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300902
Du, YLv, J J Anesth. Anesthesia and protection in an emergency cesarean section for pregnant woman infected with a novel coronavirus: case report and literature review.19 May 2020ChinaAsia1Neonatalhttps://link.springer.com/article/10.1007/s00540-020-02796-6
Savasi, VCetin, IObstetrics & GynecologyClinical Findings and Disease Severity in Hospitalized Pregnant Women with Coronavirus Disease 2019 (COVID-19)19 May 2020ItalyEurope57Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/Clinical_Findings_and_Disease_Severity_in.97347.aspx?sessionEnd=true
Yu, YShen, Y Int J Gynecol ObstetSevere COVID‐19 in a pregnant patient admitted to hospital in Wuhan19 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13232
Lokken E. M. Rah, SAmerican Journal of Obstetrics and GynecologyClinical Characteristics of 46 Pregnant Women with a SARS-CoV-2 Infection in Washington State19 May 2020USA North America8Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305585
Yang, HXiong, GArchivesEffects of SARS-CoV-2 infection on pregnant women and their infants: A retrospective study in Wuhan, China19 May 2020ChinaAsia24Neonatalhttps://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2020-0232-SA
London, VMinkoff, HAM J PerinatolThe Relationship between Status at Presentation and Outcomes among Pregnant Women with COVID-1919 May 2020USANorth America55Neonatalhttps://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0040-1712164.pdf
Cook, JGupta, ALCAHHorizontal transmission of severe acute respiratory syndrome coronavirus 2 to a premature infant: multiple organ injury and association with markers of inflammation19 May 2020UKEurope1Neonatalhttps://doi.org/10.1016/S2352-4642(20)30166-8

This is a single case report of an ex-27 week preterm male infant, who presented on the 30/03 to King’s College Hospital, London at 8 weeks of age (35 weeks CGA). He had a relatively stable NICU course requiring 3 days of ventilation and had been discharged 10 days prior to presentation. Household members were asymptomatic and there were no cases of COVID 19 prior or post his discharge from NICU. Symptoms (not specified) had commenced 2 days prior to admission. At presentation he was in presumed septic shock with unrecordable BP, lactic acidosis and respiratory distress and was intubated and commenced on 4 antibiotics and acyclovir. Investigations on admission included a CXR (bilateral airspace opacification), nasopharyngeal swab (positive for SARS COV2) and blood culture (grew Staph. epi). Urine, CSF and respiratory secretions were negative and subsequent 2 blood cultures were negative. 2 further nasopharyngeal swabs on day D7 and D15 of admission continued to be positive. On D8 there was respiratory deterioration (repeat CXR showing worsening bilateral opacification) and he was commenced on HFOV with iNO. Remdesivir was also commenced at this time and continued for a 10 day course. Ferritin and LDH peaked just before D8 and IL6 and IL10 were the highest on D8 (no levels available prior to D8). CRP was highest on admission and had quickly declined, with no rise associated with the respiratory deterioration. He was switched back to conventional ventilation on D16, extubated to Highflow on D22 and off all respiratory support on D24. He was discharged from PICU to the general paediatric ward on D25 to continue weaning off sedation (no neurological sequalae reported). There was evidence of liver (raised AST and GGT) and renal (raised creatinine with peak around D7) impairment along with bone marrow dysfunction (drop in platelet and WCC) initially which improved during the admission. There was no change in the viral load between admission and D16-17 of admission.

This case report is the first to chart the clinical course of a SARS COV 2 related hyperinflammatory state in a baby with a background of being born very preterm. The timing from NICU discharge to symptom onset makes it likely that the SARS COV 2 infection was acquired post discharge. The report does not explain why the ETT is barely visible/not present on the second CXR. It is not possible to say whether the IL6 and IL10 peaks were on the day of deterioration or whether this may have preceded it (as was the case in LDH and ferritin levels), since there were no interleukin levels prior to D8. Unlike ferritin and LDH, interleukin levels are not routinely tested outside tertiary centres. Therefore, the former two markers are a more feasible option for purposes of basing day to day clinical decision-making but may not be specific to SARS COV2 related hyperinflammation. CRP levels did not correspond to the respiratory deterioration. It is unclear whether the drop in all WCC lines and platelets suggestive of the marrow suppression and the acute renal and liver dysfunction were secondary to the shock at presentation or part of the hyperinflammatory state. It would have been helpful to know about the coagulation and fibrinogen status in this case. It is also noteworthy that Remdesivir did not change the viral load during the acute period of the admission. Therefore, it stands to reason that administration of this antiviral did not contribute to the clinical improvement, as suggested by the authors.

Future studies need to look at whether the specific inflammatory markers delineated in this case report could be used to predict which infant is susceptible to hyperinflammatory state and help steer the early course of management (e.g. early switch to HFOV).

Ahmed, I.Tan, B.K.British Journal of HaematologyFirst Covid‐19 maternal mortality in the UK associated with thrombotic complications18 May 2020United KingdomEurope1Neonatalhttps://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16849?af=R
Patane, LCornolti, GAJOG MFMVertical transmission of Covid-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with Covid-19 positive mothers and neonates at birth18 May 2020ItalyEurope2Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300896
Panichaya, PUthaisan, JEur J Obstet Gynecol Reprod BiolProlonged viral persistence in COVID-19 second trimester pregnant patient18 May 2020ThailandAsia1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233222/pdf/main.pdf
Fang, HDunjin, CObstetrics & GynaecologyBe aware of misdiagnosis—Influenza A H1N1 in a pregnant patient with suspected COVID‐1918 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13183
2. Dumpa, VNoor, A Cureus Neonatal Coronavirus 2019 (COVID-19) Infection: A Case Report and Review of Literature17 May 2020USANorth America1Neonatalhttps://www.cureus.com/articles/32203-neonatal-coronavirus-2019-covid-19-infection-a-case-report-and-review-of-literature
Mehta, HRezai, FElsevierNovel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report16 May 2020USANorth America2Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229956/pdf/main.pdf
Cooke, WSoulsby, KEur J Obstet Gynecol Reprod Biol. SARS-CoV-2 infection in very preterm pregnancy: Experiences from two cases15 May 2020United KingdomEurope2Neonatalhttps://www.ejog.org/article/S0301-2115(20)30276-1/pdf
Doria, MSilva, PTEur J of O&G & Reproductive BiolCovid-19 during pregnancy: a case series from an universally tested population from the north of Portugal15 May 2020PortugalEurope11Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227580/pdf/main.pdf
Calderaro AChezzi CInt J Infect DisSARS-CoV-2 infection diagnosed only by cell culture isolation before the local outbreak in an Italian seven-week-old suckling baby14 May 2020ItalyEurope1Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30342-8/fulltext
Kirtsman, MSha, PcmajProbable congenital SARS-Cov-2 infection in a neonate born to a woman with active SARS-Cov-2 infection 14 May 2020CanadaNorth America1Neonatalhttps://www.cmaj.ca/content/cmaj/early/2020/05/14/cmaj.200821.full.pdf
Perlman, JPace, JOJAAPDelivery room preparedness and Early Neonatal Outcomes During COVID19 pandemic in New York City14 May 2020USANorth America247Neonatalhttps://doi.org/10.1542/peds.2020-1567

is a prospective cohort study of women delivering at New York Presbyterian Hospital between 22/03/2020 and 15/04/2020. Specific infection control protocols (figure 1) were implemented for minimising risk of horizontal transmission from mother to their babies and to the staff involved in deliveries, transfer and/or admission to NICU. There were 326 deliveries, all of whom were tested with initial result turnaround time of 24hrs reducing to 2hrs by the end of the study. 31 mothers tested positive for SARS COV2 (15 asymptomatic and 16 symptomatic) and 9 were classified as patient under investigation (PUI), with results being awaited at the time of delivery. 2 babies from positive mothers (both preterm 33+2 and 32+3) and 4 babies from PUI mothers required CPAP and were admitted to NICU and placed in isolation. The 4 babies of the PUI mothers who were admitted to NICU were moved out of isolation following a negative test result in their respective mothers. The 2 preterm babies were tested at 24hrs, 48hr, 7 days and 14 days of life with all tests being negative. They were moved out of isolation after 2 negative tests and separated from their mothers for 14d from the onset of maternal symptoms. However, no symptoms listed for one of the mothers, therefore separation length unclear. All other swab +ve mothers (n=29) were kept with their babies in the well-baby nursery (WBN) with breast feeding allowed. All 29 WBN babies tested (x1) negative within 24hrs of birth and were discharged within 48 hours.

The effectiveness of the infection control measures used is only reliably demonstrated in the 2 preterm admissions to NICU, where there was repeated testing and in whom there was postnatal separation from their SARS COV2 positive mother. As almost half of the positive women were asymptomatic (one of whom had the preterm delivery), the results highlight the importance of universal testing with rapid turnaround times, to allow efficient PPE use to minimise horizontal transmission and prevent unnecessary separation of mother and baby. Given the negative swab status of babies born to positive mothers, vertical transmission is unlikely but cannot be ruled out without testing for the immunoglobulin status.

Taghizadieh, A Valizadeha, HRespiratory Medicine Case ReportsAcute kidney injury in pregnant women following SARS-CoV-2 infection: A case report from Iran.13 May 2020Iran Middle East1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219375/
Baergen, RHeller, DPediatr Devel PatholPlacental Pathology in Covid-19 Positive Mothers: Preliminary Findings.12 May 2020United states North America20Neonatalhttps://journals.sagepub.com/doi/pdf/10.1177/1093526620925569

This is a rapid communication letter in a pathology journal describing 20 placentas of Sars-Cov-2 positive mothers at Weill Cornell Medical Center, New York. Clinical details of both mothers and infants are also described. This hospital screened all expectant mothers for Sars-COV-2 by RT PCR. These are results of the examination of the first 20 placentas received by the pathology department

Clinical features; 4 woman were symptomatic peripartum; 2 had fever on presentation, 1 had been admitted with hypoxia and pneumonia but discharged pre delivery, 1 was re-admitted day 3 postpartum for hypoxia and shortness of breath, the rest were asymptomatic. Mothers were aged median 31 years (13.5 years) 4 women had pre-existing conditions ( 1 sickle trait, 1 chronic diabetes, 1 hypertension, 1 hypothyroid). No woman required ICU admission.

There was 19 singletons, and 1 set of twins. No infant tested positive for Sars CoV-2. Five infants were born at 32 - <37, and the rest from 37 weeks gestation. All infants had 5-minute Apgars of 8 or 9, were admitted to the well-baby nursery, and discharged home.

Pathology Features; Placental tissue was not tested for Sars Cov 2. Nine placenta (45%) had evidence of fetal vascular malperfusion. In three cases this was intramural fibrin deposition it one or two areas; in two cases there was foci of stromal-vascular karyorrhexis, and in the other four there was widespread foci of stromal-vascular karyorrhexis. In all cases vascular malperfusion was graded as mild. In one woman who had pneumonia and acute hypoxia, placenta showed evidence of ascending infection with acute chorioamnionitis and acute funisitis. Four other cases showed chronic villitis though its relationship to SArs COV 2 is unclear.

Conclusion; Authors conclude that Sars Cov2 in mothers, may be associated with a propensity for thrombosis in fetal circulation. However, they caution this might also be unrelated and further work is needed.

Lorenz, NGrober, KThe Pediatric Infectious Disease JournalNeonatal Early-Onset Infection With SARS-CoV-2 in a Newborn Presenting With Encephalitic Symptoms12 May 2020GermanyEurope1Neonatalhttps://journals-lww-com.libproxy.ucl.ac.uk/pidj/Citation/9000/Neonatal_Early_Onset_Infection_With_SARS_CoV_2_in.96175.aspx

This is a letter describing a case of encephalitic and respiratory symptoms in a neonate with positive SARS-CoV-2 nasopharangeal and rectal swabs.

The mother was symptomatic (mild respiratory infection, loss of smell and taste, fever 38.1C) during delivery and confirmed SARS-CoV-2 positive after delivery.

The baby, born at 40+3 weeks gestation by vacuum extraction, developed lethargy and therapy refractory fever at 24 hours of life, progressing by 54 hours of life to symptoms described as encephalitic (lethargy with hyperexcitability, high pitched cry). Nasopharyngeal and rectal swabs were positive for SARS-CoV-2 (CSF was negative). No other viral or bacterial pathogens were isolated from blood/CSF/nasopharyngeal or faecal samples.

Respiratory symptoms developed from day 4 requiring oxygen and continuous positive airway pressure therapy, and a viral pneumonia was diagnosed on day 10. The baby recovered and was discharged on day 14 (SARS-CoV-2 swabs still positive at discharge).

Liu, PZhang, YJ Allergy Clin ImmunolThe immunologic status of newborns born to SARS-CoV2-infected mothers in Wuhan, China11 May 2020ChinaAsia51Neonatalhttps://www.sciencedirect.com/science/article/pii/S0091674920306400
Polonia-Valente, RRodriguez, TEur J Obstet Gynecol Reprod Biol.Vaginal delivery in a woman infected with SARS-CoV-2 – The first case reported in Portugal11 May 2020Portugal Europe1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211642/
Perrone, SEsposito, SActa BiomedReport of a series of healthy term newborns from convalescent mothers with COVID-19.11 May 2020ItalyEurope4Neonatalhttps://europepmc.org/article/med/32420961
Knight, MKurinczuk, JNDPHCharacteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV 2 infection in the UK: A national cohort study using UK obstetric surveillance system11 May 2020UKEurope247Neonatalhttps://doi.org/10.1101/2020.05.08.20089268

As a pre print this study should be interpreted with caution until it has undergone peer review.

This is a prospective observational national cohort study carried out across all 194 consultant-led maternity units in the UK. It captured data from women admitted to hospital with confirmed SARS CoV 2 between 01/03/20 and 14/04/20, with tests having been carried out only if the woman was symptomatic. 427 women were studied and compared to a historical control sample of 694 women admitted between 01/11/17 – 31/10/18 (a historical sample was chosen to avoid confounding by including asymptomatic or minimally symptomatic carriers of COVID). The total number of maternities in the study period was 86293 and therefore the incidence of admission the SARS CoV 2 confirmed women was 4.9 per 1000 maternities. The median gestation at admission was 34 weeks (IQR 29-38 weeks), with 81% of admissions in the 3rd trimester. The results showed that there was a statistically significant risk of admission with SARS CoV 2 patients who had the following factors:

From a Black and Minority Ethnicity group: adjusted OR 4.49 (3.37-6.00). Even after sensitivity analysis which excluded women from London, West Midlands and North West England which had high rates of general infection OR 3.67 (2.55-5.28)

Overweight: adjusted OR 1.91 (1.37-2.68)

Obese: adjusted OR 2.20 (1.56-3.10)

Pre-existing medical condition (asthma, hypertension, cardiac disease or diabetes):adjusted OR 1.52 (1.12-2.06) Maternal age ≥ 35: adjusted OR 1.35 (1.01-1.81)Being a current smoker reduced the risk of admission, with adjusted OR 0.3 (0.17-0.51).The odds ratio for each significant factor outlined above was adjusted for the other significant factors which became confounding variables. There were 40 admission to level 3 critical care with 4 requiring ECMO. There were 5 maternal deaths recorded, 3 of whom had been admitted to critical care. SARS CoV 2 associated maternal mortality was 5.6 (1.3-13.1) per 100,000. Only 9 women were treated with antivirals (oseltamivir, lopinavir/ritonavir and/or remdesivir). 61 women were given corticosteroids for the maturation of fetal lung.

247 women in this cohort gave birth (singleton/multip proportion not stated) to a live infant (n=243) or had a pregnancy loss (n=4). 59% of women gave birth via c-section with 20% under general anaesthetic compared to 29% of the control group with 7% of women delivering under GA. There were 63 (26%) preterm births (<37 weeks) and 29 of these were documented as being secondary to COVID 19 infection; the other reasons stated were iatrogenic, fetal compromise and other obstetric conditions. This is compared to 8.9% of births in the control group being born preterm. There were 5 neonatal deaths, including 3 stillbirth; in two of the cases of stillbirths, it is unclear whether COVID 19 infection contributed to death. The rate of pregnancy loss, still birth, livebirth and neonatal death was not statistically different between the groups. The NICU admission rate was 26% (majority for prematurity) and 5% in the cohort and comparison groups, respectively. 12 infants tested positive for SARS CoV 2, with 6 being within the first 12 hours of life (early). 1 in the early positive and 5 in the later positive groups were admitted to NICU.

This is a national study reporting on the largest cohort of SARS CoV 2 positive pregnant women admitted to hospitals with symptoms. There is likely to be an underestimation of the true effect size presented in this report as analysis was carried out in only those patient in whom data was returned and not on the entire cohort of admissions in the specified time period. The results convincingly show important risk factors (maternal age, black and minority ethnicity, BMI, and pre-existing medical condition) for admission and thus confers the severe of infection in these risk groups. The black and minority ethnicity risk factor, which existed even after the sensitivity analysis, requires urgent further analysis and study as it was the biggest risk factor and one which has not been demonstrated to be the case in other coronavirus strains. The supposed protective factor of current smoker status is not explained in this report but could reflect lower current prevalence of smoking in pregnancy in general compared to the prevalence at the time of the historical sample. The report also highlights that most of the admission with SARS CoV 2 was in the second and third trimester thus providing weight for the precautions currently being taken in this group of women. However, they also correctly identify that there may be a sampling bias as those in the first trimester may be being admitted to hospital via routes other than the maternity services. There was a higher rate of preterm deliveries (statistical significance unknown) which is difficult to interpret but raises questions as to what extent the maternal infection may cause fetal compromise triggering preterm birth.

2% of babies tested positive for SARS CoV 2 suggesting a risk of vertical transmission, especially since 3 of the positive cases were pre-labour, c-section delivered babies. However, the IgG or IgM status of the infants is unknown and there were no placental, umbilical cord, etc samples taken/reported. The discussion states that mothers and infants were kept together with infection control measures (surgical face masks) and the low rates of neonatal infection supports continuation of this practice. However, 6 of the 12 infants testing positive for SARS CoV2 required neonatal unit admission, majority of whom were classed as late infections as they tested positive after 12 hours of life. There is no information provided on the reason for these admissions and what support and/or treatment was required during this time. It is important to point out that the report does not specially say that all other infants born to this cohort of mothers were tested for SARS CoV 2 and found to be negative. Further questions are raised in the two cases of stillbirth which may have been caused by COVID 19. There is also no clarification on the characteristics of the cases of neonatal death (e.g. were they preterm, was mother critically ill in ITU, etc) which would have added greatly to the analysis of this report.

Although this study does not provide enough detail to draw firm conclusions, it provides an important basis for further avenues where research is needed

Kuhrt, KShennan, AAm J Obstet Gynecol MFMPlacental abruption in a twin pregnancy at 32 weeks’ gestation complicated by coronavirus disease 2019 without vertical transmission to the babies08 May 2020UKEurope2Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300781
Algarroba, GVintzileos, AAJOGVizulaisation of SARS-CoV-2 virus invading the human placenta using electron microscopy08 May 2020USANorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305494
Blauvelt, CGaw, SObstet Gynecol.Acute Respiratory Distress Syndrome in a Preterm Pregnant Patient With Coronavirus Disease 2019 (COVID-19)08 May 2020USANorth America1Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/Acute_Respiratory_Distress_Syndrome_in_a_Preterm.97348.aspx
Vallejo, V.Ilagan, J.G.Obstetrics & GynecologyA Postpartum Death Due to Coronavirus Disease 2019 (COVID-19) in the United States.08 May 2020USANorth America1Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/A_Postpartum_Death_Due_to_Coronavirus_Disease_2019.97350.aspx
Lang, G.JZhao, H Zhejiang Univ-Sci B (Biomed & Biotechnol) Can SARS-CoV-2-infected women breastfeed after viral clearance?*08 May 2020ChinaAsia1Neonatalhttps://link.springer.com/content/pdf/10.1631/jzus.B2000095.pdf
Fox, APowell, RmedRxivEvidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-1908 May 2020USANorth America15Neonatalhttps://www.medrxiv.org/content/10.1101/2020.05.04.20089995v1.full.pdf
Munoz, A CBoukas, KNEJMLate-onset neonatal sepsis in a patient with covid-1907 May 2020USANorth America1Neonatalhttps://www.nejm.org/doi/full/10.1056/NEJMc2010614
Govind, AYoong, WEur J Obstet Gynecol Reprod Biol .Re: Novel Coronavirus COVID-19 in Late Pregnancy: Outcomes of First Nine Cases in an Inner City London Hospital07 May 2020United KingdomEurope9Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204671/pdf/main.pdf
Ochiai, D.Tanaka, MInt J Gynaecol Obstet. Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan06 May 2020JapanAsia52Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13252
An, P.Ye, Y.CMAJPostpartum exacerbation of antenatal COVID-19 pneumonia in 3 women06 May 2020ChinaAsia3Neonatalhttps://www.cmaj.ca/content/cmaj/early/2020/05/06/cmaj.200553.full.pdf
Ng, KTang, JPediatr Infect DisCOVID-19 in Neonates and Infants: Progression and Recovery06 May 2020UKEurope8Neonatalhttps://journals.lww.com/pidj/Abstract/9000/COVID_19_in_Neonates_and_Infants__Progression_and.96180.aspx
Li, JChen, DInt J Gynaecol ObstetCritically ill pregnant patient with COVID-19 and neonatal death within two hours of birth05 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13189
Wu, YHuang, HBJOGCoronavirus disease 2019 among pregnant Chinese women: Case series data on the safety of vaginal birth and breastfeeding05 May 2020ChinaAsia5Neonatalhttps://pubmed.ncbi.nlm.nih.gov/32369656/

This is a retrospective case-controlled study of 43 women who had presented to 2 affiliated hospitals in New York City between 13/03/20 and 27/03/20 and had positive nasopharyngeal swabs for SARS CoV 2 PCR. The average BMI of these women was 30.9 (60.5% had a BMI ≥30) and 18 women had co-morbidities (mild asthma being the most common). 29 women had COVID-19 related symptoms and underwent testing at presentation. 3 of these women were admitted for management of COVID-19 symptoms and 4 were admitted (unclear when in the two-week study period) for obstetric indications. 14 women were asymptomatic and had presented for obstetric reasons. 2 of these women were tested due to COVID-19 symptom onset during admission and went onto require ITU level care. The other 12 asymptomatic women were tested as part of the universal testing on admission to the delivery unit. Of the 18 women admitted for obstetric indications, 10 were planned admissions (9 inductions and 1 elective section). 4 COVID-19 symptomatic women (incl.1 preterm labour) and all asymptomatic women gave birth to a total of 18 babies (10 vaginal deliveries and 8 c-sections for obstetric reasons) with good APGAR scores. All babies had nasopharyngeal swabs on day 0; 15 babies were negative, 2 babies had initial unclear and then negative on repeat swab on day 1-2 and 1 baby had an indeterminate result and was clinically managed as ‘presumptive negative’. There were 3 admissions to NICU (n=1 preterm 34+6 n=1 antenatal diagnosis of multicystic dysplasic kidney and n=1 Resp distress with suspected sepsis – COVID-19 swab -ve). Babies not requiring NICU were kept with mothers and breast feeding encouraged with advice on strict hand hygiene and mask wearing. All babies have been discharged home.

There are two clear inconsistencies noted in this paper. Firstly, there is a different mean age of pregnant women stated in the table to that which is stated in the body of the text. Secondly, there is a mention of ‘3 of the 28 babies’ being admitted to NICU whereas elsewhere in the paper it consistently quotes 18 babies; this maybe a mis-print. There is also ambiguity in the way that results are presented for the symptomatic women for whom treatment was not required for their COVID-19 symptoms on initial presentation; the flowchart figure shows 26 patients with mild disease with 4 admissions for obstetric reasons, but the text reports 25 patients were stable for discharge. The most striking finding in this paper is the number of women who present with obstetric reasons and with no COVID-19 symptoms, who tested positive for COVID-19. This is even more poignant given that the 2 women requiring ITU level care were asymptomatic at presentation and were the only ones to require this level of support in this report. It is also important to note that 5 of the inductions of labour were in asymptomatic women for worsening pathologies such as cholestasis, reduced fetal movement and chronic and gestational hypertension and that one of symptomatic women went into preterm labour. It is reassuring that all neonates born, regardless of COVID-19 symptom status at presentation, did well clinically with most babies being kept with mothers post partum. The neonates were not assessed for IgG and IgM status.

Hirshberg, A.Srinivas, S. K. Am J Obst & GynCare of critically ill pregnant patients with coronavirus disease 2019: a case series.03 May 2020USANorth America3Neonatalhttps://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930515-9
D. BuonsenoValentini, PAJPNeonatal late onset infection with Severe Acute Respiratory Syndrome Coronavirus 202 May 2020ItalyEurope2Neonatalhttps://pubmed.ncbi.nlm.nih.gov/32359227/

This is a case series of 2 neonates born to mothers admitted to a hospital in Rome, Italy. Mother of Neonate 1 was admitted 19/03 with respiratory symptoms with positive nasopharyngeal swab for SARS CoV-2 and was commenced on anti-virals and hydrossichloroquine. On 26/03, her baby was born at 38+3 weeks via c-section (reason not stated) in good condition. Amniotic fluid, placental swabs, and baby’s nasopharyngeal swabs on day 1 and 5 were negative. Neonatal blood IgM was negative, but IgG was slightly positive. Baby remained clinically well during their 5-day inpatient stay and breast milk tested each day remained negative. Mother who has discharged on the same day as baby, was still positive for SARS CoV-2 at discharge. At home she breastfed baby whilst wearing a mask. At follow-up on day 15 baby tested positive on nasopharyngeal swab but remained clinically well (breastmilk remained negative). On day 25 the baby continued to remain clinically well. Mother of Neonate 2 was admitted 23/03 with respiratory symptoms requiring oxygen with positive swab and was commenced on the same treatment. On 28/03 her baby was born at 35+5 weeks via emergency c-section due to fetal bradycardia, in good condition. The placental swab and cord blood were positive but amniotic fluid and nasopharyngeal swabs on day 1 and 3 were negative. Breast milk was positive on day 1, 2 and 4. Baby was discharged on day 13 along with mother who was negative at discharge. Baby was given expressed breastmilk at home by father. On day 18, the baby was clinically well with negative swabs and the breast milk was also negative. On day 24 the baby remained clinically well. In both cases mother and baby were separated at birth and both babies were formula fed during their inpatient stay.

The result of a positive swab at follow-up in Neonate 1 (having previously been negative), on the background of being clinically well and breast fed by a mother a who was positive at discharge suggest colonisation rather than late onset infection. It would have been useful to have tested immunoglobulin levels at this point and again at later follow-up to look for the presence of IgM. It also might suggest the need for extra distancing measures as that taken by the family of Neonate 2 during feeding. However, as neonate 1 remained clinically well, there is not enough evidence to suggest that disrupting direct breastfeeding confers any benefit. There is ambiguity in the maternal admission for neonate 2 with the figure suggesting admission at 34+4 weeks gestation with commencement of treatment, but the body of text stating admission at 35+0 weeks. This may represent a readmission and if so, brings into question the need for much more careful monitoring of COVID positive pregnant women to reduce the risk severe infection and thus fetal compromise which led to the preterm delivery. It is noteworthy that in Neonate 2’s case, the placental swabs, umbilical cord blood and breast milk were positive, which in previous studies have not been the case. However, immunoglobulins were not tested on Neonate 2. Given the negative swabs at birth and no mention of respiratory support requirement or clinical instability following birth, it is unlikely that the positive results indicate a risk of vertical transmission.

De Socio, G. V. Francisci, DMed J Hematol & Infect disDelivery in Asymptomatic Italian Woman with SARS-CoV-2 Infection.01 May 2020Italy EuropeNeonatalhttps://www.mjhid.org/index.php/mjhid/article/view/2020.033/3768
Baud, DPomar, LJAMASecond-Trimester Miscarriage in a Pregnant Woman With SARS-CoV-2 Infection30 Apr 2020SwitzerlandEurope1Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2765616
Xu, L.Wang, L.Sci Bull (Beijing)Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates28 Apr 2020ChinaAsia5Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186128/
Sun, MZhang, JBJAEvidence of mother-to-newborn infection with Covid-1927 Apr 2020ChinaAsia3Neonatalhttps://bjanaesthesia.org/article/S0007-0912(20)30281-6/fulltext
Ferrazzi, ECetin, IBJOGVaginal delivery in SARS‐CoV‐2 infected pregnant women in Northern Italy: a retrospective analysis27 Apr 2020ItalyEurope42Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.16278

This is a retrospective clinical notes analysis of women with SARS-CoV-2 (confirmed on nasopharyngeal swab prior to, or within 36 hours of, delivery) who were admitted to, and delivered in, hospitals within Lombardy and Units of Padua and Modena between 1 March 2020 and 20 March 2020. Women and newborns were followed up until discharge from hospital or 25 March, whichever came first.

42 women were included in the study. Five were diagnosed with COVID-19 in the 36 hour post-partum period. The majority suffered mild or moderate symptoms of COVID-19. Nineteen (45%) were diagnosed with pneumonia, 4 of whom admitted to critical care unit.

Over half (24, 57%) delivered vaginally. Of the remaining 18 women who had elective caesarean sections, 8 were for obstetric reasons unrelated to COVID-19 and 10 were due to worsening respiratory compromise. There were no emergency c-sections.

There were 3 preterm deliveries before 34 weeks (details of more specific gestation are not given). Two of these were delivered by caesarean section because of maternal respiratory compromise secondary to COVID-19. One mother spontaneously delivered vaginally before 34 weeks.

The paper doesn’t state whether there were any multiple births, so it is presumed 42 babies were delivered. Three babies were admitted to NICU, 2 because they were preterm and 1 because of respiratory distress. This baby was born vaginally in good condition but separated immediately from his mother because of post-partum haemorrhage. He developed gastrointestinal symptoms on day 1 and respiratory failure on day 3 requiring mechanical ventilation on NICU. His SARS-CoV-2 swab result was equivocal on day 1 but positive 3 days later.

Women known to have COVID-19 but asymptomatic or with only mild symptoms were allowed to breastfeed wearing a surgical mask.

Three babies tested positive for SARS-CoV-2: the neonate with respiratory failure described above and 2 other babies whose mothers were diagnosed COVID-19 within 36 hours after delivery and who had breastfed their babies without wearing a mask. These 2 babies tested positive on days 1 and 3, respectively. No other babies tested positive for SARS-CoV-2 during the study period.

The authors are clear that their data is only relevant to pregnancies in the third trimester. However, their data supports the theory that maternal SARS-CoV-2 infection does not increase the risk of preterm birth. Their results also suggests that vaginal delivery may be appropriate in mild cases of COVID-19-19, reserving caesarean section for women with severe respiratory compromise where delivery will improve maternal respiratory function, and does not confer a high risk of intrapartum SARS-CoV-2 transmission to the neonate.

Buonsenso, D.Moro, F.Ultrasound in Obstetrics & GynecologyClinical role of lung ultrasound for the diagnosis and monitoring of COVID ‐19 pneumonia in pregnant wome26 Apr 2020ItalyEurope2Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/uog.22055
JustinMulveyAnn. Diagn. Pathol.Analysis of Complement Deposition and Viral RNA in Placentas of COVID-19 Patients25 Apr 2020USANorth America5Neonatalhttps://www.sciencedirect.com/science/article/pii/S1092913420300708?via%3Dihub
Lu, DYang, XJ Med VirolAsymptomatic COVID-19 infection in late pregnancy indicated no vertical transmission24 Apr 2020ChinaAsia1Neonatalhttps://onlinelibrary.wiley.com/doi/10.1002/jmv.25927
Zhou, C. G.Caughey, A. B. J Matern Fetal Neonatal MedAntenatal corticosteroids for pregnant women with COVID-19 infection and preterm prelabor rupture of membranes: a decision analysis.24 Apr 2020USANorth America0Neonatalhttps://www.tandfonline.com/doi/full/10.1080/14767058.2020.1763951
Hu, XChen, LObstet GynecolSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vertical Transmission in Neonates Born to Mothers With Coronavirus Disease 2019 (COVID-19) Pneumonia24 Apr 2020ChinaAsia7Neonatalhttps://journals.lww.com/greenjournal/Citation/9000/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.97384.aspx
Sharma TBhatla NInt J Gynaecol ObstetManagement of the first patient with confirmed COVID‐19 in pregnancy in India: From guidelines to frontlines23 Apr 2020IndiaAsia1Neonatalhttps://doi.org/10.1002/ijgo.13179
Yan, JYang, HAJOGCoronavirus Disease 2019 in pregnant women: a report based on 116 cases23 Apr 2020ChinaAsia116Neonatalhttps://doi.org/10.1016/j.ajog.2020.04.014

This is a retrospective cohort observational study of pregnant women with admissions to 25 different hospitals in China with a diagnosis of COVID pneumonia. A total of 116 women were captured during the study period of 30/01/20 - 24/03/20. 65 women had lab confirmed SARS COV2 on rt-PCR from pharyngeal swabs. 51 cases were clinically diagnosed based on the New coronavirus pneumonia prevention and control programme, published by the national health commission of China (all had abnormal CT chest findings on admission). The commonly reported symptoms were fever and cough, but in 23.3% of cases there were no symptoms. Mean maternal age at admission was 30.8 (SD +/- 3.8) There were 9 women with gestational diabetes and 5 women with hypertension, 4 of whom had pre-eclampsia. 8 women required ITU admission with 1 case requiring ECMO, 76 women had been discharged and there were no maternal deaths at the study end point. Below is the breakdown the women who presented before 37 weeks of gestation.

A total of 99 women delivered 100 babies (x1 set of twins) with 85 women delivering via c-section. 86 neonates underwent pharyngeal swabs, 10 of whom had paired amniotic fluid and cord blood testing, with all samples being collected in the operating or delivery room. There was also 6 vaginal swab tests and 12 women had their breast milk tested. All tests were negative for SARS COV2. The rate of all- cause preterm birth was 21.2% (21/99). The rate of spontaneous preterm birth, where there was spontaneous preterm rupture of membranes, was 6.1% (6/99). There were 47 babies admitted to NICU for further management, with one neonatal death secondary to neonatal asphyxia following delivery at 35+2 due to severe maternal pneumonia (required ECMO).

This report provides a useful comparison to the national cohort report published by UKOSS. There are similar rates of maternal ITU admission, ECMO requirements and neonatal death rate being reported in the two studies. There is a 26% preterm delivery rate with UKOSS compared to the 21% reported in this study. There is a higher rate of c-section deliveries in this report compared to UKOSS (59%). Unlike the 2% of babies testing positive for SARS COV2 in UKOSS, there were no positive cases in this cohort. There are overlaps in the results from 4 other smaller case series already published, with 33 of the cases having already been reported on. The neonatal outcome data is incomplete with not all babies having been tested with nasopharyngeal swabs, no breakdown of reason for NICU admission and level of support required and important data on the specifics of the infection status of the neonatal death not reported. The authors accept that maternal infection with COVID does increase the rate of preterm births <37 weeks but report that there is no increase in the rate of spontaneous preterm births. There is no control group or national statistic given for this comparison statement. The report does not expand on what clinical criteria were met for 23.3% of women who had no symptoms to warrant a diagnosis of COVID pneumonia, i.e. did they undergo CT chest without the presence of any symptoms.

Salvatori GCampana ABreastfeeding medicineManaging COVID-19-Positive Maternal–Infant Dyads: An Italian Experience22 Apr 2020ItalyEurope2Neonatalhttps://www.liebertpub.com/doi/full/10.1089/bfm.2020.0095?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

This is a case report from Italy of two neonates who’s mothers contracted coronavirus postnatally. Their mothers tested positive on NPA after developing symptoms. At the time of presentation the neonates were 10 and 18 days of age. Both babies tested positive on NPA however only one displayed any symptoms (cough, diarrhoea, poor feeding.) Neither baby required admission.

Expressed breast milk samples of both mothers were analysed and SARS-CoV-2 was not detected by RT-PCR.

The authors conclude that based on this mothers who test positive should be encouraged to continue breast feeding.

Al-Kuraishy, HAli, ZAsian Pacific Journal of Reproduction 9(3): 156-158. COVID-19 pneumonia in an Iraqi pregnant woman with preterm delivery21 Apr 2020IraqMiddle East1Neonatalhttp://www.apjr.net/preprintarticle.asp?id=282984
Lyra, JGuimaraes, MActa Med PortCesarean Section in a Pregnant Woman with COVID-19: First Case in Portugal20 Apr 2020PortugalEurope1Neonatalhttps://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/13883
Liao, J.Li, J.Gynaecology and Obstetrics Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID‐19 pandemic19 Apr 2020ChinaAsia10Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/ijgo.13188
Zamaniyan, MAzizi, SPrenat. Diagn.Preterm delivery in pregnant women with critical COVID-19 pneumonia and vertical transmission17 Apr 2020IranMiddle East1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.5713?af=R
Parat, MRatner, AJClin Infect Dis. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress17 Apr 2020United States North America2Neonatalhttps://doi.org/10.1093/cid/ciaa452

This is a case series of two infants presenting with fever to a hospital in New York during on week in March 2020. Neither presented with respiratory symptoms, and both had Sars Cov2 infection confirmed without other aetiology despite febrile infant work ups.

First; a 25-day old full-term male infant, presented with fever, irritability and facial rash. Parents had sore throat and subjective fever but had not sought medical attention for themselves. Full routine work up with CSF, blood, urine samples and routine respiratory PCR panel was taken. SARS CoV2 PCR positive on nasal swab. Treated empirically until cultures negative at 48 hours, recovered well.

Second; a 56-day old ex 35-week male infant, presents with fever only. He had no other symptoms, and no sick contacts. Bloods, urine and routine respiratory PCR panel was taken. Infant did not have lumbar puncture. SARS CoV2 PCR was positive on nasal swab. Treated empirically until cultures negative at 36 hours.

Authors discuss the need to maintain high index of suspicion for SARS-CoV-2 infection in febrile infants during a community outbreak, and the importance of strict infection control measures in paediatric emergency department.

Koumoutsea, EVMalinowski, AKJournal of tjrombosis and haemostasisCOVID‐19 and acute coagulopathy in pregnancy17 Apr 2020CanadaNorth America2Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14856
Li, MLi, XPLoS OneThe SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study16 Apr 2020ChinaAsia0Neonatalhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230295

The study explores the presence of Angiotensin-converting enzyme 2 (ACE2) within the placenta and the developing baby by analysing online available data on RNA sequencing from areas of the maternal-foetal interface and from various foetal organs. They found ACE2 was highly expressed in a variety of cells in the decidua and placenta, as well as a variety of foetal organs including heart, liver and lung, but not kidney. They suggest these findings demonstrate potential routes for vertical transmission, placental dysfunction and pregnancy complications, and call for further clinical analysis to ascertain the relevance of these results.

Han, MSChoi, EHClin Infect DisSequential analysis of viral load in a neonate and her mother infected with SARS-CoV-216 Apr 2020KoreaAsia1Neonatalhttps://academic.oup.com/cid/article/doi/10.1093/cid/ciaa447/5820869

This is a case report of a 27 day-old female neonate with confirmed SARS-CoV-2 infection. Over the course of a short and reasonably mild illness, samples were tested from the nasopharynx, oropharynx, plasma, urine, stool and saliva. SARS-CoV-2 RNA was detected in all samples. Early in the infection, viral load was highest in the nasopharynx and oropharynx, decreasing to undetectable at day 17. Viral load in stool, however, remained high throughout, despite cessation of gastrointestinal symptoms. This was in contrast to the mother's stool sample in which viral load was undetectable earlier.

Patek, PKhandhar, PClinical PediatricsSARS-CoV-2 Infection in a 2-Week-Old Male With Neutropenia15 Apr 2020USANorth America1Neonatalhttps://journals.sagepub.com/doi/full/10.1177/0009922820920014?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&
Lowe, BBopp, BAustralian & NZ Journal of Obstetrics & GynaecologyCOVID‐19 vaginal delivery – a case report15 Apr 2020AustraliaOceania1Neonatalhttps://doi.org/10.1111/ajo.13173
Zhoujie, PShi, YJ Infect Public HealthUnlikely SARS-CoV-2 vertical transmission from mother to child: A case report11 Apr 2020China Asia1Neonatalhttps://doi.org/10.1016/j.jiph.2020.04.004
Xiong, XPang, QJournal of Medical VirologyVaginal delivery report of a healthy neonate born to a convalescent mother with COVID­‐1910 Apr 2020ChinaAsia1Neonatalhttps://doi.org/10.1002/jmv.25857

This is a case report of a 25-year-old primiparous woman. She was 33+1 gestation at presentation to hospital in Bejing on the 29th of January, with symptoms of suspicious of COVID-19 infection and having recently travelled from Wuhan. Following a positive result on rt-PCR for SARS COV2 from a throat swab and abnormal findings on chest x-ray, she was treated with antiviral and corticosteroids (does not specify). She was discharge home on the 4th of February. Follow-up rt-PCRs were negative and CT chest was normal. She underwent a normal vaginal delivery on the 7th of March, giving birth to a 38+4 weeks gestation male infant with a BW of 3.07Kg and no requirement for resuscitation. All samples collected at the time of birth were negative for SARS COV 2 (maternal cervical secretions, maternal rectal swab, neonatal throat swab, neonatal rectal swab, amniotic fluid and breast milk). Detection for placental presence of N-protein of SARS COV2, (a structural component of the viral particle) using immunohistochemical analysis, was negative. Serological antibody testing carried out at birth (using INNOVITA detection kit) showed that the mother was positive for IgG and IgM antibodies to SARS COV-2 whereas baby was negative to both. Mum and baby were discharged on the 10th March. The report does not mention whether there was infant separation from mother postnatally nor the reason for the inpatient stay following birth.

The negative rt-PCR result from key samples from mother and infant collected at birth, adds to the existing evidence against vertical transmission of COVID-19 infection. It is also encouraging to note that the pregnancy continued post infection and resulted in an outwardly healthy term infant. The absence of viral N-protein from placental tissue does not discount the placenta as a site of viral replication as there was no clinical evidence of an active infection at the time of delivery. The absence of IgM in the infant’s serology on a background of positive IgM in the mother seems to suggest that the infant did not suffer the infection in-utero. However, IgG antibodies which regularly cross the placenta, being negative in the infant whilst being positive in the mother raises questions of validity of the test in the infant.

Cao, DSun, GInt. J. Infect. Dis.Clinical analysis of ten pregnant women with COVID-19 in Wuhan, China: A retrospective study10 Apr 2020ChinaAsia11Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30263-0/fulltext
Alzamora, MCLa Rosa, MA, J PerinatolSevere COVID-19 during Pregnancy and Possible Vertical Transmission08 Apr 2020USA or Peru (not clear)Unclear1Neonatalhttps://www.thieme-connect.com/products/ejournals/html/10.1055/s-0040-1710050

This is a case report of one pregnant patient presenting to a hospital in March 2020. It is unclear from the article whether this was in Lima, Peru or Texas, USA (both institutions are listed).

The mother had presented to another hospital three days earlier with four days of fatigue, fever, malaise, and later shortness of breath. She was known to have diabetes mellitus. She was admitted for three days and then deteriorated, requiring transfer and intubation. Maternal serology on postpartum day 1 was negative for IgG and IgM, but was positive for both when testing was repeated on postpartum day 4.

A caesarean section was performed at 33/40 due to maternal respiratory compromise. The baby had Apgars of 6 and 8, and weighed 2970g. The neonate was intubated (thought to be due to maternal sedation side effects) in another room and was isolated immediately. There was no breastfeeding. Neonatal serology at birth was negative for IgG and IgM. Neonatal nasopharyngeal swab at 16 hours was PCR positive. The baby was ventilated for 12 hours and then extubated onto CPAP. Although initially improving, on Day 6, the neonate had mild respiratory difficulty and cough requiring oxygen via nasal cannula.

This case report suggests the possibility of vertical transmission.

Zhang, ZBi, YEuropean Respiratory JournalNovel Coronavirus Infection in Newborn Babies Under 28 Days in China08 Apr 2020ChinaAsia4Neonatalhttps://doi.org/10.1183/13993003.00697-2020

This study aimed to identify neonates (<28 days) who were COVID positive. Data was  retrieved from central government and local health departments across China. The data was screened for newborn babies <28 days of age with positive COVID nucleic acid detection between 8th December 2019 and 13th March 2020. Patients identified were then interviewed and further info was collected from local hospitals.

Out of 81026 COVID cases, four neonatal cases were identified. Three of these were male, and the ages were: 30 hours; 17 days; 5 days; 5 days

One patient had shortness of breath; one had fever, cough, and vomiting; one had fever only; and one was asymptomatic.

Radiology: Three had CT - increased lung markings in all.

Bloods: no information reported

Maternal info: All four mothers were positive for COVID (3 before delivery, 1 after delivery). All born by c section. Three were separated from mothers after birth and were not breastfed. One stayed with the mother and was breastfed for 16 days until symptoms started.

Outcomes: all four were hospitalised. None required intensive care or intubation/ventilation. None had severe complications.

The authors suggest these findings indicate intrauterine transmission is possible.

Yang, PZhao, DJournal of Clinical VirologyClinical characteristics and risk assessment of newborns born to mothers with COVID-1908 Apr 2020ChinaAsia7Neonatalhttps://www.sciencedirect.com/science/article/pii/S1386653220300986
Wu, XWang, XIJGORadiological findings and clinical characteristics of pregnant women with COVID‐19 pneumonia08 Apr 2020ChinaAsia21Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13165
Yang, HJin, ZjinfClinical features and outcomes of pregnant women suspected of coronavirus disease 201907 Apr 2020ChinaAsia57Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152867/pdf/main.pdf
Kalafat, EKoc, EUltrasound in Obstetrics and GynaecologyLung ultrasound and computed tomographic findings in pregnant woman with COVID‐1906 Apr 2020TurkeyAsia1Neonatalhttps://doi.org/10.1002/uog.22034

This is a single case report of a 32-year-old primiparous woman in Ankara, Turkey. She has thalassemia trait but was not anaemic and was 35+3 weeks at the time of developing symptoms on the 20th of March. She presented to the outpatient obstetric clinic on the 23rd of March with worsening symptoms. The lung ultrasound was abnormal but she self-discharged. No swabs were taken at this time. She re-presented on the 25th of March with worsening symptoms, abnormal vital signs and reduced fetal movement. She underwent a repeat lung ultrasound (abnormal), repeat swabs (positive for SARS COV-2) and a CT scan (changes typical of COVID-19 infection). An elective c-section was performed in view of her worsening lung function.

Baby was born in good condition without the cover of steroids as the team were uncertain about the effect this may have on the COVID 19 infection. Cord blood, swabs from the maternal and fetal side of the placenta, baby’s NPA and throat swabs and breast milk were all negative on rt-PCR for SARS COV2. Baby remained well without respiratory support requirement and feeding with expressed breast milk. It is unclear whether mother and baby were separated from birth, as mother was initially stable after delivery but went on to be intubated on the 27th of March.

The focus of this case report was on the early recognition of COVID 19 in pregnant women through lung ultrasound. From a neonatal standpoint, it continues to support previously published evidence of a good outcome for neonates born to COVID 19 positive mothers and the absence of SARS COV2 on rt-PCR from key samples taken at the time of delivery that might otherwise have suggested vertical transmission. However, it is important to note that no antibody testing was performed on baby.

Gidolf, SJosefsson, HActa Obstetricia et Gynecologica ScandinavicaCOVID‐19 in pregnancy with comorbidities: More liberal testing strategy is needed06 Apr 2020SwedenEurope2Neonatalhttps://doi.org/10.1111/aogs.13862

Case report of a primigravida mother who presented with symptoms of malaise, hoarseness and mild headache after being referred to hospital due to hypertension and proteinuria at 36 weeks gestation. Mother had NPA sent for 'Covid-19 RNA' which was positive. A cesarean section was performed due to developing signs of eclampsia. The mother maximally required 1-3L oxygen via nasal cannulae, CRP peaked at 88 and CT chest showed signs typical of Covid-19 pneumonia. 

Both babies stayed with mother after delivery and were tested for Covid-19 via NPA at 34 hours and 4.5 days of age. Tests were negative. Twin 1 required CPAP for 40 minutes, nil else. Twin 2 was well. Covid-19 tests on breastmilk and vaginal secretions on day 5 also negative

Kamali Aghdam, MEftekhari, KInfectious DiseasesNovel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report01 Apr 2020IranMiddle East1Neonatalhttps://www.tandfonline.com/doi/full/10.1080/23744235.2020.1747634

This brief case report from Iran is of a 15 day old male from Mousavi Hospital in Zanjan, Iran. Date of admission was not available. Symptoms were fever and lethargy with his parents having fever and cough. He initially appeared tachycardic and febrile with sats of 93% on RA. He was given Vancomycin, Amikacin and Oseltamivir. SARS-CoV-2 was detected on RT-PCR. His parents were not tested as they did not meet the testing criteria at the time (hospitalisation).

Radiology: Chest X-ray had nil findings

Bloods: WCC 6.7, Lymphocytes 36%, Neutrophils 42% and CRP 1 (normal).

Comorbidities: There was an incidental finding of patent foramen ovale on Echo.

Outcome: He had improvement by day 2 of admission and was cleared for discharge on day 6.

Iqbal, SRuiz, MNEJMAn Uncomplicated Delivery in a Patient with Covid-19 in the United States01 Apr 2020USANorth America1Neonatalhttps://www.nejm.org/doi/full/10.1056/NEJMc2007605
Lee, DAn, JKorean Journal of AnesthesiologyEmergency cesarean section on severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) confirmed patient.31 Mar 2020South KoreaAsia1Neonatalhttps://doi.org/10.4097/kja.20116
Chen, SShao, YJournal of Medical VirologyClinical analysis of pregnant women with 2019 novel coronavirus pneumonia28 Mar 2020ChinaAsia5Neonatalhttps://doi.org/10.1002/jmv.25789
Breslin, ND'Alton, MAmerican Journal of Obstetrics and GynecologyCOVID-19 in pregnancy: early lessons27 Mar 2020USANorth America7Neonatalhttps://doi.org/10.1016/j.ajogmf.2020.100111
Dong, LYang, JJAMAPossible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn26 Mar 2020ChinaAsia1Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2763853

This is a case report that would suggest that vertical transmission of COVID-19 can occur. A 34+2 primiparous woman was diagnosed with COVID-19 (she was symptomatic with fever and respiratory difficulty and had classic CT chest findings and a positive nasopharyngeal swab for SARS-CoV-2). She was treated with antiviral medications, antibiotics and corticosteroids.

Her female infant was delivered by caesarean section 4 weeks after the onset of her mother’s symptoms in good condition with Apgars of 9 and 10. Although the infant’s nasopharyngeal swabs were negative, her IgM antibodies against SARS-CoV-2 were raised at 2 hours post-delivery and cytokine levels were elevated. The risk of environmental infection was minimised: the caesarean was performed in a negative pressure room, the mother wore an N95 mask and did not hold her infant and the infant was immediately isolated in NICU. Maternal vaginal secretions were negative for SARS-CoV-2, which would also suggest the infection did not happen at birth. As IgM antibodies do not cross the placenta, the infant’s elevated IgM antibody levels suggest that she was infected in utero. Moreover, IgM antibodies usually do not appear until 3 to 7 days after infection. The infant also had raised IgG antibodies, but IgG is transferred placentally so this may reflect maternal or infant infection. The mother’s breast milk was negative for SARS-CoV-2 1 week following delivery.

Zeng, LZhou, WJAMA PedNeonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China26 Mar 2020ChinaAsia3Neonatalhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2763787

This is a cohort study following 33 neonates born to COVID-19 positive mothers, recruited Wuhan Children’s Hospital, Hubei Province, China, between January 2020 and February 2020. The authors describe three cases of early-onset neonatal COVID-19, which they suggest implies vertical transmission. However, amniotic fluid, cord blood and maternal breast milk of the mothers of all 3 positive neonates were negative for SARS-CoV-2, therefore it is unclear whether the infection was transmitted vertically or environmentally.

Three of the 33 neonates tested positive for COVID-19 on day 2 of life (positive nasopharyngeal or anal swabs). All 3 were born by caesarean section, two at term and the third at 31+2 for premature rupture of membranes and foetal distress.

Clinical features: The two term COVID-19 positive neonates had fever, although the authors don’t define what temperature they consider fever. These two neonates were also lethargic, but neither had respiratory distress. Neonate 3 was the most unwell, although this may be due to prematurity, poor condition at birth and sepsis rather than COVID-19. He was born at 31+2, required resuscitation at birth and had poor Apgars of 3, 4 and 5 at 1, 5 and 10 minutes, requiring non-invasive ventilation for respiratory distress. His blood cultures were positive for Enterobacter agglomerates.

Bloods: Neonate 1 (fever and lethargy) had normal bloods except raised procalcitonin (0.09 microgram/L). Neonate 2 (fever, lethargy and vomiting) had a leucocytosis, lymphocytopenia and elevated CK. Neonate 3 (premature with sepsis) had leucocytosis, thrombocytopenia and coagulopathy with prolonged PT (21 sec) and APTT (81.9 sec).

Radiology: All 3 had radiological evidence of pneumonia on CXR.

The authors state that because strict infection control and infection prevention procedures were implemented during delivery, SARS-CoV-2 isolated from their upper respiratory tracts or anuses was therefore maternal in origin. However, although it is stated in the illustration that one neonate was immediately quarantined after birth, it’s not clear whether this was the case for the other two babies. Plus, the negative amniotic fluid and cord blood does raise the question as to whether these neonates were truly infected in utero or not.

Zeng, HFan, JJAMAAntibodies in Infants Born to Mothers With COVID-19 Pneumonia26 Mar 2020ChinaAsia6Neonatalhttp://jamanetwork.com/article.aspx?doi=10.1001/jama.2020.4861

This report outlines the course of 6 mothers who were symptomatic for COVID-19 in their last trimester, and gave birth to 6 liveborn infants. This study is notable for antibody testing of both mothers and infants. The accuracy of the antibody tests are suspiciously high given current struggles to produce adequate tests around the world, and should be treated with a high degree of caution.

All 6 infants were born in good condition, and all tested negative for SARSCoV-2 viral throat swabs and blood PCR. Unsurprisingly all infants had elevated IgG or SARS-CoV-2 (as this crosses the placenta), but notably 2 infants had raised IgM (39.9AU/ml and 16.25AU/ml). This raises the possibility of intrauterine infection, similar to another case of an infant with raised IgM (Dong et al JAMA). Issues with cross reactivity of IgM are well described, and so whilst full validation of these tests is awaited internationally, this should be treated with caution.

Zheng, QJin,LReprod Dev MedSingle cell RNA expression profiling of ACE2 and AXL in the human maternal-fetal interface25 Mar 2020N/AN/A0Neonatalhttp://www.repdevmed.org/article.asp?issn=2096-2924;year=2020;volume=4;issue=1;spage=7;epage=10;aulast=Zheng;type=0

This paper reports analysis of a public single cell RNA sequencing database for the mRNA expression profile from cells from the decidua and placenta, which represent the mother-foetus interface. The authors specifically examined angiotensin converting enzyme 2 (ACE-2) receptor expression. They compared this to AXL receptor tyrosine kinase expression, which plays a key role in Zika Virus transmission because of the known vertical transmission in that disease.

They found that expression of ACE-2 was low in these mother-foetal interface cells, and that expression of AXL was higher in several of these. They conclude with the speculation that "the ratio of SARS CoV 2 infected mother to fetus transmission will be significantly lower than that of Zika Virus, because the expression of ACE2 is very low in early maternal–fetal interface cells". More research is needed.

Zambrano, LRodrigues-Morales, ATravel Medicine and Infectious DiseaseA pregnant woman with COVID-19 in Central America25 Mar 2020HondurasNorth America1Neonatalhttps://doi.org/10.1016/j.tmaid.2020.101639
Yu, NWu, JLancet: Infectious DiseasesClinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study24 Mar 2020ChinaAsia7Neonatalhttps://doi.org/10.1016/S1473-3099(20)30176-6

This is a retrospective study of 7 pregnant mothers infected with COVID-19 between Jan 1st and Feb 8th at Tongji Hospital in Wuhan, China. They were all at term (range 37/40 – 41+2/40). The mothers were all symptomatic, mainly with fever, cough, shortness of breath and diarrhoea. They all delivered via emergency caesarian section. All mothers did well.

The babies were all born with normal apgars. 4 babies were discharged home and not tested for SARS-CoV-2 and never developed symptoms (including at 28d follow up phone call. 3 children were tested, of which one was positive at age 36hrs (reported in separate study, Wang et.al Clinical infectious Diseases, but did well with no fever or cough and mild shortness of breath). The other 2 tested negative and were later discharged without complication.

Fan, CWang, SClinical Infectious DIseasesPerinatal Transmission of COVID-19 Associated SARS-CoV-2: Should We Worry?17 Mar 2020ChinaAsia2Neonatalhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa226/5809260

This is a case series of two women (both physicians) infected with SARSCoV-2 during the third trimester in late January, Wuhan China. They gained consent to collect swabs from the mother, specimens of maternal serum, cord blood, placental tissue, amniotic fluid, vaginal swab and breast milk. All the above tested negative for SARS-CoV-2 by PCR

The first neonate was isolated immediately following delivery via caesarean section, and no swabs were positive for SARS-CoV-2. The baby was treated for lung infection on day 3 due to low grade fever and “diffuse haziness” on both lung fields with lymphopaenia.

The second neonate was also delivered via caesarean section and reportedly developed mild neonatal pneumonia and lymphopaenia, treated again with antibiotics (no indication of time course). Similarly there was no evidence of vertical transmission with all products of conception testing negative, as did the infant. There were no maternal complications in either case.

This paper provides further reassurance that there is no evidence of vertical transmission, and of a relatively mild disease course for mothers. In the event of both children being treated for pneumonia but testing negative, it is hard to know if this was understandable overcautiousness or true infection. In either case, the infants did well.

Lui, WWong, ZFront. Med.Clinical characteristics of 19 neonates born to mothers with COVID-1917 Mar 2020ChinaAsia19Neonatalhttps://link.springer.com/content/pdf/10.1007/s11684-020-0772-y.pdf

This is a case controlled study of 19 women who were admitted to 2 different hospitals in Wuhan, China between 31/01/2020 and 29/02/2020. All women were in the third trimester of pregnancy with the lowest gestion at symptom onset being 35+2. Women were aged between 26-38 years with no underlying co-morbidities. 10 women were confirmed with positive results from SARS COV-2 RT PCR and 9 were diagnosed clinically. All women had CT chest changes consistent with viral pneumonia. 6 women received antiviral (umifenovir) for a 5 day course which was completed prior to delivery. All women delivered in isolated room; 18 c-sections and 1 vaginal delivery. All 19 infants were born in good condition (mean gestational age 38.6 and birthweight 3.293Kg) and separated from mother immediately after birth for a 14-day period. Neonatal throat swab, gastric fluid straight after birth, urine and stool were all negative for RT PCR on the neonate. Amniotic fluid and cord blood of 19 babies and 10 breast milk specimens were all negative. However, all neonates were formula fed. In the neonate, there was no clinical, radiological (no time point mentioned as to when the x-ray was taken) haematological or biochemical evidence of COVID 19 infection (blood tests carried out at 24 hours of life).

Results are consistent with previously published studies showing that key samples collected from mother and baby at time of delivery show no evidence of vertical transmission. The difference in this study was that blood test and chest x-ray were all normal. Zhu et al had previously published abnormal blood results (thrombocytopenia and raised LFTs) and pneumothorax and shortness of breath in neonates born to COVID 19 positive mothers. This study does not carry out antibody testing on the neonate which would be a crucial element in disproving the occurrence of vertical transmission. It also important to note that the results are only applicable to babies born in their last trimester with otherwise uncomplicated pregnancies to mothers who are otherwise healthy with no underlying co-morbidities.

Chen, YLiu, YFrontiers in Paediatrics: NeonatologyInfants Born to Mothers With a New Coronavirus (COVID-19)16 Mar 2020ChinaAsia4Neonatalhttps://doi.org/10.3389/fped.2020.00104

This is a case series of 4 mothers symptomatic with COVID-19 in Wuhan. All babies were born after 37/40 with reasonable APGARS. All babies were then isolated from their mothers and formula-fed. All tested negative for SARSCoV-2. Two babies had a rash (which sound very much like normal newborn rashes) and one had transient tachypnoea of the newborn, briefly requiring CPAP and made a full recovery. There was no evidence of vertical transmission.

Li, NYang, LMedRxIVMaternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study13 Mar 2020ChinaAsia17Neonatalhttps://doi.org/10.1101/2020.03.10.20033605

This was a case-control study (Jan 24 – Feb 29) in Wuhan, China16 women with confirmed COVID-19 pneumonia and 18 suspected cases (typical CT chest findings but PCR negative) were used as cases, and 121 women randomly selected from the same period were selected as controls, and a further were 121 selected from 2019 as controls to avoid the impact of mental stress from lockdown.Complications in mother were found in 70% in COVID19 cases – much higher than in controls. We will mainly focus on infants. 17 babies were delivered to the 16 mothers (15 singletons, one set of twins) with confirmed COVID-19. Preterm delivery was higher in the cases, with 23.5% of confirmed COVID19 mothers birthing prematurely compared to 5% of controls. However, mean gestation was still 38+2 in the cases.There was no difference in APGAR scores, no cases of vertical transmission and no neonatal complications.

Wang, SFeng, LClinical Infectious DiseasesA Case Report of Neonatal 2019 Coronavirus Disease in China12 Mar 2020ChinaAsia1Neonatalhttps://doi.org/10.1093/cid/ciaa225

This study from the US assessed the transmission of SARS-CoV-2 infection within 17 selected schools in Wood County, Wisconsin between August 31st to November 29th 2020. During the study period, the majority of students attended in-person learning (estimated 12.4% attending virtually) and infection mitigation measures were employed at all schools including mask wearing for all students and teachers, limitations on mixing between classes and between staff. Community transmission of SARS-CoV-2 in Wood County during the study period was high with test positivity ranging from 7% up to 40% from community samples.

All cases occurring in students or staff during the study period were reported. For each case, infection source was determined though case investigation conducted by the public health department or school administration. Contact tracing was carried out with close contacts required to quarantine at home with further investigation undertaken for contacts who experienced symptoms during quarantine. Surveillance testing and routine testing of contacts was not undertaken.

A total of 4,876 students attending in-person (1,529 primary and 3,347 secondary) and 654 staff were included. A total of 191 of cases were reported within schools; 133 student and 58 adults. Incidence in schools was 37% lower than in the surrounding community (3,454 vs 5,466 cases per 100,000 persons). Of 191 cases, only 7 (3.7%) were associated with in-school transmission, all occurring between students; no staff infections were linked to in-school transmission. No transmission between students and staff or between students in separate classrooms was documented. Compliance with mask wearing in classrooms ranged from 92.1% to 97.4% according to teacher survey responses.

This study adds to a growing body of data demonstrating limited transmission of SARS-CoV-2 in schools with a variety of infection mitigation measures. In contrast to a number of these recent papers, the low number of cases of in-school transmission here was observed despite high levels of transmission in the surrounding community. The authors acknowledge that the study did not include surveillance testing of children, and therefore asymptomatic transmission was not assessed, but highlight recent epidemiological data suggesting asymptomatic cases are much less likely to transmit SARS-CoV-2. Notwithstanding this limitation, the results here suggest that keeping schools open, even in the setting of moderate to high community transmission may be possible with minimal in-school SARS-CoV-2 transmission, provided appropriate mitigation strategies are employed.

Mogharab, VJavdani, FJournal of the Formosan Medical AssociationThe first case of COVID-19 infection in a 75-day-old infant in Jahrom City, south of Iran08 Mar 2020IranMiddle East1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0929664620301078?via%3Dihub
Theuring, SMockenhaupt, FMedRxivSARS-CoV-2 infection and transmission in school settings during the second wave in Berlin, Germany: a cross-sectional study21 Jan 2021GermanyEurope352Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.27.21250517v1

This article is a pre-print and has not been peer-reviewed.

Methods: This was a cross-sectional analysis of a longitudinal study conducted in Berlin, Germany during the second wave. The initial sampling took place in June 2020 during the period of low incidence and the second sampling took place during the first 2 weeks of November 2020, when the incidence was comparatively high. Schools were divided into 3 socio-economic strata and in each stratum, two districts were randomly selected. Within the 2 districts, 2 primary schools and 2 secondary schools were randomly selected: a total of 24 schools. 65% of students participated (range: 13%-96%). A brief medical history, forehead temperature, oro-nasopharyngeal swabs and finger-prick blood samples were taken from students and staff. Household members attended a mobile clinic for symptom assessment and finger-pricking. Self-collected swabs were collected with instructions given prior. Participants undergoing quarantine or isolation were visited at home. SARS-COV-2 infection was determined by RT-PCR and antibodies were detected by ELISA. For classes with detected SARS-COV-2 infection, all associated students, staff and household members were re-tested after one week via self-sampling. No re-testing was done if the positive participant was quarantined.

Results: 1119 participants in 24 schools consisting of 177 primary and 175 secondary students, 142 staff and 625 household members were enrolled. 19 participants withdrew consent (17 students and 2 staff). Median age of primary and secondary students was 11 and 15 respectively. Half of students were female, and staff were predominately mid-aged and female. (91.2% 114/125). Most household members were adults (73.8% 461/625).

Fever was present in 1.7%, 8.0% and 2.9% of primary school students, secondary school student and staff respectively. Current symptoms were reported in 15.8%, 20.1% and 21.3% respectively. The most common complaints being rhinorrhoea, headache, sore throat and cough. Symptoms in the 2 weeks preceding were reported by 60% of participants with headache (37.3% 121/324), sore throat (15.7% 51/324) and rhinorrhoea (14.8% 48/324) being the most common.

All schools implanted basic hygiene measures such as hand washing and air ventilation at least 3 times daily. 10/22 schools had a hygiene commissioner and most students and staff reportedly adhered to hand hygiene and sneezing etiquette. 18/24 classes had fixed teaching groups but mixing of classes outside of school was possible in almost all schools (22/24). 15 classes did not have facemask obligation in the classroom (15/24) but outside the classroom, it was obligatory for almost all schools (22/24).

SARS-COV-2 infection occurred in 8/24 classes affecting 1-2 individuals per class (6 primary school students; 2 in one class and 3 secondary school students; 2 in one class). All positive participants were isolated within an average of 3 days (1-5 days). Schools being the origin of infection was possible in 3/8 households.

6/9 infected students were asymptomatic, and prevalence increased with inconsistent face mask use in school or during contact outside of school. No new school-related infections of students or staff were observed at re-testing which was conducted 1 week after a positive test. However, there were 7 new infections detected among individuals associated with the affected classes and not included in the study. The attack rate in households connected to positive classes was 1.1%

Discussion:

Only 3/8 household infections originated in schools which suggests that attending lessons may not be the primary reason for infection. An increase in prevalence was observed in those who had inconsistent facemask use, case contacts outside of school, those who attended social gatherings and walked to school in groups. Therefore, the closure of schools may decrease the transmission of the virus amongst students and staff; however, this is related to the events preceding and proceeding lessons. One member of staff was infected (1/140) which is in line with other studies and argues against the increased risk of infection for staff in schools. The study did find that the majority of students who tested positive were from the low socio-economic stratum. Insufficient social distancing related to household crowding and the inability to effectively isolate may be a contributing factor to increase the transmission of the virus.

The limitations to the study include the use of self-swabs in household members. Although instructions were provided to individuals, the possibility of incorrect method of sampling cannot be completely excluded. In addition to this, selection bias could have been an issue as participation was voluntary and patient responses to questionnaires were not evidenced or confirmed. Those who knowingly participated in social gatherings and did not adhere to IPC guidance may have incorrectly completed some questions to avoid embarrassment; this would have resulted in incorrect data and results. However, it is understandable that this factor would have been difficult to control. The study has however reduced the possibility of bias through the random selection of schools across Berlin, the use of laboratory methods such as RT-PCR and ELISA.

Atherstone, CNeatherlin, JMMWR Morb Mortal Wkly RepSARS-CoV-2 Transmission Associated with High School Wrestling Tournaments — Florida, December 2020–January 202129 Jan 2021USANorth America130Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm7004e4

Amongst the mass of ‘big data’ reports on transmission of Covid-19, anecdotal case studies can still be illuminating. This brief report from the Centers for Disease Control (CDC) in the US, shows how a single case can play out when infection control restrictions are inadequate.

In December 2020, high school wrestling tournaments were still permitted in the state of Florida. Two such tournaments were held on 4th and 5th December, and just one of the participants tested positive for SARS-CoV2 on PCR, on 7th December. Ten high schools from two counties had participated, involving 130 people (118 students and 12 supervising adults). Public Health officials tested 54 (41%) of these, and 38 (70%) were positive. Of these, 446 close contacts at home and school were identified. 95 (21%) of these were tested, and 41 (43%) were positive. Eight were asymptomatic. Attack rates were highest amongst fellow wrestlers (20%), and household contacts (30%). One adult contact died. As a result of the ensuing isolation and quarantine of all these contacts, an estimated 1700 in-person school days were lost. In the county with the most participating schools, this one outbreak had the effect of lifting it into the highest category for SARS-CoV-2 transmission.

Before this episode, contact sports in Florida were permitted with mitigating precautions – face-coverings, distancing etc. except when actually wrestling, which this study has demonstrated was ineffective at preventing transmission.

Reukers, Dvan den Hof, SmedRxivHigh infection attack rates of SARS-CoV-2 in Dutch households revealed by dense sampling26 Jan 2021NetherlandsEurope117Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.26.21250512v1.full

This article is a pre-print and has not been peer-reviewed.

Methods: This is a prospective cohort study of household secondary attack rates of SARS-CoV-2, carried out in the region of Utrecht (the Netherlands) between 24th March and 6th April 2020.

Population: Complete households were enrolled and followed-up for 4 to 6 weeks. Index cases (any adult testing positive for SARS-Cov-2 on an upper respiratory tract swab, with at least one child in their household) were sourced from reports from the local Public Health Service and contacted by research staff to request enrolment in the study. Persons living in the same household as the index case -except for infants under 12 months of age- were defined as household contacts using the following strata: adults: ≥ 18 years of age, adolescents: 12 to 17 years of age and children: 1 to 11 years of age.

Study procedures: Three home visits were scheduled during the follow-up period. Demographics and baseline characteristics of the household contacts were recorded through study questionnaires at visit 1; symptom diaries were filled-out by the household contacts for two-weeks after the first study visit, and further follow-up was completed 2 to 3 weeks (visit 2) and 4 to 6 weeks (visit 3) after enrolment to ascertain any history of symptoms suggestive of COVID-19 since the last contact. The day of symptom onset, as reported by the study participants, was set as the first day of illness. Transmission within the household was excluded if household contacts reported day of symptom onset 2 weeks prior the first day of illness (or first positive test result) of the index case. Naso (NP) and oropharyngeal (OP) swabs were collected at enrolment and at visit 2. Serum, oral fluid, and faeces were collected at each home visit. Detection of SARS-CoV-2 in NP, OP, oral fluid and faeces was carried out by RT-qPCR; SARS-Cov-2 antibodies in serum were detected using a commercial ELISA.

A primary case was defined as the most likely first case on the household, based on laboratory confirmation, symptom onset and travel history. A household contact was defined as primary case if SARS-CoV-2 infection was laboratory confirmed and the symptom onset occurred between 2 and 14 days before the index case.

Statistical analysis: Secondary attack rates were estimated excluding the index case but including the primary case through logistic regression, using generalised estimating equations with household as the unit of clustering. A stochastic SEIR transmission model was fitted to estimate transmission routes in the house.

Results: Fifty-five households with 242 participants (all household members) and 55 index cases were included. Among 187 household contacts, 70 were children aged between 1 and 11 years and 46 were adolescents, between 12 and 17 years of age. No transmission was detected in 17 households and in 11, every member got infected with SARS-CoV-2. Not every index case was the primary case (n = 10/55).

Laboratory confirmed SARS-Cov-2 infection was detected in 21/70 children (30.0%), 21/46 adolescents (45.7%) and 36/71 adults (50.7%). The overall household secondary attack rate was 43% (95% CI 33%-53%), being lower in children (35%, 95% CI: 24%-46%) compared to adolescents (41%, 95%CI: 27%-56%) and adults (51%, 95%CI: 39%-63%). These findings were confirmed by transmission models.

In the univariate analysis, no significant association was found between sex, household size, severity of the infection of the index case and being a healthcare worker. In a multivariate analysis adjusted by age group and sex, being a child was associated with decreased probability of infection (95%CI not provided; p = 0.006). Severe cases (i.e. a history of dyspnoea, visit to the emergency department or admission to hospital) were described in adults (7/36; 20.0%) and adolescents (2/21; 10.0%) but not in children.

Considerations: transmissibility of SARS-Cov-2 within households was investigated using a prospective cohort study and frequent testing. A dense sampling protocol and a follow-up period of at least 4 weeks may explain high household secondary attack rates across all the age groups. Children remained less susceptible compared to adolescents and adults.

Kubiak, JMYang, YJAJOGSARS-CoV-2 serology levels in pregnant women and their neonatesPre-proof. Accepted 21 JAN 2021USANorth America39Neonatalhttps://doi.org/10.1016/j.ajog.2021.01.016

The impact that Sars-CoV-2 infection has on pregnant women and their fetuses has been the focus of many reports over the past year or so. Inferences drawn from existing data are somewhat at variance: a recent RCM/RCOG report states that “there is no good quality evidence comparing the risk of severe COVID-19 infection in pregnant women and non-pregnant women of the same age”1 while a recent information video on the RCOG web-site advises that “if a pregnant woman does have coronavirus she does not appear to be more likely to be more severely unwell compared to others”.2 In contrast, in the US, a CDC review of the evidence states that “intensive care unit admission, invasive ventilation, extracorporeal membrane oxygenation, and death were more likely in pregnant women than in nonpregnant women”.3 There is also debate about the extent to which materno-fetal “vertical” transmission occurs.4

The paper by Kubiak et al et al is a report of a study which measured “semi-quantitatively” serum IgG and IgM concentrations in pregnant women and their newborn babies. The study was conducted at the Weill Cornell Hospital in New York from March to May 2020, after universal SARS-CoV-2 antibody testing had been introduced for all women giving birth at the hospital. At that time 10-15% of all parturient women in the city were positive to SARS-CoV-2 RT-PCR testing. A total of 88 women were included – 67 who tested positive as a result of universal screening and 21 who were tested “due to suspicion of SARS-CoV-2 infection or exposure”. Umbilical cord blood was also taken from the babies of these mothers for SARS-CoV-2 antibody testing. The gestational ages of the pregnancies is not given for either group. Of the 88 women 10 were found to have IgM antibodies only, 24 had both IgM and IgG antibodies and 54 had IgG antibodies only.

For the first part of the study a retrospective “chart review” was performed to document any symptoms reported by these mothers at the time of, or prior to, delivery; the mothers were then categorised as either “symptomatic” (37/88 = 42%) or “asymptomatic” (51/88 = 58%). It was found that both symptomatic and asymptomatic pregnant women mounted a detectable IgM and IgG response but IgG levels were significantly higher in the symptomatic mothers compared with asymptomatic mothers.

The second part of the study sought to determine the time course of antibody appearance and disappearance in symptomatic women. Information concerning the timing of the onset of symptoms was available for only 34 of the women. Analysis of the 34 available data points showed that IgM levels peaked at about 15 days after the onset of symptoms and IgG levels started to peak at about 30 days, some of which “could last over 90 days”.

For the neonates, umbilical cord blood was available for 50 of the original 88 mothers. Of these, 39 (78%) had detectable antibodies, all of which were IgG: 24 were born to mothers who were IgG positive, 14 to mothers who were both IgM and IgG positive and one to a mother who was IgM positive at a low concentration. All 39 babies were negative on RTR-PCR testing for SARS-CoV-2. It was further found that:

- the mothers of neonates with SARS-CoV-2 specific IgG had significantly higher IgG levels than the mothers of neonates without IgG

- there was a positive correlation between the IgG levels in the cord blood and the maternal serum IgG levels

- maternal IgG levels (but not IgM levels) and oxygen supplementation were predictive of cord blood IgG levels.

The authors comment that, first, the pattern and timing of the appearance of IgG and IgM in the serum of pregnant women mirrors that of the general population and, second, that an immune response is mounted in asymptomatic pregnant women, albeit weaker than in those who are symptomatic, again, similar to the general population. They suggest that a “certain level” of IgG in the mother may be necessary for sufficient antibody to be transferred to the fetus.

The significance of these findings, particularly with regard to protection of the fetus, is uncertain. The study cohort was small and no information concerning outcomes for the neonates or clinical details concerning the mothers or the pregnancies was provided. The authors acknowledge that a prospective longitudinal study is required to investigate the course of antibody levels in mothers contracting SARS-CoV-2 infection at different stages of pregnancy and to determine whether they are relevant to neonatal outcomes. They speculate that the “classic” patterns of IgG and IgM responses seen, which are similar to those reported in previous vaccination studies of pregnant womenn relating to other infections, may provide reassurance for those involved in future studies of SARS-CoV-2 vaccination in pregnant women.

Buonsenso, DValentini PmedRxivPreliminary Evidence on Long COVID in children26 Jan 2021ItalyEurope129Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1

This article is a pre-print and has not been peer-reviewed.

This report of an ongoing cross-sectional study investigating the persistence of symptoms after COVID-19 in children in Italy was posted on medRxiv on 26th January 2021.

Study population: 129 children aged 18 years and under diagnosed with microbiologically-confirmed COVID-19 at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (the largest hospital in Rome) between March and November 2020 were included in the study. 62 (48%) female; mean age 11 years. Reported ethnicity: white 89%, black 3%, Latino/Hispanic 7%, Arab 1%. Comorbidities: 13/129 (10%) neurology, 6/129 (5%) dermatology, 5/129 (4%) asthma, 4/129 (3%) allergic rhinitis, 3/129 (2%) obesity, 1/129 (1%) each of cardiology, gastroenterology, oncology, immunology, genetic disorder, rheumatology.

Severity of acute phase of COVID-19 in cohort: 33/129 (25.6%) were asymptomatic and 96/129 (74.4%) were symptomatic at the time of initial illness. 6/129 (4.7%) were hospitalised. 3/129 (2.3%) were admitted to PICU. The high hospitalisation and ICU admission rate indicate the symptomatic children represent the more severe end of the clinical spectrum of disease.

Complications after acute phase of illness in cohort: 3/129 (2.3%) were diagnosed with MIS-C and 2/129 (1.6%) developed myocarditis. 3/129 (2.3%) were diagnosed with asthma.

Collection of data: Caregivers were interviewed about their child’s health after COVID-19 using a questionnaire developed by the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) Global Paediatric Long COVID Working Group for the evaluation of persisting symptoms. Interviews were carried out by two paediatricians from 1 September 2020 to 1 January 2021, either online or in the outpatient department. Time from COVID-19 diagnosis to interview: < 60 days 31/129 (24%), 60-119 days 30/129 (23%), 120 days or more 68/129 (53%). The average time from diagnosis to interview was 162.5113.7 days. The study is designed to continue periodic assessments until 24 months after COVID diagnosis and to include household members of different age groups, with or without COVID-19, as a control group.

Persistent symptoms at follow-up: 54/129 (41.9%) had no symptoms at interview, 46/129 (35.7%) had 1 or 2 symptoms and 29/129 (22.5%) had 3 or more symptoms. The most frequently reported symptoms were insomnia (24/129, 18.6%), respiratory symptoms (19/129, 14.7%), nasal congestion/rhinorrhoea (16/129, 12.4%), fatigue (14/129, 10.8%), muscle pain (13/129, 10.1%), joint pain (9/129, 6.9%) and concentration difficulties (13/129, 10.1%). Symptoms were more common in symptomatic or hospitalised children, but they were also described in those individuals who were asymptomatic during the acute phase. 29/68 (43%) of children assessed at 120 days or more after diagnosis were still distressed by these symptoms. A detailed table in the report lists occurrence of different persisting symptoms at follow-up interview categorised into asymptomatic/symptomatic patients at time of acute illness, hospitalised or not and number of days from initial diagnosis.

The major limitation of this study is a lack of control group, especially of healthy children. Respiratory symptoms and nasal congestion are extremely common in children of all ages, and many of the other reported symptoms are vague and might be more common to children during emotionally stressful times such as the pandemic and lockdowns. Reports of prolonged symptoms in children who initially had no symptoms at all are especially difficult to interpret.

Schoeps AZanger PmedRxivCOVID-19 transmission in educational institutions August to December 2020, Rhineland-Palatinate, Germany: a study of index cases and close contact cohorts08 feb 2020germanyEurope14594Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.04.21250670v1

This is a preprint that has not undergone peer review.

Introduction: This is a case control study of transmission of Covid 19 in educational and daycare settings from August to December 2020 in the Rhineland-Palatinate region of Germany. This area is one of 16 Federal states of Germany with a population of 4.1million people. Schools were open after summer break from August 2020 with infection control measures and were closed on December 16th due to a hard lockdown in the region.

Methods: Covid 19 cases included in this study, if it was in a child or teacher who attended a school or day care centre, for at least one day of the infectious period. Cases were notified to the district public health authority (DPHA) and contact tracing commenced. All “Category 1” contacts were offered testing. In general terms in Germany, Category 1 contacts are regarded as someone who stayed <1.5 meters for 15 minutes or longer with a positive case, or was in the same room (i.e. irrespective of distance) for 30 minutes or longer. For schools and educational settings Category 1 contact is “all persons in crowded or unclear situations, or when resources at the DPHA do not allow for an individual risk assessment”.

A “secondary case” was defined as having contact with the index case and testing positive within the quarantine period of the index case. Of note contact persons and secondary cases not attending the educational setting were not included in this study. Secondary attack rates (SAR) defined as the proportion of secondary cases among contact persons of a given index case.

Results; 16% of the 74,733 COVID-19 cases notified in Rhineland-Palatinate in 2020 were younger than 20 years, which approximated the population proportion of 18·3% in this age group. 1,954 notifications fitted the criteria for the study, with 84% of which were notified during the study period. 784 independent notified index cases attending an educational institution prior to diagnosis of a SARS-CoV-2 infection (591 students/children, 157 teachers, 36 unknown role). Full information on PCR-testing was available for 441 of these index cases with 14,591 contact persons (median 25 contacts per index case, IQR 17-40).

Secondary attack rate was higher for teacher > student/child, IRR=3·17, p<0·001), and in day centres > secondary schools IRR=3·23, p<0·001), SAR was lower in pre-/asymptomatic < symptomatic ( IRR=0·47,p=0·02).

Including the further 343 index cases with complete information on secondary cases, but missing information on number of contact persons tested, cluster level risk was also associated more with teachers, and day care centres. 83% of index cases led to no in school secondary cases. Average cluster size was 2.5 cases.

Discussion: The authors conclude low transmission of Covid 19 cases in educational settings under preventative measures with high community incidence rates. They found approximately 1·3% of school contacts of an index case will become positive. The risk of causing a cluster and the mean number of secondary cases was higher when teachers were identified as index cases compared to students. They recommend increase attention to work place safety in an educational and day care setting with a focus on contact between teachers.

Ouldali, NAngoulvant, FJAMAAssociation of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children01 02 2021FranceEurope111Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2776054

To date there have been no comparative data to inform optimal therapy for MIS-C / PIMS-TS with treatment largely based on Kawasaki disease guidelines using IVIG with or without steroids. In this retrospective cohort study of children with MIS-C from France, treatment outcome with IVIG & methylprednisolone was compared to that of IVIG alone.

All cases of MIS-C fulfilling the WHO criteria reported to the French national surveillance system between 1st April and 22nd October 2020 were included; reporting of suspected MIS-C cases was mandatory in France from April 2020. The primary endpoint was treatment failure defined as persistent fever at 48 hours from treatment initiation or recrudescence of fever within 7 days. Children treated with IVIG and methylprednisolone as initial therapy were compared with those receiving IVIG alone using. To account for differences between the groups, propensity score matching based on baseline clinical data (age, sex, co-morbidities, hospital, symptoms, cardiac dysfunction, CRP, PICU admission before treatment and positive SARS-CoV-2 serology) was used to compare the two treaments (1:2 ratio).

A total of 111 patients with confirmed MIS-C were identified, 106 who received treatment with IVIG with or without methylprednisolone. Median age was 8.6 years (IQR 4.7-12.1), 94% had gastrointestinal symptoms, 47% had left ventricular dysfunction, 67% were initially admitted to PICU, 41% were received haemodynamic support and 26% ventilatory support. A total of 34 children received initial treatment with IVIG & methylprednisolone and 72 with IVIG alone. The methylprednisolone dose used was 0.8-1mg/kg twice daily for 5 days (30 of 34 children) or 15-30mg/kg daily for 3 days (4 of 34 children). The children receiving combination therapy had a more severe initial presentation and were more likely to have ventricular dysfunction (65% vs 39%) be admitted in PICU (91% vs 58%) and be receiving haemodynamic support (62% vs 32%).

Treatment failure occurred in 9% (3/34) of children treated with IVIG & methylprednisolone compared with 51% (37/70) treated with IVIG alone. In the propensity score matched analysis (32 children in the IVIG & methylprednisolone matched with 64 children with IVIG alone), combination treatment was associated with a 28% absolute reduction in treatment failure (9% vs 38% OR 0.25 (95% CI 0.09-0.70)). Similarly, combination therapy was associated with a lower odds of requiring second line treatment (OR 0.19 (95% CI 0.06-0.61)), subsequent haemodynamic support (OR 0.21 (95% CI 0.06-0.76)) and development of new left ventricular dysfunction (OR 0.20 (95% CI 0.06-0.66)). On follow up to 6th January 2021 no long-term cardiovascular complications of persistent inflammatory syndrome had been reported.

The findings of this study suggest that initial treatment with methylprednisolone in combination with IVIG leads to improved outcomes in children with MIS-C compared with IVIG alone.

Smith, BWang, DmSphereSeroprevalence of SARS-CoV-2 antibodies in children and adults in St Louis, Missouri, USA03 FEB 2021United StatesNorth America555Epidemiology - Transmissionhttps://doi.org/10.1128/mSphere.01207-20

Aim: Serological studies provide information on the risk for transmission and the immunological state of the population. The aim was to determine in a sero-prevalence study, the extent of SARS-CoV-2 infection in adult and paediatric cohorts from the St. Louis metropolitan area early in the pandemic.

Methods: The adult serum/plasma samples were residual samples sent to Barnes-Jewish Hospital for vitamin D testing between 27 April 2020 and 12 May 2020. Residual paediatric specimens came from either the emergency department or outpatient clinics at St. Louis Children’s Hospital between 14 April 2020 and 8 May 2020.

An in-house enzyme-linked immunosorbent assay (ELISAs) was used using the spike protein of SARS-CoV-2 to estimate IgG seropositivity to SARS-CoV-2.

Results: The paediatric cohort had 555 children (286 females, 269 males) with a median age of 9 years (range, 2 days to 17 years). Adult samples included 503 individuals (296 females, 207 males) with a median age of 61 years (range, 18 years to 93 years)

A Bayesian regression model was used that accounted for test performance. The estimated seroprevalence rates in adults was 3.11% (95% CI, 0.92% to 5.32%) and in children was 1.71% (95% CI, 0.04% to 3.38%). Further estimates were given per age band. There was lower estimated seropositivity in children under 5 years than in adults in any age band, and none of the samples from children under 4 years of age were identified as seropositive.

Authors’ conclusions: Children and adults are susceptible to SARS-CoV-2 infection and develop antibody responses. The results are consistent with other evidence that young children may be infected by SARS-CoV-2 at a lower rate than adults. The results are not generalizable to the general St. Louis population as the samples were taken from medical patients early in the pandemic and given that the dates overlapped with a stay-at-home order this may have led to the samples originating from sicker patients as routine medical visits were significantly curtailed.

Comments: this seroprevalence study is of limited value as the samples came from a group of patients attending hospital clinics and as such are unlikely to represent the general population of St Louis.

Choe, YJLee, SWEmerg Infect Dis 27(4).Surveillance of COVID-19-Associated Multisystem Inflammatory Syndrome in Children, South Korea.04 Feb 2021South KoreaAsia3Clinical - PIMS-TShttps://wwwnc.cdc.gov/eid/article/27/4/21-0026_article

An early release report of a prospective national surveillance system from S Korea, between May-Nov 2020. During this time, S Korea had 2287 cases of SARS-CoV-2 in children aged 0-19 years. 9 cases of possible MIS-C were reported, and 3 were confirmed by the Case Assessment Committee as having evidence of COVID-19 exposure (3-4 weeks previously).

Age range 11-14 years. Two male and 1 female. None had pre-existing medical conditions. All had GI symptoms/signs, hypotension, “marked” leucocytosis, and “elevated” inflammatory markers (no detail given). 2 had mucocutaneous symptoms/signs. Cardiac involvement: L coronary a. dilatation, mitral regurgitation, LV dysfunction. Pulmonary involvement: oedema, effusion. Abdominal involvement: mesenteric lymphadenitis, hyperechoic liver, hypertrophic gall bladder.

All 3 received IVIg and aspirin, and 1 was subsequently given Anakinra and pulsed methylprednisolone. 2 were admitted to ICU and given inotropes. None required mechanical ventilation. Duration of hospitalization 10-19 days. Duration of ICU stay 6-7 days. No deaths and no major sequelae reported to date.

This survey suggests that the increase in Kawasaki Disease (KD)-like presentations associated with SARS-CoV-2 seen in Europe and the US, where KD has a relatively low incidence, is not seen in S Korea, where KD has a relatively high incidence.

In previous studies, GI involvement in KD has been associated with a higher risk of failure to respond to IVIg therapy, and this was seen in 1 of the 3 cases of MIS-C reported here. The authors suggest this association merits further study.

Gillespie DZenilman JmedRxivThe Experience of Two Independent Schools with In-Person Learning During the COVID-19 Pandemic29 Jan 2021USANorth AmericaEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.26.21250065v1

This article is a pre-print and has not been peer-reviewed.

This pre-print, posted on 29 January 2021, reports the experience of 2 large independent K-12 schools in the United States during the first term of the 2020-21 academic year, from August to December 2020, as they implemented a range of SARS-CoV-2 mitigation strategies, including periodic universal testing.

Background: Schools closed across the US from March 2020 because of the COVID-19 pandemic and transitioned to virtual learning. Due to continuing high levels of infection over summer 2020, most school districts delayed in-person education or used a hybrid virtual/in-person approach for the first term of the 2020-21 academic year. However, the two K-12 independent schools (5 to 18 year olds) investigated in this report, located in the South (School A, 2320 students and staff) and Mid-Atlantic (School B, 1200 students and staff), returned to in-person learning for the term, using a collaborative approach following the Centers for Disease Control and Prevention (CDC)’s guidelines designed to prevent the transmission of SARS-CoV-2, while also implementing aggressive laboratory screening similar to that which colleges and universities were using. The two school reopening plans, developed in consultation with medical advisers, had some differences, but were based on 4 major elements: stakeholder engagement, physical infrastructure, policies and operations, and laboratory screening and testing of students and staff for SARS-CoV-2.

Interventions undertaken to sustain in-person education in both schools: Stakeholder engagement included a community contract (implied for School A and electronically signed by parents for School B) covering agreement to avoid large gatherings, quarantine the entire family if one member had a positive test, report COVID-19 symptoms proactively to the school and reduce in-community activities. Physical infrastructure measures included spacing of desks, staggered class starts, block scheduling, limited numbers in restrooms, hand sanitising, disinfection of frequent-touch surfaces (including UV light disinfections of classrooms at school B at the end of the day), MERV air filters, window opening in classrooms and buses, and temperature checking at main school entrances. Changes in policies and operations included social distancing at drop-off, mask wearing (removed only for eating and drinking), cancellation of most extracurricular activities (varsity sports continued at School A, but with regular testing of players and small pod training), no conversation during lunch (except if eating outside, movies shown during lunch to limit talking), no all-school congregating, quarantine policies off campus of 10 days (School A) and 14 days (School B) for positive pupil and 14 days (both schools) for family of positive pupil. Both schools had detailed contingency plans for transitioning to virtual learning if necessary, using metrics such as community positivity rate, in-school positivity rate and presence of in-school transmission.

SARS-CoV-2 testing procedures during the term: A case was defined as a person with a positive laboratory test for SARS-CoV-2. Testing protocols differed slightly between schools and evolved during the term based on testing options, availability and logistics. School A conducted 9 rounds of universal testing (UT) of the entire student body and staff from August to December 2020 (number of tests conducted in each round varied from 1934 to 2687 tests); School B conducted 8 rounds (from 743 to 1666 tests per round). Both schools also tested the entire school population after the Thanksgiving break. Both schools transitioned from nasal swab PCR to saliva-based tests as the term progressed, enabling more frequent testing. Saliva specimens were pooled (up to 24 specimens per pool); if a pool was positive individual samples were tested. Each universal testing event required 2-3 days to implement and obtain all results. Both schools also tested contacts of positive cases and athletes. School B also conducted twice weekly sewage testing, but these results were not useful in real-time, because of delays in obtaining results and the difficulty in interpreting them in a 1200 person school. Contact tracing for positive cases was implemented by school officials in partnership with local health authorities to determine the likely source of exposure. Parents were encouraged to report any test results obtained outside school.

Categorisation of positive cases: Positive cases were grouped into 3 categories: Self-reported (SR) if the person was symptomatic or had a known contact and was tested at school or independently; universal test (UT) if the person was asymptomatic and tested as part of regular screening; or converted during quarantine (CDQ) if the person was identified as a known contact due to UT or contact tracing and was quarantining when they tested positive. A cluster analysis was used for each case to identify common linkages, source of introduction and potential route of transmission. Those who tested positive were grouped into clusters based on the site of exposure (family, community or school). A cluster was defined as any event involving 2 or more linked cases in school. The average reproductive rate was calculated as the number of secondary cases generated by contact with the infectious person. It was assumed that each outbreak represented only one generation of transmission (assumed to be valid since the overall infection rate was low).

Number of positive cases during term: School A had 112 cases (4.9% of students, faculty and staff) between 5 August and 20 December 2020. Categorised as: SR 30/112 (27%), UT 60/112 (54%), cases through contact tracing based on UT-identified cases 22/112 (20%). 11/112 (10%) were identified during the initial testing from 5 to 10 August, i.e. before term started. 59/112 (53%) were identified during the 3 weeks following the Thanksgiving break. The largest outbreak at School A was linked to a non-school sanctioned, sports-related event. School B had 25 cases (2% of students, faculty and staff) between 24 August and 20 December 2020. Categorised as: SR 3/25 (12%), UT 21/25 (84%), cases through contact investigation resulting from a UT case 1/25 (4%). In both schools, cases peaked in the period after school breaks (summer holiday, fall break, Thanksgiving break).

Presence of symptoms in different age cohorts: Combined for both schools: lower school students (grades 1-6): 1/39 symptomatic (3%); middle school students (grades 7-9): 5/20 symptomatic (25%); upper school students (grades 10-12): 5/57 symptomatic (9%); adults: 10/21 symptomatic (48%). No cases required hospitalisation.

Community incidence and positivity rates: Community incidence rates correlated with school infections (Pearson correlation 0.9, p<0.01 for School A; 0.8, p<0.05 for School B). There was no correlation between community positivity rates and in-school introduction (correlation 0.57, p>0.1 for School A; 0.27, p>0.1 for School B). Using multipliers based on contemporaneous seroprevalence studies, in-school rates were consistently below community infection rates.

Virus introductions into each school: 45 cases were determined to have been introduced into School A and 24 into School B; these numbers exclude positive cases from before school started (round 1 of UT), SR cases occurring more than 1 week before UT, all cases linked with an off-campus, non-school sanctioned event over Thanksgiving break at School A, all secondary cases and all SR cases occurring after the last round of UT (this probably underestimates transmission, since only cases with tracking data are analysed).

In-school transmission: In School A the 45 introduced cases (as defined above) resulted in 5 secondary infections; in School B the 24 introduced cases resulted in 1 secondary infection. Combined, there were 6 secondary cases from 69 traceable introduced cases (9%). Chance of an outbreak per infected individual: School A 5/47 (11%, 95% CI 4-22%), R0 0.49, overdispersion parameter k 0.05 (95% CI 0.014-0.15); School B 1/22 (4.5%, 95% CI 0.5-19.3%), R0 0.02, overdispersion parameter k 300 (not overdispersed). Chance of an outbreak per introduction: School A 5/45 (11%, 95% CI 4-23%), R0 0.5, overdispersion parameter k 0.05 (95% CI 0.01-0.14); School B 1/24 (4.2%, 95% CI 0.5-17.9%), R0 0.04, overdispersion parameter k 200 (not overdispersed). 72% of in-school transmission cases in School A were associated with noncompliance with school mask wearing rules. There was no evidence of student-to-teacher or teacher-to-student transmission in either school.

Outbreak clusters: There were 6 outbreaks in School A, with a minimum number of 3 secondary cases. The largest outbreak had 28 cases and was traced to an off-campus party. The relative lack of single case transmissions, but many non-transmission events, suggests an overdispersed chance of transmission in School A. School B was not overdispersed, since the only outbreak had a single transmission event. In 6/7 clusters across both schools, there was clear noncompliance with mitigation protocols (e.g. close proximity in classrooms or cafeteria, off-campus socialising). Major off-campus sources identified were family exposure (including siblings returning from college) and off-campus activities including parties and other gatherings. However, the source of the majority of infections could not be determined.

Conclusions: School leadership acknowledged that introductions related to community exposures outside school would occur at community rates, but wanted to be certain that schools did not play a role in amplifying cases, i.e. that in-school transmission was limited. Both schools were able to successfully maintain in-person schooling for the full term, despite rising community numbers and other neighbouring school closures. The majority of cases identified did not lead to larger chains of transmission. Outbreaks mainly occurred when mitigating protocols were not followed, in and out of school. There was no correlation between in-school infections and community positivity rates, but there was a correlation with community incidence rates. In the schools, positivity rates (positive tests/total number of tests) and case incidence (positive tests/population) were the same, because everybody was tested; whereas only a small proportion of the community is tested. Transmission (secondary infections) was bimodal, with 91% of traceable introduced cases having no secondary transmission and 9% of introduced cases accounting for all identified clusters. The rate of positive cases was highest following school breaks and when there was clear evidence of students attending social or family events in the community, and lowest when in-person schooling continued uninterrupted. In-school infections peaked each time students returned from a prolonged school break. Few cases occurred in staff and these all seemed to have had out-of-school introduction sources. There were no severe cases among students or staff; most cases were asymptomatic and none required hospitalisation. R0 estimates were consistently below 1, indicating that in-school transmissions did not represent sustainable outbreaks. The testing protocols served as a gauge of the effectiveness of mitigation protocols, identified risky activities, enabled school officials to adjust protocols in real time and provided reassurance for families and faculty. Temperature screening was not useful, because most cases were asymptomatic. Sewage surveillance was also not useful. The major limitation of this data is that it reflects the experience of two schools with substantial financial and organisational resources, which are not available to most schools; the school populations are likely to have a lower burden of chronic disease and better access to medical care, so results may not be generalisable. Additionally, the testing protocols changed over time and initially began with lower frequency of testing than ideal, so school transmissions might have been missed during this period. Testing frequency increased when less expensive and easier to implement pooled saliva testing became available. Challenges include asymptomatic infections, out-of-school social activities, violation of face mask rules and return to school after extended breaks.

Deep, ARamnarayan, PCrit Care MedAcute Kidney Injury in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic: Experience from PICUs across United Kingdom01 Dec 2020United KingdomEurope116Clinical - PIMS-TShttps://pubmed.ncbi.nlm.nih.gov/33044282/

Introduction: The authors present a multicenter observational study from 24 PICU’s in the United Kingdom, 15 of which provided data for the study on 116 children. Their aim was to study the prevalence, evolution, and clinical factors associated with acute kidney injury (AKI) in children admitted to PICUs with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 (PIMS-TS) between March 14, 2020, and May 20, 2020.Initial presenting features of 78 of these patients have been reported previously, although no details regarding AKI in this cohort have been published previously. Cardiac features in 6 and renal features in 23 patients have also been presented in single-center reports.

Results: De-identified data collected as part of routine clinical care were analyzed. All children were diagnosed and staged for AKI based on the level of serum creatinine above the upper limit of reference interval values according to published guidance. Severe AKI was defined as stage 2/3 acute kidney injury. Uni- and multivariate analyses were performed to study the association between demographic data, clinical features, markers of inflammation and cardiac injury, and severe AKI.

Any-stage AKI occurred in 48 of 116 patients (41.4%) and severe AKI in 32 of 116 (27.6%) patients, which was mostly evident at admission (24/32, 75%). In univariate analysis, body mass index, hyperferritinaemia, high C-reactive protein, Pediatric Index of Mortality 3 score, vasoactive medication, and invasive mechanical ventilation were associated with severe AKI. In multivariable logistic regression, hyperferritinaemia was associated with severe AKI (compared with non-severe AKI; adjusted odds ratio 1.04; 95% CI, 1.01–1.08; p = 0.04). Severe AKI was associated with longer PICU stay (median 5 days [interquartile range, 4–7 d] vs 3 days [interquartile range, 1.5–5 d]; p < 0.001) and increased duration of invasive mechanical ventilation (median 4 days [interquartile range, 2–6 d] vs 2 days [interquartile range, 1–3 d]; p = 0.04).

Conclusions: The authors found severe AKI occurred in just over a quarter of this cohort of children admitted to United Kingdom PICUs with PIMS-TS. They concluded that the prevalence of AKI in PIMS-TS is high, and most patients who develop AKI do so either at admission or within 48 hours. Factors associated with severe AKI include high BMI, raised CRP, hyperferritinaemia, and high PIM3 score at admission. Hyperferritinaemia was significantly associated with severe AKI. Severe AKI was associated with increased duration of stay and ventilation. The authors conclude though short-term outcomes for AKI in PIMS-TS for this cohort appear good, long-term outcomes are unknown and less well understood, indicating the need for close follow-up by a multidisciplinary team.

Cohen C AValkenburg S AmedRxivSARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection02 Feb 2021Hong KongAsia24Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.02.02.21250988v1.full-text

SARS-CoV-2 infections in children are widely reported to cause mild illness. The authors at the University of Hong Kong and Hospitals (Kowloon West Cluster (KW/EX-20-039 (144-27)), Kowloon Central / Kowloon East 136 cluster (KC/KE-20-0154/ER2) and HKU/HA Hong Kong West Cluster (UW 20-273, UW20- 137 169), Joint Chinese University of Hong Kong) carried out an ex-vivo quantitation of cellular T and B cell response and monocyte response to coronavirus infection in children and adults seeking to explain possible reasons for the observed factor.

Assessed were 24 children (aged 2-13 yrs) and 45 adults aged ( 20-65 years), symptomatic and asymptomatic but SARS-CoV-2 RT-PCR confirmed, admitted to Hong Kong Hospitals ( 1- 14 days) whom they followed up through discharge (6-60 days) and through convalescence (61-180 days). Asymptomatic blood donor SARS-CoV-2 RT-PCR negative adults were used as controls.

Nine (38%) children and 9(20%) adults were asymptomatic. They had 55 early acute samples and 95 longitudinal samples available for the ex-vivo analysis from 46 subjects.

Using observation of the induced gamma interferon (IFNγ+), they assessed CD4+ and CD8+ T cell response to structural, accessory and non-structural SARS-CoV-2 proteins and compared those responses between SARS-CoV-2 positive and negative adults and with SARS-CoV-2 positive children. They found that the majority (94%) of SARS-CoV-2 infected adults gave a higher IFNγ+ CD4+ T cell induced response to structural proteins than 79.4% SARS-CoV-2 positive children (p=0.0031) and 50% of SARS CoV-2 negative adults (p=<0.01). Infected children had significantly reduced CD8+ recposnes to SARS-CoV-2 structural or non-structural proteins when compared to both SARS-CoV-2 positive adults and SARS-CoV-2 negative adults. Infected children had reduced total monocyte reaction and reduced inflammatory type monocytes. They also showed bone marrow monocyte recruitment comparable to SARS-CoV-2 negative adults comparted to infected aults.

The authors observed stable CD4+ T call responses over time but increasing CDF8+ T cell responeses with age. CD8+ T cell response therefore appears to be less experienced and maturted in children at the time that they may become infected with SARS-CoV-2 than in adults.

Specific IgG response to SARS-CoV-2 was similar between SARS-CoV-2 infected children, infected adults, and negative adults.

Limitations: This is a small sample providing a situation analysis.

Graff, KAbuogi, LPediatr Infect Dis JRisk Factors for Severe COVID-19 in Children01 Feb 2021USANorth America454Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Risk_Factors_for_Severe_COVID_19_in_Children.95881.aspx

This retrospective cohort study aimed to identify risk factors associated with hospital admission and development of severe COVID-19 in children and young people infected with SARS-CoV-2. They report extremes of age (within the paediatric population), comorbidity and raised CRP as predictors of severe disease.

Cohort: The study analysed data from every SARS-CoV-2 positive (on PCR) patient <21 years old within Children’s Hospital Colorado between 15 March and 8 July 2020, amounting to 454 children and young people. Median age was 11 years, 42.1% were female. Almost 55% were Latino or Hispanic, which represented a significantly greater proportion of cases than the general paediatric population at the hospital, or in the wider community.

Results: Of the 454 children testing positive, 85 (18.7%) required hospital admission. 19 of those were asymptomatic and admitted for reasons other than COVID-19, so weren’t included in further analysis. 36 children with symptomatic SARS-CoV-2 infection required respiratory support, which ranged from low flow oxygen therapy via nasal cannulae to ECMO (1 case). 11 children required critical care. There was 1 death (ECMO patient).

Risk factors for admission were young age (0-3 months) and age >20 years, as well as comorbidities. Obesity also increased the odds of admission. Similar risk factors were associated with need for respiratory support, including age 0-3 months or >20 years, gastrointestinal disease and asthma. Those children that required critical care had a significantly higher CRP on admission than those that did not need critical care. There were more males than females testing positive for SARS-CoV-2, but male sex wasn’t predictive of more severe disease. Latino/Hispanic ethnicity was overrepresented in the study population, and associated with higher odds of needing respiratory support on univariable analysis, but not on multivariable analysis.

Discussion: This study had a relatively large cohort and analysed a large amount of data. Its findings are a very useful addition to the body of evidence on management of COVID-19 in children. Young infants and young adults were at greatest risk of hospital admission and severe disease, with underlying comorbidities being another risk factor. Ethnicity appeared to be relevant, although lack of support on multivariable analysis meant the factors underlying this remain unclear. Raised CRP on admission was predictive of severe disease. Obesity also emerged as an apparent risk factor for admission and respiratory support, although had to be excluded from multivariable analysis due to missing data.

Allan-Blitz, JTKlausner, JDPediatr Infect Dis J 40(3): e132-e133Prevalence of Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Youth01 MAR 2021USANorth America54501Epidemiology - Transmissionhttps://journals.lww.com/pidj/Fulltext/2021/03000/Prevalence_of_Asymptomatic_Severe_Acute.31.aspx
Brookman, SGupta, ALancet Child Adolesc HealthEffect of the new SARS-CoV-2 variant B.1.1.7 on children and young people10 Feb 2021UKEurope80Epidemiology - Disease Burdenhttps://doi.org/10.1016/S2352-4642(21)00030-4

It is a comparison of data, relating to SARS-CoV-2 infection in children and young people (CYP), gathered during 1 March to 31 May 2020 and 1 Nov 2020 to 19 Jan 2021 in the United Kingdom.

In the first wave (March to May 2020), 20 CYP (aged 18 years or younger and positive for SARS-CoV-2) were admitted to King’s College Hospital in south London. In the second wave (Nov 2020 to Jan 2021), 60 CYP positive for SARS-CoV-2 were admitted.

The authors state that during the second wave, the B.1.1.7 variant accounted for an estimated 70% of infections in London, whereas during the first wave infection was predominantly with earlier lineages.

No significant differences were found in age, proportion of patients with comorbidities, proportion of patients from Black, Asian, and minority ethnicity background, or deprivation score between CYP admitted to hospital and positive for SARS-CoV-2 in the two waves.

More CYP were admitted during the second wave. The authors conclude that this was due to an increased prevalence of SARS-CoV-2 within their local community, which was also reflected in a larger number of adults being admitted in the second wave.

The authors state that they found no evidence of more severe disease in children and young people during the second wave, indicating that infection with the B.1.1.7 variant does not result in an appreciably different clinical course to the original strain.

Zimmerman, KBenjamin, DPediatricsIncidence and Secondary Transmission of SARS-CoV-2 Infections in Schools 08 01 2021USANorth America773Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/01/06/peds.2020-048090

Amongst the growing number of studies examining transmission of SARS-CoV-2 in schools, many are not from settings with persistent high community SARS-CoV-2 transmission. In this study from North Carolina, USA, data on SARS-CoV-2 incidence in school districts participating in the ABC Science Collaborative (ABCs) following re-opening of schools in August 2020 are analysed. Participating schools used a hybird model of in-person and virutual learning with 50% of children receiving in person instruction on Monday/Tuesday and 50% on Thursday/Friday. Community transmission remained high (>1 PCR confirmed case per 1000 residents / fortnight) in the participating districts for the majority of the study period.

ABCs is a partnership between Duke University, the University of North Carolina and school districts which was formed with the aims of 1) educating school leaders, staff and the community, 2) have school-specific data to drive decision making, and 3) generate new science to improve health-outcomes in children. Mitigation strategies were in place at all participating schools including (i) universal masking of all >/= 5 years of age (ii) 6-foot distancing and (iii) hand washing; daily symptom monitoring and temperature checks were also performed. The primary outcome of this study was number of within-school transmissions of SARS-CoV-2 as determined by contact tracing by the local health department through the 9-weeks following schools re-opening.

Of 115 school districts, 56 participated in ABCs and 17 were open for in-person learning through the entire 9-week term. Data was analysed from the 11 of these 17 schools which reported weekly SARS-CoV-2 incidence and secondary (in-school) transmission. These 11 districts comprised more than 90,000 students and staff who attended in-person schooling during the study period.

There were a total of 773 community-acquired SARS-CoV2 infections documented during the study period. Only 32 cases of in-school transmission were reported through the 9-week school term: 6 in pre-kindergarten, 11 in elementary (primary) schools, 6 in middle schools, 5 in high schools, and 4 in K-12 schools. No cases of child-to-adult transmission were documented. All three clusters (of >/= 5 cases) of in school transmission in participating schools were linked to absence of face coverings either during meals, in very young children or in children with substantial special needs. Instances of child-to-child and adult-to-child transmission were not analysed due to confidentiality concerns.

Key contributors to the success of the program were identified by superintendents of participating districts including high rates of adherence to masking, clear communication and reporting of confirmed cases, efficient contact tracing, sharing of resources and detailed scheduling of the school day to allow adherence to mitigation measures. Challenges included the need to quarantine individuals (total of >3000 children and staff over the 9 weeks), compliance fatigue and ensuring family cooperation with contact tracing.

This study is limited by the lack of universal testing of contacts, which was not enforced as a requirement for return to school. Although this may have led to an underestimation of secondary cases, especially amongst asymptomatic individuals, the relative lack of large clusters or ongoing chains of transmission despite participating schools remaining open are consistent with limited SARS-CoV-2 transmission in this setting. This study adds to the growing body of evidence that in-school transmission of SARS-CoV-2 is limited in the setting of appropriate mitigation measures, even with high levels of transmission in the surrounding community. The success of the ABCs collaboration in North Carolina highlights the strength of a data-informed policy approach, as well as the importance of education, clear communication and cooperation between school districts.

Hobbs, CFlannery BmedRxivEstimated SARS-CoV-2 Seroprevalence in Children and Adolescents in Mississippi, May Through September 202008 FEB 2021USANorth America1603Epidemiology - Disease Burdenhttps://doi.org/10.1101/2021.02.05.21250792

Question: What is the extent of infection with SARS-CoV-2 among children and adolescents in Mississippi during the period from May to September 2020.

Methods: retrospective seroprevalence study using one of two methods (Ortho VITROS and CDC ELISA), depending on sample volume, to measure antibodies to SARS-CoV-2 in blood samples that had been collected for clinical reasons from patients aged less than 18 years of age. CDC ELISA was used in sample volumes of <0.3mls.

Setting: University of Mississippi Medical Center which provides clinical laboratory services for university hospitals and 12 other hospitals in the state of Mississippi.

Results: 175 samples out of 1603 (10.9% (9.4–12.4)) tested positive overall. A higher rate of prevalence of antibodies was seen in: children aged less than 1 year, non-whites and in those tested using the CDC ELISA technique. There were no sex differences. The seroprevalence increased from May to September from 2.6% (0.3–5.2) to 16.9% (9.9–24.2). The ratio of estimated infections based on seroprevalence to the cumulative number of reported COVID-19 cases by the previous month in the state of Mississippi was 69.6 (8.2 – 141.9) in May 2020 decreasing to 13.0 (7.6 – 18.7) in September.

Discussion: The authors concluded that in children and adolescents under 18 years of age the seroprevalence of SARS-CoV-2 infection increased as the months went, that the extent of COVID-19 infections in children and adolescents was underestimated during the months of May through to September 2020. With better contract tracing and identification this improved. There was a higher seroprevalence in non- whites’ minorities as seen in adult seroprevalence studies.

Comments: the main drawback of this study is the likelihood of sample bias, which the authors acknowledge in the Discussion. Higher seroprevalence was found in the youngest age, which is a surprising finding. However, the seroprevalence by age bands are uninterpretable given that the figures have not been adjusted for population in each age band nor for differences in the ethnic/race distribution. The seroprevalence was higher with the CDC ELISA assay, which was used if the sample was small, a situation most likely to arise in the youngest children. There is no information on distribution of the 2 assays per age band. The authors do not address this. It is not clear why the months from May to September were chosen nor was any information given as to where in the epidemic curve was Mississippi at the time of the study.

González-Donapetry, PGarcía-Rodriguez, JPediatr Infect Dis JThink of the Children Evaluation of SARS-CoV-2 Rapid Antigen Test in Pediatric Population23 January 2021SpainEurope440Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/Think_of_the_Children__Evaluation_of_SARS_CoV_2.95859.aspx

A study undertaken in the Paediatric Emergency Department, La Paz, Spain between 25th September and 14th October 2020. Paired nasopharyngeal swabs were taken from a total of 440 children aged 0-17 years, median age 3 (IQR 1-7), 59.1% of whom were male. The paired samples were tested for SARS-CoV-2 using a rapid antigen detection test and reverse transcription quantitative PCR.

Only 18 (4.1%) children age range 0-15, median age 6 (IQR 0-8) tested positive by reverse transcriptase PCR and of these 14 were positive by the rapid antigen test. No child with a positive antigen test had a negative RTqPCR. The sensitivity and specificity of the rapid antigen test were 77.78% (95% CI 51.92 - 92.63) and 100% (95% CI 98.88 - 100) respectively with a Kappa coefficient of 0.87 (p<0.001)

The authors conclude “The sensitivity of COVID-19 Ag Rapid Test Device is lower in children than in adults. Nevertheless, considering the good values of specificity, negative and positive predictive values this test could be used as a frontline test to obtain quick results, although the negative values with COVID-19 high clinical suspicion should be confirmed using RT-qPCR

Pace, RMcGuire, Mmbio Characterization of SARS-CoV-2 RNA, Antibodies, and Neutralizing Capacity in Milk Produced by Women with COVID-1909 Feb 2021USANorth America18Neonatalhttps://mbio.asm.org/content/12/1/e03192-20

The primary aims of this prospective study from the US are expressed in the title of the paper. Eighteen lactating women, with an average age of 34.2 ± 4.7 years, who tested positive to SARS-CoV-2 within eight days of recruitment, were included. Fifteen had symptoms of COVID-19 , at some stage, but none were hospitalised because of COVID-19. The “mean time post partum (s.d.)” was stated to be 6.8 months (+/- 7.8), the mathematics of which I am still trying to get my head round. Breast milk and breast swabs were collected in the participants’ homes using “virtual” instructions or, for two inpatients, in hospital. The milk was analysed for IgA and IgG targeting SARS-CoV-2 and for the ability of the samples to neutralize SARS-CoV-2. Well established laboratory methodologies were used and validated between two laboratories. Thirty seven samples were collected and analysed. Milk samples collected prior to the pandemic were analysed as controls. In addition the milk Na+ and K+ concentrations were measured, a ratio of >0.6 having been shown to indicate subclinical mastitis, which has been found to be associated with high viral content in breast milk. Nipple/areola swabs were collected by 15 women, before and after cleaning of the breast with soap and water, and tested for SARS-CoV-2 RNA.

A key study outcome was that none of the milk samples contained detectable SARS-CoV-2 RNA, using Rt-qPCR. With regard to antibodies, 76% (26/34) of milk samples contained SARS-CoV-2-specific IgA and 80% (22/27) contained SARS-CoV-2-specific IgG; the concentrations of IgA were higher than those of IgG. Both classes of SARS-CoV-2-specific antibody were also found in the pre-pandemic control group samples but the milk produced by women with COVID-19 had higher anti-RBD* IgA and IgG concentrations than milk collected from women before the pandemic (P=0.00013 and P=0.03 respectively). Functionally, 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity in vitro, whereas milk samples from the control group did not do so. The milk Na/K ratios were >0.6 in 12 (36%) samples, suggesting subclinical mastitis in 9 participants; however, as no SARS-CoV-2 RNA was found in the samples, the authors concluded that the mastitis was unlikely to be attributable to SARS-CoV-2 virus. Of the 70 breast swabs, eight had evidence of SARS-CoV-2 RNA, only one reaching the threshold value for conclusive SARS-Co-V positivity.

The absence of detectable virus in the milk samples, together with the presence of neutralising antibodies, led the authors to conclude that their data did not support mother-to-infant transmission of SARS-CoV-2 via milk but did support recommendations to encourage breastfeeding in women with mild-to-moderate COVID-19 illness. They also concluded that there findings were consistent with the recommendations of the World Health Organisation that there is no need for mothers who have confirmed or suspected COVID-19 to wash their breasts before feeding unless they have coughed over their exposed breasts, in which case they should gently wash the breast with soap and warm water before feeding.

These findings are broadly in line with a recently published systematic review of studies of the presence of the SARS-CoV-2 genome and/or antibodies in breast milk, which reported that the genome was present in the breast milk of 5% of women with confirmed COVID-19 and that anti-SARS-CoV-2 antibody was found in the milk of 83%.1

*RBD = receptor-binding domain

Metbulut, AMisirlioglu, EPediatr Allergy ImmunolEvaluation of Cutaneous Symptoms in Children Infected with COVID-1908 Feb 2021TurkeyAsia5143Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pai.13467

This is a prospective study evaluating the incidence and types of cutaneous manifestations associated with COVID-19 infections in children.  The study was conducted in Ankara City Children’s Hospital in Turkey between 11 March and 30 September 2020.

In the study period, there were a total of 5143 children who tested positive for Covid-19.  Of these, only 13 (0.25%) developed cutaneous lesions.  The median age of these children was 6 years and 77% were boys.  The most common skin manifestation associated with Covid-19 in the study was maculopapular exanthema (61.5%, n:8) followed by urticaria (23%, n:3).  Two of the patients with maculopapular exanthema had Multisystem Inflammatory Syndrome in Children (MIS-C) which is known to be associated with a rash.  Two other patients presented with severe cutaneous adverse reactions (SCARs); namely Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS).   The use of any drug therapy suspected to be causing a rash was terminated during the study.   The patient with SJS died and all other patients recovered and were discharged home.

This study confirms that skin manifestations are rarely associated with Covid-19 infection with children.  When present, the cutaneous symptoms vary from mild to severe.  The authors note that 6 of the 13 children had a history of drug usage and it is unclear whether their cutaneous symptoms were secondary to Covid-19 infection itself or the drug given.  They conclude that more studies would help to confirm and understand the skin involvement in COVID-19.

Neeland, MSaffery, RNat. Comm.Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children.17 Feb 2021AustraliaOceania48Clinical - Clinical Featureshttps://www.nature.com/articles/s41467-021-21414-x
Chua, GTKwan, MYWEmerg Microbes and infectSaliva viral load better correlates with clinical and immunological profiles in children with coronavirus disease 201920 Feb 2021ChinaAsia91Clinical - Clinical Featureshttps://doi.org/10.1080/22221751.2021.1878937

Background: Pediatric COVID-19 studies focusing on the association between clinical outcomes and immunological profiles in children with COVID-19 are lacking. Furthermore, the association between respiratory tract viral load and immunological profiles has yet to be explored.

Methods: Demographics, immunological profiles, nasopharyngeal swab (NPS), and saliva samples collected on admission, and hospital length of stay (LOS) were assessed in children below 18 years with COVID-19 admitted to the Princess Margaret Hospital or Queen Elizabeth Hospital in Hong Kong between 12 March and 8 August 2020

Results: 91 patients were included between March and August 2020. NPS and saliva viral loads were correlated (r = 0.315, p = 0.01). Symptomatic patients had significantly higher NPS and saliva viral loads than asymptomatic patients. Serial NPS and saliva viral load measurements showed that the log10 NPS (r = −0.532, p < 0.001) and saliva (r = −0.417, p < 0.001) viral loads for all patients were inversely correlated with the days from symptom onset with statistical significance. Patients with cough, sputum, and headache had significantly higher saliva, but not NPS, viral loads. Higher saliva, but not NPS, viral loads were associated with total lymphopenia, CD3 and CD4 lymphopenia (all p < 0.05), and were inversely correlated with total lymphocyte (r = −0.43), CD3 (r = −0.55), CD4 (r = −0.60), CD8 (r = −0.41), B (r = −0.482), and NK (r = −0.416) lymphocyte counts (all p < 0.05).

Conclusion: Saliva viral load appeared to correlate better with clinical symptoms, hospital length of stay and immunological profiles than NPS viral load. Symptomatic children had higher NPS and saliva viral loads on admission, which predicted longer hospital stay regardless of the antiviral treatment. Saliva viral load correlated well with NPS viral load. Patients with total, CD3, and CD4 lymphopenia were more likely to have higher saliva viral load, but not NPS viral load. Both B lymphocyte counts and IgG levels were predictors of hospital LOS. Larger-scale studies are needed in the future to compare the sensitivity and specificity of using NPS versus saliva viral load for the detection of SARS-CoV-2 in children.

Neeland, MSaffrey, RNat CommunInnate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children17 02 2021AustraliaAustralia48Epidemiology - Disease Burdenhttps://www.nature.com/articles/s41467-021-21414-x

This study, published on 17 February 2021, reports the acute and convalescent immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2 presenting to the Royal Children’s Hospital Melbourne, Australia, between April and August 2020.

Background: Children with SARS-CoV-2 have predominantly mild or asymptomatic infection compared to adults, but any underlying immunological basis for this difference between younger and older age groups is unclear. This study aimed to supply data on the cellular immune response in non-hospitalised children with mild disease, the commonest clinical course of children with COVID-19, compared with the cellular immune response in adults. It also looked at the immune response of children and adults exposed in their households to SARS-CoV-2 infection, but consistently testing PCR negative.

Study population: Participants were families presenting for SARS-CoV-2 testing at the Royal Children’s Hospital Melbourne between April and August 2020, divided into two groups: 1. SARS-CoV-2 positive individuals (27 children and 25 adults), who were non-hospitalised patients with a nasopharyngeal swab positive for SARS-CoV-2 and mild symptoms (including coryza, headache, nausea, fever, cough, sore throat, malaise and myalgia); 2. SARS-CoV-2 exposed individuals (21 children and 45 adults), who had a positive household close contact (defined as having face-to-face contact for more than 15 minutes and sharing a closed space with a confirmed case of COVID-19), but were SARS-CoV-2 PCR negative on repeated nasopharyngeal swabs (up to 5 repeat PCR tests at 5-7 day intervals for 4 weeks). Acute blood samples were collected within 2 weeks of the first positive PCR result and convalescent samples were collected 4-7 weeks from the first positive PCR result. These were not longitudinally collected samples from the same paediatric and adult patients, thus there were 8 groups in the study cohort: children vs adults, SARS-CoV-2-positive vs SARS-CoV-2-negative but exposed to SARS-CoV-2, acute vs convalescent sample. Median age for children in the SARS-CoV-2 positive group was 4.5 yrs (range 1-14) for 11 acute samples and 10 years (range 1-17) for 16 convalescent samples; median age for adults in the SARS-CoV-2 positive group was 35 years (range 19-62) for 17 acute samples and 40 years (range 20-62) for 8 convalescent samples. Median age for children in the SARS-CoV-2 exposed (but repeat PCR negative) group was 9 years (range 3-17) for 7 acute samples and the same age profile for 14 convalescent samples; median age for adults in the SARS-CoV-2 exposed (but repeat PCR negative) group was 38 years (range 21-50) for 21 acute samples and 41 years (range 22-56) for 24 convalescent samples.

Monocytes, dendritic cells and natural killer cells: Children with SARS-CoV-2 infection had low proportions of total monocytes during the acute phase that were restored in convalescence (median 0.67% vs 3.0% of PBMCs, p=0.0031). This was true of all three circulating monocyte subsets, with largest differences between acute and convalescent in the intermediate (CD14+CD16+, median 0.07% vs 0.14%, p=0.005) and non-classical (CD14lowCD16+, median 0.04% vs 0.33%, p=0.0003) subsets. This was also seen in adults for non-classical monocytes (median 0.19% acute vs 1.1% convalescent, p=0.01), but not for classical and intermediate subsets. Children also had a reduction in dendritic cells during the acute phase of infection that were restored in convalescence (median 0.26% vs 0.50%, p=0.0004), but this was not seen in the dendritic cell population of adults. SARS-CoV-2 positive children had reduced natural killer cells during the acute phase compared with SARS-CoV-2-exposed children (median 4.8% vs 8.3% of PBMC, p=0.06); whereas positive adults did not have different proportions of natural killers cells relative to exposed (but PCR negative) adults (median 9.1% vs 8.8%, p=0.99).

CD63+ neutrophil response: Total proportions of neutrophils and eosinophils were not significantly different between groups in children or adults, but there was an increase in the proportion of CD63+ neutrophils in SARS-CoV-2 infected children relative to SARS-CoV-2 exposed children in the acute phase (median 22% vs 1.7%, p=0.0002), which decreased from 22% to 8.1% in convalescence. CD63 is upregulated on the surface of neutrophils after activation and involved in the release of pro-inflammatory mediators as part of the anti-viral immune response. This response was not seen in SARS-CoV-2 infected adults. Other markers of innate cell activation (including HLADR, CD11b and CD11c) were not different between groups.

Low-density immature neutrophils: Children and adults exposed to SARS-CoV-2 but negative on PCR testing displayed increased proportions of low-density immature neutrophils that could be observed up to 7 weeks post-exposure.

Conclusions: In this study comparing the innate immune responses of children and adults with mild SARS-CoV-2 infection, infection in children was characterised by increased activation of neutrophils and low circulating proportions of all monocyte subsets, dendritic cells and natural killer cells, in contrast to infected adults who showed reductions in the non-classical monocyte fraction only. The reduction of innate cell populations in the circulation suggests that these cells may be recruited to sites of infection. This has been demonstrated in previous studies in adults (e.g. a study comparing blood and lung profiles of patients with severe COVID-19, where non-classical monocytes were seen to preferentially migrate from the blood into the lungs during disease). Additionally, this study showed that exposure to SARS-CoV-2 induces changes in the immune response in the absence of virological confirmation of infection, highlighted by the emergence of low-density immature neutrophils up to 7 weeks post-exposure in both children and adults. Longitudinal studies comparing responses from the same patients throughout infection and recovery would provide further insight into the immune mechanisms contributing to age-related differences in severity of disease after infection with SARS-CoV-2. Further investigation of cellular immune responses in adults and children exposed to SARS-CoV-2, but PCR negative, would also cast light on protective immune responses.

Lachassinne, EAupiais, CLancet Child Adolesc Healthwww.thelancet.com/child-adolescent Published online February 8, 2021 https://doi.org/10.1016/S2352-4642(21)00024-9 1 SARS-CoV-2 transmission among children and staff in daycare centres during a nationwide lockdown in France: a cross-sectional, multicentre, seroprevalence study08 Feb 2021FranceEurope327Epidemiology - Transmissionhttps://doi.org/10.1016/S2352-4642(21)00024-9

This is a cross sectional prevalence study in France, assessing prevalence of SarsCov2 antibodies in children of frontline workers who attended day care during initial lockdown (March 15 to May 9 2020) and comparing them to day care worker, and matched adult controls

Methods: Children of essential workers, attending 24 day cares during the initial lockdown were enrolled in a cross sectional study, 4-8 weeks after the end of lockdown. Staff at the day cares were also enrolled. The comparator adult group, was hospital admin and lab staff who kept working during lockdown, but who were not patient facing, and had no regular contact with infants. All had SarsCOV-2 antibody testing by finger prick using Biosynex COVID-19 Ag BSS. Positive and negative serologies were defined respectively as the presence and absence of IgM or IgG, or both. These results were then adjusted for imperfect sensitivity and specificity of the test.

In children, for those whose parents consented, RT -PCR, by NPA and stool swab were also obtained.

Parents working in a hospital underwent Sars-Cov2 antibody testing as part of a local campaign and these results were collected retrospectively.

Data on demographics, and history of symptoms associated with SARSCoV-2 were also collected.

Results : Mean age of children was 1·9 years (SD 0.9), with 167 (51%) male. Mean age of daycare staff was 40 years (SD 12) with 195 (99%) female.

14/327 children, 14/197 daycare centre staff and 9/164 comparator adults were seropositive, resulting in estimated raw seroprevalence rates of 4·3% (95% CI 2·6–7·1) among children and 7·7% (4·2–11·6) among staff and 5.5% (95% CI 2.9-10.1) in comparator adult group.

The corrected seroprevalence rate among daycare centre staff was similar to that in the comparator group (6·8% [95% CrI 3·2–11·5] vs 5·0% [1·6–9·8]). After adjustment for age, sex, and contact with a known COVID-19 case, the odds of a positive serological status for occupational status (ie, being a daycare worker) were 1·5 (95% CI 0·6–3·9).

None of the 197 nasal swabs and none of the 261 stool swabs from the children was positive for SARSCoV-2 PCR.

Conclusions: Authors conclude that there was low seroprevalence of SARSCoV-2 antibodies in a group of young children attending daycare during a national lockdown. Also, the seroprevalence rate among daycare centre staff did not differ from that observed in a group of hospital staff who did not have occupational contact with children or COVID-19-positive patients.

Kim, EJeong, EPediatr Infect VaccineChildren with COVID-19 after reopening of schools, South Korea12 Nov 2020South KoreaAsia127Epidemiology - Transmissionhttps://www.piv.or.kr/search.php?where=aview&id=10.14776/piv.2020.27.e23&code=1153PIV&vmode=PUBREADER

Summary: This study investigated the affect of school reopening in South Korea on paediatric COVID-19 cases. They looked at cases of COVID-19 in children aged 3-18 years who attended kindergarten or school, and analyzed data on exposure and transmission to assess the effect of attending these education settings on COVID-19 rates. They found low rates of transmission in school compared to other settings.

Cohort: All children aged 3-18 years attending kindergarten or school, who were reported to the National Surveillance System with COVID-19 between 1 May (when schools reopened) and 12 July. There were 127 cases reported, with 66% of cases being males, and 36% aged between 7-12 years.

Results: Analysis of SARS-CoV-2 exposure showed the most common form of exposure was from family and relatives – this accounted for 47% of cases. Exposure was attributed to cram schools (not defined) and private lessons in 14% of cases, to multi-use facilities such as churches and karaoke venues in 6% of cases, and to kindergarten/school in just 2% of cases.

Discussion: This study adds to the body of evidence that schools, where infection prevention measures are in place as in South Korea, are relatively low risk settings for SARS-CoV-2 transmission, and supports the call to keep schools open. The findings indicate that settings where infection control measures aren’t applied or aren’t as controlled, present a much greater risk for transmission.

Perramon, ASoler-Palacin, PmedrxivEpidemiological dynamics of the incidence of COVID-19 in children and the relationship with the opening of schools in Catalonia (Spain)17 Feb 2021Spain/CataloniaEurope940000Epidemiology - Transmissionhttps://doi.org/10.1101/2021.02.15.21251781

This pre-print article describes the trends in SARS-CoV-2 transmission in children under 18 in the whole of Catalonia, Spain, from 14 Sept 2020 to 31 Jan 2021. The authors relate these trends to schools opening and closing over autumn and Christmas. Both PCR and rapid antigen tests were used. Around 943,000 tests were performed, and 5.2% were positive overall. As seen elsewhere, incidence was similar to the general population in adolescents aged 12-17, but lower in younger children.

In Catalonia, all schools were closed between March and September 2020. Their data showed that when schools eventually re-opened, the incidence rate among children remained lower than the general population. This was in spite of more testing being done. They describe all the interventions in schools to prevent transmission: mask-wearing for all over 6 years old, natural ventilation, hand hygiene, clustering in bubble groups, and 10-day quarantining of bubble groups following a positive test.

They conclude that kindergarten and primary school-age children ‘…have not played a significant role in SARS-CoV-2 dissemination in Catalonia probably due to their lower susceptibility to the virus and lesser capacity to transmit it’.

This paper has not been peer-reviewed, and there are several potential sources of bias and inaccuracy which may not have been adequately recognised: e.g. differential testing rates, whole population trends, new variants, etc. Temporal association does not always imply cause and effect. As such we should be cautious in drawing firm conclusions from these results

Gold, JVallabhaneni, SMorb Mortal Wkly RepClusters of SARS-CoV-2 Infection Among Elementary School Educators and Students in One School District — Georgia, December 2020–January 202122 02 2021USANorth America32Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7008e4.htm

This study from Georgia, USA, described clusters of SARS-CoV-2 transmission in eight public elementary schools over an 8-week period (December 1st 2020 - January 22nd 2021). Mitigation measures were in place including mandatory in-classroom mask use and placement of plastic dividers between students, but physical distancing was not possible. Community transmission in the local county was high during the study period (cumulative weekly cases rose from 194 to 704 cases per 100,000).

Cases of SARS-CoV-2 were identified either by self-report of by local public health officials. Close contacts of confirmed cases were advised to quarantine and free PCR testing was offered to all contacts within 5-10 days of in-school exposure (60% of identified contacts were tested - the remained could not be reached or declined). For positive contacts, virtual interviews were conducted to assess likelihood of in-school transmission. An estimated 2,600 students and 700 staff attended in person learning during the study period.

A total of 9 clusters were identified, involving 13 educators and 32 students. An educator was the index case in 4 clusters which accounted for 21/31 cases of in school transmission. This included one two cluster with initial educator to educator transmission for followed by educator to student transmission (15/31 cases of in school transmission). A student was the index patient in 1 cluster (2/31 cases of in school transmission) and in the remaining 4 clusters whether the index case was an educator or student could not be determined.

Investigation of in-school transmission events revealed 9/9 clusters were associated with suboptimal physical distancing (students sat <3 feet apart), 7/9 were associated with small group instruction with educators working in close proximity to students, and 5/9 occurred in settings of inadequate mask use. Of household contacts of school-associated cases, 26% (18/69) tested positive for SARS-CoV-2.

These findings demonstrate that educators may play an important role in in-school transmission of SARS-CoV-2, with clusters with an educator index cases accounting for at least two thirds of in-school transmissions. The number of in-school transmission reported here is higher compared to recent reports from elsewhere in the US, possibly owing to the absence of some mitigation measures particularly limitations in mixing between staff (as employed in Wisconsin) or physical distancing and a hybrid model of virtual and in person teaching (as employed in North Carolina). Nonetheless, similar to school studies elsewhere, the incidence of in-school transmissions in this setting is low considering the high rate of transmission in the surrounding community at the time of the study. This study is also limited by the lack of universal testing of contacts, and the lack of viral sequencing to definitively determine direction of transmission.

This study highlights the importance of mitigation measures targeted at preventing SARS-CoV-2 transmission between educators as part of a multi-faceted approach to limit in-school transmission of SARS-CoV-2 in settings with high levels of community transmission. Measures such as limiting in-person adult interactions at school, ensuring mask compliance and physical distancing during essential encounters and (although not a requirement for re-opening schools) vaccination of educators once available have potential to reduce transmission and therefore minimise interruptions to in-person learning.

Al Suwaidi, HAlsheikh-Ali, AClin Microbiol Infect.Saliva for molecular detection of SARS-CoV-2 in school-aged children.10 Feb 2021United Arab EmiratesMiddle East476Epidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S1198743X21000847?dgcid=rss_sd_all

This was a prospective observational diagnostic study looking into the accuracy of saliva samples in paediatrics when tested by RT-PCR. The study notes that diagnostic accuracy of saliva in adults has been well reported but those reporting the accuracy in paediatrics have lacked in power.

Methods: The samples were collected between 1-23rd October 2020 and included 476 paediatrics who presented to a Dubai Health Authority community-based screening centre in the UAE. Indications included contact with confirmed COVID-19 patients, presence of presumptive symptoms or testing for return to school. Both nasopharyngeal and saliva samples were collected at the same time. Saliva samples were collected from each patient after 30+ minutes of abstinence from food and NP samples were collected by a trained HCP. Both samples were sent off to a laboratory for RT-PCR testing within 3 hours. The RT-PCR was used for detection of three gene targets (N, E and RdRp genes) and the cycle threshold of ≤40 was taken as the cut-off for positive result.

Statistical Data: Based on an infection prevalence of 5%, a sample size of 400 participants was required to detect at least a sensitivity of 80% and specificity of 95%. 476 paediatric patients with a mean age of 10.8 years (±3.9SD, range 3-18) were included and 58.1% were male. 9 participants were sampled on two occasions due to discordant results, leading to the testing of 485 pairs of NP swab/ saliva RT-PCR samples. Processing time for samples were similar in both arms (NP 9.62 ± 4.34 vs saliva 10.19±4.74 p=0.06).

Results: Viral detection was present in at least one specimen type in 17.9% of specimen pairs (87/485). Prevalence of COVID-19 diagnosis by NP swab RT-PCR was 16.7% (81/485) and 15.9% (77/485) by saliva RT-PCR. 87 children were positive by either test and 39 (44.8%) of these children had reported symptoms. Most commonly reported symptoms were fever (25/39), cough (16/39) and sore throat (15/39).

With NP swab RT-PCR as a reference, the sensitivity and specificity of saliva RT-PCR was 87.7% (95%CI 78.5-93.9%) and 98.5% (95%CI 96.8-99.5%) respectively. PPV and NPV were 92.2% (95%CI 84.2%-96.3%) and 97.6% (95%CI 95.7-98.6%).

Median cycle threshold (Ct) values for E, RdRP and N gene targets in NP swab were 23.9 (IQR 17.3-31.9), 27.8 (IQR 19.8-35.5) and 26.6 (IQR 21.5-31.1) respectively. In Saliva swabs, Ct values were 27.2 (IQR 19.9-32.0), 29.5 (IQR 23.6-34.1) and 28.2 (IQR19.4-32.0) respectively. Concordance of findings between NP swabs and saliva samples did not differ by age (p=0.67) or gender (p=0.29). However, for those who self-reported symptoms compared to no symptoms, mean CT values for the E gene in both samples and the N gene in saliva samples had statistical significances.

Discussion: Diagnostic accuracy of saliva RT-PCR is comparable to the NP swab RT-PCR in ambulatory school-aged children. The results of this study are also aligned with other studies investigating saliva RT-PCR. Although children with COVID19 are largely asymptomatic, they tend to have similar viral loads comparable to adults and reportedly greater viral loads are present in those under five years old.

Therefore, it is expected that the diagnostic accuracy of saliva in children should be on par or superior when compared to adults. The results of this study found the sensitivity of saliva RT-PCR to be higher than some studies on the adult population.

There are 2 other studies which concluded that saliva RT-PCR was not useful for diagnosing COVID-19 in paediatrics. They found that RT-PCR had a low sensitivity but had very small sample sizes of 18 and 11 and were underpowered to assess diagnostic accuracy. Therefore, the reliability of the studies are questioned (Chong et al., 2020; Han et al., 2020).

The strength of this study included the high power and sample size of participants and the target of RT-PCR towards 3 different genes; E, N and RdRp which was not done in previous studies. Limitations include the collection of data from children who presented at a testing centre for screening. This may not provide a result able to be generalised to the wider population. Further research on the wider population including those under 3 would allow for better generalisability

Rha, BLangley, G J Pediatric Infect Dis SocSevere acute respiratory syndrome coronavirus 2 infections in children: Multicenter surveillance, United States, January-March 202018062020United StatesNorth America5573Epidemiology - Transmissionhttps://academic.oup.com/jpids/article/9/5/609/5859277

This paper reports the findings of a US-based multi-centre surveillance study looking at the number of Covid-19 infections in children at the start of the pandemic (January-March 2020).  The study included children <18 years old who had symptoms of an Acute Respiratory Illness (ARI) as well as asymptomatic controls.  These children were enrolled in pre-existing active, prospective surveillance of paediatric ARI by the New Vaccine Surveillance Network (NVSN) across 7 sites in the US.   Retrospective Covid-19 RT-PCR testing was then performed on existing respiratory specimens from enrolled children.

Study population: The 7 NVSN sites are based in Cincinnati, Seattle, Houston, Kansas City, Pittsburgh, Rochester and Nashville.  Each site recruited patients from 4 potential settings; inpatient, Emergency Department (ED), outpatient clinics and well-child visits.  The eligible age-groups for enrollment varied at each setting.   Children between 14 days and 5 years old were recruited from well-child clinics and served as asymptomatic controls.  All other children who were recruited presented with symptoms of an Acute Respiratory Illness (ARI).  Children less than 18 years were recruited from the inpatient and ED settings whilst only those less than 24 months of age were recruited from outpatient clinics. The following presenting symptoms/events were classified as an Acute Respiratory Illness: fever, cough, earache, nasal congestion, runny nose, sore throat, vomiting after coughing, wheezing, shortness of breath, apnea, apparent life-threatening event or brief resolved unexplained event, or myalgias.

Results: 3261 of 5573 (59%) eligible children were enrolled from January-March 2020.  The median age of all children tested was 19 months (range, 0–17 years).  43% of children were recruited from an inpatient setting, 39% from the Emergency Department, 12% from outpatient clinics and 6% were asymptomatic.  During the surveillance period, only 4 children tested positive for Covid-19 infection (0.1%).  The median age of those who tested positive was 6 months and all were symptomatic with symptoms including fever, cough, nasal congestion and irritability.   All 4 children tested positive between 20-31st March 2020.  Three cases were detected in Seattle and 1 was detected in Cincinnati, Ohio.  Community spread in the Seattle area occurred in late February and the first reported case in Ohio was in March.   No children tested positive in the remaining NVSN sites; the first reported community cases in these sites was between 5-18th March.

Discussion: This study aims to provide a more accurate insight into the prevalence of Covid-19 infections in children  through active surveillance rather than clinician-dependant testing and reporting.  The authors conclude that the low numbers of Covid-19 infection are consistent with previous US reports showing children constitute a small minority of reported COVID-19 cases.  From 12th February to 2nd April 2020, only 1.7% of cases reported to the CDC occurred in children.   They also make note of the study’s limitations which may have led to missed detections (only 59% of eligible children enrolled, differing age groups at different settings).  It is also worth noting that the study was conducted at the start of the pandemic when community transmission was low.  Ongoing active surveillance would therefore be of use.

Mensah, ALadhani, SNJ InfectSARS-CoV-2 infections in children following the full re-opening of schools and the impact of national lockdown: Prospective, national observational cohort surveillance, July-December 2020, England25 Feb 2021EnglandEuropeEpidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S0163445321000931?via%3Dihub

Methods: This prospective epidemiologic study used national and regional surveillance data to monitor age-specific and weekly-trends of SARS-Cov-2 in England from the start of the summer holiday (13th July 2020), until the end of 2020 in school-aged children (27th December 2020). The impact of national restrictions and local lockdown on SARS-Cov-2 infections rates in students and adults during November 2020, was also examined. During the study period, widespread testing for SARS-Cov-2 was available.

SARS-Cov-2 tests were categorised by corresponding school year (i.e., nursery: 2 to 3 years old; pre-school: 3 to 4 years old; reception: 4 to 5 years old, primary school years 1 (5 to 6 years old) to 6 (10 to 11 years old) and secondary school years 7 (11 to 12 years old) to 13 (17 to 18 years old)) and educational settings (preschools: nursery and preschool; primary school: reception and years 1 to 6; secondary school: years 7 to 13).

The infection rates in school-aged children were compared to all ( 18 and 64-years-olds) and young adults (18 to 29-years-old).

Results: Infection rates during summer holidays (13th July to 30th August 2020) were low across all age groups. The infection rates started to increase from August 2020 -before schools were reopened- and continued across all the educational cohorts until the end of the year. These increments occurred initially in young adults, followed by secondary and primary school-aged children, with little change in pre-school-aged children.

Similar trends in SARS-Cov-2 infections in children and adults were detected after the schools reopening in England in September 2020; however, cases in school-aged children lagged adult rates.

Regional infection rates in adults, were examined in low (July 2020) and high (October 2020) national weekly incidence. These rates were correlated with the observed in secondary (R2: 0.8594 and 0.9661) and primary (R2: 0.9221 and 0.9339) and preschool-aged children (R2: 0.8594 and 0.8347).

The schools remained open during the national lockdown in November 2020. During that period, rapid decline in young adult infection rates, followed by secondary and primary school-aged children with one-week lag was noticed. Of interest, the decline in weekly infections was more prominent in regions with high SARS-Cov-2 infection positivity rates and was followed by an increase across all age-groups, which was associated with the spread of SARS-Cov-2 B.1.1.7 variant.

Strengths and limitations: Although this study examined a large volume of regional and national SARS-Cov-2 surveillance data, the role of asymptomatic children and adults is yet to be unveiled, since the cases included for analysis presented to national testing facilities with symptoms consistent with COVID-19. Complementary genomic surveillance once schools reopen in 2021, is paramount to better understand the role of SARS-Cov-2 infection and transmission in schools.

Feldstein, LRandolph,G JAMACharacteristics and Outcomes of US children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19 24 Feb 2021United States North America1116Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2777026

Introduction : This is case series comparing children and young adults diagnosed with MIS-C with those diagnosed with severe coronavirus disease. 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states were included, with final date of follow-up was January 5, 2021.

Methods : These children were included in the “Overcoming Covid-19” registry, a network across 33 states, that was approved by Boston children’s Hospital ethics, and the CDC which allowed for a consent waiver.

MIS-C criteria was consistent with the CDC definition

Age <21 y, Fever ≥38.0 °C for ≥24 h or report of subjective fever lasting ≥24h, Laboratory evidence of inflammation, Evidence of clinically severe illness requiring hospitalization with multisystem (≥2) organ involvement (cardiac, kidney, respiratory, hematologic, gastrointestinal, dermatologic, or neurological), no alternative plausible diagnoses, Positive for current or recent SARS-CoV-2 infection by RT-PCR, antibody, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 wk prior to the onset of symptoms).

Severe Acute Covid-19 was defined as;

Admitted to the hospital with symptoms suspected to be related to COVID-19, Evidence of infection with SARS-CoV-2 based on a positive RT-PCR test result during current illness, Severe organ system involvement of at least one system, which is listed in detail in the paper.

Comparisons were made between groups including age, sex, race, ethnicity and any underlying conditions.

Results: Of 1116 cases included in the final analysis, 539 (48%) were classified as MIS-C and 577 (52%) as acute COVID-19. In patients with MIS-C, 52% had a positive PCR test result, 45% were antibody positive only, 31% were positive for both, and 19% did not have an antibody test performed. By definition all those with acute COVID-19 were PCR positive.

Compared with patients with COVID-19, those with MIS-C were younger, more likely to be non-Hispanic Black, and less likely to have 1 or more chronic medical conditions.

Presenting symptoms and signs were similar among patients with MIS-C and COVID-19 with the exception of mucocutaneous findings (66.8% MISC-C vs 10.2% Acute COVID-19).

80% of patients with both MIS-C and COVID-19 each had severe respiratory involvement; however, more patients with MIS-C had cardiac involvement (66.7%) compared with COVID-19 (11.8%).

On laboratory testing within 48 hours of admission, patients with MIS-C had a mean CRP level of 152 mg/L vs 33 mg/L, P < .001) and more thrombocytopenia (platelets <150 ×103 cells/μL) than patients with COVID-19 (41% vs 17%, P < .001).

Cardiac complications; In the MIS-C group (n=504), of the 172 patients with MIS-C and depressed LVEF, 91.0% had a normal LVEF by 30 days. 424 of the 504 MIS-C cohort had coronary arterys evaluated. 57 patients had coronary aneurysms, of which 53, were mild, 4 were moderate, and none were large/giant. Aneurysms regressed to normal internal lumen diameter (z score <2.5) in 79.1% of patients by 30 days (based on small numbers, 100% by 90 days.

Ten patients (1.9%) with MIS-C vs 8 (1.4%) with COVID-19 unfortunately died during hospitalisation

Conclusions: This case series found that non-Hispanic Black children and adolescents were more likely than non-Hispanic White patients to have MIS-C than COVID-19, after adjusting for age, sex, geographic region, and underlying conditions, whereas Hispanic patients did not appear to be at a higher risk for MIS-C than COVID-19. Most patients classified as having MIS-C and COVID-19 experienced severe respiratory involvement and it is possible that some patients may have had COVID-19 with cardiovascular involvement.

This series shows that most severe cardiovascular involvement from MIS-C, including left ventricular dysfunction and coronary artery aneurysms, resolved within 30 days. The mortality rate from both severe Covid 19 and MIS-C in children, was similar.

Husby, AKrause, TMedrxivSARS-CoV-2 infection in households with and without young children: Nationwide cohort study02.03.2021DenmarkEurope0Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.28.21250921v1.full-text

This article is a preprint and has not been peer-reviewed.

This study looks at the hypothesis that recent exposure to seasonally spreading human coronaviruses (HCoVs) might result in protection from SARS-CoV-2 infection. It is a large cohort study from Denmark where there is a central database of all residents and nationwide information on all laboratory confirmed cases of SARS-CoV-2 infections and hospitalisations.

All adults aged 18-60y living in Denmark on 01.01.2020 were included in the study cohort, and a cohort of SARS-CoV-2 test positive individuals constructed, who were followed up for hospitalisation until 30 days after their test. Cohort members were followed up from 27.2.20 until a positive SARS-CoV-2 test or 15.11 20.

Taking living with young children (10m- 5y) as a proxy for exposure to HCoVs, hazard ratios were calculated for SARS-CoV-2 infection by household type.

Other available data including age, gender, ethnicity, comorbidities, urbanicity and household composition (including older children), were used as study covariates. Details of the statistical analysis are given.

Main Results: There are around 3 million adults age 18-60 living in Denmark, around ½ million (14.6%) of these live in households with young children. More details are in the paper.

The adjusted hazard ratio of risk of SARS-CoV-2 infection in adults in households with young children compared to those without, was 1.05 (95% CI 1.02-1.09). This figure increases with the number of young children in the household.

There was strong evidence of increased risk of SARS-CoV-2 infection among adults where there were older children in the household (adjusted hazard ratio1.31 (95%CI 1.27-135)).

There was a non-statistically significant reduced risk of hospitalisation among adults living with young children compared to those who don’t but analyses were limited by low numbers [146 hospitalised adults amongst 3,039 SARS-CoV-2 test positive adults living with young children v 1,130 hospitalised adults amongst 18,542 SARS-CoV-2 test positive adults living with no young children: adjusted hazard ratio 0.84 95%CI 0.70-1.09].

Discussion: This study produced no evidence that exposure to HCoVs reduces the risk of SARS-CoV-2 infection in adults, thereby suggesting no strong preventive effect of recent exposure to HCoVs against SARS-CoV-2 infection.

This is in line with serological and epidemiological studies which suggest no sterilising cross-reactive immunity.

It is the 1st study of an entire national population and will have captured the vast majority of SARS-CoV-2 infections. However, there was no direct, serological evidence of adult exposure to HCoVs, but living with young children has been taken as a good proxy in other studies.

The authors comment that the slightly increased risk of SARS-CoV-2 infection amongst adults living with young children may be due to the increased social contacts for the adults in taking this age group to nursery etc. or because the young children bring the infection home.

They hope that similar data from other countries might explore the potential effect of HCoV exposure on the severity of SARS-CoV-2 infection (as suggested by hospitalisation rates).

Vella, LAWherry, EJSci Immunol 6(57).Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-1902/02/21USANorth America30Clinical - PIMS-TShttps://immunology.sciencemag.org/content/6/57/eabf7570

This important, highly complex paper will be of interest to expert immunologists and ID specialists. A study of 16 paediatric Covid-19 and 14 MIS-C cases presenting to a US tertiary referral centre between April – June 2020, were studied and compared to an adult population of healthy and Covid-19 patients. Median (range) and M:F split for the paediatric Covid-19 and MIS-C cases were 14yrs (0.15-18yrs) and 8:8, and 9yrs (5-17yrs) and 7:7. Detailed breakdowns of patient characteristics, and treatment and sampling regimes are given. More patients had lymphocyte as opposed to whole blood flow cytometry performed. SARS-CoV-2 infection in children resulted in marked T cell activation and proliferation. The “immune landscape” in paediatric and adult Covid-19 infections was similar but in MIS-C there was an exacerbated T cell activation, particularly for CD8+ T cells, even compared to severely ill adults. A distinct CD8+ T cell subset linked to vascular endothelial damage surveillance was raised in MIS-C, and correlated with the need for vasoactive support, but this finding did not achieve statistical significance after correction for multiple comparisons in this small dataset. Immune activation in paediatric Covid-19 and MIS-C showed differing relationships with some clinical investigations, such as LDH and D-dimer. There was evidence of persistence of SARS-CoV-2 viral RNA in MIS-C cases (12/14), suggesting chronic antigen availability, and possibly chronic inflammatory stimulation.

Lessler, JStuart, EmedRxivHousehold COVID-19 risk and in-person schooling1 Mar 2021USANorth AmericaEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.27.21252597v1

This article is a preprint and has not been peer-reviewed.

This preprint, posted on 1st March 2021, uses a large internet-based cross-sectional survey in the United States to analyse the risk of COVID-19 in households with a child attending in-person school and the effect on that risk of school-based mitigation measures, in two time periods of one month each (Nov/Dec 2020 and Jan/Feb 2021).

Background: There are over 130,000 K-12 schools (from age 5 to 18 years) in the US (mostly public schools, with around 28% of students in private or charter schools). As a result of the COVID-19 pandemic, during the 2020-21 school year there has been huge variation in the approaches to schooling across the United States, from total closure of schools to opening with no mitigation measures in place. Most schools open to in-person learning have some measures in place to mitigate transmission of SARS-CoV-2, but there is wide variety in the number and types of measures adopted. Since SARS-CoV-2 infection in children and young people generally causes mild disease, one of the main reasons for a focus on transmission in schools is not the risk to students, but the risk that in-person schooling poses to teachers and family members, as well as its impact on the trajectory of the overall epidemic. This study focuses on the risk of in-person schooling to adult household members.

Data collection: The US COVID-19 Symptom Survey is a cross-sectional survey conducted daily by Carnegie Mellon University (CMU), using Facebook as a platform to recruit participants. Selected Facebook users receive an invitation each day to participate in the survey at the top of their news feed, yielding approximately 500,000 survey responses in the US each week. The survey was developed by public health and survey experts, reviewed and approved by the Institutional Review Boards of CMU and the University of Maryland, and includes questions related to health symptoms, testing, mental health, preventive behaviours and (since late November 2020) the schooling experience of any children in the household. Stratified random sampling within US states is used to provide adequate geographic coverage. Facebook employs a two-stage weighting process to account both for the systematic demographic differences between the Facebook Active User Base (aged 18+ and living in the US) and the US population, and for bias related to non-response and coverage (using age, gender, geographical variables and other user characteristics), so that the survey population is representative of the US population.

Study population: This study analysed data collected over two time periods during the 2020-21 school year: 24 November to 23 December 2020 and 11 January to 10 February 2021 (to exclude the winter school holidays). During these time periods there were 2,142,887 survey respondents in the 50 US states and Washington DC. 576,051/2,142,887 (27%) reported at least one child in school living in their household. 284,789/576,051 (49%) of these reported a child living in the household attending school in person either full- or part-time.

Primary outcomes: 3 different primary outcomes, as reported and experienced by the survey respondents, were considered (to mitigate for bias due to varying relationships between the timeframe of reported behaviours and other exposures): 1. COVID-like illness (CLI), defined as fever, cough, shortness of breath or difficulty breathing in the last 24 hours; 2. Loss of sense of taste or smell in the last 24 hours; 3. Positive SARS-CoV-2 test in the last 14 days.

Risk of living in a household with a child attending in-person school: After adjusting for county-level COVID-19 incidence and other individual- and county-level factors, living in a household with a child in full-time in-person schooling is associated with an increase in the odds ratio of reporting CLI (adjusted odds ratio (aOR) 1.38, 95% CI 1.30-1.47), loss of sense of taste or smell (aOR 1.21, 95% CI 1.16-1.27) and positive SARS-CoV-2 test in the last 14 days (aOR 1.30, 95% CI 1.24-1.35). The association between COVID-19 outcomes and a child in the household in part-time in-person schooling is attenuated but still statistically significant for CLI (aOR 1.21, 95% CI 1.13-1.29), loss of sense of taste or smell (aOR 1.18, 95% CI 1.13-1.24) and positive test (aOR 1.09, 95% CI 1.03-1.14).

Risk stratified by school grade level: Restricting the analysis to households reporting a child/children in a single grade strata in full-time in-person schooling, the strength of the associations with the 3 primary outcomes increase with grade level, from no association in households with only pre-K and Kindergarten students to a substantial positive association in households with only high school aged students. For part-time schooling the association between school grade and COVID-19-related outcomes is less clear.

Mitigation measures reported in school: For students in any form of in-person learning, the most common mitigation measures in school to reduce the risk of transmission of SARS-CoV-2 reported were student mask mandates (88%), teacher mask mandates (80%), restricted entry to school for parents and caregivers (66%) and extra space between desks (63%). A total of 14 possible mitigation measures were reported: the other 10 were student with the same teacher all day, student with the same students all day, some or all outdoor instruction, reduced class sizes, closed cafeteria, closed playground, use of separators (desk shields) in classrooms, no school-based extracurricular activities, no sharing of books/supplies and daily symptom screening. There was a mean of 6.7 (IQR 4-9) mitigation measures in place at any school attended by a household child, with more mitigation measures for children in part-time schooling (mean 7.3) than full-time schooling (mean 6.4), and substantial geographic heterogeneity (households in South Dakota reporting the least (mean 4.6) and Vermont the most (mean 8.9)).

Association between mitigation measures and risk of COVID-19 outcomes: There was a clear association between the number of mitigation measures implemented in schools and the risk of COVID-19 outcomes among adult household members responding to the survey after adjustment for individual and county level factors, including survey respondent age, gender, occupation, masking behaviour, out-of-state travel, reporting of a visit to a bar/restaurant/café or event with 10+ people, use of public transport, household size, number of children, county two-week average attack rate, county population, percentage white population, percentage households in poverty, index of income inequality and metropolitan type. Each mitigation measure implemented was associated with a 9% decrease in the odds of CLI (aOR 0.91, 95% CI 0.89-0.92), an 8% decrease in the odds of loss of sense of taste or smell (aOR 0.92, 95% CI 0.91-0.93) and a 7% decrease in the odds of a recent positive SARS-CoV-2 test (aOR 0.93, 95% CI 0.92-0.94). Regression treating each individual mitigation measure as having an independent effect showed that report of daily symptom screening was clearly associated with greater risk reductions than the average measures, with some evidence that teacher mask mandates and cancelling extra-curricular activities were also associated with larger reductions than average. In contrast, closing cafeterias and playgrounds and use of desk shields were associated with lower risk reductions (or even risk increases). Part-time in-person schooling was not associated with a decrease in the risk of COVID-19-related outcomes compared to full-time in-person schooling once other mitigation measures were accounted for. Looking at respondents with a child attending in-person school at schools with 0, 1-3, 4-6, 7-9 and 10+ mitigation measures in place, the study found that where 7 or more mitigation measures were in place, the risks associated with in-person schooling largely disappeared, with complete absence of increased risk with 10 or more mitigation measures.

Demographic and incidence differences: There were few systematic or statistically significant deviations from the overall estimate of the relative risk associated with full- and part-time schooling when stratified analyses were performed to account for differences between urban, suburban and rural counties, local patterns of COVID-19 incidence or propensity to avoid in-person schooling.

Conclusions: There was a clear association in this study between living with a child attending school in-person and the risk of COVID-19-related outcomes in adult household members. However, school-based mitigation measures were associated with significant reductions in risk, particularly daily symptom screening, teacher mask mandates and closure of extra-curricular activities. With 7 or more mitigation measures in place, the association between in-person schooling and COVID-19-related outcomes all but disappeared. However, in-person schooling and mitigation measures are not distributed at random in the population; for example, households with a student attending in-person school tend to be in counties that are a higher percentage white and contain survey respondents who are more likely to have recently eaten out or gone to a bar. Although the analysis attempted to adjust for local incidence, individual behaviour and other potential confounders, unmeasured factors may be responsible for the observed associations. The study was unable to measure the risk posed by in-person schooling to students themselves, nor how teachers and other school staff are impacted. It provides limited insight into how in-person schooling increases risk and it is possible that classroom transmission plays a minor role, with other school-related activities (such as student pick-up and drop-off, teacher interactions and broader changes in behaviour when school is in session) driving risk. Adjustments were made for county-level measures of socioeconomic status; these factors are known to be associated with COVID-19 risk and attitudes about in-person schooling. Importantly, the study suggests that common, low cost school mitigation measures can greatly reduce the risk of COVID-19-related outcomes in adult household members of children attending in-person school.

Lyngse, FKirkeby, CmedrxivAssociation between SARS-CoV-2 Transmission Risk, 2 Viral Load, and Age: A Nationwide Study in Danish Households05 03 2021DenmarkEurope18194Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.28.21252608v1.full.pdf

This article is a preprint and has not been peer-reviewed.

This large national registry-based study from Denmark explores the association between SARS-CoV-2transmission, viral load (measured by PCR cycle threshold (Ct value)) and age.

Methods: All positive SARS-CoV-2 PCR tests performed at community testing facilities (TestCenter Denmark (TCDK)) between August 25th, 2020 and February 10th, 2021 had Ct values determined. Data linkage was used to construct households with 2-6 members, the first household member testing positive was considered the primary case. Subsequent household members testing positive 1-14 days after the primary case were defined as secondary cases (and were presumed to have been infected by the primary case). A household member testing positive on the same day as the primary case was considered a "co-primary" case (rather than a secondary case). Primary cases tested at TCDK were identified up to January 25th; secondary cases were identified from tests performed at TCDK or from hospitals up to February 10th 2021. Associations between Ct value and transmission risk, and age and transmission risk were estimated using non-parametric regression.

Results: Of over 9 million samples analysed at TCDK during the study period (74% of all tests nationally), 66,602 primary cases were identified. Of 213,576 household contacts, 88% were tested 1-14 days following the primary case, 103,389 (48%) tested positive for SARS-CoV-2 and were classified as secondary cases.

Transmission risk was highest with low Ct values (high viral loads) and decreased linearly with increasing Ct value (decreasing viral load). SARS-CoV-2 Ct values were higher in paediatric primary cases aged 0-5 (median 32, mean 31) 5-10 (median 31, mean 31) compared with adults (median 28, mean 28) corresponding with lower viral loads. Adolescent primary cases had similar Ct values (median 29, mean 29) to adults.

In univariate regression analysis, transmission risk was lower in children compared with adults aged 30-35: OR 0.87 (0-5yo), OR 0.75 (5-10yo), OR 0.67 (10-15yo), OR 0.64 (15-20yo). Amongst adults, transmission risk increased with age (OR 4.67 in 80-85yo). In multivariable regression (including Ct value, household size and gender) children 5-20yo had a lower transmission risk, however infants had a slightly elevated risk (OR 1.11) compared with adults aged 30-35. In contact matrices, increase rates of transmission were observed from the youngest children to the elderly rather than to other children, perhaps representing an increased risk of transmission to grandparents due to their increased susceptibility.

Child contacts aged <10 years tested positive less frequently than other age cohorts (9,273/29,569, 31.3%, vs 6,613/10,451, 63% of aged 65 – 75 yrs), possibly indicating reduced susceptibility compatible with findings from other household contact tracing studies.

Conclusion: The findings of this study are consistent with data elsewhere indicating higher viral loads (or lower Ct values) are associated with increased risk of SARS-CoV-2 transmission. Notwithstanding these limitations of the methods used to determine direction of transmission, the results suggest that the risk of SARS-CoV-2 transmission from child primary cases is lower compared to adult primary cases. In multivariate analysis, children aged 0-5 years had a higher risk of transmission, possibly owing to increased close contact with household members or grandparents who are more susceptible, compared with older children. Notably the median viral load was lower in this age group compared with adult primary cases (Ct value 32 vs 28), possibly impacting overall transmission risk in this analysis.

Plumb LNitsch DArch Dis ChildCOVID-19 in children with chronic kidney disease: findings from the UK renal registry19 Feb 2021United KingdomEurope5Epidemiology - Disease Burdenhttp://dx.doi.org/10.1136/archdischild-2020-319903

Every paediatric subspecialty is now reporting Covid-19 infection numbers and outcomes for children affected by chronic diseases. This brief letter adds to the list, with data from all 13 UK paediatric nephrology units from 26 March to 15 July 2020. They report that there were only 5 cases of Covid-19 in children with stage 4 or 5 chronic kidney disease, which includes all those on renal replacement therapy. All we are told is that their mean age was 11 years, 4/5 were male, and none died. This report suffers from a lack of a denominator (5 out of how many?), and no data on severity of illness. However, it was sufficient to allow a relaxation of shielding criteria for children with kidney disease, and this was incorporated into the RCPCH revised recommendations of July 2020, since adopted by the UK government.

Carles Bautista-Rodriguez, Joan Sanchez-de-Toledo, Bradley C. Clark et al, Multisystem Inflammatory Syndrome in Children: An International Survey, Pediatrics Feb 2021, 147 (2) e2020024554; DOI: 10.1542/peds.2020-024554

A retrospective International study of 183 children mean age 7.0 ± 4.7 years (range: 1.2 months–18 years) with MIS-C who were discharged or died with MIS-C between 1st March 2020 and 15th June 2020. The participants came from 33 hospitals in 14 countries in Europe, Asia, N and S America. 109 children (59%) were male, 56 were black (30.6%); and 48 (26.2%) were obese.

All children had a fever, 114 of the 183 had SARS-COV-2 infection, 117 had gastrointestinal symptoms. 78 of 183 presented with shock, 27 fulfilled the criteria of Kawasaki disease, and the remaining 78 had signs of fever and inflammation. The patients with Kawasaki disease were younger and had no shock and fewer gastrointestinal, cardiorespiratory, and neurologic symptoms.

SARS-CoV-2 PCR results were positive in 43 of 114 (37.7%) tested patients, and SARS-CoV-2 serology test results were positive in 95 of 110 (86.3%) tested patients. In total, 114 of 183 (62.3%) patients had evidence of current or recent SARS-CoV-2 infection.

As far as treatment was concerned inotropic support was needed in 72 (39.3%), mechanical ventilation in 43 (23.5%), and extracorporeal in 4 (2.2%). Intravenous immunoglobulin was used in 26 of 27 (96.2%) patients with KD-like illness and in 137 of 156 (87.8%) of the remaining patients. 15

of 27 (55.6%) patients with KD-like illness and 90 of 156 (57.7%) of the remaining patients received steroids. A variety of other therapeutics were used including azithromycin, aspirin, anticoagulation, anakinra, infliximab, and hydroxychloroquine.

Children with Kawasaki type diseases had shorter duration of hospital stay and required less intensive care support. A total of three 1.6% children died. A shorter duration of symptoms before admission was found to be associated with a poor patient outcome and the need for extracorporeal membrane oxygenation and/or death.

The authors concluded “MIS-C has emerged with a wide clinical spectrum at presentation, including KD-like, life-threatening shock and milder forms with mainly fever and inflammation. The risk for worse outcome (ECMO and/or death) is associated with a short time interval between the onset of

symptoms and admission. More studies encompassing larger numbers of patients are needed to better describe this new disease, its optimal treatment, and long-term monitoring.”

This is an interesting paper with important information relating to MIS-C but unfortunately the paper is spoilt by editorial errors. In the summary it is stated that 79 children presented with shock compared with 78 elsewhere in the paper, under treatment it says 26 of 7 children were treated with immunoglobulin.

Bautista-Rodriguez, CFraisse, APeduatricsMultisystem Inflammatory Syndrome in Children: An International Survey1 February 202113 countriesInternational183Clinical - PIMS-TS https://pediatrics.aappublications.org/content/147/2/e2020024554.long
LaRovere, KRandolph, AJAMANeurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome5 March 2021USANorth America1695Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamaneurology/fullarticle/2777392

This study is from USA between March 15, 2020, and December 15, 2020. A surveillance was performed at 61 US hospitals. Case series of patients aged <21 years with positive SARS-CoV-2 test result (PCR and/or Antibody). Patients were excluded if they had asymptomatic SARS-CoV-2 infection or anon–COVID-19–related cause for hospitalization or death.

Results: 1695 patients were identified. 22% from 52 sites had documented neurologic involvement. Neurologic deficits were defined as gross impairment in motor, cognitive, or speech and language functions. Psychiatric sequelae were not included. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 [22%]) compared with those without (113 [8%]). Neurologic signs and symptoms differed by age with seizures or status epilepticus most common in children < 5 years and anosmia and/or ageusia most common in patients between ages 13 and 20 years. Most patients with and without neurologic involvement were discharged alive (351 [96%] and 1322 [99%], respectively. 43 (12%) had life-threatening neurologic involvement associated with COVID-19. Life threatening neurologic conditions included severe encephalopathy (n = 15; 5 with white-matter hyperintensities and splenial lesions), acute ischemic or hemorrhagic stroke (n = 12), acute CNS infection/ADEM (n = 8), acute fulminant cerebral oedema (n = 4), and GBS (n = 4). Eight patients with stroke had underlying risk factors (as arteriovenous malformation). Four patients were previously healthy and did not have stroke risk factors. Children with life-threatening neurologic disease were more likely to undergo lumbar puncture, head CT and MRI. CSF results were unremarkable. Patients with life-threatening vs non–life-threatening neurologic involvement had higher neutrophil-to-lymphocyte ratios, and higher D-dimer. In patients who developed life-threatening neurologic involvement, 11 (26%) died and 17 (40%) were discharged from hospital with new neurologic deficits. Of survivors with new deficits, 16 (94%) were previously healthy, none had prior neurologic disorders, 7 (41%) met MIS-C criteria 14 (82%) required rehabilitative services on discharge.

Association of COVID-19 neurologic involvement with fatality: Fourteen patients with COVID-19 neurologic involvement died in the hospital. Causes included cardiorespiratory disease, cardiac arrest, multiorgan failure, acute fulminant cerebral edema, status epilepticus with cardiac arrest, and severe encephalopathy.

Discussion: 22% of the patients had neurological involvement. Approximately half of patients with and without neurologic involvement were previously healthy. 43 patients (12%) with neurological involvement, developed a range of life-threatening neurologic conditions. 66% of these patients had unfavorable outcomes, including death or new neurologic disability at hospital discharge. Approximately 1 in 4 patients with neurologic involvement presented with altered awareness or confusion. Five previously healthy patients who presented with severe encephalopathy, focal neurologic deficits, and visual hallucinations and had diffuse abnormal T2 hyperintensities and reduced diffusivity involving the white matter and genu or splenium of the corpus callosum on MRI. T. Three patients had unfavorable outcomes (1 died and 2 were discharged with new deficits). Seven patients had probable acute CNS infection.

Limitations: Neurologic involvement were identified only at reporting hospitals and may not accurately reflect the true range and severity of COVID-19 neurologic involvement. Neurologic presentations could be due to exacerbation of underlying neurologic conditions. Not all patients underwent neuroimaging and image acquisition was not standardized. May not have captured certain variables completely, such as the indications for procedures (eg, lumbar puncture). Some neurologic symptoms (eg, anosmia) may be underreported in very young patients. Non-standardized diagnostic workups performed under routine clinical conditions may have missed non–COVID-19–related causes of life-threatening neurological. Standardized and validated assessments of neurologic outcomes at or after hospital discharge were not performed. This is not a prospective cohort study but a case series.

Conclusions: neurologic involvement was common in children and adolescents with COVID-19–related hospitalization and is mostly transient. A spectrum of life-threatening neurologic involvement infrequently occurred and was associated with more extreme inflammation and severe sequelae. Long-term follow-up of paediatric patients with COVID-19–related neurologic involvement is needed to evaluate effects on cognition and development.

Abrams, JBelay, ELancetChildAdolescHealthFactors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study9 Mar 2021USANorth America1080Clinical - PIMS-TShttps://doi.org/10.1016/S2352-4642(21)00050-X
Soriana-Arandes, ASoler-Palacin, PClin. Infect. Dis.Household SARS-CoV-2 transmission and children: a network prospective study,12 mar 2021SpainEurope1040Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciab228

Introduction : This is a prospective observational study of Covid 19 positive children (<16 years) in the Catalonian region of Spain from July 1st 2020 to October 30th 2020.

Methods : 120 paediatricians across primary, secondary, public and private care recorded data on paediatric Covid 19 cases. Positive cases were by RT-PCR for all of study but RT-PCR and antigen testing during last week of study. Paediatricians enrolled all positive cases seen in their daily practice up to first positive 5 cases per day. Contact tracing was carried out by the study group.

A paediatric index case was when the child was the first symptomatic person in the household. A paediatric secondary case was when someone else in the household had a positive test before the child. A primary paediatric case, was when no other household contact apart from child tested positive. The study period was spilt into summer time (July 1st to Sept 15th 2020) and school time (sept 15th to October 31st).

Results: During the study period, 6.4% (26,665/417,578) of SARS-CoV-2 RT-PCRs in individuals younger than 16 years tested positive in the region. 4.9%, (1309/26,665) of these patients were enrolled, with 1040 with complete, clinical, epidemiological, and microbiological data reported on. 547 occurred during summer, with 493 in school period.

Nearly half the paediatric cases (491/1040) were asymptomatic. 52.8%, (549/1040) had mild symptoms and 2.6% (27) children required hospitalisation.

Across the whole study time period, 72.7% (756/1040) of children were cases secondary to an adult case, and 5.0% (52/1040) were secondary to another child, with 7.7% (80/1040) of children deemed household index cases. The remaining 14.6% (152/1040) were primary cases.

Even during school time, paediatric cases were much more likely to be secondary cases from household transmission (69.4%) rather than index case 8.3%. [Statistical data comparing summer and school periods not shown, raw numbers only]

Conclusions : Similar to previous studies, this study demonstrates that within their households, most paediatric COVID-19 cases were secondary to an adult case. The secondary attack rate was significantly lower in households where children rather than adults had transmitted SARS Cov2, and was even lower during the school period.

Jordan, IGratacos, EClin. Infect. Dis.Transmission of SARS-CoV-2 infection among children in summer schools applying stringent control measures in Barcelona, Spain12 03 2021SpainEurope30Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab227/6168543

In this prospective study from Barcelona, Spain, SARS-CoV-2 transmission at summer schools was assessed during the 5-week period from June 29th to July 31st, 2020.

Study details

All children aged 3-15 y.o. and staff >16 y.o. attending summer schools in Barelona Metropolitan Region were eligible for the study. Transmission mitigation measures were in place at all schools including universal masking (for all >6 y.o.), frequent handwashing, organisation of students into small groups ("bubbles" of 8-14 individuals) and most activities were conducted outdoors. Community transmission was low during the study period. Index cases attending school were identified either through active surveillance with weekly saliva PCR testing (at 22 summer schools) or through the regional (Catalonia) health surveillance symptoms via symptom-based testing or contact tracing from a positive community case (an additional 18 summer schools). Once an index case was diagnosed, all close school contacts were assessed with a COVID-19 symptom questionnaire and nasopharyngeal swabs were tested for SARS-CoV-2 PCR on day 0, 7 & 14. Secondary attack rate was calculated, and effective reproduction number (Re) was determined and compared with Re in the surrounding community.

Findings

Amongst 1905 participants (1509 students) in the 22 summer schools conducting active surveillance, 12 index cases (9 students, 3 staff) were identified. An additional 27 index cases (21 students, 6 staff) were identified through the local health service (960 individuals attending 18 other schools). The number of index cases within individual schools corresponded to the prevalence of SARS-CoV-2 infection in the district surrounding the school.

Of the 39 total index cases (30 students, 9 staff), 253 close contacts were identified of whom 230 (90.1%) consented to participation and provided samples. In total 12/253 (4.7%) contacts were confirmed to have been infected with SARS-CoV-2 infection. There were 9 cases student to student transmission, 1 of student to staff and 2 of staff to student. The Re in summer schools was 0.3, lower than in the general population during the study period where Re ranged from 1.7 to 2.0.

Discussion

The findings here are consistent with data from a large number of other studies that suggest, in the presence of appropriate mitigation measures, transmission of SARS-CoV-2 within schools is low compared to transmission in the surrounding community. A major strength of this study is the repeated PCR testing of all contacts regardless of symptoms, allowing for robust identification of all secondary cases. Interestingly, the authors plan to conduct further analysis of the close contacts in this study using SARS-CoV-2 serology testing of saliva samples at 5 weeks following exposure. The authors highlight the value of organising students into small "bubbles" which facilitated timely and comprehensive contact tracing as well as allowing quarantine of all-contacts with minimal disruption to other students. This study provides further evidence that in-school transmission is not a primary driver of the pandemic and supports policy for schools re-opening with appropriate mitigation measures.

Williamson, EKuper, HMedRxivOpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study08 Mar 2021 EnglandEurope2624353Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.08.21253112v1.full.pdf+html

This article is a pre-print and has not yet been peer reviewed.

This cohort study by Williamson et al., (2020) assessed the association between learning disability and the risk of hospitalisation and mortality from COVID-19 in adults and children in the UK. The primary outcome for this study was COVID-19 related death and COVID-19 related hospitalisation.

Background: Data from the first wave of COVID-19 showed that people with learning disability were at higher risk from mortality when compared to the rest of the population. The Oxford RCGP Research and Surveillance Centre documented an odds ratio of 1.96 (95%CI 1.22-3.18) for mortality in the first wave in the UK for those with learning disabilities compared to those without. Another study also documented that adults with Down syndrome had a hazard ratio of 10.4% (95%CI 7.1-15.2) for COVID death. However, there is a lack of data documenting the risk of COVID-19 related deaths amongst individuals with milder learning disabilities, in both adults and children. The UK national recommendation included those with severe disabilities to be included in the first 6 priority groups for vaccination. However, those with milder learning disabilities were not included.

Methods: This is a two-population observational cohort study conducted in England which included 2,624,353 children under the age of 16 and was conducted in 2 waves. The first wave between 1st March 2020 – 31st August 2020 and the second wave between 1st September 2020 -31 December 2020. These periods of time reflect the two main timeframes in which COVID-19 infection rates were highest in the UK. Participants were recruited from GP surgeries which employed the TPP system for data collection.

Statistical analyses were conducted thoroughly for the adult population. However, data for COVID-19 related deaths in those under 16 was omitted due to smaller number of outcomes.

Results: Among the 2,624,353 children under 16 included in this study, only 9,114 (0.35%) were identified as being on the learning disability register. Only 907/2635 (34%) of those with Down syndrome were registered on the disability register and only 500/4619 (11%) of those with cerebral palsy were registered on the disability register.

The authors document that there were 281 COVID-19 related hospital admissions in the first wave and 292 in the second wave. However, further details including the separation of this data with individual learning disabilities was not possible due to stringent redaction rules applied to protect patient privacy. However, data on hazard ratios for COVID-19 hospital admission among those under 16 was given. The authors found that being on the learning disability register was associated with an increased hazard ratio of COVID-19 related hospital admissions in both wave 1, HR 5.1 (95%CI 1.9-14.0) and in wave 2, HR 8.8 (95%CI 4.9-15.8). The authors also note that the elevated risk in those under 16 with learning difficulties documented has also been reported in the USA.

The authors concluded that the risk seen among those under 16 suggests that vaccination in this age group warrants further consideration. However, further research is needed to confirm this.

Limitations: Due to redacted information, it was not possible to view the data and evidence for each learning disabilities and their own hazard ratios for COVID-19 hospital related admission. In addition to this, it is not possible to identify everyone with a learning disability through medical records alone and therefore, it is likely that the hazard ratios were underestimated. There were also specific pieces of data missing from the study, particularly ethnicity, although it is not known whether this would have had a meaningful impact on the data.

Comments: Although the data of this study did look at the effects on both adults and children, the discussion was very much based towards adults with learning disabilities and less so for children. This may have been due to the smaller number of outcomes for children when assessing COVID-19 related deaths and full adjustments for comorbidities. It was also difficult to determine how many cases of the hospital admissions were due to reoccurrence in those under 16 as a result of the strict redaction rules for patient privacy.

For results on the adult arm of this study, please refer to study paper.

Telle, KKacelnik, OmedRxivSecondary attack rate of COVID-19 in Norwegian families: A nation-wide register-based study08 MAR 2021NorwayEurope14808Epidemiology - Transmissionhttps://doi.org/10.1101/2021.03.06.21252832

BACKGROUND: understanding transmission among family members by parents and children is vital for containment strategies.

AIM: To compare the SAR in family households when the index case is a child to the SAR when the index case is an adult.

METHODS: register-based cohort study. All families in Norway with at least one parent and one child below age 20 years living at same address on March 1st 2020 where one member, the index case, either parent or child had tested positive for SARS-CoV-2 at any time between March 1st 2020 and January 1st 2021. Family members who tested positive within 7 days of the index case were defined as secondary cases. SAR7 = number of non-index family members who tested positive within seven days after the date index tested positive, divided by all non-index family members x 100. Families where 2 members tested positive on the same date were excluded.

Testing: During the first wave, testing capacity was limited but became easily accessible to anyone with symptoms as well as for close contacts of confirmed cases. Percentage tested was calculated as the number of non-index family members who were tested within seven days after the date when the index family member tested positive, divided by all non-index family members.

RESULTS: The families comprised a total of 26991 individuals (12184 parents, 14808 children). There were 7548 index cases of whom 4964 (66%) were parents and 2584 were children (34%). Among children index cases, 8% were in the 0-6 years and 42% were in age band 17-20 years.

SAR7 was higher when a parent was the index case = 24% (95% CI 24 to 25) compared to 14% (95% CI 13 to 15) when the index case was a child.

If the index case was a child, the highest SRA7 was seen in age band 0 – 6y = 24% (95% CI 20 to 28) with 89% of family members tested. SAR7 dropped to 14 for age bands 7 – 12y (CI 95% 12 – 15) and 13 – 16y (CI95% 13-16) with 86% and 85% of family members tested respectively. It was lowest in age band 17 – 20y at 11% (CI 95% 10 – 13), 66% tested.

The SAR7 among parents was higher when a parent was the index case (35%, 95% CI 33 - 36) than when a child was the index case (15%, 95% CI 14 - 16). The same pattern was found, albeit attenuated, of higher SAR7 among children if the index case was a parent: 21% (95% CI 20 to 22) if a parent was the index case, and 12% (95% CI 11 to 13) if a child was the index case.

As testing became more widely available the percentage of family members tested increased from 20% in April to about 80% in December. There was an associated increase in overall SAR7 but this stabilised at around 20% once the percentage being tested rose above 50% reaching around 80% by December 2020.

Discussion

SARS-CoV-2 infection was introduced in families mainly by parents or by the older children. Transmission within the family was more common from parents and preschool children.

Preschool children may display few or no symptoms, may be less likely to be infected or might not be tested as often as older children and parents because they are more difficult to test. If they are true higher transmitters within families this may be due to more physical contact compared to children in the older age bands. Additional data on SAR at 14 days did not significantly differ from SAR7.

COMMENTS: This is a large, population-based study that appears to show that infected preschool children transmit SARS-CoV-2 to the same extent as parents. Secondary cases may be co-index cases particularly if asymptomatic transmission is not looked for, and because the incubation period varies. The figures may have been affected by differential rates of testing and this was shown by a higher percentage of family members tested if the child was the index case than if parent was index case. Testing may have been more relevant to detect potential transmission from other household members to others at school or at work. This may also have been due to younger children being more difficult to test, higher false negatives or not tested because they may have been regarded as unlikely to pass infection if being kept at home.

Cerami CLin JTmedRxivHigh household transmission of SARS-CoV-2 in the United States: living density, viral load, and disproportionate impact on communities of color12 Mar 2021USNorth America78Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.10.21253173v1.full.pdf

This is a prospective observational study carried out in the Piedmont region of North Carolina, southern United States, between April and October 2020. The study aimed to describe the secondary attack rates and risk factors associated with SARS-CoV-2 transmission in household of individuals with a positive qualitative nasopharyngeal swab for SARS-CoV-2, willing to isolate for a 14-day period and living with at least one household contact, aged > 12 months. The assessment of eligibility and enrolment were completed via phone call. A home visit took place on day 1, for the collection of serology, rapid antibody test, nasopharyngeal (NP) swab and participants self-collected nasal mid-turbinate (NMT) swabs. Follow-up visits to measure viral clearance and viral shedding took place on day 7, 14 and 21. In each one of these follow-up visits, participants self-collected NMT swabs. On day 28, blood samples for serology and rapid antibody test were also taken. A daily symptom diary, from onset until 2 days after resolution was filled in.

NP and NMT were tested following the CDC qRT-PCR protocol that targets the N1, N2 and RP regions of the virus. Where the three assays were positive, the viral load was quantified and further genotypic screening for D614G mutation completed. An in-house ELISA with previously reported high sensitivity and specificity was utilised to determine the total Ig binding to the receptor binding domain of the spike protein of SARS-CoV-2. A validated research tool was used to rapidly detect SARS-Cov2-specific IgM and IgG. The bands were read in duplicate by two independent staff members. Discrepancies were resolved through discussion. The primary endpoint was SARS-CoV-2 infection in the household confirmed via real-time PCR of NP and NMT swabs during the follow-up period, or evidence of seroconversion during the study, according to the results of antibody testing. The index case was defined based on a positive qualitative NP swab for SARS-CoV-2 at enrolment, the day of the onset of the symptoms and in some cases, where the latter remained ambiguous, baseline antibody positivity was used as evidence of recent infection. Those with evidence of prior infection were excluded from the analysis. The proportion of household contacts who remained susceptible to SARS-CoV-2 by the end of follow-up was used to calculate the secondary attack rate among household contacts.

Statistical analysis

Data were analysed using a logistic regression model with a random intercept to account for within-household variation to calculate race/ethnicity specific secondary attack rate. The primary analysis assumed that all secondary cases were due to household transmission. Sensitivity analyses excluded secondary cases infected at baseline and those that may have been acquired outside the household, owing to the date of detection (i.e. identified on day 14th or later).

Results

One-hundred and two households were recruited and two were excluded from analysis due to evidence of prior infection in all household members or lack of completion of the baseline questionnaire. The median household size was 3.5 persons. They were enrolled at a median of 6 days (IQR 4 to 7) after the onset of the symptoms of the index case; 52% were females and 42% self-identified as non-white race/ethnicity . Eight percent of the index cases were under 18 years of age (0 to 12 yo: n =2/100; 2%; 13 to 17 yo; n = 6/100; 6%); 46% have completed high school or lower; 28.3% worked in retail/hospitality and 38% had a BMI > 30. Among 204 household contacts, the proportion of females was the same as reported for index cases; 47% self-identified as non-white race/ethnicity; 34.3% were under 18 years of age (0 to 12 yo: 22.5%; 46/204 and 13 to 17 yo: 11.8%; 24/204); 48.5% completed high school or lower; 26.1% worked in retail/hospitality and 32.1 % were reported as having a BMI > 30 Kg/m2.

Those household contacts who tested positive at baseline and had the same environmental exposure than the index case (n = 22) were excluded from the transmission analysis. The overall secondary attack rate was calculated with a denominator of 176 susceptible individuals and reported as 60% (106/176, 95% CI 53%-67%); 73/176 were positive at baseline and classified as secondary cases; 33 additional secondary cases were observed during the follow-up period. Of them, the majority were symptomatic (82%) and occurred within the first 7 days after enrolment. Where the secondary cases were restricted to those that were negative at baseline, the secondary attack rate was 32%; and where the case definition was further limited to those who acquire the infection within the first 13 days post-enrolment, the secondary case ranged between 52 and 57%. Index cases with a high nasopharyngeal viral load at enrolment, were more likely to transmit the virus to their household contacts during the follow-up period (OR 4.9; 95CI 1.3 -18). Although no difference in viral load was observed according to race/ethnicity, compared to white index cases, non-white index cases were more likely to transmit virus within their household (secondary attack rate 70%; 95 CI 59-79%). Other risk factors for household transmission included higher living density or > 3 household members living in a home with less than 6 rooms (OR 5.9, 95% CI 1.3-27; secondary attack rate 91%; 95% CI 71-98%); partner of the index case (OR 4.1, 95% CI 1.3-13) and BMI > 30 Kg/m2 (OR: 5.4, 95% CI 1.4-21)).

Comments

This study is reported to be the largest single site and ethnically diverse prospective observational study on household transmission on SARS-CoV-2, combining weekly PCR testing for 21 days and antibody detection on day 28 post-enrolment. Its findings support previous modelling studies, as a great proportion of cases occur within 7 days of exposure, and also support current 14-day quarantine policies for the entire household (calculated from the day of symptom onset of the index case), as 2/3 of the household contacts were already infected at enrolment and 94% of secondary cases were detected within 14 days from symptom onset of the index case.

In household contacts who self-identified as non-white, risk factors such as obesity and overcrowding were more common than in white counterparts. The number of household contacts positive at baseline with a common exposure as the index case is perhaps higher than reported, but the authors state that according to their experience, a substantial number of these exposures still occur in the immediate household or among family members. Interestingly, households where high viral loads were detected, were more likely to have other members with high viral loads. This may translate in higher risk of disease severity. Although the sample size remained insufficient to investigate the drivers of increased transmission household transmission in non-white households, the contributions of this papers to the understanding of the impact of ethnicity and other social determinants of health on disease transmission should not be overlooked.

Clouser, KAschner, JJ Pediatric Infect Dis SocShort-Term Outcomes After Multisystem Inflammatory Syndrome in Children Treatment19 Nov 2020USANorth America20Clinical - PIMS-TShttps://academic.oup.com/jpids/article/10/1/52/5992300

This paper describes features of 20 patients admitted to hospital in New Jersey and diagnosed with multisystem inflammatory syndrome in children (MIS-C). The study period ran from 15 April to 20 June 2020 and data was collected retrospectively by reviewing medical records.

Study population: The children ranged from <1 year to 18 years with a mean of 7.3 years. 55% were male. 40% were Hispanic, 20% Caucasian, 20% Asian and 15% African American (the degree to which this reflects the local population was not noted)

Clinical features: 50% of patients were admitted to a general paediatric ward and 50% to intensive care. All patients had fever at presentation. 65% had cardiac abnormalities (raised BNP, dilated coronary arteries and/or decreased ejection fraction), 55% had gastrointestinal symptoms, 55% had conjunctivitis and 50% had a rash. 18 of the 20 patients had an initial echocardiogram and findings included pericardial effusion and decreased myocardial function – 50% had normal study. There were no cases of coronary artery dilation on initial scan but 1 patient had developed this on follow up scan.

Treatment: 50% of patients received both corticosteroids and IVIG, 15% received corticosteroid monotherapy and 10% received IVIG monotherapy. The remaining 25% were successfully treated with supportive care only. 25% required vasoactive support.

Short-term outcomes: The mean length of stay was 4.6 days. All but one patient (95%) were discharged home without any activity limitation. One patient required oxygen on discharge, which was discontinued within 30 days. By 30 days after treatment, all patients were described as having returned to normal activity for age.

Discussion: This study highlights the spectrum of severity for MIS-C and is encouraging in its report of 100% recovery to baseline, with no ongoing sequelae (at least in the short-term period analysed).

Bhopal, S Bhopal, RLancet Child Adolesc HealthChildren and young people remain at low risk of COVID-19 mortality10 Mar 2021United kingdomInternational259Epidemiology - Disease Burdenhttps://doi.org/10.1016/S2352-4642(21)00066-3

Summary: This paper reviewed Covid-19 mortality statistics (259 deaths) from children in 7 countries to February 2021; updating the previous published data from the group. Data from the following countries was obtained: USA, UK, Italy, Germany, Spain, France, and South Korea. The group found deaths from COVID-19 in children remained rare up to February, 2021, at 0·19 per 100 000 population, comprising 0·54% of the estimated total mortality from all causes in a normal year. Deaths from COVID-19 were relatively more frequent in older children compared with younger age groups.

They cautioned that differences between countries need careful interpretation due to: small numbers, possible differences in case definition and death reporting mechanisms, and the related condition paediatric inflammatory multisystem syndrome temporally associated with COVID-19, which might not always, be captured in these data.

The highest rate of deaths per 100 000 children was in Spain (0·64 for children aged 0–9 years; 0·53 for children aged 10–19 years) and the lowest in South Korea (0 deaths for children aged 0–9 years and 10–19 years). The UK data showed 7 Covid-19 deaths in children between 0-9 years and 22 10-19 years, representing rates of 0.09 and 0.29 respectively.

Conclusions: Overall, there was no clear evidence of a trend of increasing mortality throughout the period up to February, 2021, but additional deaths have clearly occurred in children and young people during periods of high community transmission, particularly in Spain, Germany, and Italy.

Although COVID-19 mortality data are contemporary and likely to accurately represent the reality in these countries, it is not possible to access such data for other causes of death. The authors used estimates from the Global Burden of Disease 2017 database, which does not account for seasonality or changes in mortality patterns in this pandemic year.

Therefore, the very low mortality described from COVID-19 compared with all-causes is likely to be of the correct magnitude. With the caveat that some children at high risk might be using extreme so-called shielding measures, children are overall not becoming seriously unwell with COVID-19,and data from England show that children are also not requiring intensive care in large numbers.Some of the measures to counteract the devastating impact of the virus on adults are having unintended negative consequences for children. They continue to caution that the virus is likely to change over time, and that these conclusions should be kept under review.

Cordery, RSriskandan, SPreprint in medRxivTransmission of SARS-CoV-2 by children attending school. Interim report on an observational, longitudinal sampling study of infected children, contacts, and the environment09 Mar 2021United KingdomEurope55Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.08.21252839v1

This article is a preprint and has not been peer-reviewed.

This is an interim report providing a descriptive analysis of the initial TraCK (Transmission of Coronavirus-19 in Kids) study findings from October-December 2020. This is an observational study conducted in nurseries and schools in London, UK looking at SARS-CoV-2 transmission by children in their school and home environments. It aims to provide a more detailed analysis on transmission risk and possible mechanisms by intercepting individual cases and performing longitudinal sampling of cases, contacts and their environment.

For context, at the time of the study, schools throughout England were operating under additional Covid-19 prevention measures such as social distancing and mask-wearing in certain schools. Any child who tested positive for SARS-CoV-2 had to self-isolate from school for 14 days, as did their close classroom contacts. Household contacts of cases were also required to remain at home in quarantine during this period. In early years and primary school, close contacts consisted of the whole class. In secondary school, close contacts were defined according to proximity and duration of contact.

Methods : From October 2020, nurseries and schools within the London region that reported a new case of SARS-CoV-2 infection in a pupil were asked to take part in the study. Cases, their households and contacts at school were recruited by gaining consent from parents/guardians. The study included children aged 2-18 years. There were 4 categories of participants: 1) Cases - children who tested positive for SARS-CoV-2 infection. 2) Bubble contacts - children who were in close contact.i.e the same “bubble” as the Case and had to isolate from school for 14 days. 3) School contact - children in a class within the same school that was adjacent in terms of age-group or proximity. These children remained at school. 4) Household contacts. Cases and contacts underwent regular RT-PCR testing including nose and throat swabs (14 days for cases and 28 days for contacts). Swabs were taken from multiple surfaces at home and school and air sampling was conducted at both sites. Environmental samples were performed weekly for up to 28 days and tested using RT-PCR.

Results : From October-December 2020, 5 cases of SARS-CoV-2 were recruited to the study from 5 different schools. The median age of the children who tested positive was 11 years old. In addition to these 5 Cases, the study included 13 Bubble contacts, 29 School contacts and 23 Household contacts (8 children and 15 adults). Importantly, there was no onward transmission of the virus to Bubble contacts detected in the study. There was also no evidence of more widespread transmission of the virus amongst other School contacts who remained at school. In one secondary school, a cluster of 3 asymptomatic school contacts was unexpectedly detected in week 2. The cluster was considered unlikely to be related to the study’s index case as they had previously had negative tests in week 1 of the study. Among household contacts, 3 adults and 1 child tested positive in week 1 with adults in these households considered to be the index case. One adult tested positive in week 2 and this was felt to be the only evidence of child-to-adult transmission within any of the households studied. There was also one case of child-to-child transmission in which a teenager, who was sharing a bedroom with the index case, tested positive. Environmental sampling showed limited contamination of the virus within the school environment but did show surface contamination amongst household items in households where children had the highest viral loads, particularly on digital equipment and electronic toys.

Discussion: In the context of the Covid-19 prevention measures at the time, this study did not detect transmission of the virus to contacts within the school environment. There was also no evidence of significant environmental contamination within the school setting. Although small, the detailed nature of this study may help inform future policies and interventions. The authors note the difficulties with participation and recruitment, particularly of Bubble contacts, which may have resulted in missed transmission events

Rottenstreich, APorat, SmedRxivEfficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination11 Mar 2021IsraelMiddle East20Neonatalhttps://doi.org/10.1101/2021.03.11.21253352

This prospective single-centre study, based at the Hadassah Medical Center in Jerusalem, Israel investigated 20 parturient-mother/newborn dyads. Women who were admitted for delivery in Feb 2021 and who had received two doses of SARS-CoV-2 BNT162b2 mRNA (Pfizer) vaccine during the third trimester of pregnancy were recruited. The median maternal age was 32 years, with a median gestational age of 393/7 weeks at the time of delivery. The median time intervals between the first and second doses of vaccine administration and delivery was 33 [IQR 30-37] and 11 [IQR 9-15] days, respectively. Spike protein S1/S2 IgG, RBD- specific IgG levels and SARS-CoV-2 IgM were measured in maternal and cord blood sera.

All women and infants were found to be positive for anti S- and anti-RBD-specific IgG. SARS-CoV-2 IgM antibodies were detected in 6 (30.0%) parturients and were not detected in any of the infants. The median placental transfer ratios of anti-S and anti-RBD specific IgG were 0.44 [IQR 0.25-0.61] and 0.34 [IQR 0.27-0.56], respectively. SARS-CoV-2 anti-S and anti-RBD-specific IgG levels in maternal sera were positively correlated with their respective concentrations in cord blood (P<0.001 and P <0.001, respectively. The levels of both SARS-CoV-2 anti-S and anti-RBD specific IgG titres in cord blood directly correlated with the time interval between the first vaccine dose and delivery, which is in accord with studies of respiratory syncytial virus vaccine.

The authors comment that the placental transfer ratios were lower than those reported in studies of vaccine-elicited antibodies to influenza, pertussis, measles, rubella and hepatitis B, in which transfer ratios ranging from 0.8 to 1.7 have been reported. The finding is consistent with those of another recent study of pregnant women who had contracted covid-19, in which low placental transfer of anti–SARS-CoV-2 IgG [9] was reported.

The authors further speculate that, given the observed kinetics of the immunoglobulin response both in pregnant women infected with the SARS-CoV-2 virus and in non-pregnant recipients of SARS-CoV-2 mRNA vaccines, vaccination early in the second trimester might be the optimal time to provide “adequate” immunity to both mother and neonate.

Gray, KEdlow, AmedRxivCOVID-19 vaccine response in pregnant and lactating women: a cohort study07 Mar 2021USANorth America10Neonatalhttps://doi.org/10.1101/2021.03.07.21253094

A prospective cohort study conducted at Massachusetts General Hospital and Brigham and Women’s Hospital, working in conjunction with Harvard Medical School, Boston, has evaluated the immunogenicity and “reactogenicity” of covid-19 mRNA vaccination in pregnant and lactating women, comparing the results with those of 37 pregnant women who had been diagnosed with covid-19 infection 4-12 weeks prior to recruitment to the study.

The study population comprised 131 women who appear to have been primarily healthcare workers from the participating hospitals. The majority were White, non-Hispanic and in their mid-30s; 84 pregnant, 31 lactating, and 16 non-pregnant subjects were enrolled. Either the Pfizer or the Moderna vaccine was administered to each of the participants, with an approximately 50-50 split between the two vaccines. In the pregnant subjects 46% received the vaccine during the second trimester and 40% during the third trimester. Titres of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at the following timepoints: baseline, prior to the 2nd vaccine dose, 2-6 weeks post 2nd vaccine and, for the pregnant group, at the time of delivery. “Reactogenicity” was evaluated by means of a questionnaire which recorded information about vaccine side effects after each dose, such as injection site soreness, injection site skin reaction/rash, headache, myalgias, fatigue, fever and chills. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups. Of the pregnant participants, the mean gestational age at first vaccine dose was 23.2 weeks but the inter-quartile ranges were 16.3 - 32.1 weeks.

The main outcomes were that vaccine-induced immune responses were equivalent in the serum of pregnant, lactating and non-pregnant women and that all titres were higher than those induced by SARS-CoV-2 infection during pregnancy. A significant rise in IgG, IgM and IgA to all antigens was observed between pre-vaccination serum samples and those taken prior to the second vaccine dose. A further rise in IgG levels following the second vaccine dose but there was no additional rise in IgM and IgA. Similar responses were observed in the breast milk of lactating women. Vaccine-generated antibodies were present in all umbilical cord blood samples. No differences were noted in reactogenicity across the groups.

The authors concluded that “robust” humoral immunity, which is greater than the response to natural infection, is generated by these covid-19 mRNA vaccines in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Further, immune transfer to neonates occurred via both the placenta and breastmilk. The authors acknowledge that potential risks to the fetus of the vaccine were not evaluated and that further studies in larger populations, across gestational ages, are required.

Golan, YGaw, SmedRxivImmune response during lactation after anti-SARS-CoV2 mRNA vaccine09 Mar 2021USANorth America0Neonatalhttps://doi.org/10.1101/2021.03.09.21253241

A prospective study from the University of California measured maternal and neonatal SARS-CoV-2 antibody levels in maternal serum (anti-SARS-CoV-2 IgG and IgM), and breast milk (anti-SARS-CoV-2 RBD IgA), after vaccination with anti-covid-19 mRNA-based vaccines during lactation. Pylon 3D automated immunoassay was used for IgG and IgM measurements and ELISA assay was used for IgA. The subjects were 23 “lactating individuals”, 9 of whom were vaccinated with the mRNA-1273 vaccine (Moderna) and 14 with the BNT162b2 (Pfizer) vaccine. Demographic details of the subjects, and information concerning the duration of lactation prior to vaccination, are not given. The number of plasma samples assayed were: 7 pre-vaccine, 12 post first vaccine and 14 post second vaccine; it is not clear how many of these samples were taken from subjects vaccinated with the Moderna vaccine and how many were taken from those vaccinated with the Pfizer. The breast milk assays used ELISA and similar sample numbers to the plasma assays at each time point seem to have been assayed, but for each of the two vaccines. In addition, three milk samples collected from “lactating individuals” who had previously contracted SARS-CoV-2 virus infections were assayed. Information concerning the timing of these infections prior to milk sample collection is not given.

The findings were that the levels of both IgG and IgM were significantly increased in maternal plasma samples on the day of the second vaccine dose when compared with pre-vaccine samples but only plasma IgG levels were significantly higher when comparing those taken prior to the second dose with those taken four weeks after the second dose. With regard to breast milk, anti-SARS-CoV2-RBD IgA antibodies were present 3-4 weeks after administration of both the Moderna and the Pfizer vaccines. The levels of anti-SARS-CoV2-RBD IgA antibody in milk of vaccinated individuals were not significantly different from those measured in the breast milk taken from the three participants who had a previous history of SARS-CoV-2 infection.

The authors concluded that the administration of anti-covid-19 mRNA vaccines during lactation leads to increased anti-SARS-CoV2 IgM and IgG levels in the plasma of lactating mothers and increased anti-SARS-CoV2-RBD IgA levels in human milk. They recommend that, pending long-term outcome studies, lactating women who receive the vaccine should continue breastfeeding their infant human milk to allow continuing transfer of anti-SARS-CoV-2 IgA antibodies to the neonate.

Golan, YGaw, SmedRxivCOVID-19 mRNA vaccine is not detected in human milk05 Mar 2021USANorth America0Neonatalhttps://doi.org/10.1101/2021.03.05.21252998

A second study from the group based at the University of California studied breast milk samples collected from six lactating women at intervals varying between four and 48 hours after they had received a dose of an mRNA covid-19 vaccine – five Pfizer and one Moderna. No demographics for the population sample are given. Of the 15 samples tested, two were taken prior to a first vaccination, 11 were taken 4-48 hours after a first vaccination and two were taken following a second vaccination. RT-qPCR was performed in triplicate using specific primers targeting the vaccines’ mRNA for SARS-CoV-2 spike protein. Pre-vaccine breast milk samples spiked with mRNA-1273 (Moderna) vaccine acted as positive controls and non-spiked pre-vaccine samples served as negative controls.

The study detected no evidence of vaccine mRNA in any of the post-vaccine breast milk samples. The authors conclude that these findings support international guideline recommendations that lactating individuals who receive the anti-covid-19 mRNA-based vaccine should continue to breastfeed their infants uninterrupted. The authors also acknowledge that the number of specimens tested was small and that studies using larger population sizes are required.

M Hall March 2021

References

1. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ 2020;370:m3320.

2. FIGO Statement: COVID-19 Vaccination for Pregnant and Breastfeeding Women

https://www.figo.org/covid-19-vaccination-pregnant-and-breastfeeding-women

Doyle, TBlackmore, CMMWR Morb Mortal Wkly RepCOVID-19 in Primary and Secondary School Settings During the First Semester of School Reopening — Florida, August–December 202026 Mar 2021USANorth America170Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm7012e2

This Early Release Report was posted on the MMWR website of the USA Department of Health and Human Services / Centers for Disease Control and Prevention on 19 March 2021. It is an analysis of data collected by the Florida Department of Health, relating to school-related cases and outbreaks of COVID-19 following the resumption of in-person instruction.

In the 2020–21 school year, 2,809,553 students were enrolled in 6,800 schools in Florida. All schools in the state suspended in-person instruction by 20 March 2020 and began to re-open in August 2020.

COVID-19 cases were identified using nucleic acid amplification or antigen detection of SARS-CoV-2, in symptomatic or asymptomatic people. School-based outbreaks were defined as two or more epidemiologically linked school-related cases.

Between 10 August and 21 December 2020, 63,654 cases of COVID-19 were identified in young people aged 5–17 years. During the same time- period, 34,959 school-related COVID-19 cases were reported: 25,094 (72%) in students and 9,630 (28%) in staff. Therefore, 39.4% of all cases reported in school-age children, were school-related. School-related cases in children occurred in <1% (25,094 of 2,809,553) of all registered students.

The median age of the children with COVID-19 was 13 years (IQR 9–15 years). Higher case rates were reported in school students from counties with the lowest population, districts re-opening schools earlier in August 2020 and those districts that did not mandate mask-wearing.

Analysis of a subset of 562 of the 695 school-based outbreaks, identified activities outside the classroom setting as being associated with 20% of the outbreaks. These activities included sports, social gatherings and transportation.

Of the school-related cases, 101 children required hospital admission and there were no deaths. 219 school staff were admitted to hospital and there were 13 deaths. Of these, 9 deaths occurred in staff with “additional risk factors” including obesity (7), age >60 years (4) and other chronic conditions (4).

The authors conclude that resumption of in-person schooling can be achieved without causing a rapid spread of COVID-19. Alongside this they emphasise that community-level and school-based measures are essential to reduce SARS-CoV-2 transmission in school settings.

This report includes no analysis of socio-economic, or racial and heritage factors associated with infection risk. The authors also offer no further conclusions about the substantial infection rate and death toll in the school staff

Doron, SCiaranello, APre-printWeekly SARS-CoV-2 screening of asymptomatic students and staff to guide and evaluate strategies for safer in-person learning30 Mar 2021United StatesNorth America2403Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.20.21253976v1

This pre-print article reports the results of a Covid-19 screening programme conducted in one school district in Massachusetts, US in the autumn of 2020. The study was conducted at a time when schools in the district were operating hybrid learning in which the school week was divided between in-person and remote learning. Schools had also adopted Covid-19 prevention measures and community testing for those with symptoms was in place. The study aimed to evaluate the incidence of asymptomatic COVID-19 in schools and the risk of in-school transmission through widespread screening.

Students and staff from one middle school and one high school were invited to participate. Students were aged 11-18 years and of the 2403 eligible students, 58-77% participated weekly. 73-83% of the 921 eligible staff participated. Weekly pooled PCR testing of saliva was performed for 18 weeks. Participant numbers varied on a weekly basis due to reasons such as school absence and forgotten samples. Individual diagnostic testing (RT-PCR) was performed to confirm positive cases and contact tracing was then conducted.

Rates of COVID-19 in the Massachusetts district increased from 5 to 32/100,000/day during the 18-week period. During the study, there were 126 positive cases of Covid-19 infection in the participating schools. 37 were identified through the screening program with the rest identified through outside testing. There was only one cluster of in-school transmission identified in the program and this was amongst 4 staff members. In another week, 7 positive asymptomatic cases in non-close contacts were identified in one school. In both cases, risk factors for transmission within the schools were identified whilst early measures to prevent further spread were implemented. In the cluster case, risk factors included lack of social distancing in staff areas whilst eating as well as high-traffic areas and shared offices.

They study concludes that in-school transmission is rare as long as infection prevention measures are adhered to. They add that widespread screening can help early identification of cases and that their implementation could further support the safe operation of schools during the pandemic. They acknowledge the limitations of screening programs such as the significant associated costs and the need for participation and acceptance from students and staff.

The Efficacy and Safety of Covid-19 mRNA Vaccines Administered During Pregnancy and Lactation

A review of four recent publications

Pregnancy and lactation were specified as exclusion criteria for recruitment to all of the clinical trials of covid-19 vaccines which have, to date, been approved by the MRHA, the EMA and the FDA. However, while recognising the gap in knowledge concerning the efficacy and safety of covid-19 vaccines in pregnancy and lactation, these regulatory bodies have all recommended that the covid-19 vaccines should be offered to those pregnant individuals who are either at high risk of exposure to SARS-CoV-2 virus or who are at high risk of complications from the disease, preferably after discussion with their health care providers.

Over the past few months evidence has been accumulating that covid-19 infection presents an increased risk of morbidity and mortality to pregnant women and an increased risk of preterm delivery and NICU admission to their babies.1 On 2nd March 2021, the International Federation of Gynecology and Obstetrics (FIGO), having gained some reassurance from animal studies and from a preliminary report that a US Study of covid-19 vaccination in 20,000 pregnant women had identified “no alarming signs”, issued the following position statement: “It is now established that pregnant women are at increased risk of severe COVID-19-associated illness compared with non-pregnant women…… FIGO, therefore, considers that there are no risks – actual or theoretical – that would outweigh the potential benefits of vaccination for pregnant women. We support offering COVID-19 vaccination to pregnant and breastfeeding women”.2

Notwithstanding this recommendation, there is still a need to convert the expectation of efficacy and safety of vaccination in pregnancy and lactation into evidence. A number of recently-published papers, all relating to mRNA vaccines, have reported on studies which were designed to help fill these knowledge gaps. The studies are mostly of small sample size and some lack detail concerning aspects such as study population and methodology but, when combined, they appear to provide some reassurance concerning short-term safety issues relating to vaccination during both pregnancy and lactation, together with evidence of positive immunological benefits for mother, fetus and baby.

A summary of the main findings of these papers is as follows:

1. Both the Moderna and the Pfizer vaccines induced IgG, IgM and IgA antibodies to SARS-CoV-2 receptor-binding domains (RBD) and to the viral spike proteins when the vaccine was administered to pregnant mothers, irrespective of the trimester of pregnancy.

2. IgG, but not IgM or IgA, concentrations showed a further increase after the second dose of the vaccine.

3. There was a positive correlation between maternal serum antibody and cord blood antibody concentrations.

4. For both vaccines, there was a positive correlation between the concentrations of SARS-CoV-2 IgG titres in cord blood and the time interval between the first vaccine dose and delivery.

5. Both vaccines induced anti-SARS-CoV-2 RBD-specific IgA antibodies in the breast milk of lactating mothers and spike-specific IgG, IgM and IgA antibodies. Only IgG showed a further increase following the second vaccine.

6. No evidence of vaccine mRNA was found in a small study of lactating women who received either the Moderna or the Pfizer vaccines.

7. Placental transfer ratios of SARS-CoV-2 antibodies may be lower than those of some other vaccines.

Different laboratory methodologies were used in these studies and different units of measurement of antibody concentrations were used which precludes a direct comparison of the measurements. The papers have not yet been subject to peer review and this must be borne in mind when interpreting the validity of the reported findings. None of the studies report on longer term outcomes.

Volpp, KNeatherlin, JMMWRMinimal SARS-CoV-2 Transmission After Implementation of a Comprehensive Mitigation Strategy at a School - New Jersey, August 20-November 27, 2020.19 03 2021USANorth America775Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7011a2.htm

This study was done in a private boarding school for Grade 9-12 students (age 14-18y) in the USA: there were 520 boarding pupils, 255 commuter students and 405 staff.

The mitigation strategy was comprehensive and included:

Testing and Screening: Quarantine for 2 weeks before travelling to school + proof of negative RT-PCR result, monitor for symptoms daily and 2X daily temperature checks throughout, 2X weekly RT-PCR test for all staff and pupils, rapid antigen testing if anyone had symptoms and they were quarantined until confirmatory RT-PCR

Distancing/ Physical barriers: Student numbers in the classroom reduced by a rotated proportion learning online, masks worn at all times outside of bedrooms, meals eaten outside, enhanced ventilation systems in communal areas, proximity tracing devices worn at all times

Compliance: all students and staff had to agree to comply with the mitigation strategies, encouraged by ongoing educational and motivating messages, breaking of the rules resulted in a sanction. 10 students received 3 sanctions and were sent home for 2 weeks.

Results: 8,955 RT-PCR on staff salivary samples, 17 (0.18%) positive (+2 positive in off-site testing). 12,494 RT-PCR on student nasal swab specimens, 8 (0.6%) positive. 66 antigen tests performed for COVID-19 like symptoms: all negative. Case investigation of the 27 positive tests showed an off-campus contact as the likely source for 25 of these infections; 2 were in boarding pupils were plausibly caused by secondary transmission on campus as no other source of infection was found. All contacts (from proximity tracing device data) of the 27 cases were quarantined for 14 days and none tested positive suggesting that the mitigation strategies were effective. During the study period the incidence of COVID-19 in the local area was increasing.

This study demonstrates that SARS-CoV-2 transmission can be considerably reduced by the measures implemented.

The authors themselves note that the costs of the proximity tracing devices and of the testing and management programme are probably not affordable in many settings. Though physical distancing, mask wearing and hand hygiene is already known to be effective, teenagers, who have no sanctions to fear, may be less likely (even unlikely) to abide by these rules and so it is difficult to know how far the results of the study are useful for most schools and communities.

Cotugno, NPalma, PCell Reports 34 (11) (no pagination) (108852). Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies16 Mar 2021ItalyEurope66Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S2211124721001662

This paper studied humoral and cellular immune responses in 66 SARS-CoV-2 infected children (mean age (SD) 6.8y (5.4); 41 male), presenting to a single centre in Italy between March-April 2020, and compared them to 11 non-infected controls admitted with Covid-like symptoms who tested negative on 2 consecutive NP samples.

Blood samples were taken at admission and after approximately 48hrs and 7 days. NPS for viral load was taken every 48hrs until undetectable. The presence (37/66) or absence (29/66) of neutralizing antibodies (NAbs) did not correlate with disease severity at presentation. There was an inverse correlation between SARS-CoV-2 IgG and NAbs and viral load, time taken to clear the virus and in vitro viral replication. Evidence is presented for specific B and T cell responses in NAb+ cases compared to NAb-. Serum proteomic analysis showed 2 proteins associated with lymphocyte activation were raised in NAb+ cases. The important findings in this study are that not all children develop NAbs but those that do carry a lower viral load, achieve viral clearance sooner and may be less infective, as measured in vitro.

Hershow, RChu, VMorb. Mortal. Wkly. Rep.Low SARS-CoV-2 Transmission in Elementary Schools — Salt Lake County, Utah, December 3, 2020–January 31, 202119 03 2021USANorth America40Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7012e3-H.pdf

In this study, led by the Centre for Disease Control in the US, transmission of SARS-CoV-2 was assessed in 20 elementary schools (kindergarten - grade 6) in Salt Lake County, Utah from December 3rd, 2020 to January 31st, 2021. Community transmission in the region was high during the study period with 290 - 670 new weekly cases per 100,000 people. Of the 10,000 students, more than 80% were attending school in person. Mask use in schools was high, but distancing between students' seats in class was 3 ft (less than the previously recommended 6 ft). Other mitigation measures including cohorting of students, staggered mealtimes and limits on extra-curricular activities and large group gatherings were also in place.

All school contacts of identified index cases answered a symptom questionnaire, and were offered RT-PCR saliva SARS-CoV-2 testing, performed 5-10 days after exposure. All close school contacts (within 6ft of index patient for >15 minutes in a day) up to December 17th were ordered to quarantine, close contacts following this date were only quarantined if masking was inadequate during interaction with the index case. Household members of school contacts were interviewed and also offered testing. Whole genome sequencing (WGS) was performed for all available positive specimens to confirm source and direction of transmission. School contacts with a positive test were considered to have a school-associated case unless illness preceded first school exposure, a household member had an illness in the 14 days preceding or WGS demonstrated a non-school related lineage.

A total of 51 index cases were identified across 48 classrooms: 40 students and 11 staff. One third of index cases were asymptomatic. Of 1041 susceptible school contacts (133 staff and 908 students), testing was completed in 735 (71%) of whom 12 were positive (11 students, 1 teacher). There were five cases classified as school-associated (following exclusion of four cases with epidemiological evidence of acquisition of infection outside of school and three cases in whom WGS demonstrated a non-school related lineage). The secondary attack rate amongst school contacts was 0.7%; no outbreaks (>2 school-associated cases linked to an index case) were documented. Six of eight household members of school-associated cases subsequently tested positive for SARS-CoV-2.

The findings here add to the body of evidence that, with appropriate mitigation measures, SARS-CoV-2 transmission within schools is uncommon, even in the setting of high-community transmission. A major strength of this study is the high proportion of contacts who received PCR testing, regardless of symptoms. The low transmission despite the inability to maintain distancing of 6 feet between students suggest that 3 feet of distancing may be adequate in elementary schools in the context of other mitigation measures including high usage of masks. Similarly, the modified criteria for quarantining close contacts (only if mask use is inadequate during interaction with index case) may be adequate to prevent school-associated transmission, whilst limiting missed days of in-person learning.

Cooper, DMUlloa, EmedRxivSARS-CoV-2 Acquisition and Immune Pathogenesis Among School-Aged Learners in Four K-12 Schools26 Mar 2021USANorth America320Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.20.21254035v1

Methods

This prospective observational study carried out in four schools in Orange County, California USA aimed to test the assumption that school-aged children would be less susceptible to SARS-CoV-2 infections if they avoided onsite learning. The study was conducted in schools deemed to represent the socio-demographic diversity of this area, during a period of relatively low level of community transmission of SARS-CoV-2 (early fall 2020, COVID-19 incidence: 3 to 4 cases/100,000) and 6 to 8 weeks after, amidst a surge of COVID-19 in the community (fall-winter, COVID-19 incidence: 40 cases/100,000). A total of 320 learners aged between 7 to 17 years old (mean 10.5 ± 2.1 SD) and 99 school staff aged ≥ 18 years old were enrolled across three public (school A, B, C) and one private school (school D). Schools A and B served economically disadvantaged Hispanic children; school C special needs learners and school D, middle and upper-middle income White learners. As opposed to school D, remote learning predominated in public schools.

The study involved two-testing cycles in which every participant completed a COVID-19 symptom screening. Anterior nasal swabs for the detection of SARS-CoV-2 and co-circulating respiratory viruses via RT-qPCR were collected, and an optional phlebotomy for SARS-CoV-2 specific IgG and IgM, neutralising antibodies, immunologic markers, and lipid screening (the latter only for the cycle 2) was offered. The fidelity of face covering and physical distancing mitigation in schools were measured using momentary time sampling techniques in classroom, recess, communal dining and physical education classes by trained observers, who visited the schools between 3 and 5 times.

Results: seventeen out of 320 learners (5.31%, mean age 9.9 ± 2.1 years old), and six out of 99 staff (6.1%) had positive RT-qPCR during the second cycle of testing. No evidence of RSV or influenza was reported. No statistically significant differences in the rates of SARS-CoV-2 infections were described between onsite and remote learners across the study settings (95% CI was not provided in this pre-print). School A had the highest number and proportion of SARS-CoV-2 infected learners (9/70) and the highest proportion of infected staff (3/25); the differences in the results of RT-qPCR among the schools may reflect the differences in neighbourhood infection rates. Learners with documented SARS-CoV-2 infection were more likely to have symptoms consistent with COVID-19. They also showed SARS-CoV-2 neutralising antibodies, detectable SARS-CoV-2 specific IgM and IgG, detectable SARS-CoV-2 specific IFN- secreting CD4 T cells following exposure to SARS-CoV-2 antigens, as well as low levels of circulating monocytes, NK cells and several inflammatory immune mediators. The results of the lipid screening suggested that either low HDL or high LDL were more commonly seen in socioeconomically disadvantaged learners (schools A and B), and 26% of learners with low HDL, had a positive test for SARS-CoV-2. High levels of face covering and physical distancing compliance in classrooms, and an expected reduction of face covering and physical distancing during communal dining was also reported.

Comments: successful mitigation strategies to prevent local SARS-CoV-2 transmissions in schools are achievable yet related with socioeconomic factors and regional transmission of SARS-CoV-2. Remote learning did not avert SARS-CoV-2 infections in school-aged children. Mild symptoms of COVID-19 might be explained by strong humoral and cellular immune responses, coupled with a reduced number of circulating monocytes and inflammatory immune mediators.

Caribú, FNuciforo, PJ Clin Invest.Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission26 Jan 2021ItalyEurope37Neonatalhttps://www.jci.org/articles/view/145427

This is a cohort study of 37 pregnant women who were admitted to a hospital in Milan, Italy between 12/03/2020- 23/04/2020. They all underwent nasopharyngeal SARS-CoV-2 PCR testing on admission, some of whom also had COVID symptoms. 21 were positive on these swabs. Following delivery, placental tissue was collected and all the newborns underwent nasopharyngeal PCR testing. The placental tissue underwent quantitative RT-PCR for SARS-CoV-2, in-situ hybridisation (ISH) and a study of gene expression. Lung samples taken post-mortem from individuals who had died from COVID in Basel, Switzerland was used as controls.

All neonates born to these mothers had a negative PCR swab result for SARS-CoV-2. One woman (Patient 1) underwent an emergency c-section 1 week and 5 days after the positive PCR test for reduced fetal movement. The baby had suffered a perinatal asphyxia event and required mechanical ventilation and underwent therapeutic hypothermia. 10 out of the 21 women had positive quantitative PCR on their placental tissue; Patient 1 had a higher viral load detected with 14 PCR cycles compared to the median of 32 (IQR 31-35) from the other placentas. The placenta from Patient 1 was significantly different from all other placentas investigated and showed similarity to the lung specimens. It showed massive fibrin deposition and necrosis of syncytiotrophoblast on histology, intense positivity of perivillious trophoblast with extensive apoptosis of infected cellular compartment on ISH similar to the lung sample and a gene expression profile which was similar to the control lung specimens.

This study is useful in understanding the placental injury (and therefore the effect on the fetus) following placental exposure to high viral load of SARS-COV-2. The similarities between patient 1’s placenta on those of the lung specimen controls does offer sufficient cause for concern in this group of women. However, this is a single example of this magnitude of placental injury. Despite the nasopharyngeal swab and placental quantitative PCR positivity, the finding of negative nasopharyngeal PCR swabs in all neonates does raise the possibility that the placenta acts as an efficient barrier for vertical transmission. There was however no umbilical cord sampling or any other form of testing for antibodies in the neonate and therefore vertical transmission cannot be ruled out. It is also a single centre study with a majority white ethnic background.

Niño-Taravilla, COrtiz-Fritz, PEmerging Inf Dis JMultisystem Inflammatory Syndrome in Children, Chile, May–August 20201 May 2021ChileSouth America26Clinical - PIMS-TShttps://wwwnc.cdc.gov/eid/article/27/5/20-4591_article

Introduction and Method: Few COVID-19 articles on children and MIS-C have reviewed cases in Latin America. The authors here describe the clinical characteristics, treatment, and results of a cohort of children (26) admitted to the paediatric intensive care unit (PICU) with MIS-C in a tertiary hospital in Chile.

They collected demographic data, medical history, clinical symptoms, and physical examination findings, also results of imaging, cardiac, and laboratory tests conducted during the patient’s stay in the emergency room and PICU. Data on treatment, complications, outcome, and length of PICU and total hospital stay was analysed.

Results: Of the 33 patients with SARS-COV-2 who were hospitalized in the PICU during the study period, 26 met the definition for MIS-C.16/26 (61.5%) patients met the criteria for Kawasaki disease. Their median age was 6.5 years (IQR 2–10.5 years); 15 (57.7%) patients were male. Only 1 patient had a chronic underlying condition.

In total, 22 (84.6%) patients tested positive for SARS-CoV-2 infection, 7 (26.9%) by reverse transcription PCR and 15 (57.6%) by serologic assay. The other 4 (15.3%) patients tested negative for SARS-CoV-2 but had a COVID-19 exposure. The most frequent symptoms were fever (26, 100%), shock (24, 92.3%), abdominal pain (17, 65.4%), diarrhoea (16, 61.5%), vomiting (12, 46.2%), rash (16, 61.5%), and conjunctivitis (15, 57.7%).

Ten (38.5%) patients required mechanical ventilation for a median duration of 4 days (IQR 2.5–5 days). Only 1 (3.8%) patient met the criteria for acute respiratory distress syndrome; that patient had an oxygenation index of 25. Half (13, 50.0%) of the patients required vasoactive drugs. We used high-flow hemofiltration as salvage therapy for refractory shock in 1 patient. No patients required extracorporeal membrane oxygenation (ECMO). In total, 20 (76.9%) patients received intravenous immunoglobulin; 2 (9.1%) received a second dose. We treated 23 (88.5%) patients with corticosteroids; 1 (3.8%) required a larger dose. We prescribed immunomodulatory agents for 4 (15.4%) patients: tocilizumab for 3 patients and infliximab for 1.

In total, 18 (69.2%) patients had echocardiographic abnormalities, including 5 (19.2%) patients who met the criteria for Kawasaki disease with coronary artery abnormalities. The median duration of PICU stay was 5 days (IQR 2–7 days). None of the patients died.

Conclusions: The authors described 26 children with MIS-C in Chile. Their findings were similar to those reported in other countries. Most patients had echocardiographic abnormalities, and half required vasoactive drug support. We administered immunomodulatory therapy to most patients. Clinical trials and long-term follow-up are needed to elucidate the mechanisms of various treatments and potential sequelae of this condition.

Ladhani, SRamsay,MLancet Child Adolesc HealthSARS-CoV-2 infection and transmission in primary schools in England in June–December, 2020 (sKIDs): an active, prospective surveillance study16 Mar 2021EnglandEurope6727Epidemiology - Transmissionhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00061-4/fulltext

A prospective surveillance study undertaken in school aged children in England between June 2020 and December 2020. There were two groups in the study, one had weekly swabs for a minimum of 4 weeks, the other group had blood tests on four occasions, at the start of the study in June 2020, in July 2020, in September 2020 and in December 2020.

There was a total of 11,966 participants. 6,727 students, (49% male, 42.6% aged 4-6, 23.1%, aged 7-9 and 34.6% aged 10-12). There were 4,628 staff (84.8% female, age range 20 to ≥60 years), and 611 in whom the status of the participant was unknown (staff or student). A total of 40,501 swabs were taken in 131 schools. In 45 of these schools, blood sampling was also taken.

In June 2020 the weekly SARS-CoV-2 infection rates, as determined by swab, were 4·1 per 100,000 for students and 12·5 per 100,000 for staff.

At recruitment in June 2020, in 45 schools, 91 of 816 students and 209 of 1,381 staff members were positive for SARS-CoV-2 antibodies. Antibody positivity varied across the different English regions and between students and staff but was similar to the regional seroprevalence during the same week. A school clustering effect was significant for staff members but not students. For both students and staff, seropositivity was associated with non-White ethnicity and health-care workers in the household. There was no association between seropositivity and school attendance during lockdown. In July 2020 603 of 816 students and 1015 of 1381 staff members were still participating in the surveillance, and five (four students, one staff member) had seroconverted. By December 2020, 55 of 1085 participants who were seronegative at recruitment had seroconverted, including 19 of 340 students and 36 of 745 staff members.

The authors found very low rates of symptomatic or asymptomatic SARS-CoV-2 infection in students and staff following partial and full reopening of primary schools in England in June 2020. Community SARS-CoV-2 infection rates were low during the summer half-term and high during the autumn term. The authors conclude “the results indicate that primary schools were not sites of significant transmission before the emergence of new variants of SARS-CoV-2 in the UK. Further work is needed to understand the effect of new variants within educational settings.”

Hu, SYu, HNature CommunicationsInfectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China09 Mar 2021ChinaAsia00000000000000Epidemiology - Transmissionhttps://www.nature.com/articles/s41467-021-21710-6

Many publications have described transmission patterns of SARS-CoV-2 within populations, but this report is more authoritative than most. It includes people of all ages, but there are some important messages relating to children. It comes from the Chinese province of Hunan, which has a population of 67 million, and is adjacent to Hubei province, where the pandemic began. They were able to rapidly institute an effective test, track and trace system, and they record here how the virus spread, between 13th January and 2nd April 2020.

Much of it confirms what we already knew, but with bigger numbers and more reliable data. Starting with a cohort of 1178 people who were PCR positive (1019 symptomatic, 159 asymptomatic), they traced 15648 potential contacts. Of these, 471 tested PCR positive. Mean generation time between contact and positivity was 5.7 days, with infectiousness peaking at 1.8 days. Presymptomatic transmission has been a defining feature of this pandemic, and their rate was 59% - greater than some other reports have suggested. There was no significant difference in onward transmission rates between symptomatic and asymptomatic people. 831/1178 index cases were epidemiologically linked, in 210 identified ‘clusters’. In pairs where a single infector could be linked to a specific infectee, in 14% the infectee’s symptoms preceded those of their infector.

There are more data in this report than can be summarised here, but some points relevant to children include:

- Susceptibility to infection (not transmission) increased with age (under 15 vs over 15 years)

- Transmissibility did not differ significantly between these age groups: lower virus carriage rates in children may have been compensated for by more individual contacts, at least while still in school

- Fewer PCR-positive under-15s had symptoms, and in this age group almost as many were asymptomatic as symptomatic.

- Household contacts carried highest risk of transmission

- First generation of contacts carried higher risks of onward transmission than subsequent contacts

- Comparing the periods before and after 23rd January, the mean serial interval increased from 4 days to 7 days: this may reflect more intensive tracing and isolation.

This is important confirmatory evidence of the potential for children to transmit the virus significantly, even if largely asymptomatic. However, much has changed since April 2020 and new variants of the virus, as well as changing public health policies, may reduce the generalisability of these findings.

Belay, EGodfred-Cato, SJAMA PediatrTrends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic06 APR 2021USANorth America1733Clinical - PIMS-TShttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2778429

This is a retrospective study of 1733 children with MIS-C (PIMS-TS), who were notified to the Centers for Disease Control and Prevention surveillance database in the USA, between March 2020 and January 2021. Data from these patients were analysed for temporal and geographic trends.

Case definition: Age < 21y AND Fever, laboratory evidence of inflammation and admitted to hospital AND Involvement of ≥2 organs (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological, or neurological) AND No alternative plausible diagnosis AND Either laboratory confirmation of SARS-CoV-2 infection OR known COVID-19 exposure before symptom onset.

Demographics: The median age of patients was 9 years (IQR 5–13) and 57.6% were male.

71.3% were either Hispanic or non-Hispanic Black (39% of children in the USA come from Hispanic and non-Hispanic Black backgrounds).

Clinical features: Of the 1733 children who met the criteria for MIS-C, 1567 (90.4%) had involvement of at least 4 organ systems. The most common signs and symptoms, in addition to fever, were abdominal pain (66.5%), vomiting (64.3%), rash (55.6%), diarrhoea (53.7%) and conjunctival injection (53.6%). Cough, shortness of breath and chest pain were reported in less than 30%. Hypotension occurred in 50.8% and 36.8% developed shock. Cardiac dysfunction was reported in 31.0%, pericardial effusion in 23.4%, myocarditis in 17.3% and coronary artery dilatation or aneurysms in 16.5%.

Younger children aged 0-4 years had less multiple organ involvement. Older patients, aged 18-20 years, were more likely to have myocarditis and ARDS. Of the total cohort, 1009 (58.2%) were admitted to intensive care and 24 (1.4%) died.

Temporal trends: Three peaks for MIS-C were identified, in early May, early August, and December. The first 2 peaks followed the peaks for the COVID-19 pandemic by 2 to 5 weeks. The third peak also appears to be following a rise in paediatric COVID-19 cases.

Geographic trends: The incidence of MIS-C ranged from 0.2 to 6.3 for states reporting children with MIS-C. The incidence of MIS-C was highest in the Northeast of the USA, while most of the states with high paediatric COVID-19 rates were in the West and Midwest.

Conclusions: The authors conclude that the geographic and temporal occurrence of MIS-C in close as- sociation with the COVID-19 pandemic is consistent with the hypothesis that the emergence of MIS-C is due to delayed immunologic responses to infection by SARS-CoV-2. MIS-C disproportionately affects Hispanic and Black children and adolescents, most probably due to long-standing inequities in the social determinants of health.

Pierce, CHerold, BJCI InsightNatural mucosal barriers and COVID-19 in children06 Apr 2021USANorth America12Clinical - Clinical Features https://insight.jci.org/articles/view/148694
Paul, ABuchan, SmedRxiv Pediatric household transmission of SARS-CoV-2 infection31/03/2021 CanadaNorth America9861Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.29.21254565v1.full#ref-22
Dawson, PSalzer, JMorb Mortal Wkly RepPilot Investigation of SARS-CoV-2 Secondary Transmission in Kindergarten Through Grade 12 Schools Implementing Mitigation Strategies — St. Louis County and City of Springfield, Missouri, December 202026 03 2021USANorth America24Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7012e4.htm?s_cid=mm7012e4_x

In this study from Missouri, USA, transmission of SARS-CoV-2 in K-12 schools in Springfield and St Louis County was assessed from December 7th-18th, 2020. SARS-CoV-2 incidence in the surrounding community was high during the study period (cumulative 711 cases per 100,000 population).

Mitigation measures were in place in all schools, including mask mandates (100%) spacing of desks >3ft (100% - including 27% of schools with >6 ft spacing), physical barriers between teachers and students (98%) and increased ventilation (98% - predominantly opening windows, use of fans and decreased occupancy of closed spaces). During the study period 70% of students (21,342 / 30,588) attended in-person schooling at least part-time.

All students and staff who tested positive for SARS-CoV-2 during the study period and attended school whilst potentially infectious and associated close contacts were approached to participate. Close contacts were followed for 14 days with SARS-COV-2 PCR saliva testing at 5-8 days after last exposure. In St Louis, all close contacts were instructed to quarantine according to CDC guidelines. In Springfield, close contacts were only required to quarantine if there was prolonged close physical contact with a case, contact outside of the classroom or a breach in mask use.

Of 56 index cases with SARS-CoV-2 infection, 37 (66%) agreed to participate along with 156 of 270 (58%) close contacts. Students made up 65% (24/37) of index cases and 88% (137/156) of close contacts. Of 156 contacts, 54 declined PCR testing; of 102 tested close contacts, only 2 had a positive PCR for SARS-CoV-2. Both episodes (one student to student, one teacher to student) were deemed "probable" school transmission events based on symptom onset and epidemiology; one case was confirmed by whole genome sequencing. Both contacts had been instructed to quarantine (one because of prolonged close physical contact with a case and one because of contact outside of the classroom). There were no school outbreaks identified.

In Springfield, 51% (41/82) of participating close contacts met criteria for exemption from quarantine. None returned a positive SARS-CoV-2 test result (21 of 41 tested).

This study provides further evidence that, in the presence of mitigation measures, in school transmission of SARS-CoV-2 is rare, even in settings with high levels of community transmission. In this case incidence of cases due to in-school transmission was almost 100-fold lower than in the general community (~8 vs 711 per 100,000 persons). The follow up of contacts using modified criteria for quarantine suggest that in school learning may be able to continue for some close school contacts, thereby minimising disruptions, but this approach requires further study.

Mo, HHu, KPediatr NeonatolDetectable antibodies against SARS-CoV-2 in newborns from mothers infected with COVID-19 at different gestational ages26 Mar 2021ChinaAsia6Neonatalhttps://doi.org/10.1016/j.pedneo.2021.03.011

AIM: to understand changes in the antibody levels to SARS-CoV-2 in newborns after maternal infection at different gestational ages.

METHOD: At delivery and monthly for 6 months, throat swab and blood samples were taken from 6 affected women and their babies. The swabs were tested for viral nucleic acid and blood antibody levels to SARS-CoV-2 were measured using either qualitative or quantitative detection.

RESULTS: Maternal infection, confirmed by nucleic acid testing, occurred in the 2nd trimester in one woman (17 weeks and 5 days) and in the third trimester in 5 (28 weeks and 4 days, 29 weeks and 5 days, 34 weeks and 1 day, 36 weeks and 1 day and 37 weeks and 2 days). Viral shedding had a median duration of 29.0 days (range 18.8 – 42.3) in the

All newborns were born at term ranging from 37 weeks and 5 days to 40 weeks and 5 days.

Three women delivered during the acute phase of COVID-19. The other three women delivered 37, 56, and 111 days after recovery from COVID-19. Although 3 women are said to have been delivered during the acute phase of infection, none of the six women, nor their babies tested positive for PCR after delivery, nor did they have any symptoms of COVID-19.

The 3 mothers who had COVID-19 at 17 to 29 weeks gestation had evidence of IgG but not of IgM at birth. Their IgG was still detectable at more than 4 times the cut off value at 6 months. Their infants didn’t have any IgM at birth but had IgG levels persisting for 5 months in 1 and 6 months in the other 2. The 3 mothers with COVID-19 at 34 weeks or later had IgM and IgG. There was IgM detectable until 60 days and 90 days but in the third mother in this group there was no detected IgM at 30 days. Their IgG lasted 120 days in two and 150 days in the third mother. In their infants the IgG lasted 60 days in one and 120 days in the other two.

DISCUSSION: After delivery, women with COVID-19 between 17 and 29 weeks and their babies had a longer duration of detectable IgG than women with COVID-19 at 34 weeks or later and their babies. It is not clear what level of antibody in infants confers protection against infection.

COMMENTS: this is a small study which confirms previous findings of placental passive transmission of maternal IgG antibodies to their babies which last several months. They seemed to last longer in babies born to mothers who had had COVID-19 earlier in pregnancy (at 17, 28 and 29 weeks) compared to babies whose mothers had COVID-19 closer to term. This may be explained by these mothers in the second group not having reached peak production of IgG by the time their babies were born. The Supplementary file for the maternal and neonatal clinical details did not contain the relevant material on clinical features in mothers and babies. Women were wrongly described as being in the second trimester if the gestational age at infection was 28 and 29 weeks. No details were given on nucleic acid testing of swabs. There were contradictory statements regarding the presence of COVID-19 symptoms or positive PCR at birth: all negative but 3 mothers were described as being in the active phase of infection at the time of delivery.

Haapanen, MKuitunen, IeclinmThe impact of the lockdown and the re-opening of schools and day cares on the epidemiology of SARS-CoV-2 and other respiratory infections in children - A nationwide register study in Finland.30 03 2021FinlandEurope40535Epidemiology - Transmission https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00087-0/fulltext

This is a retrospective study of data in the Finnish national registry. The incidence of 9 respiratory pathogens in children, including SARS-CoV-2 (age 0-19 for SARS-CoV-2, 0-14 for the others) is plotted by week from January to late August 2020. This includes their first school closures as part of COVID-2 reduction measures (weeks12-20) and their school summer holidays (week 23-33). Incidence by age group is presented. The incidence of respiratory pathogens, other than SARS-CoV-2, in 2020, is also compared with 2017-19.

All the cases had positive PCR tests on nasopharyngeal swabs, taken on a clinical basis. Many were in 2o care but some for Influenza A/B and RSV were taken in 1o care.

Results: As expected, the numbers of respiratory pathogen infections (other than SARS-CoV-2) generally reduced following the closure of the schools and by more than the expected seasonal fall shown by the figures from previous years (exception rhinovirus).

However, the incidence of SARS-CoV-2 infections seems to continue to rise during the 1st 2 weeks of school closure then plateau, only showing a sustained fall from week 18. This may not reflect the true picture as the testing was increasing from a very low level. The level of SARS-CoV-2 infections seem to start to rise before the return to school (week 33).

Limitations: Testing for SARS-CoV-2 was extremely limited at the beginning and only used for children with quite severe symptoms and known exposure: it gradually increased through the year. By August, any child with even mild URTI symptoms was tested leading to backlogs and results taking up to a week.

Asymptomatic children were only tested in some special circumstances.

It is unclear how far “nasopharyngeal swabs, taken on a clinical basis” will reflect the true incidence of respiratory infections in the population.

The COVID-2 restrictions were less strict than elsewhere with gatherings of up to 10 people allowed, possibly indoors (not clear from the paper). Mask wearing was not introduced until week 33.

Comment: The authors stated aim was to describe the effect of implementing and easing broad restrictions on the epidemiology of respiratory pathogens in the nationwide paediatric population of Finland. The data does not seem robust enough to attribute all the changes described to opening and closing schools and day care.

Sermet-Gaudelus, IEloit, MEuro Surveill 26(13)Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 202001 Apr 2021FranceEuropeClinical - Clinical Featureshttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.13.2001782

Seasonal coronavirus (HCoV) antibodies in 69 children seen or admitted at a French tertiary centre for reasons other than Covid (but including 15 with a multisystem inflammatory syndrome - MISC) between 01/04-01/06/21 but subsequently found to have SARS-CoV-2 antibodies, were compared to 115 sex/age matched controls. Median age 9.6 (SD 5.1), range 0-18 years. Past infection with seasonal coronaviruses did not seem to protect against SARS-CoV-2 infection or MISC. Neither was the SARS-CoV-2 antibody response any different between those with or without evidence of past HCoV infection. Given that reinfection with seasonal coronaviruses is well recognized, this study not only suggests that past HCoV infection is unlikely to prevent SARS-CoV-2 infection but also that the concept of herd immunity from vaccination or natural SARS-CoV-2 infection may not occur. This study does not examine any possible effect of past HCoV infection on severity of SARS-CoV-2 disease.

Beharier OKovo MmedRxivEfficient Maternal to Neonatal transfer of SARS-CoV-2 and BNT162b2 antibodies6 Apr 2021IsraelMiddle East213Neonatalhttps://www.medrxiv.org/content/10.1101/2021.03.31.21254674v1

This study is a pre-print and has not yet been peer reviewed

Methods: Observational study carried out in eight centres across Israel between April 2020 and March 2021. The study evaluated the maternal production and placental transfer of SARS-Cov-2 antibodies in gravidae immunised with BNT162b2 mRNA-based vaccine during pregnancy, versus unvaccinated pregnant women with a history of COVID-19 during pregnancy confirmed via a positive nasopharyngeal swab RT-PCR test. These groups were matched to unvaccinated parturients according to clinical features. Pregnant women younger than 18 years old or with active COVID-19 disease at delivery were not eligible for this study. Maternal and foetal blood samples were collected prior to delivery and from the umbilical cord after delivery, respectively. Serum specific SARS-Cov-2 IgG and IgM were detected using a multiplex assay.

Results: The cohort involved 1094 pregnant women: 105 had been vaccinated; 94 unvaccinated with a history of COVID-19 and 895 unvaccinated without prior history of COVID-19. Among the latter, 66 were selected as controls (matched comparison group) based on clinical characteristics. Matched maternal cord blood serology results were available for 213 mothers and their newborns; 86 vaccinated; 65 unvaccinated with a history of past SARS-CoV-2 positive RT-PCR and 62 non-infected, unvaccinated. Maternal age was lower in the group with past RT-PCR positive for SARS-CoV-2, compared to unvaccinated/non-infected and vaccinated mothers (95% CI not provided. Kruskal- Wallis one way ANOVA p = 0.0011). Other clinical maternal and newborn parameters of interest did not differ among the study groups.

Transfer rates of IgG to S1, S2, RBD and N were higher in participants infected before week 30 (n =25/65) compared to those who had a positive PCR after week 30 of gestation (n = 21/65) (95% CIs unavailable; Wilcoxon rank sum test S1 p = 0.0013; S2 p = 0.0231; RBD p = 0.0010; N p = 0.0003). A subset of participants in the control group were identified as serologically positive for N, S1, S2 and RBD (n = 9/62); a subgroup of vaccinated pregnant women were identified as positive for N (n = 7/86). A rapid IgG response to S1, S2 and RBD but not N, resulting in high titres by day 15 post-vaccination was detected in participants receiving a first dose of BNT162b2, with further increase following the second dose. Compared to women with past RT-PCR positive for SARS-CoV-2, foetal IgG for S2 and N were significantly lower in cord bloods of vaccinated women (p < 0.0001; p < 0.0001 respectively; no confidence intervals are available), but no difference was found between foetal IgG for S1 and RBD (p = 0.70017, p = 0.6887 respectively; no confidence intervals are available). Significant positive correlations between foetal and maternal antibodies were found for all groups and antigens, and no difference in the correlation slopes of SARS-Cov-2 infected/non-vaccinated versus the vaccinated group in any type of antibodies were also detected. Foetal IgM response to BNT162b2 was negligible. Within the PCR positive group, 4/65 newborns had robust SARS-Cov-2 specific IgM responses to all antigens and 1/65 neonates showed a “partial” immune response which may indicate compromised placenta barrier or potential vertical transmission.

Comment: Maternal IgG humoral response to BNT162b2 mRNA-based vaccine appears to be robust in non-infected participants. These antibodies transfer across the placenta to the foetus and are detectable within 15 following the first dose. Self-reporting time of the positive RT-PR among those in the SARS-Cov-2 (recall bias) as well as enrolment of participants during the day (selection bias) are potential limitations of this study. Regarding the latter, it appears unlikely that those women admitted in the evening mounted a different immune response to vaccination or SARS-Cov-2 infection. No RCTs on the efficacy of mRNA-based vaccines against SARS-Cov-2 infections included pregnant women. Although this study shows sounded evidence regarding the immune response elicited by BNT162b2 in the dyad mother-newborn, safety trials focusing on maternal immunisation are warranted.

Gettings, JVallabhaneni, SClin Infect DisSARS-CoV-2 transmission in a Georgia school district - United States, December 2020-January 202117 Apr 2021USANorth America5300Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab332/6232104

Summary: This epidemiological prospective cohort study assessed in-school SARS-CoV-2 transmission in a public school district in Georgia, USA, which included elementary, middle and high schools. This district serves an ethnically and socioeconomically diverse population of 8,500 students and employs 1,400 staff members. The study period was from December 1st 2020 to Jan 22nd 2021 and included a 16-day holiday. Notably, the local COVID-19 incidence (7-day cumulative number of new cases/100,000 persons) increased from 192 cases on December 1st 2020 to a peak of 705 cases on January 13th 2021.

SARS-CoV-2 transmission was assessed using contact testing and cluster analysis and analysed by school setting, index case role, symptom status, and month of transmission. In-school transmission was highest when the index case was a staff member, had symptoms or index case contact occurred in an indoor sports setting. More than half of contacts who tested positive were asymptomatic. Recommendations include caution with respect to indoor sports, measures to reduce staff infection (e.g. education, vaccination) and testing of contacts irrespective of symptom status.

Methods: SARS-CoV-2 index case identification and contact tracing was carried out by public health and school officials. Investigators approached in-school contacts for consent to RT-PCR testing (5-10 days post-exposure or at symptom onset) and surveillance of symptoms. RT-PCR testing was offered to family members of study participants with positive tests. Secondary attack rate (SAR) was calculated as positive contacts/number of contacts tested for different scenarios. Whole genome sequencing (WGS) was used to identify clusters (index case epidemiologically linked with ≥ 2 positive contacts in school) and assess likelihood of in-school transmission.

Results/Discussion: Approximately 5,300 students attended school in-person over the study period. Of 98 index cases identified, 86 cases were assessed (33 staff, 53 students), generating 1,119 contacts. Of 688 (63.1%) contacts who were tested, 59 contacts tested positive attributable to in-school transmission, and overall SAR was 8.7% (95% confidence interval [CI]: 6.8–10.9). Fifteen (17.4%) of the index cases were associated with clusters. Of 55 index cases with symptom data, 31 (56.4%) were asymptomatic. SARs were highest for indoor sports settings (23.8%, 95% CI 12.7, 33.3) and staff interactions (18.2%, CI 4.5–31.8). The SAR was higher for elementary (9.5%, CI 6.5–12.5) than high school classrooms (1.6 %, CI 0.0-4.7), although in-person attendance for high school students was lower. For high school students, most positive contacts (93.7%) and all clusters were linked with sports.

SAR was higher for staff (13.1%, CI 9.0–17.2) than student (5.8%, CI 3.6–8.0) index cases, and for symptomatic (10.9%, CI 8.1-13.9) than asymptomatic (3.0%, CI 1.0-5.5) index cases. Outside of sports settings, the majority of positive staff contacts (87.5%) and positive students contacts (72.2%) were linked with a staff index case. Disproportionately more staff members were identified as index cases (40% index cases vs. 20% in-school population).

Siegel, MDanyluk, GMMWR Morb Mortal Wkly Rep Notes from the Field: SARS-CoV-2 Transmission Associated with High School Football Team Members — Florida, September–October 202019 Mar 2021USANorth America0000000000Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7011a3.htm#suggestedcitation

This is one of what appears to be a series of short reports from the American Centers for Disease Control (CDC), intended to warn educators, health professionals and the public about the potential for SARS-CoV-2 transmission in school settings. This one focuses on football (presumably American football, not soccer). In September 2020, a single player at a Florida high school tested positive. All 49 fellow players and coaches were then quarantined, but in spite of this, three days later, 6 additional players tested positive. Health officials investigated, and ultimately a further 19 cases were linked to this index case: 12 fellow players, 2 coaches, 2 classroom contacts and 3 home contacts. Seven were asymptomatic.

They established that immediately preceding the outbreak, the team had held regular practices, and 3 matches against other schools. This involved frequent close contact, including indoor exercises with ‘infrequent’ mask use. Other risks included shared bus transport, shared drinking vessels, and poor locker-room disinfection. There were no confirmed cases amongst the other schools’ teams. The consequences of this one case were the quarantining of 267 students, and the loss of 2243 person-days of school attendance.

Rather belatedly, they make recommendations for limiting virus transmission in school sports.

Shlomai, AEventov-Friedman, SPaediatricsNeonatal SARS-CoV-2 Infections in13 Apr 2021IsraelMiddle East55Neonatal https://pediatrics.aappublications.org/content/early/2021/04/09/peds.2020-010918
Haag, LArmann, JmedRxivPrevalence and Transmission of SARS-CoV-2 in Childcare Facilities: A Longitudinal Study18 Apr 2021GermanyEurope318Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.16.21255616v1

This article is a pre-print and therefore has not yet been peer reviewed.

This longitudinal study by Haag et al., (2021) was conducted to gain further knowledge on prevalence, transmission and spread of SARS-CoV-2 among preschool children aged 1-6 years, their parents and caretakers.

Background: Since the beginning of the SAR-CoV-2 pandemic, school and childcare closures were one of the main strategies to limit the transmission of the virus and it was assumed that children had a similar role in transmitting the virus as they do in transmitting influenza. It was therefore assumed that the closure of schools and childcare was effective in lowering the overall transmission rate. Many studies in the UK, Norway and Germany noted a lower proportion of cases in children compared to their population size and very limited spread in primary and secondary schools.

Method: Children, parents and childcare workers in 14 childcare facilities in Dresden, Germany were invited to participant in the study. Adults had 5mL of peripheral venous blood collected for serological testing for IgG-antibodies against SARS-CoV-2. Stool samples were collected from children by the parents every two weeks. The stool samples were tested using PCR. All samples were collected between July 2020 and January 2021. Participants with detectable antibodies in at least two assays were considered seropositive. The study period was divided into a low-prevalence and a high-prevalence period (15th July 2020 – 15th November 2020 and 16th November 2020 – 31st January 2021 respectively). Only children with at least two donated stool samples were included in the study: 232/318 (73.0%) in the low prevalence phase and 222/318 (69.8%) in the high prevalence phase. No positive stool samples were excluded by these criteria.

Results:

Low Prevalence Period: At baseline, no participants were SARS-CoV-2 seropositive. During the low-prevalence phase, 2 study participants, one childcare worker (1/154 – 0.7%) and one parent (1/196 – 0.5%) became seropositive. Both were confirmed via PCR and they did not attend the same childcare facility. During this time, there were 2 positive stool samples (2/232 – 0.9%). The two children attend different childcare facilities.

High Prevalence Period: During the high prevalence phase, 25/236 (10.6%) parents and 23/187 (12.3%) childcare workers were seropositive. There was no statistical significance between the two groups (p=0.64). Parents whose children were in emergency childcare reported higher seroprevalence than parents whose children were not in childcare during that time (12/64 – 18.8% vs 13/152 – 8.6% respectively). Seroprevalence in childcare workers assigned to administrative work was significantly higher than those with mainly childcare related duties (10/48 – 20.8% vs 8/99 – 8.1% respectively)

SARS-CoV-2 Positive Children: 15/222 children in the second study period had at least one positive stool sample. These occurred at 8 different institutions. In 4 childcare facilities, a possible epidemiological link between a maximum of 3 children each could be identified. In 6 cases, there was no connection to other children.

Conclusion: This study strengthened the hypothesis that childcare facilities are not a major source of uncontrolled clusters of SARS-CoV-2. Around 50% of SARS-CoV-2 infections in children could not be connected to a secondary case within the study population. The higher rate of seropositivity in parents whose children attended emergency childcare may have been a result of their working environment. The fact that administrative staff had a significantly higher rate of seropositivity compared to those with mainly childcare duties suggests that transmission between adults may occur more frequently than between children.

Comments: Strengths of the study included the use of antibody testing instead of PCR testing in parents and childcare workers to reduce the possibility of missed undetected SARS-CoV-2 cases. The use of stool testing instead of NP swabs may have been a strength as viral excretion in stool is thought to be longer than in the upper airway, therefore being more sensitive.

Armann, JBerner, RBMJ Paediatrics openSARS-CoV-2 transmissions in students and teachers seroprevalence follow-up study in a German secondary school in November and December 202024 March 2021GermanyEurope247Epidemiology - Transmissionhttps://bmjpaedsopen.bmj.com/content/5/1/e001036

A study undertaken in 302 subjects (247 students and 55 teachers) in Dresden, Germany in November and December 2020. The students median age was 15years (14-17) 53% of whom were female, and the teachers 51 years (44-56) 23% female. Blood samples were taken in November from these 302 subjects to determine the number who were seropositive. These numbers represent 53% of all students in grades 8–12 and 79% of teachers in the school.

Five students had detectable antibodies against SARS-CoV-2 in at least two different assays and were therefore considered seropositive, indicating a seroprevalence of 1.7% (0.3%–3.3%). While one of the seropositive participants reported to have no knowledge of a previous SARS-CoV-2 infection, the other four seropositive students reported to have been tested positive for SARS-CoV-2 previously by PCR. The ratio of undetected to detected cases was therefore 0.25.

6 weeks later 219 of these subjects (180 students and 39 teachers) had repeat blood testing and an additional 17 students and one teacher were sampled for the first time. These sample numbers represent 42% of students and 57% of teachers.

16 participants were seropositive, including the five seropositive students from the initial visit. Six seropositive participants reported a previous SARS-CoV-2 infection diagnosed by PCR and nine reported a SARS-CoV-2-positive household contact, leading to a ratio of undetected to detected cases of 0.33. The seroprevalence rate was 6.8% (3.8%–10.1%) representing a fourfold rise in seroprevalence within 6 weeks. Since 4 out of the 16 seropositive students were only sampled at the second visit, the authors also analysed the group of participants with two blood samples (n=219) separately. This showed a 2.4-fold seroprevalence increase, from 2.3% (0.5%–4.6%) to 5.5% (2.3%–8.7%). Fifty participants reported to have been in an officially mandated quarantine at least once between the two visits. Five (10%) out of those quarantined newly developed SARS-CoV-2 antibodies, three of these newly seropositive participants reported to have been tested SARS-CoV-2 positive by PCR and one reported a SARS-CoV-2-positive household contact leading to a ratio of undetected to detected cases of 0.25 in this subsample.

In summary the seroprevalence increased from 1.7% (0.3–3.3) to 6.8% (3.8–10.1) during the study period. This mirrored the increase of officially reported SARS-CoV-2 infections during this time. The ratio of undetected to detected SARS-CoV-2 infections ranged from 0.25 to 0.33.

The especially important conclusion of the authors was “We could not find evidence of relevant silent, asymptomatic spread of SARS-CoV-2 in schools neither in a low prevalence setting nor during the second wave of the pandemic, making it unlikely that educational settings play a crucial role in driving the SARS-CoV-2 pandemic.”

Chmielewska, BKhalil, ALancet Glob HealthEffects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis31 Mar 2021Global - systematic reviewGlobal - systematic reviewEpidemiology - Transmissionhttps://doi.org/10.1016/S2214-109X(21)00079-6

The evidence to date indicates that, when SARS-CoV-2 is contracted during pregnancy, there is an increase in potential adverse outcomes for those pregnancies, including the risk of the mother requiring intensive care with a possible increase in maternal mortality, and the pregnancy ending in preterm delivery1. However, the global effect of the Covid-19 pandemic and of the population control measures introduced to mitigate its effects, on maternity outcomes for all pregnant women – both infected and non-infected - is less clear. This systematic review conducted by academic clinicians based in the UK and Turkey and published in Lancet Global Health has sought to address this issue.

The aim of the study is stated in the introduction section as being “to assess the collective evidence on the effects on maternal, fetal and neonatal outcomes of the pandemic” and in the abstract as “to assess the collateral effects on maternal, fetal, and neonatal outcomes of the global COVID-19 pandemic”. A more precise understanding of the research question can be found in the study protocol registered on Prospero in October 2020 where the elements of the PICO framework which was used to direct the literature search were specified as follows:

P (Population) - the whole obstetric population, not limited to those women infected with COVID 19

I (Intervention) - the COVID-19 pandemic and subsequent healthcare service restructuring

C (Comparator(s)/Control(s)) - the equivalent population in the period preceding the pandemic

O (Outcome) – Primary: stillbirth:

Secondary: preterm birth, pregnancy hypertension, gestational diabetes caesarean

section, neonatal death and morbidity and maternal mortality or severe

morbidity

This was, therefore, a systematic review of studies which reported on population, rather than specific patient, outcomes which were recorded “before and after” the COVID-19 pandemic. The literature databases which were used to identify relevant studies were confined to Medline and Embase; studies published between January 202 and January 2021 were eligible for inclusion, with no language restrictions. In addition the Oxford COVID-19 Government Response Tracker was used to identify national government-level interventions which were introduced in the countries in which the studies originated. The search terms used reflected the listed outcomes. Details relating to the process of the literature do not seem to have been provided. Standard Covidence software was used for data extraction and analysis.

The literature search identified 40 studies which met the inclusion criteria. Meta-analysis was performed on the 21 outcomes for which two or more studies reported data. The main findings were that:

- there was a statistically significant increase in both maternal deaths and stillbirths associated with the pandemic

- there was no overall change in the prevalence of preterm births when both high-income countries (HICs) and low-income and middle-income countries (LMICs) were combined in the analysis

- there was a decrease in preterm births <37 weeks gestation (but not <34, 32 or 28 weeks) of all causes in HICs and specifically in spontaneous (rather than iatrogenic) preterm births

- mean Edinburgh Postnatal Depression Scale scores were higher during the pandemic

- there was an increase in surgically-managed ectopic pregnancies.

No effect of the pandemic was found on maternal gestational diabetes, hypertensive disorders of pregnancy, labour induction, post-partum haemorrhage, mode of delivery, low birthweight (<2500 g) or neonatal death.

For the outcomes of stillbirths and preterm birth the number of pregnancies included in the meta-analyses was ~170,000 for both, and studies from both HICs and LMICs were included; the observed changes, therefore, may be representative of global trends. For 17 of the other 19 outcomes, however, fewer than 10 studies were available for meta-analysis and the only two studies reporting maternal deaths were from LMICs; this limits the ability to extrapolate or generalise the findings among diverse global settings.

In their discussion of the outcomes of the review the authors suggest that the increased rate of adverse outcomes was driven primarily by the inefficiency of health-care systems and their inability to cope with the pandemic, rather than by the restrictions imposed by pandemic mitigation measures. The possible reduction in preterm births appeared to apply to those which were spontaneous, rather than iatrogenic, and the authors conclude that It is more likely that changes in health-care delivery and population behaviours were the more important contributing factors to the reduction in preterm births rather than changes in obstetric management.

The authors acknowledge a number of limitations to interpretation of the reported outcomes, including possible publication bias, the retrospective design of the included studies, heterogeneity of the study populations and differences in definitions and measurement of outcomes.

A final comment is that, given the population-based approach of this study, the inclusion of measurements of maternal morbidities such as depression and anxiety, and speculation in the discussion section about the impact of domestic violence on pregnancy outcomes, I wonder whether, if the study were to be repeated, a broader range of literature databases might be used, to include those which focus on epidemiology, mental health and social sciences in addition to the medically-focused Embase and Medline.

1. Pregnant People. At increased risk for severe illness from COVID-19.

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnant-people.html

Preston, LGoodman, AJAMACharacteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-1909 Apr 2021USA North America20714Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347

Introduction: The authors conducted a cohort study to estimate adjusted associations between demographic and clinical characteristics and severe COVID-19 among hospitalized pediatric patients.

Methods: Discharge data from 869 medical facilities that contributed inpatient and emergency department encounters to the Premier Healthcare Database Special COVID-19 Release (PHD-SR) database capturing approximately 20% of US hospitalizations, were used to describe patients 18 years or younger who had an inpatient or emergency department encounter with a primary or secondary COVID-19 discharge diagnosis from March 1 through October 31.Severe COVID-19 was defined as care requiring treatment in an intensive care unit or step-down unit, involving use of invasive mechanical ventilation, or resulting in death. Race/ethnicity was defined by information in patient medical records in the PHD-SR.Adjusted odds ratios (AORs) and 95% CIs for severe COVID-19 were calculated using a multivariable generalized estimating equations model adjusting for within-facility correlation, age, sex, race/ethnicity, insurance type, and presence of chronic conditions. The a priori significance level was set at P = .05; all hypothesis testing was 2-sided.

Results: Among 20 714 pediatric patients with COVID-19, 10 950 (52.9%) were girls, 11 153 (53.8%) were aged 12 to 18 years, 8148 (39.3%) were Hispanic or Latino individuals, 5054 (24.4%) were non-Hispanic Black individuals. Among these patients with COVID-19, 6047 (29.2%) had 1 or more chronic conditions.

Among the cohort of 2430 pediatric patients (11.7%) who were hospitalized with COVID-19, 756 (31.1%) experienced severe COVID-19. An increased association of severe COVID-19 was observed among patients with 1 or more chronic conditions vs those with none (AOR, 3.27; 95% CI, 2.44-4.37); in children aged 2 through 5 years or 6 through 11 years vs those aged 12 through 18 years (AORs, 1.53; 95% CI, 1.11-2.13 and 1.53; 95% CI, 1.04-2.23, respectively); and in male vs female patients (AOR, 1.52; 95% CI, 1.26-1.83). There was no statistically significant association between race/ethnicity or insurance type and severe COVID-19.

Discussion: In this cohort study, nearly one-third (756 [31.1%]) of hospitalized pediatric patients with COVID-19 experienced severe COVID-19, which is consistent with previous findings. Analysis revealed an increased association of severe COVID-19 in younger children (those aged 2-11 years) compared with older children (those aged 12-18 years). Although admission to an intensive care unit for younger children may indicate an abundance of caution by clinicians or facility and administrative requirements rather than disease severity, this finding has important clinical and resource planning implications for facilities and clinicians.

The results suggest that existing chronic conditions and male sex are independently associated with severe COVID-19. Consistent with previous reports, non-Hispanic Black and Hispanic or Latino children with COVID-19 were overrepresented compared with all pediatric patients in the PHD-SR. The authors found no statistically significant association between severe disease and race/ethnicity among hospitalized patients when controlling for covariates.

Although most children with COVID-19 experience mild illness, some children develop serious illness that leads to hospitalization, use of invasive mechanical ventilation, and death. Understanding factors associated with severe COVID-19 disease among children could help inform prevention and control strategies.

Lugon, PBrasil, PPediatricsSARS-CoV-2 Infection Dynamics in Children and Household Contacts in a Slum in Rio de Janeiro01 Apr 2021BrazilSouth America377Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/04/14/peds.2021-050182

This prospective study, conducted in Brazil from May to September 2020, examined rates of SARS-CoV-2 infection, measured by nasopharyngeal and rectal swab PCR and IgG serology, in children under 14 years and their household contacts, over a series of home visits, to evaluate the direction of transmission of infection.

Study population: 323 children under 14 years of age who visited a primary healthcare clinic in northern Rio de Janeiro for any reason, including accompanying relatives, and additional children in this age group who shared the same residential address, were recruited. The clinic provides primary care and immunisation services to Manguinhos, an impoverished urban slum (favela) lacking sanitation and electricity. Following enrolment, children and their household contacts (54 adolescents aged 14-19 years and 290 adults older than 19 years of age) were visited at home at 1, 2 and 4 weeks after enrolment, then quarterly. Recruitment and follow-up took place between 18 May and 24 September 2020; 259 households were studied.

Testing for SARS-CoV-2: At enrolment and during subsequent home visits, PCR assays (on nasopharyngeal and rectal swabs, and some saliva samples) and IgG serology were performed on all children and their household contacts, regardless of symptoms. A participant was defined as positive if any of their serial samples collected during the study was positive. 45/323 children under 14 years were PCR positive (13.9%). Higher rates were seen in children under 1 year old (25%) and 11-13 year olds (21%). 13.2% of contacts aged 14 years or older were positive. Of those who had IgG serology performed, 32.6% of children under 14 years old and 31.2% of older household contacts were positive. The 11-13 year age group had the highest proportion of IgG positivity, followed by over 60 year olds. Asymptomatic infection was more prevalent in children under 14 years of age (74.3%) than those 14 years and older (51.1%). Median CT values for PCR-positive children under 14 years of age were not significantly different between naso-oral, saliva and rectal samples, nor between different age groups or household sizes. There were no severe cases of COVID-19 among the children and their household contacts, including siblings.

Infection dynamics: These were assessed by looking at PCR-positive children under 14 years of age to see if they had an adult contact who was IgG positive or had a clinical history suggestive of past COVID-19, defined as a recent respiratory illness accompanied by anosmia or ageusia. Of the 45 children who were PCR-positive, 26 had an adult contact who provided specimens for testing; all 26 were either PCR or IgG positive. The remaining 19 adult contacts had a clinical history of suspected COVID-19. The assumption was that this indicated that transmission was primarily from adults and adolescents to children.

Conclusions: All children with PCR-positive SARS-CoV-2 infection had an adult or adolescent household contact with suspected or confirmed SARS-CoV-2 infection before the child’s diagnosis, compatible with the hypothesis that the children were infected after or concurrently with household contacts, mostly their parents, implying that children were not the primary source of infection in the household. Of note, schools remained closed during the study period, while adults continued to work outside the home. Approximately one-third of children and their household contacts in the study were IgG positive, indicating that they had already been exposed to SARS-CoV-2 by August 2020, which is a higher prevalence of infection than that reported for the general population of Rio de Janeiro during that time period (7.5%). The study was limited by the logistical challenges of enrolment and home visits in this community.

Bark, DChoi, AmedRxivSARS-CoV-2 transmission in K-12 schools in the Vancouver Coastal Health Region: a descriptive epidemiologic study18 May 2021CanadaNorth America517Epidemiology - Transmissionhttps://doi.org/10.1101/2021.05.15.21257271

This article is a pre-print and has not yet been peer reviewed.

It is an analysis of data from the Vancouver Health Coastal Region’s electronic COVID-19 case and contact management platform, comparing school-related cases and outbreaks of COVID-19 to those in the general population between the 10th of September and 18th December 2020.

Schools in the region under study reopened following the summer holidays on 10 September 2020. There were 699 COVID-19 cases identified in schools during the study period. There were 71 school clusters comprising 251 of these cases. There was school-based transmission of SARS-CoV-2 in 26 of the clusters (37%), resulting in 55 secondary and 10 tertiary cases. School staff accounted for 54% of the index cases (14/26) and 25% of secondary cases (14/55).

The weekly incidence of SARS-CoV-2 infection in the school population rose and peaked at 6.6 per 10,000 in the 10 weeks following school reopening. This compared with a peak weekly incidence of 9.4 per 10,00 of the population as a whole at the same time. The incidence of new cases in schools and in the population as a whole followed similar trends over the time of the study, although incidence was always lower in the schools. The authors conclude that schools are not a significant driver of SARS-CoV-2 transmission and where school-based transmission occurs, the number of secondary cases is limited.

Bellon, MEckerle, I Clin Infect DisSARS-CoV-2 viral load kinetics in symptomatic children, adolescents and adults5 May 2020SwitzerlandEurope279Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab396/6265276

This study looks at the Covid-19 transmission risk posed by symptomatic children by using viral load as a surrogate for the presence of infectious disease. The study analysed the samples of symptomatic individuals of all ages who were diagnosed via a positive Covid-19 RT-PCR specimen in one institution in Switzerland. The samples were taken between the spring and winter of 2020 (exact months unspecified). The viral load (SARS-CoV-2 RNA load) of each specimen was measured and analysed in relation to the onset and number of symptoms of the tested individual. They aimed to use this data on viral shedding kinetics to compare how infectious children and adolescents were compared to adults in the first week of illness.

In total, 8027 positive specimens were included (279 children aged 0-13 years, 639 adolescents aged 14-19 years and 7109 adults). For all age-groups, a peak in viral load was seen in 1-3 days after symptom onset. 58% of children and 61% of adolescents had viral loads above the threshold for infectious virus presence at the time of diagnosis. This number was significantly higher in adults compared to children. The mean viral load was slightly lower in children than adolescents and adults although the small effect size means it may not be of practical significance.

Ultimately, the authors conclude that symptomatic children and adolescents are able to transmit Covid-19 infection for the majority of their first week of illness but that they may have slightly lower viral loads and be infectious for a shorter time than adults. These findings should be taken into context with the study’s limitations as recognised by the authors. The study includes symptomatic children only although we know a large proportion of children are asymptomatic. It relies on pooled data from multiple individuals to reach conclusions about infectiousness over time rather than performing consecutive swabs on the same individual. Finally, it assumes that viral load is the main driver of transmission and does not include other factors such as behaviour and environment.

Mossong, JWilmes, PBMC Infect DisSARS-CoV-2 transmission in educational settings during an early summer epidemic wave in Luxembourg, 202004 MAY 2021LuxembourgEurope390Epidemiology - Transmissionhttps://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06089-5#:~:text=Transmission%20of%20SARS%2DCoV%2D2,mitigating%20transmission%20within%20educational%20settings.

Background: Several studies have reported a limited role for children in transmission of COVID-19 however, epidemiological data of transmission within educational settings are scarce. All schools in Luxembourg were closed on 19th March with a gradual return to in person teaching during the first week of May. Luxembourg reunited all classes to normal sizes, despite experiencing an early second wave of infections in June-July 2020 and social distancing and face masks were made mandatory. An epidemiological analysis of the second wave of infections were conducted by comparing the incidence of infections in school-age children and teachers to that of the general working population. The study also estimated the number of secondary transmissions occurring at schools.

Methods: All positive SARS-CoV-2 infections were detected by RT-PCR and reported to the health directorate. COVID-19 surveillance data was linked to national database and therefore details including employers and school class identifiers were retrieved. Determination of the source of transmission was conducted manually by epidemiologists. If contact with a known positive case occurred within an incubation interval of less than 14 days, this case was considered as the probable source. Sources were categorised as family, school, friends, or others (sports or multiple probable sources). Complex cases with more than two probable sources were reviewed by two independent epidemiologists.

Results: During the first wave in March-April 2020, the incidence of SARS-CoV-2 infection was substantially lower in school-age children when compared to the older adult population. Data during the peak week of March 23-29 found that the incidence was 28 per 100,000 for those aged 0-19 years old compared to 208 per 100,000 for the rest of the population (Incidence rate ratio (IRR) 0.13, 95%CI 0.09-0.19, p<0.001). During the peak week of the second wave of COVID-19 infections (July 20-26) , there was no difference in incidence observed between school-aged children and other adults.

Incidence rates of SARS-CoV-2 infection in teachers and the general working population were similar during the first wave but slightly lower in teachers during the second wave. Incidence was significantly lower in pupils compared to teachers during the first wave (IRR 0.20, 95% CI 0.12-0.34, p<0.001) but was higher during the second wave.

Incidence rates were significantly lower in pre-primary school pupils (IRR 0.18, 95%CI 0.04-0.76, p<0.05) and in primary school pupils (IRR 0.21 95%CI 0.08-0.55, p<0.001) than in high school pupils during the first wave, but these differences were less marked during the second wave. (IRR 0.61, 95%CI 0.32-1.16, p<0.05) and (IRR 0.72, 95%CI 0.46-1.14, p<0.05) respectively.

Data collected between 4th May- 25th July 2020 identified 390 cases of confirmed SARS-CoV-2 infection in pupils and 34 cases in teachers. 37.5% of cases had no identifiable cause. The most frequent observed source of infection was family/household (42.5%) followed by school transmission (11.6%). For 123 (29%) cases, there was no data available to ascertain whether the individuals were present at school, while 73 cases (17.2%) were not present at school and therefore posed no infection risk.

Of the 228 cases present at school, 150 did not give rise to any secondary cases, while 29 cases gave rise to a total of 49 secondary cases. Of these 49 cases, 38 (78%) were pupil-to-pupil transmission, seven (14%) teacher-to-pupil, three (6%) pupil-to-teacher and one was teacher-to-teacher transmission.

In total, 179 positive cases who went to school were estimated to have transmitted SARS-CoV-2 infection to 49 secondary cases, which corresponded to an effective reproductive rate of 0.27 when considering only the school setting.

Comments: This study agrees with the view that currently COVID-19 outbreaks in educational settings appear uncommon and that the incidence of infections in educational settings is correlated with that of the general population.

Toh, Z QLicciardi, P VEmerg Infect DisPersistence of SARS-CoV-2-Specific IgG in Children 6 Months After Infection, Australia20 May 2021AustraliaAustralasia22Clinical - Clinical Features https://wwwnc.cdc.gov/eid/article/27/8/21-0965_article

This research letter describes a study looking at humoral immune response to SARS-CoV-2 infection in children (and adults) over time. It showed seroconversion in around 80% of children by 6 weeks, despite all being asymptomatic or having mild disease, and this seropositivity persisted at 6 months.

Participants and their family members were recruited after testing positive for SARS-CoV-2 infection by rt-PCR at Melbourne Children’s Hospital, Australia. All had mild disease or were asymptomatic, none were hospitalised. The study included 22 children, median age of 4 years (0-18 years).

At 6 weeks, 79% of children (15/19) had seroconverted and this IgG response persisted at 3 months and 6 months (14/17 children, 82%). Seropositivity rates were similar in the adult cohort.

Participant numbers were small and the time period limited to 6 months, but the findings of good and lasting humoral responses after mild disease, at least in the medium term, is encouraging.

Lyngse, FKirkeby, CmedRxivIncreased Transmissibility of SARS-CoV-2 Lineage B.1.1.7 by Age and Viral Load: Evidence from Danish Households19 Apr 2021DenmarkEurope1214Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.16.21255459v1

This article is a pre-print and has not yet been peer reviewed.

Introduction: The B.1.1.7 lineage was first identified in the southeast of England in September 2020. In Denmark, B.1.1.7 was first detected on November 14, 2020, and by March 2021 comprised more than 90% of the circulating lineages. The aim of this study was to estimate the household transmissibility SARS-CoV-2 for lineage B.1.1.7 compared with other lineages, by age and viral load and to estimate any multiplicative effect.

Methods: Data from the Danish register was assessed from January 11th to February 7th 2020. This register included the full population of Denmark, all RT-PCR tests for Sars-Cov-2 and all positive tests which has whole genome sequencing (approx. 70% of samples), CT value, and presumed Sars-cov-2 lineage. The Danish civil registration number was linked to a national register of address codes, to analyse presumed household transmission.

Results: 8,093 household primary cases were identified, of which 82% (6,632) were selected for WGS, and 65% (5,241) generated a high-quality SARS-CoV-2 genome. Lineage B.1.1.7 was found in 15% (808) of these genomes. The primary cases lived in households comprising 2-6 persons with a total of 16,612 potential secondary cases, of which 4,133 tested positive. This implies an attack rate of 25% (4,133/16,612).

The age specific transmissibility followed a U-shaped pattern with the lowest transmission from primary cases in the 10 to 30 years age range, higher from younger children, and highest from elderly casesIn households where the primary cases were infected with B.1.1.7, the attack rate was 38%, compared with 27% when the primary cases were infected with other lineages.

Discussion: Sars Cov 2 lineage B.1.1.7 had a household transmissibility 1.5-1.7 times higher compared with other lineages even after adjusting for CT values. Sars Cov 2 lineage B.1.1.7 generally follows the pattern of other lineages, where teenagers are the least transmissible within households. However, B.1.1.7 was consistently more transmissible per age group compared with other lineages.

This paper adds to the data for Sars Cov 2 lineage B.1.1.7 being more transmissible than other previous lineages, and may have public health implications, ie contact tracing for variable with higher transmissibility should be prioritised. This data implies that any model that is used as a tool for decision makers on further public health interventions must take into account the predominant lineage in the population and its transmissibility.

Galow, LArmann, JJ InfectLower household transmission rates of SARS-CoV-2 from children compared to adults27 04 2021GermanyEurope17Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(21)00209-7/fulltext

In this seroprevalence study from Dresden, Germany, transmission between individuals with confirmed SARS-CoV-2 infection and their household contacts was assessed. PCR-positive SARS-CoV-2 individuals identified by the local public health office from June 2020 were invited to participate. SARS-CoV-2 seropositive individuals identified in a separate seroprevalence study in schools were also invited. All household members of confirmed cases were tested for SASR-CoV-2 IgG antibodies and information on infection prevention measures implemented within households was collected.

A total of 150 households were included; 139 based on a SARS-CoV-2 PCR-positive household member and 11 based on a seropositive member. Serostatus was available on 88% (414/470) of all household members. Over half (51%, 211/414) were seropositive. The secondary attack rate (SAR) was 0.35 overall. SAR was significantly lower for the 17 child index cases (0.15 (95% CI 0.05-0.27)) compared with the 126 adult index cases (0.38 (95% CI 0.32-0.45)). Avoiding shared spaces (employed in 42% of households) and masking of the index case (14% of households) both significantly reduced risk of household transmission.

A strength of this study is the use of SARS-CoV-2 serostatus to assess household transmission, thereby minimising the likelihood of under-detection of secondary cases. This study is however limited by the lack of longitudinal data to accurately determine direction of transmission, with the first case identified by PCR or antibody testing determined to be the index case. Notwithstanding this, the results of a significantly lower household SAR for children compared with adults, along with the small number of paediatric index cases, is consistent with existing evidence that children are less susceptible to and less likely to transmit SARS-CoV-2 compared with adults.

Say, DTosif, SLancet Child AdolescPost-acute COVID-19 outcomes in children with mild and asymptomatic disease20 04 2021AustraliaAustralia171Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00124-3/fulltext
Somekh ISomekh EJAMA Netw. OpenComparison of COVID-19 Incidence Rates Before and After School Reopening in Israel26 Apr 2021IsraelMiddle East148564Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778940

Aim: to understand whether school reopening was associated with SARS-CoV-2 infection in children aged 0 to 9 years of age.

Methods: national data from Israel obtained from the Ministry of Health to calculate SARS-CoV-2 age group–specific weekly incidence rates and test positivity rates for the following age groups: 0-9 years, 10-19 years, 20-39 years, 40-59 years and 60 years and older. These rates were adjusted for the number of tests performed and for the proportion of each age group in the general population. Using adjusted incidence rate ratios (IRRS) and test positivity rate ratios (RRs)s the rates were compared between the 3 weeks in September 2020 following reopening of the schools on the 1st September and the last week in August. An infection surge led to schools being closed on 14th September. Rates were compared between November through to December with that from the last week in October following schools being reopened on 1st November 2020. Linear regression was used to look at how the incidence rate varied during the first 3 weeks in September.

Results: data were analysed from 47260 children aged 0 – 9 years, 101 304 youths aged 10 to 19 years, 151 295 adults aged 20 to 39 years, 103 056 adults aged 40 to 59 years, and 63 438 adults aged 60 years and older. Children aged 0 – 9 years had the lowest increase in IRRS (p<0.001) and RRs in September and in Nov-Dec 2020 (p<0.001).

Age group Sept 2020 IRR (incidence rate ratio) Nov-Dec 2020 IRR (incidence rate ratio) Sept 2020 RR (test positivity rate ratio) Nov-Dec 2020 RR (test positivity rate ratio)

0 to 9 years 1.1 (95%CI, 1.0-1.14) 1.34 (95%CI, 1.23-1.45) 0.77 (95%CI, 0.7-0.8) 0.75 (95%CI, 0.7-0.8)

10-19 years 3.1 (95%CI, 2.96-3.3) 1.9 (95%CI, 1.74-2.06) 1.5 (95%CI, 1.4-1.6) 0.97 (95%CI, 0.95-1.1)

20-39 years 3.2 (95%CI, 2.96-3.4) 2.5 (95%CI, 2.3-2.7) 1.6 (95%CI, 1.5-1.66) 1.3 (95%CI, 1.25-1.4)

40-59 years 3.1 (95%CI, 2.9-3.3) 2.43 (95%CI, 2.3-2.6) 1.5 (95%CI, 1.45-1.6) 1.28 (95%CI, 1.2-1.4)

≥60 years 2.2 (95%CI, 2.0-2.3) 2.95 (95%CI, 2.6-3.3) 1.1 (95%CI, 1.0-1.2) 1.48 (95%CI, 1.35-1.6)

The youngest age group also had the lowest slope when plotting incidence rate versus week in September.

Authors’ Conclusions: These analyses suggest that children in this age group do not have substantial rates of SARS-CoV-2 infection during school attendance and are unlikely to play a substantial role in the spread of infection.

Comments: The study suffers from a number of limitations, e.g. there is no information on extent of symptomatic and asymptomatic testing. No raw data were provided, only ratios, there was little detail on statistical analyses. The labelling of parameters in the figures did not correspond to those in the methodology. The pattern of results could be explained by other factors such as differential testing, by differences in social behaviour not considered by the authors.

Chua, GKwan, MJAMAClinical Characteristics and Transmission of COVID-19 in Children and Youths During 3Waves of Outbreaks in Hong Kong03 May 2021Hong KongAsia397Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779416

Methodology: A cross-sectional study of individuals under the age of 18 years with PCR confirmed SARS-CoV-2 in Hong Kong. Data was collected from 9 paediatric wards over 3 waves of COVID-19; January 23rd to March 21st, 2020, March to July 4th, 2020 and July 5th to December 2nd 2020. Information on study participants was prospectively captured in a central database by physicians included in a territory-wide paediatric COVID-19 study. Retrospective analysis of demographics, clinical characteristics and close contacts aimed to compare clinical features across the three COVID-19 waves of infection and determine the most common sources of infection.

Results: 397 children and youths were identified between January 23rd and December 2nd 2020, of which 14 were confirmed in wave 1, 118 were confirmed in wave 2 and 265 were confirmed in wave 3. 55.4% (220) of participants were males and the mean (SD) age was 9.95 (5.34). 51.4% (204) of infections within this cohort were contracted locally.

394 (99.2%) of individuals within the cohort only developed mild symptoms. Only 4.3% (17) had anosmia and 3.5% (14) ageusia in the cohort. Across the 3 waves, fever and cough was more common in the first wave (fever 71.4% (10), cough 42.6% (6)) than the second (fever 18.5% (22), cough 12.7%(15)) and third (fever 37.0% (98), cough 19.6% (52). 3 individuals demonstrated COVID-19 manifestations including toe chilblains, multisystem inflammatory syndrome (MIS-C) and steroid-dependent autoimmune haemolytic anaemia, all of which were treated successfully. No patients within the cohort developed pneumonia nor did they need oxygen or intensive care treatment.

Imported cases were more common in wave 1 (78.6%) and wave 2 (93.2%), however, in wave 3 local infections were more common (72.8%). Of the 91.2% (186) local cases who reported close contact with another COVID-19 case, 90.0% reported family members with COVID-19. Overall, 68.8% (273) of individuals reported close contact with a confirmed case of COVID-19, and of these 98.9% (270) reported family members as their close contacts. 3 individuals in the first wave, 6 individuals in the second wave and 3 individuals in the third reported close contact with an COVID-19 confirmed schoolmate. Unknown contact history was common. Within wave 1 and part of wave 2, full school closures were implemented, half school closures were implemented in part of wave 2 and parts of wave 3 and full school opening were implemented in part of wave 3.

Comment: Children and youth captured within this cross-sectional study in Hong Kong demonstrated mild illness in majority of cases. Complications namely MIS-C, chilblains and steroid-dependent autoimmune haemolytic anaemia were rare, occurring in only 3 cases that were treated successfully. Evaluation of close-contacts showed that a COVID-19 positive family member was significantly more common than classmates, however school closures were apparently for most of the study period.

Aguilera-Alonso, DCalvo, CArch Dis ChildPrevalence of thrombotic complications in children with SARS-CoV- 230 April 2021SpainEurope537Clinical - Comorbiditieshttps://adc.bmj.com/content/early/2021/05/24/archdischild-2020-321351.info

Methods: Epidemiological multicentre prospective cohort study in Spain. Included children less than 18 years with active SARS-CoV-2 or MIS-C and attended at 49 hospital from 1 March to 30 September 2020.

Thrombotic complications were defined as any radiologically confirmed thrombosis, arterial or venous, occurring close to the diagnosis of SARS-CoV-2 infection (up to 3 weeks).

Results: 537 children diagnosed with SARS-CoV-2. 368 (68.5%) were hospitalised. 58 (10.8%) cases required PICU. Forty-seven (8.8%) cases were diagnosed with MIS-C. Anticoagulant drugs (heparin in all cases) were administered to 29 (5.4%) patients: as prophylaxis in 24 (82.8%) cases, and as treatment in 5 (17.2%) cases. Most of the patients on thromboprophylaxis had severe COVID-19. Four cases (0.7%) out of the global cohort, developed thrombotic complications. Three out of these four patients were adolescent girls. None of the cases was diagnosed with MIS-C. Two patients (patients 1 and 2) had several significant thrombotic risk factors. Patients 3 and 4 did not have any previous personal or family risk factors for thrombosis. However, patient 3 was diagnosed later with lupus anticoagulant. The only patient receiving thromboprophylaxis before thrombosis was patient 2. D-dimer levels were severely increased in patients 1 and 4. All cases had thrombosis affecting the limbs, with cerebral venous sinus thrombosis and pulmonary embolism in one of them. All patients were treated with heparin and discharged without sequelae.

Discussion: Prevalence of thrombosis is slightly higher than that previously described in hospitalised children without COVID-19. Only two of our four cases had significant thrombotic risk factors, highlighting the difficulty of predicting thrombotic complications in children with COVID-19 to initiate anticoagulant prophylaxis.

Thrombosis is very uncommon in patients under 18 years old, and systemic anticoagulant prophylaxis may have adverse events that outweigh its benefit.

The authors conducted a systematic search to review reported paediatric patients diagnosed with COVID-19 infections with any thrombotic complication. Ten cases were found; one of them is already included in this cohort. Three (3.8%) and four (2.2%) cases diagnosed with MIS-C from two other national cohorts developed a venous thrombosis.

In this cohort, 8 of 169 (40.2%) had a D-dimer value >1500 μg/L. However, only 2 of 68 (2.9%) cases developed a thrombotic complication. Therefore, the use of the D-dimer value is not specific enough to make decisions regarding anticoagulant prophylaxis in children.

In the authors opinion, other factors, such as the age, coexistence of risk factors, or MIS-C diagnosis, should be considered when initiating anticoagulant prophylaxis in children with COVID-19.

Limitations: As some children were diagnosed on basis of serology rather than PCR, it is unclear if these cases were related acute infection. On patient was both negative on PCR and serology, so it is unclear on which basis the diagnosis was made. Additionally, since ultrasound was not routinely performed in all patients, subclinical thrombosis may not have been diagnosed.

Conclusion: Except in the MIS-C, unlike adults, thrombotic complications seem very uncommon in children with SARS-CoV-2. Adolescence and previous thrombotic risk factors may be considered when initiating thromboprophylaxis in children with COVID-19.

Thielecke, MMockenhaupt, FPEur J Public HealthSARS-CoV-2 infections in kindergartens and associated households at the start of the second wave in Berlin, Germany - a cross sectional study6 May 2021GermanyInternational155Epidemiology - Transmissionhttps://academic.oup.com/eurpub/advance-article/doi/10.1093/eurpub/ckab079/6270920

Methods: Cross-sectional study carried out in Berlin between September 28 and October 2, 2020. Twelve out > 2700 kindergartens were randomly chosen to assess the prevalence of SARS-Cov-2 infections and IgG seropositivity among preschool children, educators and household contacts, during the beginning of the local second wave of the COVID-19 pandemic. For the selection of the study sites, each local district was stratified by socioeconomic status. From each stratum, two districts were randomly selected, and from them two kindergartens were randomly chosen. Where feasible, 20 children and 5 staff were recruited from each kindergarten; their household contacts were also invited to participate.

Research staff visited each study site, interviewed and examined the study participants, collected finger prick blood samples, as well as swabs from the nasal vestibules and oropharynx. Household contacts self-collected their swabs and took them to mobile clinics set up off the kindergartens for this study. Five self-reported ill participants were visited at home.

Results; Seven-hundred and twenty participants were assessed (155 pre-school children, 78 educators and 487 household members). The children’s age ranged between 1 and 6.3 years old (median 4.4 years old); 40% were female (60/150); 24.2% (4/152) had one or more current symptoms suggestive of COVID-19, and 57.0% (73/128) had at least one symptom compatible with this illness in the previous two weeks. Educators were mostly females 86.8% (66/76), aged between 18 and 78 years old (median: 44 years old).A third of them had current signs and/or symptoms of COVID-19 (28.9%; 22/76) and 74.6% (50/67) a history of symptoms of this disease in the previous two weeka. Household members were aged between 0 and 90 years (median: 36 years old); 58.4% (215/368) had a history of any symptoms in the preceding two weeks, but none were symptomatic at enrolment. Physical distance between staff (8/12) and between staff and parents (11/12), obligatory facemask wearing by staff for contacts (5/12) and for contacts among colleagues (1/12) were implemented in accordance with local regulations. Daily training on good hygiene practices against COVID-19 were reported in most facilities, and attendance irrespective of upper respiratory symptoms was allowed in ¾ of the surveyed centres.

While IgG antibodies against SARS-Cov-2 were detected in one kindergarten worker (1 /672 samples) who denied a current or past history consistent with COVID-19 infection, no nasal and oropharyngeal swabs were positive for SARS-Cov-2 (samples were collected from 152/155 children; all educators and 471/487 household contacts).

Comment: during the study period no SARS-Cov-2 infections were detected in kindergarten children during the beginning of the second wave of community transmission in Berlin. Although there was no evidence of SARS-Cov-2 transmission within these schools at the time of the assessment, outbreaks in these and similar settings may occur. These findings reinforce the importance of good hygiene and other transmission mitigation practices, frequent testing and vaccination of educators and school staff.

Fontanet, AHoen, BEuropean communicable disease bulletinSARS-CoV-2infection in Schools in a Northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 202015 April 2021FranceEurope749Epidemiology - Transmission https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.15.2001695

This retrospective observational study undertaken in Northern France in early 2020 involved 664 participants from a high school and 1,340 participants from 6 primary schools. This was a time when there was unsuspected SARS-CoV-2 circulating in the general population and there were limited control measures. 239 children from the high school (8 <12 years of age, 235 age 12-17years) and 510 children from the six primary schools in the region had blood taken for serological analysis. Serological investigations were also undertaken in staff from the schools (80 high school staff and 69 primary school) and parents and relatives (345 high school, 761 primary school).

All school staff, as well as pupils and their parents and relatives were invited to complete a questionnaire covering symptom history since 13 January 2020.

In the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils’ parents and relatives (p < 0.001).

In the primary school, infection attack rates were 8.8% (45/510), 7.3% (3/41) and 3.6% (1/28), in pupils, teachers and none teaching staff respectively vs 11.8% (76/642) and 7.1% (1/14) in the pupils’ parents and relatives (p>0.1).

In the primary schools overall, antibody prevalence in pupils sharing classes with symptomatic cases was higher than in pupils from other classes: 15/65 (23.1%) vs 30/445 (6.7%) (p < 0.001). Among 46 SARS-CoV-2 seropositive pupils < 12 years old, 20 were asymptomatic. There was no evidence that past HKU1 and OC43 seasonal coronavirus infection protected against SARS-CoV-2 infection in 6–11 year olds.

In the authors discussion of their results, they make several comments. Firstly, while the high school experienced a noticeable outbreak of symptomatic infections, the circulation of the virus in the primary schools was partly silent, with a large proportion (43.5%) of asymptomatic infections among children under 12 years old.

Secondly, parents and relatives of infected pupils were more likely to be infected compared with those of non-infected pupils, particularly for families of primary school pupils.

Thirdly, infected children less than 12 years of age experienced mild forms of disease, with no specific symptoms, or were asymptomatic, whilst teenagers and adults experienced similar forms of disease. Adults and children developed neutralising antibodies at a similar rate, with a higher proportion of those with neutralising antibodies among symptomatic compared with non-symptomatic participants.

Finally, past infection with seasonal coronavirus HKU1 and OC43 was very common (>95% of primary school-aged children), precluding the possibility of studying any effect of past infection with these two coronaviruses on the risk of acquiring SARS-CoV-2 infection.

The authors conclusions are “Our investigations identified SARS-CoV-2 circulation in both a high school and primary schools at the very early onset of the pandemic, in a context of unsuspected circulation in the community and absence of control measures. Decisions to reopen or close schools should be considered carefully in the context of the extent of transmission in the wider community. Ongoing monitoring for possible resurgence in infections would be needed, as well as strategies to limit transmission in the school setting, including testing of all those with symptoms, rapid isolation of cases and quarantine and testing of contacts, hand hygiene, physical distancing, respiratory etiquette, cohorting of classes, and the wearing of masks for older pupils.”

Osmanov, I. M.Munblit, DMedrxivRisk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study.26 Apr 2021RussiaAsia518Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.04.26.21256110v1

This article is a pre-print and has not yet been peer reviewed.

Telephone follow up study of persisting symptoms in 518 children from a cohort of 853 SARS-CoV-2 RT PCR positive cases admitted to a tertiary hospital in Moscow, Russia, between 02/04/20-26/08/20. Median age (IQR), 10.4 years (3-15.2). 55.2% female. Median interval (IQR) to the follow up call, 256 days (223-271). Parents of 24.3% of the children reported persisting symptoms. The commonest were fatigue (10.6%), sleep disturbance (7.2%), sensory problems (6.2%), GI disturbance (4.4%) and non-eczematous dermatological problems (3.6%). 8.5% reported symptoms from >1 category, of which the commonest combination was fatigue and sleep disturbance. Multivariate logistic regression of demographic features, pre-existing conditions and features of the initial Covid illness identified age 6-11 years or 12-18 years and allergic disease as significant predictive factors for persisting symptoms. The most significant weaknesses of this study is the lack of any matched control data on persisting symptoms in non-Covid cases admitted to hospital, since hospitalization itself can trigger psychological/psychosomatic features in children.

Kushner L EMathew RHosp. Pediatr.“For COVID” or “With COVID”: Classification of SARS-CoV-2 Hospitalizations in Children18 May 2021USANorth America117Epidemiology - Disease Burdenhttps://hosppeds.aappublications.org/content/hosppeds/early/2021/05/18/hpeds.2021-006001.full.pdf

This short reports aims to assess the impact of incidental findings of SARS-CoV-2 positivity on hospital metrics for “hospitalisations” of children with COVID-19. They set out to establish a method of characterising admissions as being “likely”, or “unlikely” to have COVID-19

The authors also wondered what the interrater differences might be in both the existing hospitalisation categorisations and their novel “likely” and “unlikely” to have COVID-19 categorisation they advance.

They retrospectively assessed children hospitalised to the Santa Clara County Department of Public Health (DPH), a quaternary care children’s hospital in Northern California, during the period May 10, 2020 to February 10, 2021 and who had undergone universal testing for SARS-CoV-2 including children readmitted after 90 days of the first admission and children negative to SARS-CoV-2 at admission but who became ill or deteriorated with it later on the ward.

The hospital established infection by a positive result of SARS-CoV-2 RNA via real-time reverse transcriptase polymerase chain reaction (rtPCR).

The authors then looked at the previously published categorization system that classified patients as either asymptomatic, mild/moderate, severe, critical, or the Centers for Disease Control and Prevention (CDC) definition of multisystem inflammatory syndrome in Children(MIS-C). Using information from the children’s admission notes and discharge notes, the authors recategorized each of the above stems into “likely” or “unlikely” to have required admission based on severity of SARS-CoV-2 infection.

They gathered 117 children in the cohort most of whom were Hispanic/LatinX 83(70.9%), followed by White Non-Hispanic 13(11.1%) and Asian 11(9.4%) and a few Native Hawaiian/ Pacific Islander (3) and Black/African American (2). There were about equal numbers of boys and girls and the age range was 1.5years to 18 years.

By the previously published categorisation for SARS-CoV-2, the authors found that 15(12.8%) were critical cases with nearly 100% interrater agreement that SARS-CoV-2 infection was correct (one case in critical care for respiratory failure after cardiac surgery, asymptomatic for SARS-CoV-2 at admission but positive later with worsening symptoms while hospitalised). 14 cases(12%) were SARS-CoV-2 MIS-C cases with 100% interrater agreement, 9(7.7%)severe cases, 33(28.2%) mild / moderate cases. There were 46(39.3%) asymptomatic admissions with interrater agreement of just below 95% (kappa 0.85%).

On the “likely/unlikely” to have SARS-CoV-2 yardstick for admitting the children to hospital, they found SARS-CoV-2 should have likely been the cause of admission in 64 (54.7%, 95% CI 45.2 – 63.9%) patients and unlikely in 53 (45.3%, 95% CI 36.1 – 54.8%) patients.

Using this method of determining necessity of admission for SARS-CoV-2, a number of cases would have been overlooked. 5/33 (15%) of the mild/moderate cases admitted for SARSCoV-2 would have been counted as admitted for other than SARS-CoV-2, 3/9 (30%) of severe cases but 44/46(96%) of asymptomatic cases would have been excluded from those admitted due to SARS-CoV-2 infection. The researchers’ interrater agreement was 89% (kappa 0.78). Examples of causes of interrater differences occurring included brief resolved unexplained respiratory episodes (BRUES), new/worsening seizures, and SARS-CoV-2 negative at admission but symptomatic while hospitalised.

The authors conclude that both the existing and the possible novel hospitalisation categorisations are adequate even if not perfect. They however acknowledge that more and more is being learnt about clinical manifestations of SARS-CoV-2 (specificity may thus be achieved in the future). The authors also point to clinical symptoms common between SARS-CoV-2 and other diagnoses possibly contributing to the blurring of differentiation of SARS-CoV-2 as reason for admission when “likely”/ “unlikely” to have SARS-CoV-2 were applied as admission category for this cohort.

This report is seeking a more accurate and fair enumeration of SARS-CoV-2 disease burden in children that does not socially and educationally disadvantage them. However, there are limitations in the report for a number of reasons. Firstly, the likely /unlikely to have SARS-CoV-2 categorisation would currently have to be applied with hindsight. Secondly, this report was a situation analysis and the sample size was small. The results give an indication that incidental findings of SARS-CoV-2 positivity in hospital admissions may be an important consideration in interpreting hospitalisation metrics. The methods utilised by the authors for determining this may not be generalizable to others settings.

Verberk, JBruijning-Verhagen, PMedRxivTransmission of SARS-CoV-2 within households: a prospective cohort study in the Netherlands and Belgium – Interim results26 Apr 2021Belgium and NetherlandsEurope00000000000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.23.21255846v1.full

This pre-print report describes a detailed study of selected households in the second wave of the pandemic, in September-December 2020. Whenever there was a positive PCR test for SARS-CoV-2, all other household members underwent serial testing with PCR swabs, and dried blood-spot antibody testing. Infants under 2 also had stool PCR tests. Symptoms were also reported daily. This continued for about 40 days. They were thus able to estimate secondary attack rates (SAR) for their community.

They recruited 117 households (20 in Belgium, 97 in the Netherlands), involving 117 index cases and 265 household members. Some interesting results emerged, confirming what has been found elsewhere. From the index cases, 74 secondary infections were confirmed, giving a household SAR of 44%. Of these, 20 (27%) were detected by seroconversion only without PCR, and 13 (18%) were asymptomatic. Not surprisingly, index cases with acute respiratory symptoms were more infectious to their co-habitees (SAR 52%, vs SAR 22% for those with mild symptoms). Transmission occurred early, with 2/3 household contacts being already infected at recruitment. More transmission occurred in larger households.

Of more significance to paediatricians was the confirmation that children were much less infectious than adults: child-to-parent SAR was only 9%, compared to parent-to-child SAR of 28%, and adult-to-spouse SAR of 36%.

With near-universal antibody testing, they were able to establish that only 78% of those with PCR-confirmed infection developed antibodies: which raises doubts about how much protection is afforded by natural infection, and is further confirmation that vaccination is required for everybody.

There are some potential flaws to this study, which has not yet been peer-reviewed. The families may not have been typical: many were health-care workers; specimens were taken by families and may have been unreliable; the index cases may in fact have been secondary, with the true index undetected initially; some may have been infected outside the household.

Most importantly, this study was done before either the arrival of new variants that are known to be far more transmissible, or the introduction of mass vaccination, therefore the generalisability of the findings may be limited.

Rosen HYinon YJ Clin MedFetal and Perinatal Outcome Following First and Second Trimester COVID-19 Infection: Evidence from a Prospective Cohort Study16 May 2021IsraelMiddle East29Neonatalhttps://doi.org/10.3390/jcm10102152

There have been a number of published studies, including systematic reviews, reporting on the outcomes for mother and foetus of pregnancies in which the mother contracted Covis-19 infection. In these studies a large proportion of the infections were diagnosed in the last trimester of pregnancy. This paper from Israel reports on a prospective, single-tertiary-centre, study of pregnant women who developed evidence of SARS-CoV-2 infection in the first two trimesters of pregnancy.

The majority of women were identified either because they had symptoms of SARS-CoV-2 infection or they were contacts of cases; three were diagnosed as a result of routine testing prior to amniocentesis. The diagnosis of SARS-CoV-2 infection was based on a positive result on real-time reverse-transcriptase polymerase chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens.

The study protocol included serial sonographic examinations every 4–6 weeks to assess foetal well-being, growth, placental function, foetal anomalies and signs of foetal infection; amniocentesis was offered to assess amniotic fluid SARS-CoV-2-PCR (polymerase chain reaction) and foetal brain magnetic resonance imaging (MRI) was offered at 30–32 weeks gestation. Perinatal outcomes were recorded. Demographic, obstetric and neonatal data were collected from history intake, medical charts or by telephone survey.

The study recruited 55 pregnant women with laboratory-proven SARS-CoV-2 infection contracted prior to 26 weeks gestation; 51 of the pregnancies were singleton pregnancies and four were twin. The mean maternal age was 29.6 +/-6.2 years. The infection was diagnosed in the first trimester in 28 of the women and in the second trimester in 27. The clinical illness severity was classified as “asymptomatic “or “mild” in 54, although six developed respiratory symptoms which led to hospital admission for observation. One woman developed severe myocarditis after recovery from the SARS-CoV-2 and was reported to have made a full recovery from the myocarditis.

Of the 22 who underwent amniocentesis none had evidence of SARS-CoV-2 in the amniotic fluid. Serial targeted sonographic scans were performed in 38 women and major fetal anomalies were identified in two; it was not possible to determine whether these resulted from SARS-CoV-2 infection. Five MRI scans were performed, all of which were reported to be normal.

A summary of the main finding of the study is as follows:

- there was no evidence of vertical SARS-COV-2 transmission from amniotic fluid PCR testing or cord blood serology at delivery

- there was no evidence of adverse foetal effects on serial ultrasound anatomy scans

- no increased rates of obstetric complications were found

- most deliveries occurred at term and birthweights were appropriate for gestational age

- neonatal outcome was overall reassuring.

-there was no significant difference for the above outcome measures when comparing first to second trimester infections.

While the outcome data from this study are reassuring, the sample size is small and only 29 of the pregnancies had reached term at the time of submission for publication. More precise estimates of the risks associated with maternal Covid-19 contracted during the first two trimesters of pregnancy must await the completion of larger-scale studies which are currently in progress.

Loenenbach, ABuchholz, UMedrxivSusceptibility and infectiousness of children and adults with SARS-CoV-2 variant B.1.1.7 deduced from three daycare centre outbreaks and related household situations; Germany, 202117 MAY 2021Germany Europe47Epidemiology - Transmissionhttps://doi.org/10.1101/2021.05.12.21256608

The authors investigated three SARS-CoV-2 variant B.1.1.7 kindergarten outbreaks in Germany and related household situations, a total 47 out of 171 children were affected. Despite group cohorting, cases occurred in almost all groups, i.e. also among persons without close contact. Secondary attack rates (SAR) of children were similar to adults (day care: 23% vs. 30%; p=0.15; households: 32% vs. 39%; p=0.27), and also child-induced household outbreaks led to similar SAR compared to adults.

In summary, the author’s investigation confirms increased transmissibility of B.1.1.7. In addition, the data presented suggest that both susceptibility and infectiousness of children 1-5-years-old is substantially higher compared to the pre-Variant of concern era, and may be converging to those among adults.

Angelidou, A Belfort, MJAMA Network Open.Association of Maternal Perinatal SARS-CoV-2 Infection With Neonatal Outcomes During the COVID-19 Pandemic in Massachusetts23 Apr 2021USANorth America250Neonatal https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779051
Havers, FTaylor, CMMWRHospitalization of Adolescents Aged 12–17 Years with Laboratory-Confirmed COVID-19 — COVID-NET, 14 States, March 1, 2020–April 24, 202111 Jun 2021USANorth America376Epidemiology - Disease Burdenhttp://dx.doi.org/10.15585/mmwr.mm7023e1

This Early Release Report is an analysis of data collected by the Coronavirus Disease 2019 - Associated Hospitalization Surveillance Network (COVID-NET), relating to hospital admissions of young people aged 12-17 years with COVID-19. In this report, data from 1 January 2021 to 31 March 2021 are analysed in detail and then compared to data and trends from 1 March 2020 to 24 April 2021.

Between 1 January and 31 March 2021, 376 adolescents with a positive SARS-CoV-2 test result were hospitalised and notified to the COVID-NET registry, which covers 14 US states and approximately 10% of the population of that country. Of these, 172 (45.7%) were analysed separately because their primary reason for admission was not directly COVID-19–related.

Among the 204 patients who were admitted primarily for COVID-19–related illness 52.5% were female, 31.4% were of Hispanic heritage and 35.8% were of non-Hispanic Black heritage. 31.4% of these patients required ICU admission and 4.9% required mechanical ventilation. There were no deaths.

Among the patients admitted primarily for COVID-19–related illness, 70.6% had one or more underlying medical conditions, which included obesity (35.8%) chronic lung disease including asthma (30.9%) and neurologic disorders (14.2%).

Between March 2020 and April 2021, weekly COVID-19–associated hospitalisation rates among adolescents, peaked at 2.1 per 100,000 in early January 2021, declined to 0.6 in mid-March, and then rose again to 1.3 in April. The overall rate was 12.5 times lower than in adults aged over 18 years, but higher than in children aged less than 12 years.

Rates of COVID-19–associated hospitalisation among adolescents were also 2.5–3.0 times higher than rates of seasonal influenza-associated hospitalisation during comparable periods.

The authors conclude that although COVID-19–associated hospitalisation rates in adolescents in the USA are lower than in adults, nevertheless severe disease does occur, including that requiring ICU admission and mechanical ventilation. They point out the frequent occurrence of underlying illness in these hospitalised adolescents. They also emphasise that two thirds of adolescents hospitalised with COVID-19 were of Hispanic or non-Hispanic Black heritage, although they do not identify reasons for the disparity in hospitalisation rates between different ethnic groups.

This authors also point out that the Pfizer-BioNTech COVID-19 vaccine was administered to some adolescents aged 16–17 years during this study period, which may have modified hospitalisation rates amongst adolescents in that age band, as well as the overall hospitalisation rate for all adolescents.

Lu, LTambayah, P AJ Infect DisRole of Asymptomatic Children in Community Severe Acute Respiratory Syndrome Coronavirus 2 Transmission16 Mar 2021SingaporeAsia16Epidemiology - Transmissionhttps://academic.oup.com/jid/article/223/10/1834/6174435

This Singapore-based study investigated the role of children in the transmission of SARS-CoV-2 and found no evidence of children acting as a community reservoir of infection.

The authors recruited SARS-CoV-2 positive families with asymptomatic children (within which they included symptomatic children who had a negative swab). Families were designated as “linked” households, being those with confirmed epidemiological links to other cases, or “unlinked” households, being those with no discernible link to other cases after contact tracing. The authors hypothesised an excess of SARS-CoV-2 positive children in the “unlinked” households, if children were acting as a community reservoir of infection.

The study included 16 children from 12 households, all under 12 years. These comprised 9 “linked” households and 3 “unlinked”. All were tested for SARS-CoV-2 infection by pharyngeal swab PCR as well as having convalescent serology at least 3 weeks after index case diagnosis. The 2 groups were well matched other than that the time between index case diagnosis and serological testing was significantly longer in the “linked” vs “unlinked” households.

8 of 9 “linked” households had children who tested positive for SARS-CoV-2 (either on PCR or serology). None of the children in the “unlinked” households tested positive. The data in this study suggests children were not acting as a community reservoir of infection. The findings are encouraging in this respect, although limited by sample size.

Snapiri, OBilavsky, EPediatr Infect Dis JTransient Cardiac Injury in Adolescents Receiving the BNT162b2 mRNA COVID-19 Vaccine20 May 2021IsraelMiddle East7Clinical - Clinical Features https://journals.lww.com/pidj/abstract/9000/transient_cardiac_injury_in_adolescents_receiving.95800.aspx

Israel led the world in instituting mass vaccination early in 2021, using mainly the Pfizer BioNtech mRNA vaccine BNT162b2. The population vaccinated included those aged 16-18 years. This case series describes 7 cases of perimyocarditis, all in Jewish boys aged 16-18, all temporally related to receiving BNT162b2 vaccination 1-3 days before onset of symptoms. Data were gathered through an informal network of paediatricians at 3 centres, rather than any formal surveillance.

All cases were mild, and none had symptoms typical of Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Covid-19 infection itself can rarely cause peri/myocarditis, but all these had repeatedly negative SARS-CoV-2 PCR swabs. In 6/7 the symptoms began after their 2nd dose. All had chest pain, and some also had cough, dyspnoea and/or nausea. 6/7 had ECG features (ST segment elevations), and 3/7 had pericardial effusions on echocardiogram. CRP was at least mildly raised in all, and all had a raised troponin, markedly so in 4/7. Full investigation for other causes proved negative in all. They were all admitted to hospital, with length-of-stay ranging from 3-6 days. None required intensive care, and all appeared to make a full recovery.

All 7 were diagnosed in Jan-Feb 2021 during which time nearly 200,000 16-19-year-olds in Israel had received at least one dose, so assuming all cases were identified, the prevalence of this association must be very low. However, it seems to be higher than the background level: the same centres saw only two 16-18-year-olds, and only 11 children of any age, with peri/myocarditis in the whole of 2020, before vaccination started.

So, is there any plausible biological mechanism for this association? A number of older vaccines have been associated with rare cases of myocarditis, but all these were based on live or attenuated organisms: it seems less likely that mRNA, which should not disseminate beyond the injection site, could provoke an inflammatory response in a remote organ. No putative mechanism is suggested here.

Nonetheless there have been a number of reports of similar associations in recent months, mostly in young adult men and with good outcomes (doi:10.1001/jamacardio.2021.2821). In the US, the CDC has acknowledged a possible association but in the UK the MRHA are still monitoring the situation (doi: 10.1136/bmj.n1635). It may become a factor in the JCVI’s difficult decision on vaccinating secondary school-age children.

Kompaniyets, LGoodman, AJAMA Network OpenUnderlying medical Conditions Associated with Severe COVID-19 Disease07 06 2021USANorth America43465Clinical - Comorbiditieshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780706

This is a large cross-sectional study done by the US CDC. The sample was 43,465 children (aged18 and under) presenting to an Emergency Department or treated as an inpatient, with a diagnosis of COVID-19 illness from a database collecting data from 872 hospitals, between March 2020 and January 2021. Demographic data is given. Outcomes considered were i) hospitalisation and ii) severe illness when hospitalised (ICU treatment, mechanical ventilation or death). The study assessed 2 exposures of interest a) specific underlying medical conditions b) medical complexity.

Result: The presence of chronic disease was significantly associated with hospitalisation and severe disease, and complex chronic disease even more so.

The cross-sectional analysis showed that children with type1 DM, cardiac and circulatory congenital anomalies, obesity, essential hypertension, epilepsy, neuro-psychiatric disorders and asthma, as well as children with chronic disease were at an increased risk of hospitalisation or severe COVID-19 illness. Over half the children were 12-18 and sub analyses of different age groups give different results eg prematurity being associated with increased risk of hospitalisation or severe disease in children of 1 or under. 28.7% of the sample had 1 or more underlying conditions but this rose to 62.9% of the hospitalised children.

Asthma was the most frequent diagnosed condition significantly associated with hospitalisation (risk ratio 1.23) but not severe disease. Thus, the role of asthma in severity of infection both in adults and children remains unclear.

Comment: Previous small studies have suggested that being younger than 1 year, or having an underlying health condition such as congenital heart disease, asthma, obesity, diabetes or neurological conditions are risk factors for more severe COVID-19 disease. This study, with its large sample, provides strong evidence of many of these risk factors.

Interestingly it finds neuro-psychiatric conditions (including ADHD, autism, anxiety, depression) carry a higher risk of hospitalisation but not severe disease and the authors speculate that this may be for family support or lack of other input during the pandemic.

Race/ethnicity data was collected but no associations are commented on.

The authors list the limitations of this study:

• misclassifications or underestimations may have occurred (e.g., 2.5% of the sample and 10.2% of hospitalised children had an obesity diagnosis but 18.5% of children in US are obese).

• The only indicator of socio-economic status was payer type

• Only children presenting to a hospital were included in the sample, and so are not representative of all children with COVID-19

• This analysis was limited to frequent chronic conditions which may have led to the omission of acute or rare conditions that are risk factors for severe COVID-19 illness

Brotons P Muñoz-Almagro CClin Infect DisSusceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Children and Adults: A Seroprevalence Study of Family Households in the Barcelona Metropolitan Region, Spain15 June 2021SpainEurope672Epidemiology - Transmissionhttps://academic.oup.com/cid/article/72/12/e970/5979490

This is a cross-sectional seroprevalence study conducted in Barcelona, Spain assessing the susceptibility of household contacts to SARS-CoV-2 infection. The study was conducted between 28th April and 3rd June 2020 when there was a strict home quarantine order in place in Barcelona.

The study included 381 volunteer households who reported an adult index case (SARS-CoV-2 positive on RT-PCR) during the study period. Within these households, there were 672 child contacts (under 15 years) and 412 adult contacts. Participants had serology tests (lateral flow assays) performed 3–12 weeks after the first-reported case.

Based on this household serological study, children appear to have similar susceptibility to SARS-CoV-2 infection as adults. 17.5% of children and 18.7% of adult contacts tested positive for SARS-CoV-2 antibodies. The vast majority (99.9%) of positive child contacts reported no or very mild symptoms.

This study has the advantage that contacts were confined to their houses, therefore, both adult and child participants experienced similar conditions and exposure to infection. One limitation is the relatively low sensitivity of lateral flow assays which were chosen for ethical and pragmatic reasons.

Somekh, ISomekh, EPediatr. Infect. Dis. J.INTRAFAMILIAL SPREAD AND ALTERED SYMPTOMATOLOGY OF SARS-COV-2, DURING PREDOMINANT CIRCULATION OF LINEAGE B.1.1.7 VARIANT IN ISRAEL10 06 2021IsraelEurope72Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/INTRAFAMILIAL_SPREAD_AND_ALTERED_SYMPTOMATOLOGY_OF.95798.aspx

This study measured the secondary attack rate (SAR) of SARS-CoV-2 in household clusters in Bnei Brak, a "young and crowded" city in Israel from January-February 2021 (during which time B 1.1.7 had become the predominant circulating variant locally). All household members of a positive case underwent PCR testing regardless of symptoms.

The study included 15 family clusters: 11 with an adult index case, 4 with a child index case (17.5 yo, 13.5 yo, 13yo and a 6yo). Of 98 household contacts, 76 (78%) were infected. The SAR was highest in adults contacts (90.4%) followed by children 6-17 yo (75%) and children 0-5yo (72%). The SAR in these 2021 clusters was higher than the SAR amongst 37 clusters in the same region during April-May 2020 (59% in adults, 32.5% in 6-17yo and 11.8% in 0-5yo). Infection was either mild (53%) or asymptomatic (47%) in children 0-17yo (n=68).

The results of this small study are consistent with data from the UK and elsewhere, demonstrating that the increased transmissibility of the B 1.1.7 variant across all age groups, including children. The higher SAR seen in young children in this setting compared with data from the UK may be due to the crowded living conditions in Bnei Brak. Reassuringly all infections in children in this study were mild or asymptomatic.

Fraley, ABradley, TCell. Mol. Immunol.Cross-reactive antibody immunity against SARS-CoV-2 in children and adults31 May 2021USANorth America86Clinical - Clinical Featureshttps://doi.org/10.1038/s41423-021-00700-0

Previous studies have provided some evidence that children may have a higher degree of pre-existing cross-reactive immunity to SARS-CoV-2 which protects them from severe infection. This study aimed to explore whether children have a higher pre-existing cross-reactive immunity to SARS-CoV-2 compared to adults.

METHODS: IgG antibody responses to SARS-CoV-2 nucleocapsid protein (NP) and three spike protein subunits (S1, S2 and receptor binding domain (RBD)) were measured.

Subjects:

44 adults of diverse age, sex and race/ethnicity, mostly Hispanic who had a positive SARS-CoV-2 PCR test in the previous 2-133 days, none of whom had been hospitalised.

44 healthy adults recruited in early 2019 not previously exposed to SARS-CoV-2, all female, ethnicity unknown.

86 children recruited in 2016 / 2017 prior to the COVID-19 outbreak: 17 aged 0-1 year, 37 aged 2-10 years and 32 aged 11-15 years.

Detection threshold was defined as 230 MFI (sum of the average and standard deviation of the highest negative control beads without antigen). When comparing pre-existing immunity in the different age groups the average MFI values in the non-exposed group plus the standard deviation was used for each viral antigen. High resolution mapping of antibody epitopes was carried out using overlapping peptide microarrays covering fully the SARS-CoV-2 spike protein.

RESULTS:

SARS-CoV-2 PCR positive group: All had positive IgG to S2 and RBD, 38 also to NP and 41 also to S1.

SARS-CoV-2 non-exposed adults and children: 41/44 adults and 57/86 children had detectable IgG antibodies against the SARS-CoV-2 spike S2 subunit. 41 adults and 46 children had detectable antibodies to NP. Pre-existing immunity to the S1 antigen was rarely detectable (1 adult and 3 children). Levels of SARS-CoV-2 antibodies in adults and children were, on average, an order of magnitude lower than those soon after natural infection.

Age comparisons of pre-existing immunity in non-exposed: 6% (1/17) aged 0-1 year had IgG-RBD antibodies, there were no other positive responses to S1, S2 or NP. Adults and children aged 2 and over had similar positivity rates: in adults between 13.6% and 18.3% for the S1, S2, and RBD and NP antigens, in children between 16% and 12.8% for S2 and RBD but a lower frequency of antibodies to S1 and to NP (averaged 3.2%).

High resolution of antibody epitopes: this was carried out in 14 SARS-CoV-2 PCR positive adults at an average of 25 days after a PCR positive result, 7 non-exposed adults and 7 non-exposed children.

Immunodominant regions in the S1 subunit, S2 subunit and RBD were found in both SARS-CoV-2 PCR positive group and the non-exposed individuals. The sequences of these peptides are conserved among closely related and emergent group B coronaviruses such as SARS-CoV-1 but not group C beta-coronaviruses such as Middle Eastern Respiratory Syndrome (MERS).

11 peptides were found with significantly higher binding in the SARS-CoV-2 PCR positive group compared to the non-exposed group. 28 other peptides showed significantly higher binding in the non- exposed group compared to the SARS-CoV-2 PCR positive group.

CONCLUSIONS: SARS-CoV-2 non-exposed adults and children above the age of 2 years had similar detectable IgG cross-reactive antibodies to SARS-CoV-2 viral antigens, with the highest responses to S2, RBD, and NP and rare responses to the S1 subunit. Infants aged 0–1 year old did not have detectable cross-reactive antibodies. These results identified regions in the spike protein that are commonly recognized by antibodies from SARS-CoV-2-infection or SARS-CoV-2 cross-reactive antibodies in non-exposed individuals and could serve as a guide for future vaccine design.

Comments: the report of pre-existing cross-reactive antibodies to SARS-CoV-2 was interesting. These were found in broadly similar proportions in unexposed children and adults. This finding did not support their hypothesis that these might exist preferentially in children, protecting them from severe COVID-19 disease. This could have been addressed more fully in the discussion of their results. There was instead some conjectural discussion on the potential use of the epitopes found in the high resolution peptide array for vaccine development, which probably falls outside the scope of the study as there were no data related to their role in protection from infection or from severe disease.

Gandini, SScorrano, LLancet Reg Health Eur 5: 10009A cross-sectional and prospective cohort study of the role of schools in the SARS-CoV-2 second wave in Italy26 Mar 2021ItalyEurope7376698Epidemiology - Transmission https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00069-7/fulltext

A cross-sectional prospective study of SARS-Cov-2 infections in schools in Veneto region, between 30/09/20 and 28/02/21, during Italy’s 2nd wave of SARS-CoV-2, covering 7976 schools, 7.4M students, 0.77M teachers and 0.2M non-teaching staff. SARS-CoV-2 incidence was lower amongst students than the general population, whereas incidence in teachers was similar. Secondary cases occurred after 1% of school cases and were more likely if the case was a teacher. Clusters of ≥2 secondary cases occurred in 5-7% of schools. In 2 regions, school closures preceded other measures to contain the 2nd wave but this did not affect the rise in cases when compared to regions which closed schools later. This study does not support a role for schools as a driver for the 2nd Covid-19 wave in a large region of Italy.

Cendejas-Bueno ESARS-CoV-2 Working GroupJ InfectLower nasopharyngeal viral loads in pediatric population. The missing piece to understand SARS-CoV-2 infection in children? 13 Jun 2021SpainEurope126Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(21)00289-9/fulltext

This retrospective study compared the relative viral loads of SARS-Cov-2 in positive nasopharyngeal swabs from children under 17 years old, and adults. The samples were obtained between July and December 2020, during the second and third waves of the COVID-19 pandemic in Madrid, Spain. The samples were re-tested by RT-PCR and the comparative DCt method. They corrected their results dependent on the amount of human RNAse P in the sample – a measure of human tissue which allows comparison depending on sample quality (more nasal epithelial cells present imply a higher quality sample).

One-hundred and twenty-seven samples from adults, and 126 from children (35 from 0 to 5 years old;36 from 6 to 11 years old and 55 from 12 to 17 years old) were recovered. The average viral load was lower in the samples from paediatric patients, compared to those obtained in adults. One fourth of the children had viral loads lower than the fifth percentile of the adult population.

Of note – the levels of RNAse P were much more consistent across the paediatric samples than adult samples, showing that sampling was performed better in children than adults. The authors suggest this might be due to the smaller size of childrens nasal passages compared to adults, allowing swabs to spend more time in contact with the mucosal lining. This provides evidence contrary to the common opinion that lower rates or viral loads are sometimes found in paediatric samples due to poor quality sampling.

Because most of the samples were sent from primary care centres, the authors did not have access to clinical records. Furthermore, most of these patients were followed -up by their primary care providers and therefore, it was assumed that they had mild to moderate symptoms or were asymptomatic.

Ladhani, SRamsay, M.EClinialMedicineSARS-CoV-2 infection, antibody positivity and seroconversion rates in staff and students following full reopening of secondary schools in England: A prospective cohort study, September–December 202009/06/2021EnglandEurope1189Epidemiology - Transmissionhttps://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00228-5/fulltext?rss=yes#seccesectitle0001

Introduction: This is a prospective cohort study of secondary school students and teachers across geographical locations in England, who had SarsCoV2 PCR and antibody testing in September 2020 (Round1) and December 2020 (Round 2). These two time frames represented the start and end of new school term.

Methods: Schools were recruited where a paediatric investigation team could be assembled: Derbyshire, West London, East London, Greater Manchester, Hertfordshire and Birmingham. Schools were open for in person schooling with national guidance for infection control measures, including reducing in after school activities, and mask wearing in communal areas, but not in classrooms. Consent was taken from students, parents and staff. Participants completed a questionnaire, head teachers provided information on school bubbles etc. participants had a nasal swab and a blood test taken.

Results: In round 1, there were 1,825 participants, 948 (51.9%) students and 877 (48.1%) staff. In round 2, 367 participants did not return for their second test (239 [25.2%] students, 128 14.6%] staff) and 384 new participants (241 students, 143 staff) were enrolled, resulting in 1,842 participants (950 [51.6%] students, 892 [48.4%] staff) in round 2.

PCR positivity rates were not significantly different between students and staff between Round 1 (5/948; [0.53%] vs. 2/876 [0.23%]; p = 0.46) or round two (10/948 [1.05%] vs. 7/886 [0.79%];p = 0.63), and were similar to national prevalence at corresponding times.

Overall, antibody prevalence was 11.0% (193/1754; 95%CI: 9.612.6) in round 1 and 13.3% (234/1765; 95% CI: 11.714.9;p = 0.041) in round 2.

In round 1, antibody positivity was higher in students (114/893 [12.8%], 95% CI: 10.615.1) than staff (79/861 [9.2%], 95% CI: 7.311.3; p = 0.016), but similar in round 2 (students: 117/893 [13.1%], 95% CI: 11.015.5; staff: 117/872 [13.4%], 95% CI: 11.215.9; p = 0.85).

In round 1 antibody positivity in students was associated with school area, year group and additional children in the household. In round 2, antibody positivity was associated with Black ethnicity and the number of positive cases in the school.

Discussion: This prospective cohort study showed that antibody seroprevalence rates in students and staff were generally similar to regional community rates, both at the start and end of the Autumn term. Among participants who were seronegative at the start of the autumn term, seroconversion rates were 6.6% in students and 8.7% in staff by the end of term. This study adds to the body of evidence that, with appropriate infection control measures, the risk of transmission of SARS COV2 is low within the school setting.

Of note this study was conducted prior to the widespread prevalence of variants of concern.

MillerFmedRxivPrevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales02 Jun 2021England & WalesEurope4678Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.05.28.21257602v1

Methodology: Household cohort study (VirusWatch) across England and Wales consisting of 47,813 individuals of 23,059 households recruited by a range of methods including social media, SMS and letters sent to households. 4,78 of children were included as part of this study to assess the prevalence of any new symptoms that persisted for ≥ 4 weeks. Data was collected from mid- June 2020 to mid-March 2021 from children ≤ 17 years who completed one of two surveys sent via VirusWatch requesting information about persistent symptoms, 1) one of the monthly surveys (17th of February) specifically asking about persistent symptoms, 2) at least 3 weekly surveys within a 5-week period capturing participant symptoms before the 20th of January. Participants were asked “In the last year (since February 2020) have any of the household members experienced any new symptoms that have lasted for four or more weeks even if these symptoms come and go, and that are not explained by something else (eg, pre-existing chronic illness or pregnancy)?”

A history of SARS-CoV-2 was determined by a positive PCR test or positive SARS-CoV-2 IgG. Testing may have occurred as part of the VirusWatch active surveillance program or for other reasons not specified.

The prevalence of persistent symptoms was determined in children with a history of SARS-CoV-2 as well as all children who completed the persistent symptoms survey according to age, sex and presence of a chronic condition. Mixed effects logistic regression models were applied, setting risk factors as the independent variables and unique households as the intercept.

Results: 4,678 children were included in the cohort and the overall prevalence of persistent symptoms was 1.7% (80/4678). 4.6% (8/175) of children with persistent symptoms has a history of SARS-CoV-2. These children either tested positive via PCR testing (62.9%, 110/175) or via serological testing (26.9%, 47/175). Seven children had positive PCR testing attributable to the VirusWatch swabbing programme. 476 children within the cohort reported at least one chronic condition, of which 385 (80.9%) reported clinician-diagnosed asthma. Children 12 – 17 year old, less deprived children and those living in the Eastern regions of England were over-represented within the cohort.

Children with a history of SARS-CoV-2 as well as females, teenagers and children with a chronic health condition were more likely to report persistent symptoms within the cohort.

The most common category of persistent symptoms was respiratory, ENT and general symptoms. Fatigue was the most common general symptoms as reported by 22.5% (18/80) children.

Of the 18 who reported start and end dates, 46 days was the medium duration of symptoms. Severity of symptoms was not discussed within this study.

These results are similar to a number of recent studies looking at the prevalence of persistent symptoms after acute COVID-19 infection in children. A major strength is the inclusion of a comparator group to put the results in context. A limitation is that despite the large total cohort size, the number of children with a COVID-19 diagnosis was not very large, meaning there will be some uncertainty around the estimates provided.

Oliveira, EOliveira, MLancet Child AdolescClinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database10 Jun 2021BrazilSouth America11613Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00134-6/fulltext

Oliviera et al., 2021 Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database

Introduction: Since the emergence of COVID-19 in January 2020, Brazil has been one of the countries most severely affected. Epidemiological evidence has consistently documented less severe disease in paediatrics when compared to adults. It has also been highlighted that there is a greater impact of paediatric COVID-19 fatality in low-income and middle-income countries. The article states that at the time of writing, there is a lack of studies investigating the risk factors associated with severe COVID-19. The authors searched databases that described outcomes of children with COVID-19 and data available on the effects of ethnicity, comorbidities, social inequalities and health disparities on outcomes in children infected with SARS-COV-2 from middle- or low-income countries were scarce.

Methods: All cases of RT-PCR confirmed SARS-COV-2 in children and adolescents aged <20 years and recorded in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe), a nationwide database for the surveillance of severe acute respiratory infections were included. SIVEP-Gripe is the main source of information on COVID-19 related hospital admissions in Brazil and receives information from both public and private hospitals. The analysis was conducted between February 16, 2020 to January 9, 2021. The demographic patient data included age, sex, ethnicity, and geopolitical macroregion (There are historical differences in social, economic, health system capacity and coverage between the different macroregions). 82,055/1,124,689 (7.3%) reported cases of severe acute respiratory illness were <20 years old. Of these, 70442 (85.8%) were excluded as a result of negative SARS-COV-2 RT-PCR test, awaiting test result, not tested or those with inconclusive results. The final sample size was 11,613 patients with positive SARS-COV-2 RT-PCR results.

Results: The median age at admission was 5.1 years (IQR 1.0-14.3) and evenly distributed among three age groups (<2 years, 2-11 years and 12-19 years). The competing risks multivariate survival analysis showed that risk of death was increased in infants younger than 2 years (hazard ratio 2.36 [95% CI 1.94–2.88]) or adolescents aged 12–19 years (2.23 [1.84–2.71]) relative to children aged 2–11 years.

There was a small predominance of COVID-19 infections in boys (52% 6032/11600) and Black or Brown patients accounted for 63.5% of the infections (5784/9109). Compared with White patients, children of Black or Brown ethnicity (HR 1.30 [1.11–1.53]) and Indigenous ethnicity (HR 3.27 [2.17–4.93]) were also at increased risk of death.

COVID-19 cases were most prevalent in the North and Central-West regions, 330.4 cases per million and 330.0 cases per million, respectively. Using the Fine and Gray model, risk of death was increased in patients from the poorest regions, the Northeast region (HR 2.03 [1.72–2.38]) and North region (HR 1.53 [1.25–1.87]) relative to those from the Southeast region

8352 (71.9%) of patients had no pre-existing medical conditions, 2780 (23.9%) had one comorbidity, and 481 (4.1%) had two or more pre-existing comorbidities. Most common pre-existing conditions were asthma (7.5%), neurological disorders (6.1%), malignancies (5%), and heart disease (3.3%). Risk of death was increase in those with one (2.96 [2.52–3.47]), two (4.96 [3.80–6.48]), or three or more (7.28 [4.56–11.6]) pre-existing medical conditions relative to those with none.

Median time from symptom onset to hospitalisation was 3 days (IQR 1-6). 2759 patients (23.8%) were admitted to ICU. Fever (74.5%), cough (67.4%), dyspnoea (57.6%), respiratory distress (54.4%) and <95% O2 Saturations (41.1%) were the most common symptoms. With respect to signs and symptoms at presentation, the presence of respiratory distress (2.78 [2.35–3.29]) and oxygen saturation below 95% (3.66 [3.11–4.30]) were strongly associated with death, whereas fever, cough, and gastrointestinal symptoms were not associated with death.

Comments: The authors had no access to hospital data records to allow for inclusion of information regarding pharmacotherapies, laboratory results or the detailed clinical course of each patient. Complete data were not available for all variables, especially ethnicity and symptoms at presentation, so denominators differ between analyses. Mild cases of COVID-19 in which patients were not hospitalised were not included in the registry, therefore there are concerns around the limitation of the results. Data from the nationwide database showed that death was associated with age younger than 2 years or 12-19 years, indigenous ethnicity, living in the poorest macroregions, and the presence of pre-existing medical conditions.

Carolin, KArmann, JBMJSARS-CoV-2 seroprevalence in students and teachers: a longitudinal study from May to October 2020 in German secondary schools10 Jun 2021GermanyEurope1538Epidemiology - Transmissionhttps://bmjopen.bmj.com/content/11/6/e049876

The authors’ study aimed to quantify the number of SARS-CoV-2 infections in secondary schools in Saxony, Germany after their reopening in May 2020.

Method : The researchers undertook a repeated SARS-CoV-2 seroprevalence study after the reopening of schools and 4 months later. The schools were 13 secondary schools in Dresden, Germany chosen by the state office randomly without the authors input. 1538 students’ grades 8–12 and 507 teachers from 13 schools took part in the study.

The study involved serial blood sampling (5ml each visit) and SARS-CoV-2 IgG antibody assessment. In addition, participants were asked to complete a questionnaire on age, household size, previously diagnosed SARS-CoV-2 infections in themselves or their household contacts, comorbidities and regular medication. Students were also asked about regular social contacts outside their household or classroom

The authors measured seroprevalence of SARS-CoV-2 antibodies in study population and the number of undetected cases.

Results : 1538 students and 507 teachers were initially enrolled and 1334 students and 445 teachers completed both study visits. The seroprevalence for SARS-CoV-2 antibodies was 0.6% in May/June and the same in September/October. Even in schools with reported COVID-19 cases before the lockdown of 13 March, no clusters could be identified. Of 12 persons with positive serology five had a known history of confirmed COVID-19; 23 out of 24 participants with a household history of COVID-19 were seronegative.

Conclusions : The authors concluded schools do not play a crucial role in driving the SARS-CoV-2 pandemic in a low-prevalence setting. Transmission in families occurs very infrequently, and the number of unreported cases is low in this age group. These observations do not support school closures as a strategy fighting the pandemic in a low-prevalence setting.

Harwood RViner RM medRxiv preprintWhich children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis 8 July 2021Global All regions21412Clinical - Comorbiditieshttps://doi.org/10.1101/2021.06.30.21259763

Background: This comprehensive meta-analysis aims to identify the potential risk factors for severe disease in children and young people (CYP) with COVID-19 and PIMS-TS globally. Although well-described for adults, there is less available data on the subject for CYP. Addressing this question now is timely as it provides evidence for which groups of CYP are vulnerable and should be prioritised for vaccination and shielding policies.

Methods: Four major databases were searched between 1st January 2020 to 21st May 2021. Studies involving children hospitalised with SARS-COV-2 or PIMS-TS that provided information on risk factors and outcomes according to the eligibility criteria were included.

Results: 57 studies with a total of 21,412 children were included in the meta-analysis with 22 studies providing Individualised Patient Data (IPD). The studies were conducted in Asia (9), Europe (15), Africa (1), North America (21) and South America (8). Meta-analyses were performed on aggregate study-level data as well as on IPD. The study analysed the odds and risk of severe disease and death associated with sex, age and comorbidities in children hospitalised with SARS-COV-2 or PIMS-TS.

There was no association between sex and outcome. Teenagers were more vulnerable to severe disease and death from COVID-19 and PIMS-TS compared to other age groups. The presence of pre-existing conditions was the strongest risk factor for critical care admission and death for both COVID-19 and PIMS-TS, although the absolute risk compared to CYP without comorbidities was still small. One comorbidity increased absolute risk of critical care admission by 3.6% and death by 1.5% in COVID-19. In particular, cardiac and neurological conditions were associated with increased risk whilst asthma was not. In addition, Trisomy 21, with or without cardiovascular disease, and obesity, independent of other conditions, increased risk of death in COVID-19.

Strengths & limitations: The authors note the limitations of comparing studies of mixed quality from multiple countries with differing practices and resources. Most included studies were open to substantial bias such as publication bias of more severe cases and misclassification of comorbidities. Unfortunately, the data did not allow for the impact of ethnicity and socioeconomic background to be assessed which would be of value given its association with outcomes in adults with COVID-19. Despite its limitations, this meta-analysis offers an impressive global overview of current evidence on the subject and highlights areas of knowledge gaps where future research should focus.

Smith, CFraser, LResearch SquareDeaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data07 07 2021UKEurope61Epidemiology - Disease Burdenhttps://www.researchsquare.com/article/rs-689684/v1

This study examines all deaths in children due to SARS-CoV-2 in England between March 1st, 2020, to February 28th, 2021, comparing characteristics of children who died due to SARS-CoV-2 with those of children who died from all other causes.

Data on all deaths was obtained from the National Child Mortality Database (NCMD), a mandatory system that records all deaths in children <18yo including limited demographic data including age and ethnicity. NCMD data was matched with Public Health England SARS-CoV-2 testing data over the study period. All children who died and had a positive SARS-CoV-2 test (at any time) were included; including post-mortem testing in sudden unexpected deaths. In addition, possible cases of PIMS-TS identified by the NCMD coding team were included. Data on comorbidities was attained by linking NCMD data to national admissions data over the preceding 5-years using established ICD-10 codes with co-morbidities classified according to body system.

For all reported deaths in children with a positive SARS-CoV-2 test, further review of clinical data, by three consultant paediatricians, was conducted to determine if SARS-CoV-2 contributed to death. All cases where SARS-CoV-2 was clearly implicated, probably contributed or possibly contributed to death were included as deaths due to SARS-CoV-2 infection. Infection fatality rate was calculated using the estimated number of children infected with SARS-CoV-2 based on PHE modelling data, to account for likely lack of testing during the first wave.

A total of 3105 children died of all causes during the 12-month study period; 61 had a positive SARS-CoV-2 test. SARS-CoV-2 was the cause of death in 25 (41%) of the 61 children; 22 due to acute COVID-19 and 3 due to PIMS-TS. Overall case fatality rate for SARS-CoV-2 was 5 per 100,000. Mortality rate was 2 per million population, compared with 255 per million for all other causes of death during the study period. The majority of SARS-CoV-2 deaths occurred in children >10yo (72%) including all 3 deaths due to PIMS-TS. Children of Asian (36% vs 16%) and Black (20% vs 8%) ethnicity comprised a higher proportion of SARS-CoV-2 deaths compared to deaths from all other causes.

Six (24%) SARS-CoV-2 related deaths occurred in previously healthy children and 19/25 (76%) in children with underlying comorbidities. The most common comorbidity was an underlying complex neurological condition (13/25, 52% including 8/25 (32%) with neurological as well as respiratory comorbidity) followed by chronic respiratory disease (12/25, 48%). Over half (15/25, 60%) of children who died of SARS-CoV-2 had an underlying life-limiting condition. No deaths due to SARs-CoV-2 occurred in children with isolated cystic fibrosis, asthma, Trisomy 21, epilepsy, or type 1 diabetes.

Major strengths of this study include the use of comprehensive national mortality and testing data as well as the assessment of individual cases of death in children with a positive SARS-CoV-2 test to determine if infection contributed to death. The findings highlight the low mortality rate due to SARS-CoV-2 in children particularly in those without an underlying co-morbidity as well as the higher risk in older children and children with underlying complex neurological and respiratory conditions. These data are important for guiding policy on vaccination and other mitigation strategies in order to prioritise protection of children at highest risk from SARS-CoV-2 infection.

Preston, LGoodman, AJAMACharacteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-1909 Apr 2021USA North America20714Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347
Liu, DZeng, CAmerican Journal of RoentgenologyPregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: A preliminary analysis07 Mar 2020ChinaAsia11Neonatalhttps://www.ajronline.org/doi/full/10.2214/AJR.20.23072
Li, YSheng, JEmerging Infectious DiseasesLack of Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, China05 Mar 2020ChinaAsia1Neonatalhttps://doi.org/10.3201/eid2606.200287
Liu, YGuo, YJournal of InfectionClinical manifestations and outcome of SARS-CoV-2 infection during pregnancy04 Mar 2020ChinaAsia13Neonatalhttps://doi.org/10.1016/j.jinf.2020.02.028
Wang, XChen, XClinical Infectious DiseasesA Case of 2019 Novel Coronavirus in a Pregnant Woman With Preterm Delivery28 Feb 2020ChinaAsia1Neonatalhttps://doi.org/10.1093/cid/ciaa200

This brief report outlines the case of a mother in Suzhou, China, who became symptomatic and tested positive for SARS-CoV-2 in sputum whilst 30/40 pregnant. She had recently travelled to Wuhan. She had an emergency caesarean performed 6 days after presentation for worsening clinical status and concerns for the foetus due to reduced movements and foetal heart rate variability on CTG.

The infant was born in good condition and immediately isolated from the mother. Samples of amniotic fluid, cord blood, placental swabs, infant gastric secretions and throat swabs all tested negative for SARS-CoV-2. Repeat swabs from the infant on day 3 of life were still negative. Mother and baby both recovered well with uneventful postpartum and neonatal course.

chezhu
Chen, HZhang, YLancetClinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records12 Feb 2020ChinaAsia9Neonatalhttps://doi.org/10.1016/S0140-6736(20)30360-3
Zhu, HZhou, WTranslational PediatricsClinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia10 Feb 2020ChinaAsia10Neonatalhttps://doi.org/10.21037/tp.2020.02.06

This is a retrospective series of 10 neonates (including a set of twins) born to 9 mothers in Hubei province who were confirmed to have COVID-19.

4 mothers had symptoms prior to delivery, 2 mothers on the day of delivery, and 3 mothers after delivery. 7 mothers delivered via caesarean section and 2 by vaginal delivery. There was intrauterine distress recorded in 6 cases.

Of the babies, 8 were male and 2 female, 4 born at term and 6 preterm (twins at 31/40, and 4 babies around 34 – 35/40). APGARS were good for all babies. 6/10 developed some respiratory symptoms, one had some vomiting and one developed shock with DIC and multiple organ failure, who later passed away. All neonates tested negative for SARS-CoV-2, as did placental swabs.

It is hard to know what to make of this study. There is little information about how/why babies were delivered prematurely, and it would seem most symptoms are related to their early arrival. None were positive for the virus, and there was no evidence of vertical transmission. It seems contradictory to other evidence of babies delivered to mothers with COVID-19 who did well. Interpret with great caution.

Lindan, CPalasis, SLancetNeuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.15 Dec 2020https://doi.org/10.1016/S2352-4642(20)30362-X

This multicentre case series reports on the neuroradiological findings in 38 children from 13 countries who had neurological disease in association with SARS-CoV-2 infection. Cases were reported retrospectively between 30/04–08/09/20. Four children died, all of whom had CNS co-infections. Two were left with significant neurodisability. The commonest neuroradiological findings were an “ADEM-like” picture (n=16), myelitis (n=8), and neural enhancement (n=13). Splenial lesions (n=7) and myositis (n=4) were predominantly found in children with MIS-C. Demographic data incomplete. M:F ratio 21:17. Age range 0.17-16years. No information given on longer term outcomes.

Moreira, AMoreira, AEur J Pediatr (2021)Demographic predictors of hospitalization and mortality in US children with COVID-19.20 Jan 2021USANorth Americahttps://doi.org/10.1007/s00431-021-03955-x

This study is from the USA between March 2, 2020, and July 16, 2020. The Centers for Disease Control and Prevention COVID-19 associated hospitalization surveillance network “CDC COVID-NET” is a population-based system that captures laboratory-confirmed COVID-19 cases in over 250 US acute-care hospitals. The database was searched for the variables including demographics (age stratified as 0-19 and 10 – 19(, other medical conditions and outcomes (hospitalisation / death). Patients with missing data were excluded from this report.

Results: Of the total number of children (27,045), 70.0% between the ages of 10 and 19 years with a similar gender distribution. 39% had an underlying medical condition. 4.7% required hospitalization, with higher odds in children < 10 years of age who were Black or of mixed race/ethnicity, and with a medical condition. Mortality data was available for 20,096 (74.3%) individuals that were hospitalized, and death occurred in 0.19% (more in black, non-Hispanic and those with an underlying medical condition)

Discussion/Conclusion: Black, non-Hispanic and Hispanic children were 2.5 times more likely than White children to be hospitalized and 5 times more likely to die after infection. The reasons suggested by the authors included parents (act as infection vectors) who work in high “viral-contact” jobs are more likely to be minorities. Poverty is more common among minority groups (lower socioeconomic status is intricately linked to larger household sizes, crowding, and therefore more cross-infection.) A past medical history of an underlying condition was the strongest risk factor for poor outcome in US children with COVID-19.

Limitations: Although the data is derived from 14 states, it only represents 10% of the US Population. Missing data was common in the database which decreased the overall sample size from 229,052 children to 27,045 paediatric cases.

paediatric-covid-data

First authorLast authorJournalArticle titleDate of PublicationCountryRegion(n) childrenStudy typePaper linkReview
Parri, NBuonsenso, DNEJMChildren with Covid-19 in Pediatric Emergency Departments in Italy01 May 2020ItalyEurope100Clinicalhttps://www.nejm.org/doi/full/10.1056/NEJMc2007617

This report is of confirmed COVID-19 infections in children under 18 years of age who presented to a research collaboration of 17 paediatric emergency departments in Italy between March 3rd and March 27th. The median age was 3.3 years and 57/100 were male. Children under 1 year were overrepresented (40%) followed by children >10yrs (24%).

Helpfully they categorise their patients according to criteria from Dong et. al (see review in Epidemiology top 10): Asymptomatic 21%, Mild 58%, Moderate 19%, Severe 1% and Critical 1%. Only 12% of patients appeared ill on assessment. Interestingly only 4% of patients had Oxygen saturations <94%. Only 38% of children needed admission for severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below

Clinical features: Fever 54%, Cough 44%, Feeding difficulty 23%, Sore throat 4%, Rhinorrhoea 22%, Diarrhoea 9%, vomiting 10%.

Bloods: Largely unremarkable (although reports of lymphopenia unclear – state 14 patients lymphopenic but that this is 28%? – perhaps only 50 children had bloods, but this is not reported). Procalcitonin <0.5ng/L in 29/23 patients.

Radiology: Chest x-rays performed for 35 children, of which 14/35 had interstitial abnormalities, 6/35 consolidation and 1/35 pleural effusion: remaining 15/35 normal.

Comorbidities: There were 27/100 children with comorbidities – although it appears most had mild illness (did not require respiratory support). This included 6 with cystic fibrosis, 4 neurological, 4 haematological, 4 with a syndrome, 3 with prematurity, 2 with cardiac conditions, 2 immunological, 2 oncological and 1 metabolic disease.

Of the few patients who required respiratory support (9/100) a significant number had comorbidities (6/9), although the rage was broad. This included 2 children with “epileptic encephalopathy”, one of whom also had CHARGE syndrome, a child with autism, a child with a VSD, a child with propionic acidemia, and a child with thrombocytopenia and frequent respiratory infections.

One of the strengths of this study is comparisons across other studies of clinical features of COVID-19 in children. In comparison to Dong et al, CDC data and Lu et al, most features are broadly comparable. Some notable differences are a significantly larger number of infants in the Italian data (40% <1yr compared to 18% in Lu, 12% in Dong and 15.5% in CDC) and a slightly higher number of asymptomatic children (21% compared to 16% Lu, 13% Dong and 1.3% CDC). This most likely represents differences in which population cohorts presented for testing among the different studies – comparisons between cohorts is always difficult currently due to broad differences in the demoninators used. Notably there is no apparent difference in severity according to age in this Italian data, whereas CDC noted increased hospitalisation in children <1yr and Don’t et al noted higher rates of severe or critical illness in infants <1yr.

Broadly speaking this study confirms findings from China and the USA regarding significantly milder illness in children than adults with COVID-19, including many asymptomatic children. Note is made of overrepresentation of children with comorbidities in this cohort (similar to CDC data), although most of these still had mild illness - it is unclear if these children become more unwell, or are more likely to present to be tested.

Tsao, HFearon, DPediatrics Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics01 May 2020USANorth America1Clinicalhttps://pediatrics.aappublications.org/content/early/2020/05/19/peds.2020-1419/tab-e-letters?versioned=true

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2. A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Diorio, CTeachey, DBlood AdvancesEvidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.8 Dec 2020USANorth America50Clinical - Clinical Featureshttps://ashpublications.org/bloodadvances/article/4/23/6051/474421/Evidence-of-thrombotic-microangiopathy-in-children

This study investigated a group of 50 hospitalised paediatric patients with acute SARS-CoV-2 infection, classified into 3 groups (minimal COVID-19, severe COVID-19 and MIS-C), to assess whether these children met the clinical criteria for diagnosis of thrombotic microangiopathy (TMA). TMA (endothelial cell damage to small blood vessels, leading to haemolytic anaemia, thrombocytopaenia and, in some cases, organ damage) has been associated with SARS-CoV-2 infection in adults, causing thrombotic complications in severe COVID-19. A proposed mechanism for SARS-CoV-2-mediated TMA is via complement activation, which results in unregulated formation of the C5b9 membrane attack complex. An initial smaller study by these researchers of 20 of these paediatric patients (published in the Journal of Clinical Investigation on 30th July 2020), which compared clinical features and cytokines between the three groups, showed that soluble C5b9 (sC5b9), a biomarker of complement activation and TMA, may be elevated across the spectrum of manifestations of COVID-19.

Study design and population: From 3rd April to 7th July 2020, 112 patients admitted to the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania, USA were prospectively screened with 58 enrolled; the analysis comprised the 50 patients for whom complete sC5b9 data were available. All had either a positive SARS-CoV-2 RT-PCR from upper respiratory mucosa or a positive SARS-CoV-2 antibody test. Minimal COVID-19 (n=21/50, median age 13 yrs, IQR 5-17 yrs, range 2.5-23 yrs) was defined as those patients with an incidental finding of COVID-19 during routine testing before admission/procedure or those with mild COVID-19 symptoms not requiring respiratory support. All patients in the minimal group had comorbidities, including 5/21 sickle cell disease, 2/21 nephrotic syndrome, 2/21 B-ALL, T-ALL, medulloblastoma, osteosarcoma and asthma. Severe COVID-19 (n=11/50, median age 15 yrs, IQR 14-17 yrs, range 0.13-18 yrs) was defined as patients requiring new or escalation of respiratory support. All patients in the severe group had comorbidities, including 3/11 obesity, 2/11 prematurity, 3/11 hypopituitarism, HIE, hypertension, B-ALL and asthma. MIS-C (n=18/50, median age 9 yrs, IQR 7-13 yrs, range 5-17 yrs) was defined as per CDC criteria. All patients in the MIS-C group were previously healthy or had minimal comorbidities (2/18 asthma, 1/18 obesity, 12/18 previously healthy). All 21 (100%) of the minimal group and 18 (100%) of the MIS-C group were discharged. 2/11 (18%) of the severe group died and 2/11 (18%) remained hospitalised. A control group of discarded plasma samples from 26 otherwise healthy children who had been evaluated for symptoms of a bleeding disorder was obtained from the CHOP coagulation laboratory.

Data collection and criteria for thrombotic microangiopathy: Data collected from patient charts included demographic information, comorbid conditions and most extreme laboratory values from blood tests within the first 2 weeks of the positive SARS-CoV-2 test or admission for MIS-C (mostly within 48 hours of admission), plus assessment of 7 criteria for TMA (adapted from Gloude et al): raised LDH, schistocytes on blood smear, thrombocytopaenia, anaemia, proteinuria, hypertension and elevated sC5b9. The diagnosis of TMA was defined as 5 out of 7 of these criteria during the hospital admission for COVID-19 or MIS-C. A subsequent analysis used a simple set of clinical criteria (thrombocytopaenia, anaemia, schistocytes (fragmented red blood cells) and organ dysfunction) to define TMA in settings where more sophisticated diagnostics may be unavailable. Patients were assessed for renal dysfunction using the KDIGO (Kidney Disease: Improving Global Outcomes) criteria: acute kidney injury (AKI) was defined as KDIGO stage 2 or higher.

sC5b9 levels: Median sC5b9 level in control subjects (57 ng/mL, IQR 9-163) was significantly lower than minimal COVID-19 (392 ng/mL, IQR 244-622), severe COVID-19 (646 ng/mL, IQR 203-728) and MIS-C (630 ng/mL, IQR 359-932) (p<0.001 in each case). There were no statistically significant differences between the 3 disease groups. One patient with concomitantly diagnosed SLE had highly elevated sC5b9 (1568 ng/mL), therefore the analysis was repeated excluding patients with comorbidities associated with complement dysfunction (lupus, cancer, sickle cell disease, renal disease or inflammatory disease): levels of sC5b9 remained elevated in the 3 disease groups compared to the control group (p<0.001). Analysis of correlations between sC5b9 and markers of inflammation, haemolysis and coagulopathy in patients with severe COVID-19 and MIS-C (there was a high proportion of missing data in the minimal group) showed no significant correlations with ferritin, CRP, LDH, PT, PTT, fibrinogen, D-dimer, AST, Hb or platelets. Levels of SARS-CoV-2 IgG, IgM and IgA did not significantly correlate with sC5b9 levels (testing the hypothesis that raised sC5b9 in SARS-CoV-2 could be related to classical pathway activation from antiviral antibody-antigen complexes, rather than the alternative pathway complement activation of TMA).

TMA findings: Of the 19/50 (38%) patients with complete clinical criteria available, 17/19 (89%) met criteria for diagnosis of TMA, comprising 2/2 (100%) minimal COVID-19 patients, 4/4 (100%) severe COVID-19 and 11/13 (85%) MIS-C. sC5b9 levels were elevated in patients who both did and did not meet criteria for TMA. Out of the total study group (31/50 (62%) had missing data, which was counted as negative), 24/50 (48%) met criteria for TMA, comprising 4/21 (19%) minimal COVID-19 patients, 9/11 (82%) severe COVID-19 and 11/18 (61%) MIS-C. A sensitivity analysis in which sC5b9 was not included in the criteria for TMA was performed (testing the hypothesis that sC5b9 elevations could be caused by an unknown pathophysiological process other than TMA in SARS-CoV-2 patients): 15/50 (30%) patients still met the criteria for TMA (5/6 or 6/6 criteria met), 9/50 (18%) were indeterminate (4/6 criteria met) and 26/50 (52%) did not meet the criteria (3/6 or less criteria met). For 34/50 patients with peripheral blood smears, 13/34 (38%) met simpler clinical criteria for TMA (microangiopathic haemolytic anaemia, thrombocytopaenia and evidence of organ damage). Schistocytes were present in 5/11 (45%) peripheral blood smears in the minimal group, 7/8 (87%) in the severe group and 13/15 (87%) in the MIS-C group.

Renal dysfunction: There was evidence of AKI in 2/21 (10%) of the minimal COVID-19 group, 4/11 (36%) of the severe COVID-19 group and 5/18 (28%) of the MIS-C group. Only 1 child (in the severe group) required dialysis. There were significantly higher plasma sC5b9 levels in those with AKI (717 ng/mL, IQR 404-1232) than in those without AKI (433 ng/mL, 232-706) (p=0.374). Elevations in sC5b9 correlated statistically significantly with creatinine, blood urea nitrogen and GFR, but not with age.

Levels of IL-8: IL-8 levels, a marker of endothelial dysfunction, were similar in MIS-C and severe COVID-19 patients; both were significantly higher than the minimal group. IL-8 didn’t correlate with sC5b9 levels.

Limitations identified by authors: The high incidence of TMA seen in patients with complete data is confounded by ascertainment bias, since some markers (e.g. LDH) are more frequently measured in sicker children (although even when the children with missing data were included, with missing values assumed to be negative, nearly half met criteria for TMA). The hospitalised children in the minimal COVID-19 group were, by definition, admitted because of other comorbidities, which could independently cause elevated sC5b9 (this group would ideally have been asymptomatic or mildly symptomatic SARS-CoV-2 children without comorbidities). The healthy control group were patients being investigated for a bleeding disorder, which the authors believe will not affect complement activation, but this group would also ideally have been without comorbidities.

Conclusions: In all 3 presentations of SARS-CoV-2 studied (minimal COVID-19, severe COVID-19 and MIS-C), the final common pathway of complement activation was seen. Interpretation of the group called “minimal COVID-19” is difficult, due to an extremely mixed cohort of children with supposedly mild disease who were still hospitalised due to their illness, or children hospitalised for a variety of other conditions which are likely to confound the results. IL-8 was elevated in severe COVID-19 and MIS-C compared to minimal COVID-19, implying more severe endothelial damage in the 2 more clinically severe groups. The majority of children with complete clinical and laboratory data measured met the criteria for thrombotic microangiopathy, as did most patients with acute kidney injury. Elevated sC5b9 correlated with renal dysfunction, but was independent of inflammatory markers. The short- and long-term implications of complement activation in children with SARS-CoV-2 are unclear. It is not possible to generalise the results of this study to children with minimal or no symptoms in the community.

Marlais, MTulus, KArchdischildCOVID-19 in children treated with immunosuppressive medication for kidney diseases21Dec2020worldwideInternationalClinical - Clinical Featureshttp://dx.doi.org/10.1136/archdischild-2020-320616

Introduction: Initial reports of COVID-19 from the Wuhan province showed significant differences in the outcomes between children and adult patients. In children, the reported mortality rates were far below 1% while for people above the age of 70 years it was 5% or higher. It also became clear that in adult patients a number of comorbidities contributed to a worse outcome.

Based on those early findings, many children taking immunosuppressive medication were advised to ‘shield’. As well as being demanding authors have cautioned against its indirect ‘side-effects’, both physical and psychological. It is therefore important to accurately define the group of people who are extremely vulnerable to severe disease if infected with SARS-CoV-2.

However, the impact of immunosuppression is yet to be determined in this group. The multinational authors’ study aimed to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess their disease severity.

Methods: This was a voluntary-based survey on children with immunosuppressive treatment for kidney disease reported to be infected with SARS-CoV-2. It was hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. The members of these societies and the members of the PedNeph listserver were asked to include any child in their care fulfilling the inclusion criteria.

Inclusion criteria were all children (<20 years and under paediatric services) who have an underlying kidney disease and take immunosuppressive medication, with a diagnosis of COVID-19 (either laboratory confirmation with PCR or serology testing, or clinically highly suspected). The study was open for 16 weeks from 15 March 2020 to 05 July 2020 and included 8 separate reminders sent electronically to the memberships of the above organisations. Anonymised data were collected through an online platform including details of demographics, underlying kidney conditions, comorbidities and current immunosuppressive medication. Their symptoms at presentation were recorded, along with the method of COVID-19 diagnosis (laboratory or clinical). The severity and outcome of their COVID-19 was also reported.

Results : 113 children were reported in this study from 30 different countries. 104 cases were confirmed as COVID-19 by PCR or antibody testing, the remaining 9 being clinically suspected. The median age of the participants was 13 years (49% were male). The main underlying reasons for immunosuppressive therapy were: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Patients’ immunosuppressive medications included: glucocorticoids (76%), Mycophenolate Mofetil (MMF) (54%), Tacrolimus/ciclosporine A (58%), Rituximab/Ofatumumab (11%). Mean duration of immunosuppressive therapy prior to study was 9.5 months (IQR 3-39 months).

78% of the patients required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries (3 India, 1 South America) with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications. There was a difference in the severity of the disease with older children tending to have more severe disease but this did not reach statistical significance. No children developed PIMS-TS in this study.

Conclusions

The authors’ global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection.

They suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.

They find no evidence of any association between immunosuppressive medication number and the severity of COVID-19 in children.

They suggest children who are in the first few months immediately post-transplant may need some stricter social distancing measures (as were in place for many centres prior to COVID-19) as published data in this small subgroup are still limited.

Melé, MLaunes, CjinfLow Impact of SARS-CoV-2 infection among Paediatric Acute Respiratory Disease Hospitalisations21.10.20202SpainEurope110Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30655-1/fulltext

Observational study of children admitted to a Barcelona hospital with acute lower respiratory disease (ALRD) during the first pandemic peak (mid-March to mid-May), comparing those who were SARS-CoV-2 (+) to those who were SARS-CoV-2(-).

Key points

• 125 children with ALRD admitted, 110 consented to be in study

• Only 7 (6%) were SARS-CoV-2 (+)

• SARS-CoV-2 (+) children’s median age was 16.9y: the median for the SARS-CoV-2(-) children was 3.7y

• Co-morbidities: in 2 of the SARS-CoV-2 (+) (1 leukaemia, 1 obesity): in SARS-CoV-2(-) 44% had pre-existing respiratory issues and 13% neurological

• No significant differences were found in the clinical presentation of the 2 groups

• SARS-CoV-2 (+) group had significantly lower WBCs and platelets

• The SARS-CoV-2 (+) child with leukaemia had graft-versus-host and a co-infection with Influenza B and unfortunately died

The children were tested for SARS-CoV-2 when presenting at the hospital. In the 9-week period of the study, 960 children with fever &/or respiratory symptoms were seen and tested and only 56 (6%) were SARS-CoV-2 (+). The authors have then looked at detail at those children requiring admission with ALRD.

Bolanos-Almeida, CSegura, OPIDJ Clinical and epidemiological analysis of COVID-19 children cases in colombia PEDIACOVID20/10/20Colombia South America 5062Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_and_Epidemiologic_Analysis_of_COVID_19.95988.aspx

This is a retrospective study of 5062 children <18 years of age (until June 2016) who tested positive for SARS-CoV-2 and were reported to the National Institute of Health in Colombia. This cohort represented 9.2% of total cases in Colombia.

Cases were classified as symptomatic, asymptomatic, mild, moderate or severe. All children admitted to hospital with clinical or laboratory features of SARS-CoV-2 (eg. changes on chest imaging, elevated inflammatory markers, lymphopaenia) and who were characterised as an at risk or vulnerable population were classified as severe.

Majority of cases were mild (79.4%) or asymptomatic (16.8%). Overall, only 26 children required admission to intensive care (ICU) (0.51%) and 146 hospital admission (2.88%). There was a reported case fatality rate of 1.59 per 1000. Younger children were more likely to have more severe disease requiring hospital or ICU admission.

This retrospective study is the largest published cohort of children from South America and is consistent with findings from other geographical regions.

Goss, MGoss, JPaediatric TransplantationThe pediatric solid organ transplant experience with COVID‐19: An initial multi‐center, multi‐organ case series18 Sept 2020United StatesNorth America26Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/petr.13868

Five transplant centres in the United States report the outcome of 26 children ≤ 18 years of age (range 5-18 years) 16 of whom were male who developed Covid 19 between 1st April and 20th July 2020. Six were heart recipients, 8 kidney, 10 liver, and 2 lung.

The 26 COVID‐19‐positive transplant recipients had variable clinical presentations. The most common symptom was cough (n=12 (46%)) followed by fever (n=9 (35%)), dry/sore throat (n=3 (12%)), rhinorrhoea (n=3 (12%)), anosmia (n=2 (8%)), chest pain (n=2 (8%)), diarrhoea (n=2 (8%)), and dyspnoea and headache in 1 patient each (4%). Six patients (23%) did not have any symptoms (4 kidney, 1 liver, and 1 lung recipients). Eight (31%) were hospitalized, 3 of whom were already admitted for unrelated problems. None required supplemental oxygen. All patients with COVID‐19 symptoms at the time of diagnosis recovered with full resolution of symptoms within a median of 3 days. No patient experienced progressive deterioration or death.

Only two children required reduction in their post-transplant immunosuppression.

The authors conclude “Our multi-institutional experience suggests the prognosis of paediatric transplant recipients infected with COVID-19 may mirror those of immunocompetent children, with infrequent hospitalization and minimal treatment, if any, required”

Rekhtman, SGarg, AJ Am Acad DermatolMucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children18 Dec 2020USANorth America31Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585496/pdf/main.pdf

This cohort study describes the mucocutaneous features of COVID-19 and MIS-C patients hospitalised in a tertiary children’s hospital in New York. Sample size was small, but the authors observed a trend towards milder disease in those patients with rash and/or mucositis.

All patients aged 18 years or younger, admitted between 11 May and 5 June 2020 to the Cohen Children’s Hospital New York, with a diagnosis of COVID-19 or MIS-C, were included. Diagnostic criteria for MIS-C included: clinically severe illness, multisystem involvement, positive for SARS-CoV-2 on PCR/serology or exposure to positive COVID-19 case, and no alternative diagnosis. All patients in the COVID-19 group were SARS-CoV-2 PCR positive. There were 31 patients in total, 12 with COVID-19 and 19 with MIS-C. 61% of patients were male (50% of the COVID-19 group and 68% of the MIS-C group). Median age of COVID-19 patients with mucocutaneous disease was 5 years (1.75, 10) and without was 10 years (7.25, 16). Median age of MIS-C patients with mucocutaneous disease was 8 years (7, 10) and without was 10.5 years (10, 13).

Mucocutaneous features in COVID-19 group: 33% of the COVID-19 patients had a rash and/or mucositis. The rashes observed were non-specific erythema and morbilliform. The mucositis seen was limited to lip cracking. There was a trend towards younger age and milder disease in patients with mucocutaneous features compared to those without.

Mucocutaneous features in MIS-C group: 47% of MIS-C patients had a rash and/or mucositis. The pattern of rash seen was heterogenous including non-specific erythema, urticarial, purpuric and oedematous. Mucositis included lip cracking, tongue papillitis and conjunctivitis. As with the COVID-19 group, there was a trend towards milder disease in those MIS-C patients with mucocutaneous features compared to those without.

Discussion: This descriptive study is a useful addition to the literature, providing information on the prevalence of mucocutaneous disease amongst COVID-19 and MIS-C patients, as well as its morphologic pattern and distribution. The observed trend towards milder disease in those patients with mucocutaneous features is interesting and raises the question of whether this could be a prognostic indicator. The sample size is too small to draw any firm conclusions, but the study provides a good basis for further research.

Ludvigsson, JLudvigsson, JActa PaediatrCase report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-1917/11/20Sweden Europe5Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/apa.15673

This is a case report and systematic review of long-term symptoms experienced by children following acute SARS-CoV-2 infection. Although there are a number of reports of persistent symptoms in adults, this is the first systematic review of the currently available paediatric data. Long-term or persistent symptoms were defined as those lasting over 2 months from the onset of symptoms.

The case report is of 5 Swedish children identified by personal contact of their parent with the author of the manuscript. The 5 children had a median age of 12 years (range 9-15 years) and 4 were female. All were clinically diagnosed with COVID-19 without PCR confirmation and were managed conservatively, without hospitalisation. Subsequent SARS-CoV-2 serology in 4 of the 5 children was also negative. Symptoms reported by the child and/or parent most commonly included fatigue, dyspnoea, heart palpitations, dyspnoea, headaches, poor concentration, muscle weakness, dizziness and sore throat. Symptoms remain persistent 6-8 months following acute illness and none of the children have returned to school (at the time of manuscript publication).

The systematic review identified 19 articles which were relevant, however none contained further information on persistent symptoms following SARS-CoV-2 infection in children.

Although there is growing concern about persistent symptoms following acute COVID-19 infection in adults, there remains a paucity of data on children. This case report is limited by lack of PCR confirmed SARS-CoV-2 infection and selection bias. Future prospective research is required in both adults and children with a well-defined case definition to better delineate the long-term effects of SARS-CoV2.

Dannan, HRamsi, MBMJClinical course of COVID-19 among immunocompromised children a clinical case series15 Oct 2020United Arab EmiratesMiddle East5Clinical - Clinical Featureshttps://casereports.bmj.com/content/bmjcr/13/10/e237804.full.pdf

A case series of five immunocompromised children 2 boys 3 girls, aged 3-12 years from the United Arab Emirates who developed Covid-19 during 2020. They either had mild symptoms or were asymptomatic. They all had a benign course of their illness. None needed a change in their treatment regime nor had a relapse of their underlying condition. The children had prolonged duration of virus shedding post Covid 19 infection. The authors conclude “immunocompromised paediatric patients may not be at a higher risk of developing severe Covid-19.”

Kumar, LPandey, A.K Int J Pediatr OtorhinolaryngolLoss of smell and taste in COVID-19 infection in adolescents13/01/2021IndiaAsia141Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804378/pdf/main.pdf

This prospective study aimed to evaluate the prevalence of olfactory and taste dysfunction (OTD) in adolescents with mild-moderate COVID-19 who presented to a hospital in India between May and August 2020. The inclusion criteria was adolescents, aged 10–19 years, who presented to ESIC Medical College and Hospital in Faridabad with “influenza like illness (ILI)” and were detected COVID-19 positive by RT-PCR. These patients were followed up by telephone or ENT clinic consultation and the clinical course and outcomes of their OTD were documented. All the symptoms were self reported by the patients. Exclusion criteria included patients with severe COVID-19 disease, psychiatric or neurological disorders or those with existing conditions affecting their taste and smell.

Age/gender: 141 patients were included in the study, 58.9% were male and 41.1% were females. The age varied from 10 to 19 years with an average of 15.2 years.

Clinical features: 40 (28.4%) of the 141 patients in the study had olfactory or taste dysfunction. Of these 40 patients, 24.1% had olfactory dysfunction, 24.1% had an alteration in taste and 19.8% complained of both. Other common symptoms recorded by the patients were fever (48.2%), cough (20.6%), sore throat (19.9%) and malaise (14.2%). OTD was the first noted symptom in 13.9% of the patients. The duration of OTD varied from 2 to 15 days with an average of 5.7 days. There was no significant difference in OTD in different age groups or genders. All the patients reported complete recovery of their smell and taste sensations.

Conclusion: Olfactory and taste dysfunction is known to be a common presenting feature in adult patients with COVID-19. This prospective study in India shows a prevalence of OTD in 28.4% of COVID-19 adolescent patients. It concludes that the identification of OTD in the adolescent population may help in early diagnosis and reduced transmission of COVID-19 infection. Note is made of the limitations of the study including a lack of objective tools in evaluating olfactory and taste dysfunction (these were self-reported). Secondly, the study was limited to patients presenting to hospital with mild-moderate COVID-19 infection; a further study looking at the prevalence of OTD in well children found to be COVID-19 positive via community testing may be of use.

Millen, GKearns, PBr J CancerSeverity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project10 Dec 2020United KingdomEurope54Clinical - Clinical Featureshttps://doi.org/10.1038/s41416-020-01181-0

BACKGROUND: Data from adults with cancer suggests that they have an increased risk of contracting SARS-CoV-2 and develop a more severe COVID-19 illness.

AIM: To document the incidence and outcomes from SARS-CoV-2 infection in children with cancer attending all hospitals treating this population across the UK.

METHODS: Data were collected on children under 16 years of age with a diagnosis of cancer who were receiving hospital-based care who tested positive for SARS-CoV-2 from 12th March 2020 until 31st July 2020. Cases were confirmed by RT-PCR to SARS-CoV-2.

Prospective data collection started on 7 April 2020. The data were gathered as part of the UK Paediatric Coronavirus Cancer Monitoring Project, set up to record the effects of COVID-19 in children with cancer attending the 20 hospitals designated as the Principal Treatment Centres (PTCs) for the care of children with cancer in the UK. Paediatric Oncology Shared Care Units (POSCUs) linked to PTCs were encouraged to submit data. Children who had received an allogeneic stem cell transplant were excluded as data on this group of patients were being separately collected.

RESULTS: 54 children tested positive for SARS-CoV-2 during the data collection period and had complete datasets submitted. 98% of all patients had minimum of 4 weeks of follow-up data from their initial positive test result.

29 boys and 25 girls were affected with a median age of 5 years 0 months (range 10 months to 15 years, 9 months). 44% had a diagnosis of acute lymphoblastic leukaemia (ALL). 33% of children were from a black or minority ethnic background (BAME), who form 9% of the incidence of children with cancer in the UK.

Severity of illness: 49 of the 54 (91%) had mild (34) or asymptomatic (15) infections. The illness in one was moderate, in another was severe and in 3 was critical. All recovered. The cancer diagnosis in the 5 patients with moderate to critical illness were a mixture of haematological cancers and solid tumours. 87% of all symptomatic patients presented with fever while 62% had either cough or coryzal symptoms at presentation. 10% had gastrointestinal symptoms at presentation.

13 were hospitalised because of COVID-19, others 27 were in hospital for unrelated reasons, 14 were not hospitalised.

Treatment data were available for 38/54 patients (70%): 21% were receiving very myelosuppressive chemotherapy (either induction/delayed intensification chemotherapy for ALL or chemotherapy for AML). 29% were receiving less intensive chemotherapy. The remaining 50% were receiving a range of other more standard chemotherapy regimens. 26% were receiving targeted or immune therapy with or without conventional chemotherapy. None had received high dose chemotherapy within the 28 days preceding their positive SARS-CoV-2 result. The patients with moderate to critical infections were receiving oncological treatment of assorted intensities. One patient died of progressive cancer.

CONCLUSIONS: The authors of this study, carried out across all UK paediatric oncology centres, concluded that children with cancer who contract COVID-19 are not at any more risk of serious infection than children in the general population. These results are in keeping with emerging international reports. There was no trend of more serious infection in those receiving more intensive therapies. The limitations are that the numbers are small, that there was no consistent testing policy during the period of data collection, there is likely underestimation of children who have been asymptomatic or had mild symptoms. There also limitations derived from the limited sensitivity of the PCR test. The data presented are from children with a complete data set (apart from type of oncological treatment) and it is not known what proportion they make up out of all children with SARS-CoV-2 under hospital oncological care. These limitations, however, are unlikely to weaken the overall finding that children with ongoing cancer treatment are not at risk of a more severe COVID-19 illness. As a result, some of the more stringent shielding recommendations for this group of patients have been eased.

Foster, CCampbell, JRjpidsA Surge in Pediatric Coronavirus Disease 2019 Cases: The Experience of Texas Children's Hospital from March to June 202010 Dec 2020USANorth America1215Clinical - Clinical Featureshttps://doi.org/10.1093/jpids/piaa164

Methods: The Authors performed a retrospective chart review of all children, ≤ 21 years of age, presenting to the Texas Children’s Hospital (TCH) system in the greater Houston area, Texas with testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcription-polymerase chain reaction (RT-PCR) from March 10, 2020 to June 28, 2020. The children either presented to TCH or the community hospitals or clinics within the TCH system. Demographics were recorded for all patients undergoing testing and clinical characteristics and outcomes were recorded for children with positive tests. Data was sourced from charts, notes and Epic (the common electronic health record for the TCH system)

Results: Of 16,554 unique patients who were tested for SARS-CoV-2, 1215 (7.3%) patients tested positive. Infants under 1 year of age and patients aged 18-21 years had the highest percent of positive tests at 9.9% (230/2329) and 10.7% (79/739), respectively.

Children aged 1-5 years had the lowest percent of positive tests (335/5842, 5.7%). Fifty-one percent of patients with positive tests were male

Hispanic children accounted for 66% (802/1215) of positive tests, though they only represented 42.1% (6972/16554) of all children tested for SARS-CoV-2.

Of the 1215 children with a positive test, 55.7% had fever, 40.9% had cough, 39.8% had congestion or rhinorrhea, 21.9% had gastrointestinal complaints, and 15.9% were asymptomatic. Only 97 (8%) patients were hospitalized (of which 68% were Hispanic). Most patients (89/97, 91.8%) were admitted within 1 day of the collection date of the SARS-CoV-2 positive test

Most hospitalized patients had underlying medical conditions (62/97, 63.9%), including obesity.

Gastrointestinal complaints were present in 21.9% (266/1215) of patients. Almost 16% of children were asymptomatic (193/1215). Most children (90.8%) had no chest imaging.

Forty (41.2%) patients were admitted for a non-COVID-19 diagnosis including 12 (12.4%) patients admitted with acute appendicitis

Thirty-one hospitalized patients (31/97, 32%) required respiratory support and nine patients (9/97, 9.3%) received SARS-CoV-2 antiviral therapy. Two patients died. One patient had underlying congenital heart disease and developed acute respiratory distress syndrome secondary to COVID-19. The other patient expired from complications related to a new oncologic diagnosis.

Conclusions: A relatively high percentage of Hispanic children tested positive for SARS-CoV-2 and were hospitalized. Most children with detection of SARS-CoV-2 had uncomplicated illness courses, some children were critically ill, and two patients died.

The authors found that a relatively low percentage of patients with SARS-CoV-2 were hospitalized (97/1215, 8%) and furthermore over 40% of the admitted patients had a primary diagnosis other than COVID-19. Interestingly, 12 patients were hospitalized with acute appendicitis. They note there are case reports detailing clinical presentations of COVID-19 mimicking appendicitis. Appendicitis is the most common pediatric surgical diagnosis, however, and the relationship between SARS-CoV-2 and appendicitis remains unclear and warrants further investigation. Both pediatric and adult reports have found lymphopenia to be a common laboratory finding in patients with COVID-19, though this finding was only present in 30.7% of the study’s patients.

Alfraij, AAlghounaim, MJ Infect Public HealCharacteristics and outcomes of coronavirus disease2019 (COVID-19) in critically ill paediatric patients admitted to the intensive care unit: a multi-center retrospective cohort study.10 12 2020Kuwait/Saudi ArabiaMiddle East25Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120307668

This study was done in 8 paediatric centres (providing services to 12 million people) across Kuwait and Saudi Arabia from 1st March to 1st August 2021. The aim of the study was to better understand the dynamics of critical COVID-19, improve the quality of care and evaluate predictors of mortality and intubation.

From records, 43 children were identified as being admitted to ICU with positive SARS-CoV-2 PCR done on respiratory samples. 18 of these children were excluded (9 with confirmed MIS-C, 7 with asymptomatic infections identified when children admitted to ICU for other reasons, and 2 duplicate entries) leaving a study cohort of 25 children. 4 of these children died.

The authors have gathered a mass of demographic, clinical, laboratory and radiological data which is presented in tables. However, there are few findings that reach statistical significance. Interesting findings are:

Median age 2.78y

Only 3 patients were previously healthy before ICU admission

22 children were admitted to ICU because of respiratory failure, 2 for neurological compromise and 5 because of circulatory compromise

Death was significantly associated with thrombocytopaenia and circulatory collapse at time of admission: elevated procalcitonin and comorbidities were also associated with fatal outcome

Malhotra, AGaur, SPediatr Infect Dis JPediatric COVID-19 and Appendicitis: A Gut Reaction to SARS-CoV-208 Dec 2020United StatesNorth America48Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Pediatric_COVID_19_and_Appendicitis__A_Gut.95943.aspx

This study collected data on all SARS-CoV-2 positive patients admitted to a tertiary children’s hospital in New Jersey, USA during the first wave of infection, as well as on patients admitted with appendicitis. They report a temporal association between SARS-CoV-2 infection and appendicitis and suggest that is may represent another post-infectious manifestation.

Cohort demographics: Inclusion criteria were all patients admitted to the children’s hospital between 29 March and 26 July 2020 with confirmed SARS-CoV-2 infection, either by PCR or antibody testing. During this time, the hospital was admitting patients up to the age of 25 years, so this study included some patients not generally considered paediatric. There were 48 admissions, but 7 patients were excluded at the outset as they were asymptomatic. Of the remaining 41 patients, 18 were female (44%) and the median age was 9 (IQR 0.2, 17). The majority of patients were of Hispanic ethnicity (51%), with 22% black, 17% white and 10% ‘other’.

Results: The authors divided patients into 4 diagnostic categories for comparison: Pneumonia (16 patients); MIS-C (10 patients); Appendicitis (10 patients); and ‘Unconventional’ (5 patients) (defined as having symptoms and signs consistent with SARS-CoV-2 but not fitting into the other 3 categories).

The ‘Unconventional’ patients were significantly younger than patients in the other categories (median age 2 years, IQR 0.2-1.5 years). This category of patients was not included in further analysis, beyond comparison of demographic features.

Of the pneumonia patients, 94% were PCR positive and 6% (1 patient) antibody positive. This compared to 60% of MIS-C patients being antibody positive, 30% being PCR positive and 10% being both PCR and antibody positive. The appendicitis patients showed a similar pattern to the pneumonia patients, with 70% PCR positive, 20% antibody positive and 10% positive on both tests. The authors include a nice figure showing weekly admissions patterns during the study period. The shows the majority of the Pneumonia cases occurring during the first half of the study period, and correlating with the peak in SARS-CoV-2 infections in the region, whereas the MIS-C and Appendicitis cases predominated in the latter 2/3 of the study period.

The authors present data on a number of features such as severity, duration of fever, and inflammatory markers for their 3 main diagnostic categories (Pneumonia, MIS-C and Appendicitis), and these are consistent with what is already known. However, of particular interest in this study is the analysis of appendicitis in the context of SARS-CoV-2, and comparison with appendicitis patients without co-existing SARS infection. Although not statistically significant, there was the suggestion of an ethnic bias in the patients with appendicitis and SARS - 90% were Hispanic, compared to only 45% Hispanic the non-SARS infected appendicitis patients. There was also a trend to more severe disease in the SARS-infected appendicitis patients, with a 50% appendiceal rupture rate in this group compared to only 36% rupture rate in the non-SARS group.

Discussion: This study adds to the body of evidence on clinical features of SARS-CoV-2 infection in children and adds some interesting data on appendicitis in the context of SARS. The authors highlight the similarity of the temporal relationship they found between appendicitis and MIS-C in SARS-CoV-2 infected patients and suggest this may represent another post-infectious manifestation. Unfortunately, the data is not fully supportive of this conclusion as 70% of their appendicitis patients were PCR positive, consistent with current SARS-CoV-2 infection (unlike the MIS-C patients, who were, as expected, mostly antibody positive). What we also don’t know from this study is how the pattern of appendicitis presentations compares to normal (i.e. non-COVID) years and whether there is any difference.

Although it’s not possible to draw any firm conclusions from the data presented, this paper raises a number of interesting questions with respect to appendicitis and SARS-CoV-2 infection. Further studies into a possible correlation would be valuable.

Mizrahi, BSegal, ENat. CommunLongitudinal symptom dynamics of COVID-19 infection04 12 2020IsraelEurope862Clinical - Clinical Featureshttps://www.nature.com/articles/s41467-020-20053-y

In this study from Israel, data from electronic health records (EHR) from primary care visits to Maccabi Health Services 9MHS) was combined with longitudinal voluntary nationwide survey data on self-reported symptoms to explore the symptom dynamics of SARS-CoV-2 infection. Data on SARS-CoV-2 PCR testing was extracted from the EHR along with symptoms according to ICD-9 codes as documented by the primary care physician. Adults, but not children, were invited to participate in the nationwide survey via text or email to all members of MHS. Data from March 1st to June 7th, 2020 were analysed.

Data on symptoms was available for 206,377 individuals of whom 2471 had a positive SARS-CoV-2 PCR. For adults, there was relatively poor agreement between symptom report from survey and EHR data; most symptoms were more likely to be self-reported than recorded in the EHR. In SARS-CoV-2 positive adults, cough (11.6%), fever (10.3%), myalgia (7.7%) and fatigue (5.9%) were the most prevalent symptoms recorded in the EHR. Cough (21%), fatigue (19%, rhinorrhoea (17%), and headache (16%) were the most common self-reported symptoms. Loss taste of smell was self-reported in 10% of SARS-CoV-2 positive adults and was significantly associated with confirmed SARS-CoV-2 infection (OR 11.18, 95% CI 6.43-19.44) - this was the most discriminatory symptom for diagnosis of SARS-CoV-2.

Of 21,567 children included in the analysis, 862 (4%) were positive for SARS-CoV-2 on PCR. From EHR data, a smaller proportion of children had symptoms documented compared with adults. Fever (7%), cough (5.5%), abdominal pain (2.4%) and fatigue (2.3%) were the most prevalent symptoms amongst SARS-CoV-2 positive children. Most other symptoms were rarely documented (<1% of SARS-CoV-2 positive children); only 0.2% of children had documented loss of smell or taste. No individual symptom had a statistically significant association with confirmed SARS-CoV-2 infection in children. Fever (OR 0.3) and cough (OR 0.4) were in fact negatively associated with SARS-CoV-2 infection, likely due to the prevalence of other common paediatric infectious diseases resulting in primary care presentation during the study period.

Duration of illness, calculated from first positive SARS-CoV-2 PCR to a second consecutive negative PCR, was significantly shorter in children compared with adults in a Cox regression analysis (HR 1.18 95% CI 1.01-1.39).

The paediatric data in this study is limited by the reliance on EHR documentation of symptoms and the translation of this documentaion into ICD-9 codes. Thus, the reported proportions of SARS-CoV-2 positive children with each symptom are likely underestimates, as was evident in the discrepancy between the EHR and self-reported symptoms in adults. Nonetheless, the EHR data is consistent with the accumulating body of evidence that children experience a milder course of SARS-CoV-2 infection with fewer symptoms compared with adults. In addition, based on PCR data, children in this study appeared to experience a shorter duration of illness compared with adults.

Bain, RBrodie,MJournal of Cystic FibrosisClinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.03 December 2020Multinational 13 CountriesInternational105Clinical - Clinical Featureshttps://www.cysticfibrosisjournal.com/article/S1569-1993(20)30931-0/fulltext

This is a particularly important multinational study for the Cystic Fibrosis community. The authors describe 105 children, age 0-18years (median 10), 54% male, 41% homozygous for F508del CFTR mutation, from 13 countries in N and S America, S Africa, Europe, and Russia who had Sars-COV-2 between 1 February 2020 and 7 August 2020. The diagnosis of COVID 19 was made by a positive PCR test in 95 children.

Twenty nine percent of the children were asymptomatic. Of those with symptoms 73% had a fever, 38% altered cough, 30% dyspnoea, 23% gastrointestinal symptoms and 19% myalgia. The majority (71%) were managed in the community, and only one child needed intensive care. The children who were hospitalised had lower lung function and body mass index z-scores compared to those treated in the community. Of all the children 29% required new supplemental oxygen and about 1/3 had additional oral antibiotics and another 1/3 intravenous antibiotics. Fourteen percent of children had experimental antiviral therapy.

No child required ECMO and two children needed none invasive ventilation. No deaths very associated directly with COVID 19 though one child died 6 weeks after testing positive, but this was deemed to be due to worsening underlying cystic fibrosis.

What would have been interesting but has not been documented in the study would be a comparison of ppFEV1 prior to and after COVID 19 infection.

The authors conclude “SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have a pre-existing severe lung disease.”

Hizal, MCeyhan, M Pediatr PulmonolDiagnostic Value of Lung Ultrasonography in Children with COVID-1921 Oct 2020TurkeyEurope and Asia40Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.25127

This prospective multi-centre study was performed between April and May 2020 at four tertiary paediatric hospitals in Turkey. 40 children up to 18 years of age with confirmed COVID-19, both symptomatic and asymptomatic, had lung ultrasound performed compared to their other chest imaging (x-ray and/or CT) performed at the discretion of their treating clinician.

To minimise bias, bedside point of care lung ultrasounds were performed by a paediatric respiratory physician (‘pulmonologist’) blinded to the child’s symptoms and imaging findings. The ultrasound recordings were independently reviewed by a pulmonologist and radiologist, and when their findings were discrepant, they agreed in consultation on the findings. Chest x-rays and CTs were requested by the child’s treating physicians who were blinded to the lung ultrasound findings and were reported by an ‘experienced’ radiologist blinded to the lung ultrasound findings and clinical presentation. Lung ultrasound findings considered normal included: multiple horizontal A-lines and normal sliding. The presence of three or more B-lines (comet-tail artefacts, representing interstitial syndrome), or confluent B-lines was considered abnormal.

Of the 40 children, median age was 10.5 years with an age range of 0.4 to 17.8 years. Five (12.5%) were under 2 years and 12 (30%) were under 5 years.

All 40 children had both chest x-ray and lung ultrasound performed. Four children (10%) had abnormal chest x-rays with consolidation, lung opacity and pleural effusion.

Twenty-eight (70%) of the children had a chest CT, 12 (43%) of which were abnormal. Bilateral ground glass opacification and consolidation were the most frequent abnormalities seen on CT, mostly in the posterior and lower lung zones.

Lung ultrasound took between 4 and 10 minutes to perform. Eleven (27.5%) of the ultrasounds were abnormal.

Of the 12 children with abnormal CT scans, lung ultrasound was also abnormal for 10 (83.3%). Of the 10 children with abnormal ultrasound and CT, 7 (70%) had normal chest x-rays. Of the two children with abnormal CT but normal ultrasound, the lesions seen on CT were under 1cm in size.

Of the 16 children with normal CTs, ultrasound was also normal in 15 (93.8%).

All 12 children who did not have a CT had normal ultrasounds.

The two most unwell children had abnormal findings on CT, chest x-ray and ultrasound imaging.

Using CT as a standard for ‘disease positive’, ultrasound was found to have the following sensitivity, specificity, positive predictive value and negative predictive values:

CT positive CT negative

Lung US positive 10 1 PPV = 10/11 = 90.9%

Lung US negative 2 15 NPV = 15/17 = 88.2%

Sensitivity

= 10/12 = 83.3% Specificity

= 15/16 = 93.8%

The authors conducted further statistical analysis, including area under the ROC curve and confidence intervals. Confidence intervals were universally wide. The authors compared sensitivity and area under the curve for chest x-ray and lung ultrasound; these were statistically different (McNemar's test: p-value 0.016 and 0.001 respectively). Compared to CT, chest x-rays were falsely negative in 75%, while lung ultrasound was falsely negative in 16.7%.

The authors concluded that although bedside point of care lung ultrasound is not as sensitive as CT, it is still useful in the diagnostic work-up of COVID-19 in children with the undisputable advantage of reducing radiation exposure, minimising nosocomial spread of COVID-19 to other patients and staff by minimising movement around the hospital, and by using easily to disinfect portable ultrasound probe and mobile phone, which can be wrapped in cling film to further minimise contamination.

This study does have several limitations, particularly in that it was a small study, with no control group. The sensitivities, specificities, PPV and NPV have wide confidence intervals (detailed in the paper). A selection bias is also very possible as sicker children are more likely to have been more extensively investigated: some asymptomatic or only minimally symptomatic children did not have CT imaging (although the authors rightly point out that it would have been unethical to have performed CT chests on children in whom their primary clinician didn’t feel it was indicated). And, although portable probes and mobile phones are beneficial from an infection control perspective, the authors say that the image quality may have been compromised.

So what’s the study bottom line? This paper adds to the evidence that although not as sensitive as CT, lung ultrasound is a viable imaging modality in the investigation of COVID-19 in children, with fewer false negatives than x-ray and the benefit of not exposing children to ionizing radiation.

Freeman, MCWheeler, SEJ Pediatric Infect Dis SocImmunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center01 Oct 2020USANorth America485Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa123/5922694

Study of seroprevalence in 485 immunocompromised children at a paediatric quaternary centre in Pittsburgh, USA, between March and July 2020 (median age 11.9 years, range 0.79-18.9). Testing was done on residual serum taken for other reasons, and the authors point out that this limits the capacity to compare infection rates from their results to the entire paediatric population or to make comparisons between groups. 5 patients (1%) had SARS-CoV2-IgG antibodies (control population from same institution, 0.6%). 27.2% reported prior febrile or respiratory symptoms. 15.7% had a nasopharyngeal swab. 2 patients had rheumatological conditions, 2 solid organ transplant, and 1 solid organ malignancy. None required respiratory support, intensive care, or died. Only 2 patients had a positive NPS and one of these was seronegative (though the time interval between symptoms and blood test may have allowed waning of antibody levels in this case). In this study, all paediatric patients with exposure to SARS-CoV-2 based on the presence of IgG antibodies had relatively minor illness in contrast to reports in immunocompromised adults who seem more likely to be admitted and to have poorer outcomes than children.

Denina, MGarazzino, SPediatr Infect Dis JSequelae of COVID-19 in Hospitalized Children: A 4-Months Follow-Up29 Sep 2020ItalyEurope25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Sequelae_of_COVID_19_in_Hospitalized_Children__A.96024.aspx

This paper is a short report of a study that followed up children hospitalized with COVID-19 in a children’s hospital in Turin, Italy over a 4 month period, and assessed them for sequelae of infection.

Patient cohort: 25 of the 28 patients admitted with COVID-19 between 1 March and 1 June enrolled in the study, 13 male and 12 female. The age range was 0.4 to 15 years, with a median age of 7.75 years. All patients had a SARS-CoV-2 positive nasal swab on admission; 28% were described as having mild disease, 56% moderate disease and 16% severe disease. 52% of the patients had an abnormal lung ultrasound on admission showing a diffuse interstitial pattern, with 38% of these also having multiple area of subpleural consolidation. None were diagnosed with related multi-system inflammatory syndrome.

Follow-up: Patients were followed up 2 weeks post-discharge by telephone, with a subsequent medical examination together with bloods, lung ultrasound and nasal swab on average 35 days (IQR 19-46 days) after discharge. The authors report further follow up by telephone, and in person in some cases, up to 4 months post-discharge.

Imaging: 5 children continued to have abnormal lung ultrasound scans at first follow up, with 2 having persisting consolidation. Of these 2, one had resolved on repeat scan a month later. The other patient had cystic fibrosis and the ongoing lung abnormalities were felt to be related to this underlying condition.

Blood analysis: Most blood markers had normalised at first follow up, with the exception of 5 patients who continued to have some raised inflammatory markers (fibrinogen, ferritin, ESR, D-dimer). These were reported to have normalised on 2nd follow up at 6 weeks post-discharge.

SARS Co-V-2 detection: All nasal swabs were negative for SARS-CoV-2 at first follow up. 20 patients (out of 24 tested) were IgG positive on follow up, 4 were negative (despite positive nasal swabs on admission).

Summary: The findings of this study are positive and reassuring, with the authors reporting complete recovery of all patients and no sequelae of infection 4 months after discharge. This paper is a short report and the authors focus on presenting their laboratory and imaging findings. There is no information about what questions were asked at follow up and what the medical examination involved, so we have a somewhat limited picture of overall health outcomes. This study covered a broad age spectrum, however the cohort was small. Data supportive of these findings from a larger number of children is needed to add weight to the evidence that the prognosis of COVID-19 in children, even those needing hospitalisation, is good.

Bixler, DKoumans, ECDC MMWRSARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 202018 Sep 2020United StatesNorth America121Clinical - Clinical Featureshttps://www.cdc.gov/mmwr/volumes/69/wr/mm6937e4.htm

This Morbidity and Mortality Report from the CDC describes the deaths in children and young adults (<21 years of age) associated with SARS-CoV-2 in the United States (US).

Overall, 121 SARS-CoV-2-associated deaths have been reported in the US to July 31st 2020. When stratified by age: 10% occurred in children <1 year, 20% in children 1-9 years and 70% in children and young people 10-20 years of age. Of the 121 deaths, 63% occurred in males, and the most common ethnicity was Hispanic (45%) followed by non-Hispanic Black (29%). The definition of a “SARS-CoV-2” associated death was left to the jurisdictions reporting the deaths, so it is unclear precisely how this is defined; a not-trivial issue given half of deaths in the UK of children who had tested positive for SARS-CoV-2 were deemed not attributable to the virus (being infected was incidental).

Comorbidities were present in 75% of children who died. The most frequently reported medical conditions included asthma (28%), obesity (27%), neurological and developmental conditions (22%) and cardiovascular conditions (18%).

This report is consistent with previously published data showing higher mortality in individuals of Hispanic or Black ethnicity and in those with comorbidities.

Biko, DMRapp, JBPaediatr RadiolImaging of children with COVID-19: experience from a tertiary children’s hospital in the United States18 Sep 2020USANorth America313Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04830-x

This study looked at 313 SARS-CoV-2 positive children from Children's Hospital Philadelphia and affiliated hospitals with specific attention to radiological imaging performed. Only 55 had any imaging performed, with 51 children having chest X-ray and US, MRI or CT was performed for 23. children Of the 55 children with imaging, 10 met criteria for MIS-C (PIMS-TS).

Of the chest x-ray findings, one third showed abnormalities. The most common finding was related to pneumonia with interstitial opacities or alveolar opacities (total 32 cases). The interstitial opacities were mostly diffuse 10/16. Alveolar opacities were seen in 27% (14/51) of children with xrays. Children with MIS-C were more likely to have interstitial opacities (8/16) and/or pleural effusions (4/5) on chest x-ray.

Of the ten ultrasounds performed, aside from one showing acute appendicitis and another with non-obstructing renal calculi; there were no acute abnormalities.

Treatment data was also collected for the 55 patients who had imaging. Almost all (89%) required hospital admission (range 1->76days), broad spectrum antibiotics were given to 12 (22%).

Overall, most children with SARS-CoV-2 did not require hospital admission or further imaging during their care.

Vann, AMullan, CAm J Emerg MedA case series of pediatric croup with COVID-1915 Sep 2020North AmericaNorth America3Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490245/pdf/main.pdf

This series of three cases from Children's Hospital of the King's Daughters and New York Presbyterian Hospital were found through a retrospective review of children with positive SARS-COV-2 nasopharyngeal RT-PCR swab who also required nebulised non racemic epinephrine (NRE, also known as 1:1000 nebulised adrenaline) in ED. It is important to note that at the time frame searched from 1st March to July 31st 2020, the practice at these hospitals was not to perform SARS-CoV-2 testing for children if they were deemed to have a viral illness and were able to be discharged.

The three cases identified were an 11mo African American boy, 2 year old caucasian female and a 9yo female. All cases were negative for other common viral causes of croup at the time. The presentations appeared to be more prolonged and less responsive to nebulised treatment than usual croup cases with all requiring hospital admission, receiving 3 or more doses of nebulised epinephrine and all receiving >1 dose of dexamethasone due to prolonged time to resolution of stridor at rest. The 11mo boy had 1 day history of symptoms no known sick contacts and the 2 yo girl had two family members with URTI symptoms) (unknown SARS-CoV-2 status and presented with 2 days of symptoms. However the 9yo girl had a mother with positive SARS-COV-2 test 3 days prior to developing symptoms but had been advised not to present to ED until developing respiratory distress- so was seen in ED 7 days from time of symptoms onset. She was the most severe case and was initially managed in an adult ED with racemic epinephrine, codeine and lorazepam iwith initial improvement but represented 12 hours later with return of stridor at rest. She was subsequently transferred to the paediatric hospital, admitted to ICU, failed a trial of BiPap but had improvement after a second trial of Heliox with IV midazolam for anxiolytics. She required 22 hours of helix and dexmedetomidine infusion. She received 6 hours dexamethasone, had an initial dose of Ceftriaxone and given 5 days of IV Remdesivir. She required 4 days of PICU admission with intermittent helix and benzodiazepines for air hunger and respiratory distress and was able to be discharged the subsequent day. She had recovery by one week after discharge. Following these findings, the hospitals have subsequently started testing for SARS-CoV-2 in all children presenting with croup. Whilst more data is required to further understand the presentation of children with SRS-CoV-2 and croup, these cases suggest children with SARS-CoV-2 who do require nebuliser epinephrine tend towards more severe courses of illness.

Chong, CThoon, KClin Infect DisSaliva is not a useful diagnostic specimen in children with Coronavirus Disease 201914 Sep 2020SingaporeAsia18Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1376/5905581

This important pre-print letter from Singapore describes 18 children, 12 asymptomatic, mean age 6.6years, 10 of whom were boys. 53 paired samples of saliva and nasopharyngeal swabs were taken between 22 June and 22 July 2020 during the children’s admission, mean 3.1 paired samples per child.

The detection rate of COVID-18 was significantly lower in saliva than in nasopharyngeal samples with the best sensitivity of only 52.9% in the saliva samples taken between days 4-7.

The authors conclude that “saliva is not a useful specimen for diagnosing COVID-19 in children”

Nino, GLinguraru, GMPediatr PulmonolPEDIATRIC LUNG IMAGING FEATURES OF COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS14 Sep 2020Systematic review and metanalysisSystematic review and metanalysis1026Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25070

Nino et al conducted a systematic review of the literature using PubMed from 1st December 2019 to 11th July 2020 to describe lung imaging features of COVID-19 in children. They included studies that were peer-reviewed and including children aged 0-18 years with confirmed SARS-CoV-2 on reverse transcription PCR with chest imaging. If a study described both adult and paediatric cases, it was only included if paediatric cases were reported separately. Single case reports and literature reviews were excluded. 3278 articles were found and after various exclusions, the authors were left with 29 studies. They found chest x-ray descriptions were not consistently reported, with no studies describing ultrasound findings, and so when they extracted data for meta-analysis they chose to only analyse CT findings. The 29 studies had a pooled sample size of 1026 children with a mean age of 6.57 years (range 1.5 – 14.5 years).

Their findings boil down to:

• Just over a third of children had normal CT chests (35.7%l; 95% CI: 27.5%-44%). The authors compared this to a recent meta-analysis of lung CT changes in adults, stating that children are 3 x more likely to have a normal CT.

• Just under a third had bilateral lung involvement (27.7%; 95% CI: 19.9%-35.6%).

• The most common finding was ground glass opacities, reported in a little over a third of cases (37.2%; 95% CI: 29.3%-45%), somewhere in the region of half as common as in adults with COVID-19.

• The second most common finding was consolidation or pneumonic infiltrates in approximately one fifth of cases (22.3%; 95% CI: 17.8%-26.9%).

• All other lung CT findings reported in adults with COVID-19 were very uncommon (e.g. halo sign, interstitial changes, interlobular septal thickening, bronchovascular bundle thickening, crazy paving pattern, lymphadenopathy, pleural effusion or pleural thickening).

• Findings typically found in other paediatric respiratory infections, such as hyperinflation, were not seen.

The authors describe several limitations, the biggest being that only CT findings were described, despite the fact x-ray is more frequently used in children. They were also unable to correlate imaging findings with disease severity due to the lack of clinical data in the papers studied. Although the data analysed was from multi-national datasets, the majority were from China, particularly near Wuhan, and so were less international than on first appearances. The authors also explain that radiologists from different parts of the world use different terminology, giving the example “shadow” being often used to describe lung opacities, without specifying whether these were ground glass opacities, pneumonic infiltrates or something else. Perhaps more topically, there were no studies including lung imaging findings in Pediatric Inflammatory Syndrome.

What can we take away from this paper? There are two messages:

• lung CT findings in children with COVID-19 are less frequent and less severe than in adults

• typical changes seen in other paediatric viral respiratory infections do not seem to be present in children with COVID-19

This information may not be particularly useful in clinical practice, except in severely unwell children with COVID-19. Given the risks associated with ionising radiation, plus the not infrequent need for sedation, CT is not commonly used in children with COVID-19, except in extreme cases.

Han, MSChang, SHJAMA PaediatrClinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea28 Aug 2020KoreaAsia91Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2770150

This Korean case series examined children aged 0-18 years with COVID-19 who presented across 22 facilities (20 hospitals) from February 18-March 31st 2020. It focuses on clinical features and duration of SARS-CoV-2 RT-PCR detection. A total of 91 were identified by SARS-CoV-2RNA RT-PCR on nasopharyngeal/oropharyngeal or sputum swabs due to testing for one of the following reasons: symptomatic, close contact with a confirmed case, testing as apart of outbreak or screening on return from overseas.

Demographics included 53 (58%) male cases, with the median age being 11 years (range 27 days - 18 years). The majority (85, 93%) were previously well. Of the 6 with underlying medical conditions, 3 had asthma and epilepsy respectively.  Exposure was from a household contact in 57 (63%) of cases, with 15 (17%) imported, 11 (12%) cluster-associated, 4 from another contact and 4 remaining an unknown source.

Cases were mostly mild (46, 51%) or asymptomatic 20 (22%). There were 20 moderate, 2 severe cases and 3 unclassified. No children required mechanical ventilation. Fever ≥  38 as seen in 27 (30%) of patents, 54 (60%) had cough or coryza , 8 had loss of smell or taste, 5 had anosmia and 16 (18%) had gastrointestinal symptoms including diarrhoea and abdominal pain. Only one patient had gastrointestinal symptoms without fever or respiratory symptoms. Two thirds of children had symptoms prior to diagnosis (median time 3 days). The duration of symptoms for cases lasted a median of 11 days (range 1-36 days).

The children were tested for SARS-CoV-2 repeatedly to determine cessation of virus RNA detection, however intervals were not standardised, with a median of 3 days (range 1-15 days). Children who were asymptomatic had virus RNA detectable for an average of 14.1 days, and those with URTI or LRTI symptoms, at 18.7 and 19.9 days respectively (difference between these groups was not significant). Twelve children were given treatment with lopinavir-ritonavir and two with hydroxychloroquine. There was no difference in detection between the groups treated with the antiviral lopinavir-ritonavir or not.

This study confirms what many previous studies have demonstrated, which is that children with SARS-CoV-2 can remain PCR positive for prolonged periods. This study adds that this is also the case for children who do not develop symptoms. What is unclear is for how long this represents live virus with replicative potential. Culturable virus has not been detected beyond day 8 of symptoms. The authors of this study did not provide ct values which would enable some estimate of the presence of culturable virus (low ct values usually represent viral fragments).

Oterino Serrano, CBret-Zurita , MEur J RadiolPediatric chest x-ray in covid-19 infection26 Aug 2020spain Europe44Clinical - Clinical Featureshttps://www.ejradiology.com/action/showPdf?pii=S0720-048X%2820%2930425-3

Introduction: This is a radiological case series of the chest x-rays of 44 paediatric patients with confirmed SarsCoV2 infection from a tertiary paediatric hospital in Spain.

Patients <16 years from, 13th March to April 6th 2020, with positive PCR who had a clinical need for a chest x-ray were included. The indication for x-rays were not reported, so the precise nature of this cohort is unclear. All patients were admitted to hospital, so these findings likely represent the most unwell children with COVID-19. Two paediatric radiologists retrospectively and independently reviewed the chest x-ray films to determine the abnormality, distribution and evolution, if repeat x-ray was available.

Patient demographics : Of 44 patients, 29 were male (65.9 %). Median age was 79.8 months (2 weeks – 16 years). 23 (52.3%) had an underlying condition; cardiomyopathies (13.6 %), nephropathies (9%), history of prematurity (6.8 %), liver and renal transplantation (4.5 %), and neoplasm (4.5 %).

Radiological findings : 38 (86%) x-rays had peri-bronchial thickening, mainly perihilar (81%). Ground glass opacities (GCO) occurred in 40%. Consolidation was seen in 8, and a pleural effusion in 4. Four children had a normal chest x-ray. Most children recovered quickly and were discharged. Persistence or worsening of symptoms was observed in 15.9 % of the patients (7/44), they had new consolidation or worsening of features on their repeat x-ray. Unfavourable outcomes were more frequent when initial X-ray had bilateral involvement, diffuse affectation and combination of peri-bronchial cuffing and GGOs.

Conclusion: Most children with symptomatic COVID 19 requiring admission to hospital had some chest x-ray abnormalities, mainly perihilar thinking and ground glass opacities. In general the chest X-rays of children with Covid 19 are non-specific, and not sensitive to the disease.

Yonker, LFasano, AjpedsPediatric SARS-CoV-2: Clinical Presentation, Infectivity and Immune Responses19 Aug 2020USANorth America192Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31023-4/fulltext

This is an observational cohort study from Massachusetts General Hospital, Boston, USA

192 "children" (ages were 0-22 years) were enrolled when they presented with possible Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) at urgent care clinics (with symptoms or because of contact with a case) or were hospitalised with confirmed/ suspected SARS-CoV-2 or Multisystem Inflammatory Syndrome in Children (MIS-C). Dates of enrolment are not given.

Samples were collected after consent/assent: Nasopharyngeal swabs (83 samples), oropharyngeal swabs (105) and blood (100). Viral load was determined from respiratory and plasma samples, and ACE2 expression in the upper airways from the swabs.

Results

125(65%) children were SARS-CoV-2 negative, 49(26%) had acute SARS-CoV-2 infection and 18(9%) had MIS-C. MIS-C children were more likely to be younger and male.

.80% of the SARS-CoV-2(+) children had a known household contact but so did 44% of the SARS-CoV-2(-) and 45%of the MIS-C children. SARS-CoV-2(+) and (-) children presented similarly with non-specific symptoms, and anosmia occurred in 20% of the SARS-CoV-2 (+) group. MIS-C children most commonly had fever, followed by nausea and vomiting, and rash. There was no significant prevalence of any co-morbidities in any of the groups

Viral load in the respiratory samples of the SARS-CoV-2(+) was comparable to adults despite mild or absent symptom even in the youngest children. A comparison is made between children within 2 days of symptom onset and hospitalised adults after 7 days of symptoms, which is unhelpful as these time points are clearly not comparable (viral load rapidly decreases after onset of symptoms).

SARS-CoV-2 antibody response data is presented and is said to show a generalised enhancement of humoral immune responses as a marker of severe MIS-C

ACE2 gene expression of the upper airway was quantified by NP/OP swabs from both infected and non-infected children. ACE2 levels were higher in those with infection of SARS-CoV-2 and those with MIS-C (difference 10-4 – 10-5 log, p=0.004), and there was an increase of ACE2 expression with age, although with high variability. There was no association between ACE2 expression and viral load.

In summary, this study confirms a number of already known elements regarding children with COVID-19 or MIS-C, including that viral loads appear comparable to adults and that many symptoms are non-specific. This study confirms increasing ACE2 expression with age, which may in part explain reduced susceptibility to acquiring infection. Of interest is lack of correlation between viral load and ACE2 expression. Despite strong claims about transmission by the authors, the study does not address this question or add new information on this point.

Carter, MShankar-HariNat MedPeripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection18 Aug 2020United KingdomEurope25Clinical - Clinical Featureshttps://www.nature.com/articles/s41591-020-1054-6.pdf

This study examines the peripheral leukocyte phenotype of children with multi-system inflammatory syndrome in children (MIS-C).

A total of 25 children with a median age of 12.5 (range 7.7-14.4) were included. Clinical features of MIS-C were most commonly gastrointestinal symptoms (72%), polymorphous non-blanching rash (48%), and bilateral non-purulent conjunctivitis (40%). Only 2 (8%) children met criteria for Kawasaki Disease. Of note, 7 (30%) had coronary artery aneurysms. Treatments during admission included high-dose corticosteroids (80%), intravenous immunoglobulin (92%) and biologic agents (56%). Majority (84%) required admission to the paediatric intensive care, however only 2 (8%) of children required mechanical ventilation. Only 1 child (4%) was positive for SARS-CoV-2 PCR, however 17 (68%) were SARS-CoV-2 IgG antibody positive.

Leukocyte phenotyping was done during the acute (n=23), resolution (n=14), and convalescent (n=10) phase of illness. In the acute phase of illness, elevated levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T an B cell subset lymphopaenia were observed. In addition, there were decreased levels of HLA-DR and CD86 expression on antigen-presenting cells. Interestingly, the differential expression of these markers and elevated cytokines resolved as the child recovered.

This important study demonstrates that MIS-C is a distinct immunopathogenic illness. Future studies including larger cohorts of children will be critical in rational development of future therapies for this condition.

Swann, OSemple, MBMJClinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study17 Aug 2020UKEurope651Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/370/bmj.m3249.full.pdf

This large prospective observational study from 260 hospitals in the UK examines the clinical characteristics of children (<19yo) hospitalised with laboratory confirmed SARS-CoV-2 infection between 17th January and 3rd July 2020; as part of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK cohort. The main outcome measures were admission to critical care, in-hospital mortality and MIS-C.

Results;A total of 651 children admitted to 138 hospitals were included; median age was 4.6 (IQR 0.3-13.7); 35% were <12 months of age. Of patients with recorded ethnicity 57% were white, 12% south asian and 10% black. 56% were male and 42% had identified co-morbidities. 

Symptoms;The most common symptoms were fever (70%), cough (35%) nausea / vomiting (32%) and dyspnoea (30%). Three distinct clusters of symptoms were identified:- a discreet respiratory illness - cough, fever, dyspnoea, coryza and wheeze- a mucocutaneous enteric illness - headache, myalgia, sore throat, vomiting, abdominal pain, diarrhoea, fatigue, rash, lymphadenopathy and conjunctivitis- a rarer neurological ilness - seizures and confusion

Critical care and mortality;Critical care admission occurred in 18% (116/632); 8% received inotropic support; 9% received non-invasive and invasive ventilation respectively. Children of black ethnicity had higher odds of critical care admission (OR 2.82). Infants <1mo (OR 3.21, 95% CI 1.36-7.66) and children 10-14 yo (OR 3.23, 95% CI 1.55-6.99) were also more likely to be admitted to critical care. Co-morbidities including prematurity, respiratory and cardiac co-morbidities and obesity were more common in those with critical care admission compared with those receiving ward care.Six (1%) of patients died in hospital, all had serious comorbidities; 89% of children had been discharged alive and 10% remained in hospital at the time of reporting.

MIS-C;Based on the preliminary WHO case definition, 11% (52/456) of admitted children fulfilled diagnostic criteria for MIS-C. Children with MIS-C were older than those without (median 10.7 yo vs 1.6 yo) and were more likely to be of non-white ethnicity (64% vs 42%); obesity was also more common amongst those with MIS-C (10% vs 2%). Children with MIS-C were more likely to require critical care admission (73% vs 15%), receive inotropes (51%), invasive (27%) and non-invasive (35%) ventilation. There were no deaths due to MIS-C.

Of children with MIS-C differences were noted between those who were SARS-CoV-2 PCR positive (acute phase of infection - 56%) and those who were antibody positive (post-acute phase of infection - 44%). Antibody positive MIS-C patients were more likely to be of non-white ethnicity (90% vs 45%), less likely to be obese (0% vs 19%), and more likely to have conjunctivitis (71% vs 16%) and abdominal pain (95% vs 44%) compared to those who were PCR positive. Dyspnoea was more common in PCR positive patients (52% vs 14%). Cardiac complications were also more common in the antibody positive group (75% vs 35%).

Conclusion;The findings of this large prospective study are consistent with previous studies indicating that children represent a small proportion of hospitalised cases of COVID-19 (0.9% here), that outcomes in children are generally favourable and that death due to COVID-19 in children is rare. Similar to previous studies, fever and cough were the most common symptoms, although gastrointestinal symptoms (35%) were more common in this cohort; the identification of a mucocutaneous-enteric symptom cluster with overlap with WHO MIS-C criteria is a novel finding here. Children of black ethnicity were over-represented in overall cases, as well as amongst children admitted to critical care units, consistent with adult data from the UK. Similarly, obesity was associated with increased risk of critical care admission. 

The association of MIS-C with older age and non-white ethnicity are consistent with previous studies. In addition to current WHO criteria, fatigue, headache, myalgia, sore throat and low platelet count were all associated with MIS-C.  The demographic and clinical differences identified between MIS-C patients who were antibody positive compared with those who were PCR positive suggest a spectrum of clinical presentation that varies according to phase of infection and immune response.

Liu, XChen, JJ Infect DisClinical and epidemiological features of 46 children under 1 year old with coronavirus disease 2019 (COVID-19) in Wuhan, China: a descriptive study 06 Aug 2020ChinaAsia46Clinical - Clinical Featureshttps://watermark.silverchair.com/jiaa472.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArgwggK0BgkqhkiG9w0BBwagggKlMIICoQIBADCCApoGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMRenTM0H7AWkHfH5OAgEQgIICa-S2TrctCjayBEO6MxumGRv8cRCshq5YspREyle7HGSz423KjAOkoj9JVSjYnFYK-4AQk_PsUNKgNEiFcKtzxQmmPcFQb4_qXmXXRN7VEKAErKU6bCp94py_9BedSlJbOqx2wvSTyzCA3lx5EpyXjnzmnkGejTdhXYkihOkNa25518np1FWNH7Q3yt3fdkYKfpw-iC8JoXgTZeJUTVn3gwt2t62nwQFHoHNkpQN4lkSFOLRJgvs_n1BJODja2d5JhsOn8kwMg0iQNMzsqNjtaeRa9DjqjejOXaabpQIBrBHGf6HmCENuAy3DkuJTHMSPhMzvScKHa3aTV6n6ue80OZIFX__w-ak7J6YVTNidfBkPIWXL0dX3jVSJlz43rmZLjNi6ybjK5MJA3nBqcN0_ooufj4DNH649asuiXPGEYzuhWfKaIcszBlAIDDIofvOdkMo5B5f1FKWwO-dugrZaOeuO94nPclWiKD5_B_qZX45eBO_a00oSKZYejJho2I6-z19l7qtekqRqIb9ETv4zrSqcguK2sP7wctnmntr3DirqK6Pdp3xs7UCoS_TOvmZgV2o8K8KEMZWHykkK-Zt_Aw5bJNT6_T8-WqNd9saE5ic49bnVRsItNtTaiOqmTjWaOzwvdObd69sTvy6acaya1fL2N5e0fveNorCnz-5AJZtgg0cXZH9mh1Y72xmTPA8EaGRhPoIZ8tNbSfWs21pVDfFoGJNRUhMM1HpJ6V62jpoQ1mDPS-_QD3KqpStGg4QOgyv60xYT3iPz0MND03xLjlqIbbqH-dXQ7w6vuBS_PTgaW7Wa_pduFkGIY_c

This restrospective case series study analyses the clinical features of 46 infants less than 1 years old who were confirmed to have COVID-19 at Wuhan Children’s Hospital (China) between the period 26th January 2020 to 15th March 2020. It was not described how these patients were identified for the study. 25 patients (54.35%) were male and 21 (45.65%) were female. The median age was 5 months (IQR 2-7 months). The authors classed 2 patients (4.35%) as having severe or critical disease, 40 patients (86.96%) as moderate disease, 2 patients (4.35%) as mild disease, and 2 patients (4.35%) as asymptomatic. Sadly one patient (2.17%) died (age 10 months), and the remaining 45 (97.83%) were discharged home.

Cough (n=27; 58.7%) and fever (n=16; 34.78%) were the predominant features, with a minority of other patients experiencing vomiting (n=5; 10.87%); Nasal congestion and rhinorrhoea (n=3; 6.52%); dyspnoea (n=1; 2.17%); tachypnoea (n=1; 2.17%); diarrhoea (n=1; 2.17%); and sneezing (n=1; 2.17%).

With regards to complications, the following were found: liver dysfunction (n=20; 45.45%); cardiac injury (n=38; 86.36%); acute gastroenteritis (n=3; 6.52%); multiple organ dysfunction syndrome (n=1; 2.17%); required mechanical ventilation (n=2; 4.35%).

Common laboratory findings included: Lymphocytosis (n=13; 28.26%); raised ALT (n=11; 25.00%); raised AST (n=20; 45.45%); raised lactate dehydrogenase (n=23; 52.27%); raised creatine kinase (n=10; 22.72%); raised creatine kinase MB (n=38; 86.36%); raised CRP (n=8; 19.05%); raised CD3+ T cell (n=10; 28.57%); raised CD4+ T cell (n=14; 40.00%); raised CD19+ B cell (n=16 patients; 47.51%); raised IL-10 (n=15; 44.12%).

Caro-Dominguez, Pvan Rijn, RPediatr RadiolThoracic imaging of coronavirus disease 2019 (COVID-19) in children: a series of 91 cases04 Aug 2020Spain, Italy, France, Iran, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico International91Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04747-5

This international multicentre retrospective study of 91 children with confirmed SARS-CoV-2 describes the radiological findings of their chest imaging. Data was included from Spain, Italy, France, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico. Chest x-rays were reviewed independently by 3 senior paediatric radiologists. Chest CT images were evaluated by a different group of 3 senior paediatric radiologists. Impressions were shared and consensus reached for each image.

Of the 91 children, 11% had severe symptoms requiring PICU and 30 (33%) had coexisting medical conditions including 16 immunocompromised children, 7 children with congenital heart disease and 7 with long-term respiratory conditions. Six (7%) children were asymptomatic.

81 (89%) of the children in the study had chest x-rays. Of these, 10% were entirely normal despite the children being SARS-CoV-2 positive. None of the children with a normal x-ray required PICU admission. The most common abnormal x-ray findings were increased central peribronchovascular markings, bronchial wall thickening (47, 58%) and consolidation (28, 35%). Ground glass opacities and interstitial changes were less common in 16 (19%) and 13 (16%) children respectively. Pleural effusion (6, 7%), pneumothorax (2, 2%) and atelectasis (2, 2%) were uncommon.

24 (26%) of the children had a chest CT, mostly adolescents. The most frequent indication for CT was as a screening tool where the wait time for PCR testing was long. 22 (92%) of the CT scans were abnormal. The two most common CT changes were lower lobe ground glass opacification (21, 88%) and consolidation (14, 58%). The patterns seen on CT mirrored those described in adult studies: peripheral ground glass opacities in early stages, with ground glass with consolidation with or without interlobular septal thickening in more severe cases.

Only 3 children had lung ultrasound. One is described in the article as showing the characteristic B lines in the posterior and lateral left lung and pleural thickening. One asymptomatic child had an MRI for another reason which showed characteristic changes of COVID-19. Following this scan she was tested for COVID-19 on the recommendation of the radiologists.

paper contains numerous examples of x-rays, CTs and lung ultrasound images. The authors make several conclusions, which can be summarised in six points: In contract to adult studies, “bilateral, peripheral and subpleural ground glass opacities and/or consolidation” is not the typical chest x-ray finding of COVID-19 in children.Instead, chest x-rays of children with COVID-19 are nonspecific, frequently demonstrating peribronchovascular markings and airspace consolidation, seen in many other lower airway inflammatory disorders, viral infections and pneumonia. They therefore cannot be used to differentiate between COVID-19 and other childhood lung infections and should not be used as a screening tool for diagnosis of COVID-19 If radiographic imaging is required in symptomatic children, chest x-ray should remain the first imaging modality of choice, to assess for infection or pneumonia.Paediatric COVID-19 CT patterns are predominantly lower lobe ground glass opacity, as in adults, plus a more centrilobular or peribronchovascular pattern, not seen in adults, although it is not clear if this is directly due to COVID-19 or coinfection with other respiratory infectious agents. These findings are nonspecific and resemble other lower respiratory tract infections.CT should be reserved for complex cases or when there is clinical concern to assess for possible complications.In general, paediatric lung ultrasound image quality is superior to that in adults due to a thinner thoracic wall, however the role of lung ultrasound in children with suspected COVID-19 is unclear. The authors suggest lung ultrasound should be evaluated as a potential radiographic tool in paediatric COVID-19.

Heald-Sargent, TKociolek, LKJAMA PaediatrAge-Related Differences in Nasopharyngeal SevereAcute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) Levels in Patients With Mild toModerate Coronavirus Disease 2019 (COVID-19)30 Jul 2020AmericaNorth America97Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2768952

This research letter looked at 145 patients aged 1 month to 65 years old who were symptomatic and had positive SARS-CoV-2 RT-PCR on nasopharyngeal swab at a paediatric hospital in Chicago between March 23 and April 27th, 2020. Included were 46 children aged <5 years, 51 aged 5-17 years of age and 48 adults. Cycle threshold values of RT-PCR were measured and compared across the three age groups. A significant difference was found with children under 5 having lower cycle threshold values than children aged 5-17 and adults. The older children and adults had no significant difference found in cycle threshold.

These findings are at odds with most other studies of viral loads in children, which have shown little clinically relevant difference to levels found in adults (or if anything slightly lower levels). The reason is unclear, but this study confirms what was already known, that children carry viruses in their nasopharynx which is potentially transmissible (previous studies have found culturable virus in children). To what extents this correlates with how infectious children may be remains unknown.

Pavel, A.BYassky, EEJACISARS‐CoV‐2 receptorACE2 protein expression in serum is significantly associated with age29 Jul 2020USANorth AmericaClinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/all.14522

This is a peer review letter to the editor of Allergy, where ACE2 protein expression was measured in children and adults with and without atopic dermatitis using a previous cohort and their samples.

Angiotensin converting enzyme 2 (ACE2) is an integral component of the renin angiotensin system SARS COV2 cell entry is facilitated by ACE2. It is proposed that lower prevalence and maturity of ACE2 in children is one of the reasons for less illness, and less illness severity in children .

Methods: This study used samples from a previous published cohort of 19 healthy infants and toddlers and compared to 17 healthy adults and compared to 29 infants/toddlers and 55 adults with moderate to severe atopic dermatitis. Those with atopic dermatitis are not known to have increased susceptibility to SARS COV2. This cohort was generally healthy with no history of cardiovascular disease. None of paediatric control or AD groups had asthma. None of the control adults, but 17 of the AD adults had asthma.

They also investigated Cathepsin L/CTSL1 in both infant/adult and healthy/AD cohorts. CTSL1 is a protease which cleaves and primes SARS-Cov-1 spike protein, and is hypotheseized to play a similar role in SARS-CoV2.

Results: Adults had more ACE 2 expression than infants/toddlers. AD did not influence ACE2 expression. Males expressed ACE2 more than females. In a sensitivity analysis there was a trend towards increased expression of ACE2 in African American adults, and both African American and Asian toddlers.

CTSL1 was significantly greater in adults than infants/toddlers and was positively associated with ACE2 expression.

Conclusion: These results reflect what is already known, that ACE2 expression is higher in adults than infant/toddler and in men rather than women. It also suggests, and reflects what is seen clinically, that atopy does not increase risk of morbidity or mortality for Covid -19

Moraleda, CTagarro, AClinical infectious DiseasesMulti-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain25 Jul 2020SpainEurope252Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa1042

Clusters of children with a multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) have been reported in Europe and the USA. The authors describe the epidemiological and clinical features in a case series of children with MIS-C in Spain from March 1st to June 1st, 2020. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection. Children younger than 18 years with infection due to SARS-CoV-2 and attended at 49 hospitals were included in this registry. Inclusion criteria included positivity in real-time polymerase chain reaction (RT-PCR) positive, IgM or IgG in lateral-flow rapid test, ELISA or immuno-chemiluminescence serology, or severe disease suggestive of MIS-C and recent household contact with a confirmed patient with COVID-19.

Results; In the study period, 312 patients attended 49 hospitals, and 252 participants were hospitalized. Of them, 181 (72%) were admitted due to causes directly or likely related to SARSCoV-2. The remaining 71 (28%) were admitted due to causes not related with SARS-CoV-2, but were screened and found to be infected with SARS-CoV-2. A total of 31/252 (12%) children were diagnosed as MIS-C and/or Kawasaki disease by their physicians.

 

The peak of MIS-C cases were one month after the peak of admissions for other COVID-19 related reasons and decreased afterward.

Median age and interquartile range were 7.6 [4.5; 11.5] years. A total of 30 (97%) children had microbiological or serological evidence of SARS-CoV-2 infection, and the remaining patient, an 11- year old boy with incomplete Kawasaki disease and pericardial effusion, had epidemiological household contact with a COVID-19 adult patient, his father.

The World Health Organization recently released diagnostic criteria for this condition. All the described patients fulfilled the WHO case definition for MIS-C, except for 1/31 patients (3%). Rash or bilateral non-purulent conjunctivitis, or muco-cutaneous inflammation signs were found in 21/31 (67%) patients; hypotension or shock in 15/31 (48%), features of myocardial dysfunction 25/31 (80%) consisting of pericarditis, valvulitis, arrhythmias or coronary abnormalities in 19/31 (61%); 6 (19%) additional children had only an elevation of a biochemical marker of heart dysfunction (NT-proBNP); evidence of coagulopathy (specifically, elevated D-dimers) was found in 29/30 (97%), and acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain), in 27/31 (87%). No other apparent microbial cause of inflammation as sepsis or staphylococcal or streptococcal shock syndrome was found.

One child already on oral steroids for interstitial lung disease did not fit the WHO criteria for raised inflammatory markers but was included as all other criteria were met.

Thirteen children (45%) fulfilled the criteria of complete or incomplete Kawasaki disease.  Twenty (65%) patients needed admission to the Paediatric Intensive Care Unit, and 6/31 (19%) invasive mechanical ventilation. Cardiac complications consisted of myocardial dysfunction (15/31; 48%), pericardial effusion (6/31; 19%); valvular dysfunction (9/31; 29%), arrhythmias (7/31; 23%) and coronary abnormalities (3/31; 10%, among them 1 aneurysm). Four patients (13%) had renal failure.

Two (6%) patients received Remdesivir and 7/31 (23%) Lopinavir/Ritonavir. A total of 21/31 (68%) children received corticosteroids: 19 of these received methylprednisolone (13 patients received doses of 1 to 2.5 mg/kg/day; 2 patients boluses of 8 and 30 mg/kg/day for 3 days; 4 had dosing unavailable), 20/31 (65%) patients received 2 gr/kg of intravenous immunoglobulin (IVIG) and 13/31 (42%) patients received both IVIG and corticosteroids. All but three patients received broad spectrum antibiotics.

One patient with acute leukaemia and bone marrow transplant died, and one 6-month-old patient (with Downs Syndrome) developed anterior-descendant coronary aneurysm (z-score +9). The rest recovered without sequelae.

Limitations of this study include that some cases without microbiological, serological or epidemiological links may not have been included in this registry. 

The authors conclude SARS-CoV-2 could be a relevant trigger for a delayed cytokine storm and an inflammatory condition, with potentially severe consequences. Coinfections as hMPV may be present and might play a role in triggering the immune response. It is possible that some particular patients with special features such as chronic immunosuppressive treatment influencing inflammatory markers - may have MISC but not fulfil all WHO criteria.

Conclusion The authors concluded MIS-C is a potentially severe condition that presents in some children after SARS-CoV-2 infection. Physicians should be aware of this severe condition in children during COVID-19 epidemics. More studies are necessary to clarify the physiopathology of this syndrome and its treatment. 

Comment Even when removing the child without serological evidence of COVID-19 and the child which did not meet WHO criteria in this study, 29/252 or 11.5% of hospitalised patients developed MIS-C which is significant One death was reported in a patient with leukaemia and one complication in a patient with Downs syndrome but the rest of the patients (27/29, 93%) recovered without sequelae.

Prata-Barbosa, ACunha, AJ Pediatr (Rio J)Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study19 Jul 2020BrazilSouth America79Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0021755720301923

Date, patient identification and location. Between 1st March 2020 and 31st of May 2020, 79 patients aged 1 month to 19 years consecutively admitted to 19 pediatric intensive care units in Brazil with confirmed COVID-19 (RT-PCR in 72/79 and IgM and/or IgG antibodies in the other 7/79) and were included. 10 of these patients including 5 that only had positive antibodies had multisystem inflammatory syndrome (MIS-C) .

Age: median age 4 years( range 1 to 10.3 years)

Gender:43/79( 54%) male.

Ethnicity: 58% were white,25% mixed race, 15% black and 1% Asian.

Comorbidities:32/79( 41%) had previous comorbidities with neuromuscular disease predominant (28%) and chronic respiratory disease 19% , congenital heart disease 16%, diabetes 6% , undernutrition 6% and obesity 3%.

Clinical features : most common symptom was fever 59/79 (76%), followed by cough 40/79(51% ), tachypnoea 39/79 (50% )low oxygen saturation 23/79 (29%) , runny nose 17/79 (22%), diarrhoea 16/79(21%), vomiting 16/79(21%) and red throat 3/79(4%).

In MIS-C (n=10) : presentation included Kawasaki like disease 6/10 (60%), acute cardiac dysfunction 2/10(20%), toxic shock syndrome 1/10(10%), Macrophage activation syndrome 1/10(10%).

.Radiology: 42/68 (62%) had abnormal chest radiographs with 25/42(60%) having diffuse interstitial infiltrate. Chest CT with ground glass opacities in 19/38 (50%).

Bloods: Lymphopenia in 21/59(36%) of non MIS-C group and 5/10(50%) of MIS-C group.

Inflammatory markers including ESR,CRP,LDH,D-dimer, procalcitonin and ferritin were tested in varying number of cases but mainly in MIS-C group and were elevated in most tested patients.

Outcome: 32/79(41%) needed only oxygen therapy. Invasive mechanical ventilation was needed in 14(18%) for median of 7.5 days . Comorbidities were independently associated with the need for invasive mechanical ventilation (OR 5.5). Antibiotics , Oseltamivir and corticosteroids were used in 76%, 43%, and 23% respectively . The median intensive care length of stay was 5 days . There were 2 deaths (3% ) both in none MIS-C group. Age less than 1 year was not associated with a worse prognosis and patients with MIS-C had more severe symptoms, high inflammatory biomarkers but only comorbidities and chronic disease were independent predictors of severity.

Comment and Justification: this is the first study on COVID-19 in Pediatric CIU patients in Brazil which currently has one of the highest rates of infection .It has shown that the characteristics of the disease in Brazil are similar to other countries except age less than 1 year was not associated with a worse prognosis.

Kainth, MLorry, GRPediatricsEarly Experience of COVID-19 in a US Children's Hospital17 Jul 2020USANorth America65Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/07/15/peds.2020-003186

is the first comprehensive report from a major US paediatric centre. It describes all admitted cases of COVID-19 in children and young people (CYP) aged 0-22 years, from 23 Jan to 23 April 2020. It comes from the Cohen Children’s Medical Centre, just outside New York City, which serves a relatively deprived urban population. All had SARS-CoV-2 PCR positive antigen tests.

results are broadly similar to earlier reports from China and Europe, but with some interesting detail. Of the 65 admissions, the median age was 10.3 years, but there was a bimodal distribution, with 29% being infants of < 3 months, and 48% older than 12 years. Those with an underlying medical condition were over-represented (55%).

disease severity was considered mild in 60%, moderate in 26% and severe in 14%. Mean duration of hospital stay was 3.2 days. 23 (35%) went to intensive care. The older CYP did worse than the infants: 44% of 16 previously healthy CYP required any sort of respiratory support (1 ventilated), compared to 26% of 19 infants (none ventilated).

with either immunocompromise (e.g. cancer treatment) or chronic illness (e.g. chronic lung or neuromuscular disease) were identified separately. Although over-represented in the admissions, most did well: 21% of the 14 immunocompromised required oxygen or any respiratory support (3 ventilated), as did 44% of the 16 chronically ill (5 ventilated). There was one death, a toddler with advanced neuromuscular disease. Only one developed multisystem inflammatory syndrome (MIS-C).

esity was a significant risk for admission (but not for severity): 58% of the previously healthy children were obese, more than expected for the population.

expected, the most common presenting symptoms and signs were fever (86%), upper respiratory signs (34%), lower respiratory signs (60%), anorexia (40%), myalgia (34%), abdominal pain (17%) and headache (17%). Two had seizures. Anosmia was rare (1). Interestingly, only 4/10 with known asthma presented with wheezing.,

estigation findings were similar to earlier reports. Increased CRP and white cell counts were seen, showing strong associations with disease severity. Chest X-ray abnormalities were more common than might be expected from clinical status: 21 of 43 X-rayed had abnormal findings.

iviral ‘treatment’ of some sort was given to 40%, including hydroxychloroquine, remdesevir, anakinra and corticosteroids. Outcomes so far were good: 83% discharged well, 5% discharged with ‘sequelae’, 11% still inpatients.

this is further evidence, this time from an American population, that Covid-19 is less dangerous in children than adults, and that the prognosis is good in the vast majority. This is in spite of this population’s high prevalence of underlying serious conditions, obesity, and relative deprivation.

Derespina, KRMedar, SSJ PediatrClinical Manifestations and Outcomes of Critically Ill Children and Adolescents with COVID-19 in New York City.16 Jul 2020USANorth America70Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S002234762030888X

This multicenter retrospective observational study from New York City, USA, considers admissions of patients up to 21 years of age to 9 paediatric intensive care units (PICU) in New York City between 14 March 2020 and 2 May 2020. The authors consider 70 patients who are critically ill with COVID-19 positive nasopharyngeal swabs, and present their clinical manifestations, factors associated with PICU admission, and length of hospital stay. The data collection occurred prior to the definition of the multisystem inflammatory syndrome in children, therefore this presentation is not represented in this study.

he median age of patients included is 15 (IQR 9, 19). 61.4% are male. 74.3% had at least one comorbidity. 72.9% presented with fever, and 71.4% presented with cough. Bi-lateral infiltrates were the most common chest X-ray finding (50%). CRP, procalcitonin, lactate, pro-BNP and IL-6 were elevated. ARDS was associated with significantly longer duration of admission. Back/Latino race was associated with higher probability of discharge home by day 28.

NOTE – Some duplication of data :31 out of the 70 patients who are described in this paper have been discussed in other published reports.

Gaborieau, LMadhi, FJ Clin Med 9(7)Epidemiology and Clinical Presentation of Children Hospitalized with SARS-CoV-2 Infection in Suburbs of Paris14 Jul 2020FranceEurope192Clinical - Clinical Featureshttps://www.mdpi.com/2077-0383/9/7/2227

This paper presents the demographic characteristics, presenting symptoms, co-morbidities, and clinical progression of 192 children hospitalized with either confirmed nasopharyngeal PCR for SARS-CoV-2 (157) or strongly suspected but negative PCR (35) in the Ile-de-France département, in and around Paris, during their period of lockdown, from 23/03/20 to 10/05/20. The male:female ratio was 1.3:1. Those aged <1 made up 49% of the group, and those under ≤1 month, 17.7%. 29.2% had an underlying medical condition. Twenty four (12.5%) required PIC, 19 required ventilatory support (12 by mechanical ventilation) and 3 died.

Wardell, HDixit, AJ Pediatr Infect DisSARS-CoV-2 Infection in Febrile Neonates09 Jul 2020USANorth America4Clinical - Clinical Featureshttps://academic.oup.com/jpids/article/doi/10.1093/jpids/piaa084/5869489

Case reports of 4 term male neonates presenting with fever and testing positive for SARS-CoV-2, in Boston, USA, between 17/04-06/05/20. All infections were likely to have been acquired postnatally from close household contacts. Two had co-infection (1 E. coli UTI, 1 human metapneumovirus). All made a full recovery after a brief illness but 1 was still shedding virus when last tested (20 days). One had evidence of myocardial dysfunction which was postulated to be consistent with a pulmonary immunovascular coagulopathy model. This neonate did not have any co-infection and was treated with remdesivir; claimed to be the first reported use of this drug in a neonate. The only neonate with lymphopenia was that co-infected with hMPV. Authors advise continuing to screen febrile neonates for other infections even when there has been close contact with a proven case of SARS-CoV-2 and the neonate itself is positive.

Yudan, DWenbin,GFront PediatrClinical Characteristics of Children With COVID-19: A Meta-Analysis03 Jul 2020ChinaAsia396Clinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00431/full

This is a meta-analysis of papers published between 1 January and 1 April 2020 undertaken by Chinese authors. The authors undertook a literature search and identified 121 papers worldwide, only 33 studies met the inclusion criteria and more than half these were case reports. Interestingly all the included papers were from China.

396 children in total were identified with an age range 0-17 years (mean 5.5 years), just over 60% were >5 years old, 58% were male. 6.1% of all the included children had underlying diseases. In terms of the transmission route, 86.4% of the children with COVID-19 had close contact with family members with COVID-19 and 10% tested positive for other pathogens, such as influenza virus types A and B and Mycoplasma pneumoniae.

Fever (51.2%) and cough (37.0%) were the most frequent symptom, 17.4% of the children had asymptomatic infections. Furthermore, 66.7% had pneumonia, and 19% had radiologic features of pneumonia but were asymptomatic. Five developed severe or critical illness and required intensive care. The authors report that as of April 1, 2020, two child deaths were recorded in China (a 10-month-old child and a 14-year-old boy) but do not say if these two children were part of the study cohort.

The most frequent abnormal laboratory findings were leukopenia/lymphopenia (28.9%) and increased creatine kinase (20.%). Ground glass opacities were observed on CT scans in 53.9% of the children diagnosed with pneumonia.

The nineteen case reports included 25 patients. Their mean age was 4.6 years 48% were male, and 36% were older than 5 years. 76% of these were in a family cluster. No cases had underlying diseases or other pathogenic infections. Common clinical manifestations included fever (60%), nasal congestion/rhinorrhoea (28%), cough (24%), and digestive tract symptoms (24%). In addition, 11 (47.8%) of the 25 patients had pneumonia, four (16%) were asymptomatic but with imaging features of pneumonia, and one (4%) was critically ill. No deaths were reported. Five (25%) children had GGO on their CT scan. The most prevalent abnormal laboratory finding was increased creatine kinase (58.3%), followed by increased procalcitonin (55.6%), increased LDH (44.4%), and increased white blood cells/lymphocytes (36.8%)

In their discussion the authors conclude “Children are at a lower risk of developing COVID-19 and likely have a milder disease compared with adults. However, the evidence presented in this study is not satisfactory. Further investigations are urgently needed, and our data will be continuously updated.”

Denina,MGarrazino,SPEDIATRICSLung Ultrasound in Children With COVID-1901 Jul 2020ItalyEurope8Clinical - Clinical Features https://pediatrics.aappublications.org/content/early/2020/06/12/peds.2020-1157

Between March 18th and 26th 2020 8 children (age range 3 months to 10 years), 5 of whom were boys were admitted to Regina Margherita Children’s Hospital, Turin with Covid 19 respiratory tract infections. All 8 children had linear array chest ultrasound during routine medical examination. Although the number of patients analysed was small, the high concordance between radiologic and LUS findings suggested that ultrasound may be a reasonable method to detect lung abnormalities in children with COVID-19. The advantage of LUS was that the investigation could be done at the bedside, thus preventing transport of a potential infectious patient through a hospital

Wu, QXing, QPediatricsCo-infection and Other Clinical Characteristics of COVID-19 in Children 01 Jul 2020ChinaAsia74Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/05/04/peds.2020-0961

This retrospective study from 2 hospitals in China examines the clinical and epidemiological characteristics of 74 children with confirmed SARS CoV-2 infection. Consistent with other studies, the majority of children experienced a mild course of illness with only one severe case requiring non-invasive ventilation. All recovered.

Cough was present in 32%, fever in 27% and 40% were asymptomatic at the time of testing. Lymphopenia was present in only 5% of cases. Abnormal CT imaging was observed in 50%, but only 12% showed typical changes of COVID-19.

Of those tested for other respiratory pathogens 19 of 34 had co-infection. Mycoplasma pneumoniae (16) and RSV (3) were the most common pathogens. It is not clear how these pathogens were identified. The significance of Mycoplasma in particular is not entirely clear as asymptomatic upper respiratory tract carriage in children is well recognised; similarly in interpreting serology, false

positives can be problematic.

For cases where exposure history was available 65/68 were household contacts of a confirmed adult case. There was no evidence of transmission from children to others.

This data is consistent with larger paediatrics studies demonstrating a milder course of COVID-19 in children compared with adults. Notably co-infection was not uncommon, illustrating that the presence of another respiratory pathogen should not preclude SARS-CoV-2 testing in children.

Abdel-Mannan, OHacohen, YJAMA NeurolNeurologic and Radiographic Findings Associated With COVID-19 Infection in Children01 Jul 2020UKEurope55Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamaneurology/fullarticle/2767979

This is a retrospective case-series from the United Kingdom of children with neurological symptoms, identified from a larger cohort (n = 55) of SARS-CoV-2 positive children. Of the 55 children, 27 had features of paediatric multisystem inflammatory syndrome (PIMS-TS) and of these, 4 had neurological symptoms.

Clinical Features: The four children had a median age of 12 years (range 8-15 years) and interestingly, two children were of South Asian ethnicity and two of Afro-Caribbean ethnicity. Of the neurological symptoms reported, encephalopathy (4/4), headache (3/4) and brainstem signs such as dysarthria or dysphagia (2/4) were most common. Peripheral nervous system involvement was present in all patients and included proximal muscle weakness (4/4) and decreased reflexes (2/2). Neurological symptoms occurred alongside a range of systemic symptoms but were part of the initial presentation in 2 children.

Investigations: The four children had a range of investigations, including a lumbar puncture (2/4), EEG (3/4), EMG (3/4), MRI (4/4). The CSF was acellular and SARS-CoV2 negative, mild excess of slow activity was seen on EEG, and EMG showed mild myopathic and neuropathic changes. Interestingly, MRI findings were consistent in all four children, and included signal changes in the splenium of the corpus callosum. Three of the four children also had T2 hyperintense lesions associated with restricted diffusion.

Treatments: Therapeutics given varied. Three children received treatment for PIMS-TS more broadly, including methylprednisolone (2/4), dexamethasone (2/4), IVIG (2/4), anakinra (2/4), and rituximab (1/4).

Outcome: At the time of follow-up (median 18 days, range 11-13 days), 2 patients remain in hospital and have residual lower limb weakness and require a wheelchair to mobilise, and 2 patients have been discharged ambulating without support.

Overall, this paper provides a thorough description of neurological features associated with SARS-CoV-2 infection in the setting of multisystem inflammation.

Li, JDai, XJ Med Internet ResIdentification of Symptoms Prognostic of COVID-19 Severity: Multivariate Data Analysis of a Case Series in Henan Province30 Jun 2020ChinaAsia12Clinical - Clinical Featureshttps://www.jmir.org/2020/6/e19636/pdf
Acker, KHan, JClin Pediatr (Phila)Infectious Diseases Diagnoses of Children Admitted With Symptoms of Coronavirus Disease 2019 During an Outbreak in New York City27 Jun 2020North America North America42Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820944399?journalCode=cpja

This is a retrospective review of children with symptoms consistent with COVID-19 who were admitted at a single institution in New York City from March 12th to March 26th. Forty-two children were identified and had symptoms including fever (31), cough (21), increased work of breathing (17) and rhinorrhoea/congestion (16).

Of the 42 children, 5 (12%) had SARS-CoV-2 on nasopharyngeal swab, 15 (36%) had rhinovirus/enterovirus, 4 (10%) had human metapneumovirus 4, and 4 (10%) had bacterial infections. Overall, majority of children (25; 60%) had an infectious agent identified and were SARS-CoV-2 negative. Of the 5 children with SARS-CoV-2, two were neonates discharged within 72 hours with negative bacterial cultures, one was a 7 year old with MRSA bacteraemia and SARS-CoV-2 bacteraemia, one was a 14 year old with leukaemia who presented with fever, and the final patient had acute respiratory distress and required intubation, but was also positive for rhinovirus/enterovirus.

This small study demonstrates that even in the height of the outbreak in New York City, SARS-CoV-2 was responsible for a minority of admissions in children with respiratory symptoms. This highlights the importance of including SARS-CoV-2 in the list of differential diagnoses but ensuring appropriate investigations for viral and bacterial coinfections.

Götzinger, FTebruegge, MLancetCOVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study25 Jun 2020Europe (Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the UK)Europe582Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30177-2/fulltext

This European multi centre cohort study recruited from participating centres from  the Paediatric Tuberculosis Network European Trials Groups, to look at 582 cases of paediatric (<18 years old) SARS-CoV-2 infection in 21 countries with 77 healthcare centres. Centres from five additional countries reported no SARS-CoV-2 cases at the time of the study. The breakdown of centres included 454 (78%) tertiary, 54 (9%) secondary and 74 (13%) primary healthcare providers.

Cases were collected retrospectively from known cases prior to 1st April and prospectively between 1-24th April. Diagnosis was made on RT-PCR of SARS-CoV-2 alone. The age group of the population was young, with a median age of 5 (IQR 0.5-12) and 230 (40%) under 2 years of age. Just over half were male (n=311, 53%).

Index case data from history was included, with parents being the suspected index case for 324 patients (56%) and siblings accounting for 24 cases (4%). However a large number of cases (n=234, 40%) were either from someone outside of the immediate family or of unknown transmission.

The most common symptoms patients presented in were fever (n=379, 65%) and respiratory symptoms (n=313, 54% URTI and n=143, 25% LRTI). 128 (2%) had gastrointestinal (GI) symptoms and 40 (7%) had GI symptoms without respiratory symptoms. Asymptomatic patients accounted for 16% of all cases (92). There was confirmed viral co-infection in 5% (n=29) of patients. The study did not capture laboratory values. Chest x-ray was performed in 34% (n=198) of patients. Almost half of the x-rays showed findings consistent with pneumonia and ten (5%) of ARDS.

Of the patients in the study, a quarter (145) had pre-existing medical conditions. Twenty nine patients had pre-existing respiratory conditions (asthma accounting for 16) and malignancy was known in 27 patients. The study collected data on antiviral treatments administered however numbers were small and depended on local practice.

Across the cohort 363 patients (62%) required hospital admission, 48 (8%) required ICU admission. Factors increasing risk of ICU admission (n=48) were found to be age <1 month (n=7/48, 14.6%) the presence of any pre-existing medical condition (n=25/48 52%) and presence of lower respiratory tract infection signs at time of presentation (n=35/48, 73%). Mechanical ventilation was required by 25 patients (4%) and echo was used for 1 patient. Data on treatments given included antivirals: hydroxychloroquine (n=40, 7%), remdesivir (n=17, 3%), lopinavir-ritonavir (n=6, 1%) and oseltamivir (n=3, 1%). Other immunomodulators used were corticosteroids in 22 (4%), IvIG in 7 (1%), tocilizumab (n=4, 1%), anakinra (n=3, 1%) and siltuximab (n=1).

There were 4 deaths (0.69%), all of which were in children >10 years of age. Of the four deaths, one was an out of hospital cardiac arrest.

and two had pre-existing medical conditions; one patient had a stem cell transplant 15 months prior and another patient was managed palliatively due to their pre-existing illness. By time of end study 553 patients had made a full recovery and 25 patients had ongoing symptoms.

Overall, this is one of the first multi-national European studies of SARS-CoV-2 in children. Common symptoms included respiratory and fever but gastrointestinal symptoms were present in over one fifth of cases. Although eight percent of children required ICU admission, the case fatality rate was low at 0.69%. Children at greater risk of intensive care admission had pre-existing medical conditions, were less than 1 month old, or presented with lower respiratory tract symptoms. Asymptomatic infection occurred in 16% of cases. Given that at the time of the study, there were varying practices for screening criteria, it is likely that the true proportion of asymptomatic patients is higher (and true case fatality rate lower).

Zheng, G. Guo, Y.Pediatric PulmonologyClinical Characteristics of Acute Respiratory Syndrome with SARS-CoV-2 Infection in Children in South China.24 Jun 2020China Asia52Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24921
Rossoff, JMuller, WJPediatric blood and cancerBenign course of SARS‐CoV‐2 infection in a series of pediatric oncology patients23 Jun 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/pbc.28504
Gonzales Cortes, Rde Carlos-Vicente, JCIntensive Care Med A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units22 Jun 2020SpainEurope50Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00134-020-06146-8

The Spanish Paediatric Intensive Care Society have published their findings of 50 children admitted to 47 PICUs in Spain between 1st March 2020 and 1st May 2020 with SARS-CoV-2. More than 90% of PICUs in Spain were represented in this national database. During the study period there were no deaths from SARS-CoV-2 in children admitted to PICU in the participating PICUs.

The authors divided the children into two groups: those requiring ventilation and those not requiring ventilation, to assess for different characteristics between these groups. Fourteen (28%) of the children were ventilated. Twenty-seven (54%) of the 50 children in the study had suspected PIMS-TS; these children were less likely to require mechanical ventilation (4 of the 27 required ventilation) than those without PIMS-TS. Statistical significance between the two groups was found for age (median age of 2.8 years in the ventilated group, compared to 8.6 years in the non-ventilated group); co-morbidities (12, 24%, of the 50 children had comorbidities; 8 of these were ventilated); and clinical presentation with respiratory difficulties or an ARDS-type picture.

Overall, of the 50 children, 23 (46%) had haemodynamic instability, 20 (40%) had respiratory difficulties and 1 (2%) had neurological symptoms. Shock was present in half of the children (25, 50%), renal failure in 8 (15%) and cardiac dysfunction in 17 (34%).Across the 50 children, white cell count (median 9.26, IQR 5.64-14.46), lymphocytes (median 1.02, IQR 0.42-2.59) and CRP (median 13.9, IQR 4.9-27) were not statistically different between ventilated and non-ventilated children.

These are the preliminary findings from this national registry of children with SARS-CoV-2 admitted to PICU in Spain. Further results and analysis will provide more information regarding critically unwell children with COVID-19.

Rosenzweig, JKaicker, SPediatric Blood and CancerSARS‐CoV‐2 infection in two pediatric patients with immune cytopenias: A single institution experience during the pandemic21 Jun 2020USANorth America2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/pbc.28503
Hildenwall HHerleniusActa PaediatricaPaediatric COVID‐19 admissions in a region with open schools during the two first months of the pandemic21 Jun 2020SwedenEurope63Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303651/
Colmenero ITorello ABritish Journal of DermatologySARS‐CoV‐2 endothelial infection causes COVID‐19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases 20 Jun 2020SpainEurope7Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19327

Anecdotally, chilblains seem to be associated with Covid-19 in children and young adults. This case series from Madrid describes 7 children (age 11-17) presenting with chilblains on their toes during the pandemic. None had underlying conditions likely to cause chilblains, and in Spain, cold weather wasn’t responsible. The chilblains looked typical, caused only minor pain and itching, and all resolved spontaneously. All had skin biopsies, which showed a variety of inflammatory and vasculitic changes on histology, typical of chilblains: they also looked specifically for SARS-CoV-2 particles in the endothelium of the dermal vessels using immunohistochemistry and electron microscopy and found the virus in all of them.

What is remarkable is that all the children were systemically well, had either mild or no respiratory symptoms; and of the 6 that had nasal and pharyngeal swabs, all were negative for SARS-CoV-2 PCR. Only 4/7 had Covid-19 positive household contacts.The implication is that children can harbour demonstrably invasive coronavirus with minimal symptoms and negative swabs. This has epidemiological as well as clinical significance.

In conclusion, the presence of SARS-CoV-2 in the endothelium of dermal vessels in skin biopsies of children and adolescents with acute chilblains confirms that these lesions are a manifestation of COVID-19. Their clinical and histopathological features are similar to those of chilblains of other aetiologies, and virus-induced vascular damage could explain their pathophysiology. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a role in the pathogenesis of severe forms of the disease. More studies are needed to understand the reasons why previously healthy children, adolescents and young adults present

Heinz, NMartinez, MPaediatr TransplantA Case of an Infant with SARS-CoV-2 hepatitis early afterLiver Transplantation19 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/petr.13778
Xiong, XIp, PJ Pediatr.A Comparison Between Chinese Children Infected with COVID-19 and with SARS18 Jun 2020ChinaAsia244Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301144/

In this study, 244 children with SARS-CoV-2 infection from Wuhan, China are compared to 44 children diagnosed with SARS (SARS-CoV-1) in in Hong Kong in 2003. The clinical details of this series of patients from Wuhan, previously described elsewhere, are compared with those of those of children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 montsh vs 160 months). Compared with SARS-CoV-1 patients, children with SARS CoV-2 were less likely to have symptoms (20.9% asymptomatic vs 0% of SARS-CoV-1), including fever (40.2% vs 97.7%), myalgia (37.6% vs 0.8%), and chills (32.6% vs 3.7%).

Fewer children with SARS-CoV-2 required supplemental oxygen (4.7% vs 18.6%) and few in either cohort required mechanical ventilation (1.6% vs 2.3%). A single death occurred in a patient with SARS-CoV-2 (a 10 mo with intussusspection) and no cases of PIMS-TS / MIS-C were identified amongst the 244 SARS-CoV-2 infected children from Wuhan.

The most striking difference is the milder clinical illness and relative lack of symptoms in children with SARs-CoV-2 compared with those with SARS-CoV-1. The lack of asymptomatic infections in SARS-CoV-1 is also notable, similar to findings in adults. Whilst the role of asymptomatic patients in the spread of SARS-CoV-2 is unresolved, the milder clinical illness in the majority of patients along with the demonstrated earlier peak in viral shedding relative to symptom onset and resultant role of pre-symptomatic transmission are likely major reasons for the continuing widespread transmission of SARS-CoV-2, where the outbreak of SARS-CoV-1 in 2003 was more readily contained.

Del Barba, P.Barera, G.Pediatr PulmonolCOVID-19 cardiac involvement in a 38-day old infant18 Jun 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24895

First (single) case report of an infant with biochemical and echocardiographic evidence of mild cardiac involvement due to SARS-CoV-2 infection. The 38 day old male infant presented to hospital on 27/03/20. Neither the centre nor the country is identified but is likely to be in Italy. Pregnancy had been unremarkable. No delivery details given. Baby was formula fed. Both mother and father were +ve for SARS-CoV-2. He presented with a fever of 37.6oC and rhinitis but no respiratory distress and did not require oxygen therapy. Nasal and nasopharygeal swabs were +ve for SARS-CoV-2. Haemoglobin, lymphocyte count, CRP, ESR, electrolytes, liver transaminases, INR and PTT were normal. Abnormal results: LDH “mildly increased”, platelet count 525,000/μl, procalcitonin 3.28ng/ml, troponin T 8.2ng/dl, creatine kinase-MB 9.8μg/L, D-dimer 13.3 μg/ml, pro-brain natriuretic hormone 208pg/ml, fibrinogen 1.28g/L. CXR showed increased bronchovascular markings but no parenchymal changes (CT not done). A resting heart rate of 140bpm and a transient peak rate of 200bpm were the only cardiac signs (serial ECGs and 24hr recording). First echocardiogram showed no abnormalities but cardiac MR scan showed a “minimal amount” of pericardial effusion with no myocardial edema. Follow up echo 3 days after the first confirmed a 2mm effusion. A panel of other viruses linked to pulmonary and/or cardiac problems in infants was negative. He required no treatment and was discharged after 14 days. Swabs were -ve 21 and 22 days after presentation.

Meethal, LBKociolek, LKj.pedsSARS-CoV-2 Infection in Infants Less than 90 Days Old17 Jun 2020USANorth America18Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30750-2/fulltext
Ekbatani, M. S.Mamishi, S. British Journal of Biomedical Science Atypical and novel presentations of Coronavirus Disease 2019: a case series of three children.16 Jun 2020Iran Asia3Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/09674845.2020.1785102?scroll=top&needAccess=true
Li, YLi, Jpaediatric pulmunologyImmune-related factors associated with Pneumonia in 127 children with Coronavirus Disease in 2019 in Wuhan.16 Jun 2020chinaAsia127Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24907
Stewart, DStojanovic, JLancet. Child & adolescent healthRenal dysfunction in hospitalised children with COVID-1915 Jun 2020UKEurope52Clinical - Clinical Featureshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30178-4.pdf
Ranabothu, SVeerapandiyan, AActa Paediatr.Spectrum of COVID‐19 in Children15 Jun 2020USANorth America1353Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15412
Lanyon, NPeters, MArch Dis ChildhCritical paediatric COVID-19: varied presentations but good outcomes15 Jun 2020United KingdomEurope11Clinical - Clinical Featureshttps://adc.bmj.com/content/early/2020/06/28/archdischild-2020-319602

In this letter from Great Ormond Street Hospital for Children, London, 24 children, who tested positive for Covid-19, were admitted to the intensive care unit between 26th March 2020 and 31st May 2020. Thirteen of these had PIMS-TS. This letter describes the clinical features of the remaining 11.

These 11 had a median age of 5 years (range 0.4-11), 9 were boys, 9 had pre-existing medical conditions, and 4 came from the BAME community. The primary presenting feature was cough 6, apnoea 3, fever 10, gastrointestinal 6 and seizures 3 In all 11 inflammatory markers were raised, median ferritin 898 (range 254-1991), CRP 158 (27-449), LDH 1594 (802-4264) D-Dimer 158 (27-449). 4 children fulfilled the criteria for paediatric acute respiratory distress syndrome, the remaining 7 were admitted to PICU for other reason than respiratory failure. A variety of different forms of respiratory support were provided, invasive mechanical ventilation 9, prone position 4, inhaled pulmonary vasodilators 4, HFOV 2 and ECMO none. 5 children received remdesivir and 6 prophylactic anticoagulation.

All 11 children survived to hospital discharge. The authors conclude “While children can present to PICU with a pattern of illness similar to adult COVID-19 disease this is rare and three quarters of them had risk factors for respiratory infection. A larger number were found to be SARS-COV-2 coincidentally.”

Kanthimathinathan, KJyothish, DHospital PediatricsCOVID-19 - a UK Children's Hospital Experience15 Jun 2020UKEurope45Clinical - Clinical Featureshttps://hosppeds.aappublications.org/content/hosppeds/early/2020/06/06/hpeds.2020-000208.full.pdf
Pan, YZhang, LJIDEpidemiological and Clinical Characteristics of 26 Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Carriers15 Jun 2020ChinaAsia26Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/12/1940/5823633
Lee,HLytrivi,IPediatr TransplantVarying Presentations of COVID-19 in Young Heart Transplant Recipients:a Case Series15 Jun 2020United States of AmericaNorth America4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/petr.13780?af=R

This is a peer reviewed prepublication case report on the experience of Covid-19 among a population of young heart transplant patients from a tertiary centre, Columbia University Irving Medical Centre, New York.

Period Covered: first 3 months of the New York Covid pandemicHospital/Region Covered: the tertiary transplantation programme is one of the largest in the USA covering “hundreds” of patients.

Identification of Patients: 4 patients under the care of the hospital for heart transplantation are included. Case 1 was admitted after referral from secondary care with Covid symptoms and an oxygen requirement.. Cases 2 and 4 presented from home and case 3 was diagnosed during a planned admission for heart biopsy.

Age/Gender: there is a wide age range: case 1 (F)15 years, case 2 (F)25 years, case3 (M)13 months, case 4(F) 29 months.

Comorbidities and immunosuppression: The authors highlight the questions of whether the comorbidities (including immunosuppression) associated with heart transplantation lead to worse outcomes with Covid infection? Also whether immunosuppression has a protective or aggravating effect on outcome and how regimes should be managed?

Two patients (1 and2)also had renal transplants. Case 2 had connective tissue disease (elevated IL-2).

All patients were on various combinations of immunosuppressants (1,2 and 3 on steroids).In only one case (1) was this withheld during infection because of neutropenia.Clinical Features: 3 patients (1,2,3) had symptoms of acute Covid-19 and were nasal/nasopharyngeal positive. Case 1 required supplemental oxygen but no other treatment for 3 days and was then discharged.Cases 2 and 3 did not require admission. Cough: 3/3. Fever: 3/3.Sore throat: 1/3. Abdominal pain: 1/3. All remained well on follow up.

Patient 4 is likely to have had Covid-19 4 weeks prior to admission (symptoms and family history). She presented with a probable post Covid anaemia and hepatitis. She had a rash (acral papular) She was negative on nasal and hepatic Covid assay. Her liver biopsy was consistent with viral hepatitis. Her Covid serology was positive and other viral hepatitis serology negative. She received a blood transfusion

Reported Imaging: CXR:1/4. Normal. Cardiac echo:2/4. No deterioration.

Laboratory: Case1: WCC low 1460/ul, neutropenia (800/ul). ?secondary to immunosuppression or Covid. Elevated inflammatory markers: CRP, ferritin. D-dimer, pro- BNP elevated.

Case 2: no report. Case 3: normal FBC, CRP and LFTs.

Case 4: Hb 6.2 g/dl. Peak ALT elevated 1807 U/L. Peak AST 1070 U/L.

Comment: The centre maintains surveillance (telehealth) of most of it’s patients. Despite possible risk factors of comorbidities and immunosuppression only 4 cases presented. In the acute cases the illness was either mild (2,3) or moderate (1). This is the first report from a paediatric transplant centre and it will be necessary to examine the experience in other centres worldwide.

Case 4 developed hepatitis, anaemia and a rash 4 weeks after probable Covid infection. It is possible that this was Covid related. Viral hepatitis has been reported in a child post liver transplant with acute Covid infection.

Colonna, C.Gelmetti, C.Pediatric dermatologyChilblains in children in the time of Covid‐19: new evidence with serology assay13 Jun 2020ItalyEurope8Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14269
Kesici,SBayracki,BESCFulminant COVID 19 related Myocarditis in an infant12 Jun 2020TurkeyAsia1Clinical - Clinical Featureshttps://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa515/5856627

Clinical Features: 2 year old previously healthy male in contact with Covid19, hospitalized with nausea, vomiting and lethargy. On Day 2 of admission deteriorated with Respiratory distress, filiform pulse and blood pressure was not measurable. There was hepatomegaly. Child was intubated in PICU, while preparing for ECMO went into cardiac arrest. 30 minutes of CPR was performed. During ECMO biopsy of myocardium was taken.

Radiology: Initial CXR – bilateral interstitial infiltrates. Day 2: CXR Cardiomegaly with pleural effusion. ECHO: Severe heart failure

Bloods: Initial bloods negative for inflammatory markers but Troponin was elevated 30 times normal on Day 2.

PCR for viruses were negative including RT PCR for Sars_COV_2 Myocardial Biopsy showed local inflammation, Positive for RT_PCR for COVID 19

Conclusion: Single case report showing the effect of COVID 19 causing heart failure secondary to myocarditis without Kawasaki like syndrome

Zeng, QLYu, ZJTransbound Emerg DisClinical course and treatment efficacy of COVID-19 near Hubei Province, China: a multicentre, retrospective study12 Jun 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/tbed.13674
Jafari, RJavanbakht, MTravel Med Infect DisA 6 months old infant with fever, dyspnea and poor feeding, diagnosed with COVID-1911 Jun 2020IranMiddle East1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1477893920302799
Marhaeni, WR. S. Mapianto,Indian J PediatrThalassemic Child Presenting with Anosmia due to COVID-19.09 Jun 2020Indonesia Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281692/pdf/12098_2020_Article_3370.pdf
González-Dambrauskas, SKarsies, TPediatricsPediatric Critical Care and COVID1909 Jun 2020InternationalInternational17Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/06/05/peds.2020-1766.full.pdf

In preprint, González-Dambrauskas et al describe 17 children with COVID-19 admitted to international PICUs in Chile, Colombia, Italy, Spain and USA, in April 2020. These are interim results from the CAKE (Critical Coronavirus And Kids Epidemiologic) Study, recruiting between April and December 2020 from almost 60 PICUS in 20 countries. As well as describing the clinical details of each child in detail, this paper also describes four children with myocarditis associated with covid-19.

The 17 children predominantly presented with cough and fever (53% had cough, 76% had fever). Comorbidities were common in 71% of children, including underlying respiratory, cardiac, renal, liver or neurological disorders. Six children (35%) had gastrointestinal (GI) symptoms at presentation.

Of the four children with myocarditis, all were based in Europe, none had previous cardiac disease, and all presented with fever and GI symptoms. One also had a rash and conjunctivitis. These children all developed myocarditis early in their clinical picture, with average duration of symptoms prior to presentation of 3.5 days. All four children received IVIG. Three of these children also required inotropic support; one child also developed ARDS and acute kidney in addition to myocarditis, requiring non-invasive ventilation but not renal replacement therapy. None of the four children with myocarditis required mechanical ventilation. All four children survived to discharge home, with a mean hospital length of stay of 13.5 days.

Cen YLiu Y HClin Infect Dis.Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019 - a multi-centre observational study.08 Jun 2020ChinaAsia5Clinical - Clinical Features https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30341-4/fulltext
MAK, PQKwan, MPediatr.Infect.Dis.J.Anosmia and Ageusia : not an uncommon presentation of COVID-19 infection in children and adolescents.08 Jun 2020USANorth America3Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/.
Trogen, BShust, GPed. Infectious Disease J.COVID-19-Associated Myocarditis in an Adolescent08 Jun 2020USANorth America1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/COVID_19_Associated_Myocarditis_in_an_Adolescent.96126.aspx

This case report details the admission to PICU of a 17-year-old obese male (BMI 30kg/m2) with spondylolysis and a distant history of asthma (not requiring medication for > 5 yrs) who presented to a hospital in New York City during the third week of April with septic shock, after a week’s history of fever, GI symptoms and neck pain.

Clinical features: 7 day history of fever and neck pain and a 6 day history of diarrhoea and vomiting (non-bloody, non-bilious). No neck stiffness, headache, photophobia or respiratory symptoms. At presentation he was febrile, tachycardic and hypotensive (79/66 mmHg) with diffuse abdominal pain. His cardiovascular status remained labile after initial fluid resuscitation and he was admitted to PICU.

Initial bloods: Lymphocytes 0.9 x 103/L, CRP 167 mg/L, ferritin 1275 ng/mL, D-dimer 1218 ng/mL, initial Troponin I level 2.97 ng/mL rising to 6.17 ng/mL 2 hrs later, brain natriuretic peptide 2124 pg/mL, sodium 128 mmol/L, creatinine 1.25 mg/dL, creatine kinase 761 U/L, LDH 346 U/L, INR 1.5, IL-6 28 pg/mL

Microbiology: Nasopharyngeal swab RT-PCR SARS-CoV-2 positive. Other respiratory and GI pathogen PCRs negative, including enterovirus, adenovirus, CMV, EBV, HHV-6, parvovirus B19.

Radiology: Abdominal USS essentially normal. CXR: low lung volumes, normal cardiothymic silhouette and mild, hazy ground glass opacities at the lower lobes bilaterally.

ECG: T-wave inversion particularly in inferior leads.

Cardiac imaging: Initial transthoracic echocardiogram: LV ejection fraction mildly depressed with no obvious intracardiac clots or pericardial effusion. Cardiac MRI: normal sized LV & RV, LVEF 40%, RVEF 39%, area of mid-wall late gadolinium enhancement at inferior LV-RV junction corresponding to area of increased T2 signal as well as an area of hypokinesia, consistent with myocarditis.

Treatment in PICU: Blood pressure normalised on day 1, but remained febrile and tachycardic until day 4. Required 2 days of oxygen via NC. Received anticoagulation, paracetamol/ibuprofen and 48 hrs of piperacillin/tazobactam until blood cultures reported negative. No other anti-inflammatories or IVIg given. Initially started on hydroxychloroquine which was stopped on day 3 when serial ECG demonstrated prolonged QTc interval not present initially. Serial Troponin I and BNP levels normalised by discharge.

Outcome: Discharged on day 5 with 2 week course of anticoagulation (apixaban). Echocardiogram at follow-up one week after discharge demonstrated normal ejection fraction (59%) with qualitatively improved function. However, tissue Doppler imaging signals of the mitral valve annulus were still abnormally diminished with low global longitudinal strain rate, consistent with residual myocardial dysfunction. Repeat ECG showed persistent T-wave inversion in lead III.

The authors conclude with a discussion of the possible mechanisms of cardiac injury secondary to COVID-19, including viral entry via the ACE2 receptor causing direct damage to myocardiocytes, immune-mediated injury secondary to cytokine release or T-cell dysregulation, microvascular damage, endothelial shedding/dysfunction, hypoxia-mediated injury and abnormal coagulation, including DIC, increasing the risk of thrombosis and ischaemic events.

Du, WQ. LiJ Infect Public HealthPersistence of SARS-CoV-2 virus RNA in feces: A case series of children07 Jun 2020ChinaAsia10Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304913
Chen, YXiao, XJ Infect Public HealthRe-evaluation of retested nucleic acid-positive cases in recovered COVID-19 patients: Report from a designated transfer hospital in Chongqing, China07 Jun 2020ChinaAsia4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275981/
Foster, CCampbell, JJ Pediatric Infect Dis Soc.Coronavirus Disease 2019 in Children Cared for at Texas Children’s Hospital: Initial Clinical Characteristics and Outcomes06 Jun 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa072/5854294
Xing, CXu, ZWorld J Clin Cases Serial computed tomographic findings and specific clinical features of pediatric COVID-19 pneumonia: A case report06 Jun 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281042/
Li, C. Wu, B Medicine A 3-month-old child with COVID-19: A case report.05 Jun 2020China Asia1Clinical - Clinical Featureshttps://journals.lww.com/md-journal/fulltext/2020/06050/a_3_month_old_child_with_covid_19__a_case_report.92.aspx
Sun, D., XLiu, Z., SWorld Journal of Pediatrics SARS-CoV-2 infection in infants under 1 year of age in Wuhan City, China05 Jun 2020ChinaAsia36Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs12519-020-00368-y
Gorkem,SCetin,BDiagn Interv RadiolCOVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT05 Jun 2020TurkeyEurope1Clinical - Clinical Featureshttps://www.dirjournal.org/en/covid-19-pneumonia-in-a-turkish-child-presenting-with-abdominal-complaints-and-reversed-halo-sign-on-thorax-ct-167964

This is a case report of a 15 year old girl with Covid-19 from Turkey in an Epublished letter ahead of print with an early description of the “reversed halo sign”(RHS) on chest CT scan in. RHS is described as a central ground glass opacity (due to septal alveolar inflammation) surrounded by denser granulomatous airspace consolidation in the shape of a crescent or ring. It was identified in adult Covid -19 patients in early studies from Wuhan.

The patient presented with abdominal pain (epigastric tenderness). She had no respiratory symptoms and was apyrexial. Covid-19 was identified on nasopharyngeal swab. WCC 4.01x109, lymphocytes 1.92x109, CRP 1.6 mg/l rising to 10 mg/l after five days. Oxygen saturation remained above 95% in air.

Initial abdominal CT identified bilateral patchy alveolar infiltrates in the lower lobes and so an unenhanced low-dose thorax CT was performed. This identified multi focal RHS lesions within bilateral upper, middle and lower lobes. There were multiple multisegmental peripherally located alveolar infiltrations and scattered ground glass opacities.

The patient received hydroxy chloroquine. Interestingly, she did not develop any respiratory symptoms, making an uneventful recovery and was discharged after 8 days.RHS is a distinctive sign on chest CT. As well as occurring in pneumonia (including community acquired pneumonia) it can also be associated with fungal infections, immunosuppression, pneumocystis, TB, sarcoidosis, pulmonary neoplasms and pulmonary infarction. Therefore it can pose diagnostic challenges and management is guided by the clinical history. Although RHS is recognised in the adult Covid-19 literature this is a first report in a paediatric patient.

Mohammadi, A Mirza‑Aghazadeh‑Attari, MJpn J RadiolClinical and radiological characteristics of pediatric patients with COVID-19: focus on imaging findings04 Jun 2020IranMiddle East27Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293432/
Kerber, AYoussef, MIntnl J of DermatologyChilblains-like dermatologic manifestation of COVID-19 diagnosed by serology via multidisciplinary virtual care04 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/ijd.14974
Lin, EShah, AJAMA SurgeryIncidence of COVID-19 in Pediatric Surgical Patients Among 3 US Children’s Hospitals04 Jun 2020USANorth America12Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamasurgery/fullarticle/2766924
Zachariah, PSalman, LJAMA PediatricsEpidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York03 Jun 2020USANorth America50Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766920
Wu, HXiang, YJAMA Netw OpenClinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China03 Jun 2020ChinaAsia157Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2766670

In this retrospective case series from Wuhan, China, the clinical and immunological characteristics of children admitted to hospital with confirmed SARS-CoV-2 infection are examined. Details are provided for the 148 children with mild or moderate disease.

The median age was 84 months (IQR 18-123). Fever (40.5%) and cough (44.6%) and vomiting or diarrhoea (21.6%) were the most common symptoms. SARS-CoV-2 PCR became negative at a median of 7 days (IQR 4-11 days).

Lymphopenia was present in only 4.5% of patients; CD 4 lymphopenia in 1.9%. Elevation in CRP (32.4%) and procalcitonin (47.3% elevated; median 0.05 (IQR 0.04-0.08)) was observed in fewer than half of patients. Liver transaminases and LDH were significantly higher in moderate versus mild cases but the vast majority of levels fell within normal range.

Levels of inflammatory cytokines including IL2, IL6, TNG-a and IFN.y were largely normal; the authors note that one patient with severe disease had elevated IL-6 (3869 pg/mL). IL-10 was increased in 14%.No deaths occurred amongst mild and moderate cases and all 148 patients were discharged.

In this large case series of children with mild or moderated SARS-CoV-2 infection, laboratory measures of inflammation were largely normal. Specifically the significant elevations in IL-6, D-dimer, and ferritin characteristic of severe COVID-19 in adults and also PIMS-TS / MIS-C in children were absent in these milder cases. The authors postulate that the relative preservation of CD4 T-cells and the higher levels of IL-10 compared with adults with severe COVID-19 may indicate these as important components of a protective immune response.

As yet our understanding of the drivers of variation in individual immune response to SARS-CoV-2 remains incomplete.

Parri,NLazzerini,MEur J Pediatr Characteristic of Covid-19 infection in paediatric patients: early findings from two Italian Pediatric Research Networks 03 Jun 2020Delayed access or provision of care in Italy resulting from fear of COVID-19Europe130Clinical - Clinical Features https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269687/pdf/431_2020_Article_3683.pdf

This study is published as a short communication describing the clinical presentations and outcomes in children with identified Covid-19 in 61 centres in Italy between 3rd and 26 March 2020.Study Design: A retrospective study coordinated by the CONFIDENCE and COVID-19 Italian Paediatric Study Network’s involving 53(86.9%) hospitals and 8(13.1%) outpatient centres in 10 mainly northern regions. All children (0-18 years) diagnosed positive on screening and testing for Covid-19 by nasal/nasopharyngeal RT-PCR assay were entered into the study. Clinical, laboratory and imaging data was collected on standardised forms.

Study Population: 130 children and adolescents recruited (112 hospital;18 outpatient). <2 years 41 (31.5%), 2-9 years 35 (26.9%)’10-17 years 45 (34.6%). Male 73 (56.2%). Female 57(43.8%) p=0.47.Comorbidities 34 (26.2%) most frequent cardiovascular, respiratory and neuromuscular. No information on ethnicity. One patients data unobtainable.

Disease Severity: The majority of subjects were categorised as being asymptomatic or having mild disease 98/130 (75.4%). 11 (8.5%) were moderate severity, 11 severe and 9 (6.9%).critical. 75 (57.7%)were hospitalised with 15.(11,5%)needing respiratory support (5 needing oxygen, 2 non invasive ventilation and 2 mechanical ventilation). 9 cases were admitted to ICU with 6 being less than 6 months. 3 of the latter were less than 2 months and did not require respiratory support. Children less than 6 months had an increased risk of critical disease than older children: 6/35 (17.1%) vs 3/86 (3.5%) p=0.34. OR 5.6 CI 1.3 to 29.1.

Symptoms: Common symptoms were fever 67(51.5%), dry cough 38(29.2%) and productive cough 16(12.3%). Other symptoms were rhinorrhoea25(19.2%), respiratory distress 17(13%), vomiting 15(11.5%);diarrhoea 10(7.6%); sore throat 9(6.9%). Thoracic pains (3%), somnolence, febrile convulsions (1.5%) and lower limb pains (1.5%) were reported as novel symptoms.

Oxygen saturation at presentation: 91-92% 1(0.8%). <90 1(0.8)

Radiology: 41 (31.5%) of children had CXRs. These were normal in 15 (36.6%). The commonest abnormalities were ground-glass opacities in 17 (41.5%). Focal consolidation was seen in 4 (9.8%). Laboratory: 71 children were reported to have had laboratory tests. The authors report leukopenia (WCC %<5.5x109) and lymphopenia (<1.2x109) in 7/19 patients and 3/19 patients, respectively. They report elevation in aspartate transaminase >50U/l in 11/60 (18.3%) and alanine tranasaminase >45U/l in 8/68 (11.8%).

Outcomes: There were no deaths and all children were reported to have recovered. Comment: The study obtained data on all but one child found Covid-19 positive in this largely hospital based population. The authors acknowledge that there is a bias toward more ill patients with their population than community studies and this may explain the 57.7% admission rate. Also this is reflected in the amount of comorbidity. However, the majority of patients were either asymptomatic or had mild disease and small numbers required respiratory support or ITU. The authors identify the increased likelihood of critical disease in those less than 6 months and their being the majority of ICU cases. They also comment on new presenting symptoms (thoracic pain, somnolence, febrile convulsions and lower limb pains).

Pandey UDien Bard JMedRxIVPediatric COVID-19 in Southern California: clinical features and viral genetic diversity02 Jun 2020CaliforniaNorth America35Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.05.28.20104539v2.full.pdf

A study of 35 children age range 18 days to 18.5 years (median12.5), 57% of whom were boys, seen over an 8 week period in Southern California. Patients were identified by nasopharyngeal swabs submitted to Los Angeles Children’s Hospital between 11 March 2020 and 11 May 2020. 37% were hospitalised with a median inpatient stay of 4 days. Symptoms were diverse with fever and cough being the most common, 1/3 were symptomless. Whole genome sequencing was undertaken on Covid-19 samples. There was an association between disease severity and viral load. Children < 5 years age had a higher viral load and all were symptomatic. There was limited variation in the viral genome though a calculated evolutionary rate was like other RNA viruses. No correlation was identified between disease severity and genetic variation.

Frauenfelder, CBamford APediatricsInfant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir01 Jun 2020United KingdomEurope1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/06/16/peds.2020-1701
Escalera-Antezana, JP Rodríguez-Morales, AJLe Infezioni in MedicinaRisk factors for mortality in patients with Coronavirus Disease 2019 (COVID-19) in Bolivia: An analysis of the first 107 confirmed cases01 Jun 2020BoliviaInternational9Clinical - Clinical Featureshttps://www.infezmed.it/media/journal/Vol_28_2_2020_15.pdf
Manzoni, P Polastri, RoThe Pediatric Infectious Disease Journal: Uncommon Presentation of Coronavirus Disease 2019 Infection in a Child 01 Jun 2020italyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/Uncommon_Presentation_of_Coronavirus_Disease_2019.96134.aspx
Jones, B. A. ." . Slater, B. J. Journal of Pediatric Surgery Case ReportsNon-operative management of acute appendicitis in a pediatric patient with concomitant COVID-19 infection31 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261356/
Alsofayan, YAssiri, AJ Infect Public HealthClinical characteristics of COVID-19 in Saudi Arabia: A national retrospective study31 May 2020Saudi ArabiaMiddle East74Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304925
Valente, PBuzzonetti, LJournal of AAPOSOcular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report30 May 2020ItalyEurope27Clinical - Clinical Featureshttps://jaapos.org/article/S1091-8531(20)30115-4/fulltext?rss=yes

27 paediatric patients were identified between 16/03/2020 – 15/04/2020, from Bambino Gesù Children’s Hospital, Rome, Italy. It was not clear how patients were identified/recruited. The mean age was 84 months (range=8 days to 210 months). 74% were male (n=20); 26% were female (n=7).

Clinical features present: - Cough and/or dyspneoa = 15 patients (56%); - Vomiting and/or diarrhoea = 8 patients (30%); - Ocular manifestations consistent with viral conjunctivitis = 4 patients (15%);

In the abstract it states that "At admission, all patients showed ocular manifestations", however there is no other reference to further information in the paper.Radiology/bloods: N/a

Other investigations: Nasopharyngeal swab to COVID-19 tested positive in all 27 patients.Of the 4 patients with apparent viral conjunctivitis, 1 patient resulted positive for SARS-CoV-2 on RT-PCR from conjunctival swab.Of the other patients (n=23), two more patients had positive findings for SARS-CoV-2 in their conjunctival swab without developing clinical signs of conjunctivitis.Outcomes: 27 (100%) discharges. Other salient features: Some preliminary evidence to suggest that SARS-CoV-2 shedding is low in eye secretions/tears.

Olisova, OYShnakhova, LMDermatol TherCutaneous manifestations in COVID‐19: a skin rash in a child30 May 2020RussiaEastern Europe and Northern Asia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13712
Cai, JHe, GJ Med VirolClinical features and the treatment of children with COVID-19: a case series from Wenzhou, China30 May 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26092
Kakuya, FKinebuchi, TJapanese Journal of Infectious DiseasesThe first pediatric patients with coronavirus disease 2019 (COVID-19) in Japan; The risk of co-infection with other respiratory viruses29 May 2020JapanAsia3Clinical - Clinical Featureshttps://www.jstage.jst.go.jp/article/yoken/advpub/0/advpub_JJID.2020.181/_pdf
Zhao, WZhang, FClin PediatrCharacteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge28 May 2020ChinaAsia14Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820928057

In this study from Beijing, China, serial nasopharyngeal swabs were performed on children discharged between January 21st and April 18th 2020 following hospital admission with confirmed SARS-CoV-2 infection. Criteria for hospital discharge included clinical improvement and 2 negative RT-PCR tests for SARS-CoV-2 on consecutive nasopharyngeal swabs. Follow up swabs were performed fortnightly following discharge; the authors report on children with subsequent positive RT-PCR on follow up.

In total 14 children were followed, 7 of whom had a subsequent positive SARS-CoV-2 PCR result, none of whom had significant symptoms at the time (one with a temperature of 37.5). There were no significant clinical or laboratory differences between the group with subsequent positive tests compared with those who remained negative.

The authors refer to those who have subsequent positive SARS-CoV-2 PCR as having "reactivation" of infection. This is a misnomer as the persistent shedding of viral RNA has been well recognised in adult studies. This includes a large cohort of over 200 patients from Korea with positive tests following negative PCR results, similar to the children in this study. Importantly no onward transmission from these "re-positive" cases was found amongst 790 contacts in the Korean cohort, suggesting the viral RNA detected in patients with prolonged shedding is not viable. Indeed in a recent in vitro study including 90 SARS-CoV-2 PCR positive samples, only samples taken within 8 days of symptoms onset were capable of infecting cells. This is in keeping with contact tracing data suggesting peak transmissibility occurs before and immediately after symptom onset with limited transmission beyond 5 days of symptom onset.

The likely explanation of the "reactivation" described here is prolonged shedding of non-viable viral RNA with an interim "false negative" samples prior to hospital discharge. Given the available data, it is unlikely that these "re-positive" discharged patients represent an infection risk to others

Oualha, MRenolleau, SArchives de PédiatrieSevere and fatal forms of COVID-19 in children28 May 2020FranceEurope27Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0929693X20301172

The 27 children described here constitute the biggest series to date of children sick enough to need high dependency care during active COVID infection. The criteria for admission were oxygen requirement > 1L/min or underlying disease.

The cohort of 27 were admitted within days of onset of first symptoms and 24 were positive for COVID-19 by PCR of nasal swabs. This is consistent with active virus, rather than PIMS-TS, the Kawasaki like post-COVID syndrome.

24 had respiratory disease, mostly with radiological or CT findings consistent with COVID. 6 had cardiovascular disease and 4 renal problems.

9 required invasive ventilation with median duration 5 days. 10 received non-invasive ventilation and 23 were treated with oxygen. 4 received catecholamines, one ECMO and one renal replacement therapy. The median length of hospital stay was 6 days.

Mean laboratory findings in the group were of elevated CRP, procalcitonin, fibrinogen and D-dimers, consistent with an inflammatory and prothrombotic state. Neutrophil and lymphocyte counts were normal. T cell subsets and cytokine levels were not measured. 70% had underlying conditions, but the spectrum was different from adult experience, with neurological and respiratory problems or sickle cell disease being most common.Three of the five who died had previously been in good health. A teenage girl whose clinical course was suggestive of the cytokine storm seen in adults died within hours of admission. A teenage boy and a 6 year old girl co-infected with other pathogens both died after long PICU stays.

This description confirms that severe illness is rare in children with COVID and shows that even those admitted for HDU care had a shorter illness and better prognosis than that seen in adults. Nonetheless, occasional children do suffer a prolonged illness with multi-organ dysfunction.

Garcia-Salido, ASerrano-Gonzalez, APediatr Crit Care MedChildren in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital27 May 2020SpainEurope7Clinical - Clinical Featureshttps://journals.lww.com/pccmjournal/Abstract/9000/Children_in_Critical_Care_Due_to_Severe_Acute.98028.aspx
Kumar, KJayanthi, CRIJOPresence of viral RNA of SARS-CoV-2 in conjunctival swab specimens of COVID-19 patients25 May 2020IndiaAsia4Clinical - Clinical Featureshttp://www.ijo.in/temp/IndianJOphthalmol6861015-4225372_114413.pdf
Gefen, AMSethna, CPediatric NephrologyPediatric COVID-19-associated rhabdomyolysis: a case report23 May 2020USANorth America1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00467-020-04617-0
Torrelo AColmenero IPaediatric DermatologyErythema multiforme-like lesions in children and COVID-1923 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14246
Armann, J.Berner, R.Dtsch Arztebl IntHospital Admission in Children and Adolescents With COVID-1922 May 2020GermanyEurope128Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271745/
Docherty, ASemple, MBMJFeatures of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study22 May 2020United KingdomEurope310Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/369/bmj.m1985.full.pdf
de Ceano-Vivas, MCalvo CArch Dis ChildSARS-CoV-2 infection in ambulatory and hospitalised Spanish children22 May 2020SpainEurope58Clinical - Clinical Featureshttps://adc.bmj.com/content/archdischild/early/2020/05/22/archdischild-2020-319366.full.pdf

Study design: A retrospective case series of all children seen at a tertiary centre, who were found to have positive PCR for SARS-CoV-2. Testing for SARS-CoV-2 was only conducted in those children who had respiratory symptoms and “criteria for hospitalisation” or who had “underlying chronic pathology”. Children with mild symptoms were not tested even if there was a confirmed case in the household. Comparisons were made between the characteristics of those admitted to hospital and those treated as outpatients. The study was conducted between March 11th and April 9th 2020 at Hospital La Paz, Madrid, Spain.

Inclusion criteria: All children who underwent PCR for SARS-CoV-2 in nasopharyngeal smear, N=349. Of whom 58 (16.6%) had a positive PCR and were the cases analysed.

Key findings: Of the 58 cases: Male 37 (63.8%), Median age 35.5 months (range 3.3-146), Underlying conditions 23 (39.7%), Temperature >39.7degC 41 (70.7%), Cough 42 (72.4%), Rhinorrhoea 33 (56.9%), Breathing difficulty 10 (17.2%), Vomiting 9 (15.5%), Headache 8 (13.8%), Loss of taste 1 (1.7%), Anosmia 1 (1.7%).

Radiology: 40 (69%) had a CXR of which 35 (87.5%) were abnormal: Perihilar infiltrates, ground glass pattern, lobar or multilobar consolidation.

Bloods: 43 (74.1%) had a blood test, median WCC 9145/mm3, median lymphocyte count 2390/mm3.Outcomes: 33 were hospitalised and 25 were treated as outpatients. Of the inpatients, 14 (42.4%) received oxygen therapy for a median of 3 days. 5 were admitted to the PICU (15% of those hospitalised): 3 with severe COVID-19, 1 with a hypertensive crisis and 1 with diabetic ketoacidosis. 31 (53.4%) were treated with hydroxychloroquine, 3 patients were treated with remdesivir. 2 patients with an inflammatory syndrome were also treated with tocilizumab. There was 1 death of a 5/12 old infant with dilated cardiomyopathy and Hurler’s syndrome. The comparisons between the inpatient and outpatient group provide almost no additional useful information.

Comment: As the authors concede, the retrospective nature of the study is a significant weakness. Patients were selected for testing on the basis of symptoms and/or underlying conditions and many other children who could have been infected were never tested. The study is useful in describing the range of symptoms, treatment and outcome in the large selected group of children who tested positive for SARS-CoV-2. It does not, however, add anything new to what is already known about the condition in children.

Scheier, EBalla, UEur Rev Med Pharmacol Sci Lung ultrasound cannot be used to screen for Covid-19 in children21 May 2020IsraelMiddle East1Clinical - Clinical FeaturesCOVID-19 Associated Pediatric Multi-System Inflammatory Syndrome
Li, BYu, CIndian PediatricsRadiographic and Clinical Features of Children With Coronavirus Disease (COVID-19) Pneumonia21 May 2020ChinaAsia22Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1816-8.pdf
Leung, CLeung, CPediatric PulmonologyClinical characteristics of COVID‐19 in children: Are they similar to those of SARS?21 May 2020China Asia43Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/ppul.24855
Zachariah, PGreen, DClin Infect DisSymptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children20 May 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa608/5841161

This research letter details the viral loads of children with confirmed SARS-CoV-2 infection from Columbia University Irving Medical Centre in New York. All children admitted and discharged between March 14th to April 24th 2020 were included, timing of test relative to onset of symptoms, clinical severity along with viral load were compared between infants <1yo and children >1yo.Of 57 patients with positive SARSCoV-2 PCR, 20 (35%) were under 1yo. Compared with older children, viral load was higher amongst infants <1yo (mean cycle threshold 21.05 vs 27.25, p<0.01 - where lower cycle threshold=greater viral load). Infants were tested earlier on average (2 vs 3.8 days from symptom onset) and fewer had severe disease compared with older children (5% vs 32.4%).

In this small hospital-based study symptomatic infants appear were found to have higher viral loads and milder disease compared with older children. This is in contrast to data from some adult studies where a higher viral load correlated with more severe illness.

Amongst several possible explanations for this observation are that:- infants were more likely to be tested early in illness when viral load peaks - declining thereafter- thresholds for hospital presentation may differ between infants and older children- test performance and sample quality may differ between infants and older children- there may possibly be differences in host biology according to age

Although some data suggest that higher SARS-CoV-2 viral load is associated with the presence of viable virus / in vitro infectivity, the exact implications of the findings here in terms of risk of transmission from infants compared with older children is unclear. Further studies examining SARS-CoV-2 viral load dynamics and correlation with clinical course in children are required to better understand potential variation between different age groups.

Venturini, EGalli, LJ PaediatrSevere neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection 19 May 2020ItalyEurope2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236669

This case report from the Meyer Children University Hospital, Florence, published as a letter describes two infants with SARS-CoV-2 with transient severe neutropenia (<0.5 x109/l) Clinical Features: The two female infants, aged 23 days and 39 days were admitted with mild respiratory symptoms and low grade fever. Nasopharyngeal swans were positive for Covid-19. There was no clinical deterioration in their condition during admission.

Radiology: not described

Treatment: not described.

Haematology: leukocytes and neutrophils normal on admission. At 5 days neutrophil counts fell to 0.244 x 109/lnand 0.482 x 109/l. Subsequently both improved.

Apart from age and gender there is no other demographic information nor any on treatments.Although neutropenia is described in 6% of cases of Covid-19, severe neutropenia has not been described. In the report cases it was not associated with any change in clinical state. The authors suggest consideration of performing FBCs 5 to 7 days into the illness to identify neutropenia.It requires further studies to see if these findings are replicated and whether they are clinically significant. The severity of the neutropenia could be age dependent reflecting bone marrow maturity as one patient was in the neonatal range and the other just beyond it.

Xiong XTam, PGutComparative study of the clinical characteristics and epidemiological trend of 244 COVID-19 infected children with or without GI symptoms19 May 2020china Asia244Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/05/19/gutjnl-2020-321486.info
Dallan, CSahyoun, CLancetSeptic shock presentation in adolescents with COVID -1919 May 2020SwitzerlandEurope3Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30164-4/fulltext
Giacomet, VZuccotti, GPIDJAcute inflammation and elevated cardiac markers in a two-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with cardiac symptoms 19 May 2020ItalyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/ACUTE_INFLAMMATION_AND_ELEVATED_CARDIAC_MARKERS_IN.96157.aspx
Dugue, RMishra, NNeurologyNeurologic manifestations in an infant with COVID-1919 May 2020USANorth America1Clinical - Clinical Featureshttps://n.neurology.org/content/neurology/early/2020/05/18/WNL.0000000000009653.full.pdf
Shaw, RYuki, KJ Pediatr Surg Case Rep.Intubation precautions in a pediatric patient with severe COVID-1918 May 2020USANorth America1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S2213576620301299
Guarneri, CNunnari, GThe Lancet, Infection diseasesSilent COVID-19: what your skin can reveal18 May 2020Italy (assumed) Europe3Clinical - Clinical Featureshttps://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30402-3/fulltext#coronavirus-linkback-header
Yoo, SKim, D Pediatrics InternationalReactivation of SARS-CoV-2 after Recovery18 May 2020KoreaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ped.14312
Li, YWu, BBMC PediatricsChest CT imaging characteristics of COVID-19 pneumonia in preschool children: a retrospective study18 May 2020ChinaAsia8Clinical - Clinical Featureshttps://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-020-02140-7
Turbin, RNimchimsky, EOrbitOrbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-1918 May 2020USANorth America2Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/01676830.2020.1768560
Wang, Y.Li, L.The Journal of Infectious DiseasesClinical Outcomes in 55 Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Who Were Asymptomatic at Hospital Admission in Shenzhen, China17 May 2020ChinaAsia15Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/11/1770/5807958
Voinsky, IGurwitz,DJ Infect.COVID-19 Associated Pediatric Multi-System Inflammatory Syndrome. J Paediatric Infect Dis Soc16 May 2020IsraelMiddle East933Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30303-0/fulltext

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Duramaz, BTurel, ODermatol TherAppearance of Skin Rash in Pediatric Patients with COVID-19: Three Case Presentations15 May 2020TurkeyWestern Asia, Southeastern Europe20Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/dth.13594
Diotallevi, FOffidani, AJ Med VirolSkin Involvement in SARS-CoV-2 Infection: Case Series15 May 2020ItalyEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/jmv.26012
He, GCai, JIndian PediatricsSerial Computed Tomography Findings in a Child with Coronavirus Disease (COVID-19) Pneumonia15 May 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1824-8.pdf
Mastrolonardo, MFoti, CDermatologic TherapyThe management of the outbreak of acral skin manifestationsin asymptomatic children during COVID-19 era14 May 2020ItalyEurope38Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13617
Craver, RFinger, LFetal Pediatr PatholFatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c)13 May 2020USANorth America1Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/15513815.2020.1761491
Cordoro, KMMcCalmont, THPediatric DermatologyClustered Cases of Acral Perniosis: Clinical Features, Histopathology and Relationship to COVID‐1912 May 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14227
DeBiasi, RWessel, DJ Pediatr.Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region12 May 2020United StatesNorth America177Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30581-3/fulltext

This is retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at Children’s National Hospital, Washington DC US. Children and young adults were detected through symptomatic presentation at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalised, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features associated with hospitalisation, or critical care.

Of note this hospital served as a regional centre for providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. Overall patient age range was from 0.1 - 34.2 years, with a median of 9.6years. Of the total group 12/177 were > 20 years of age, and 37/177 were between age of 15 – 20years.

Results: Age; There was no significant difference in age between the hospitalised and non-hospitalised patients, however in the hospitalised cohort, the critically unwell group were significantly older than the non-critically unwell hospitalised group (17.3 years versus 3.6 years; P =.04) Sex; There was equal representation in total cohort showed (n = 177 52% male, 48% female), as well as the hospitalised cohort (n=44 50% male, 50% female). However males made up 67% of the critically ill cohort (n =9, 67% male, 33% female); but this was not statistically significant (p=0.26)Race/ethnicity: data not provided, authors describe plans to do so in follow up analysis Underlying conditions; 39% of positive patients had an underlying condition (classified as asthma, diabetes, neurological, obesity, cardiac, haematological, oncological). Though asthma was the most common underlying condition (35/177 20%), it was not more common in hospitalised patients (7/44 16%), nor of those admitted, those who were critically unwell (2/9, 22%). Though the numbers where small, specific underlying conditions such as neurological, cardiac, haematological, or oncological underlying conditions were more common in the hospitalised cohort than the non hospitalised cohort. But were not more common in the hospitalised critically ill compared with the hospitalised non critically ill. The authors noted there was no underlying condition present in 96/177 (55%) of overall SARS-CoV-2 infected patients overall, 16/44 (37%) of hospitalized patients and in 2/9 (22%) of critically ill patients.Symptoms; 76% of infected patients presented with respiratory symptoms (rhinorrhea, congestion, sore throat, cough or shortness of breath) with or without fever. Fever was present in 116/177 (66%) but was not more common in the infected hospitalized cohort (34/44, 77%) compared with the non-hospitalized cohort (82/133, 62%; p=0.46). 

Shortness of breath was more common in the hospitalized cohort (11/44, 26%) compared with non-hospitalized (16/133, 12%; p=0.04). Patients in the critically ill cohort were not more likely to have fever or any other specific symptom compared with the non-critically ill cohort.

Critical Care: 9 patients required critical care; which represented 5% (9/177) of total cohort and 20% (9/44) of admitted patients. 4 required intubation (3 ARDS, 2 multiple organ failure); 3 required BiPAP, 1 RAM cannula and 1 High flow nasal cannula. One patient had features consistent with the recently emerged Kawasaki disease-like presentation with hyper-inflammatory state, hypotension and profound myocardial depression; a 4 year male with no underlying conditions.

Summary: A very clear description of 177 patients with Sars CoV 2, in one large centre in Washington DC. 25% of patients needed hospitalisation and 5 % needed critical care. Older teenagers and adults who required admission, were then overrepresented in requiring critical care. Though underlying conditions were more common in hospitalised patients, they were not significantly more common in the hospitalised patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalised patients than non-hospitalised patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of recently described hyperinflammatory state.

Bai, KLi, CPIDJClinical analysis of 25 Novel Coronavirus Infections in Children 12 May 2020China Asia25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_Analysis_of_25_Novel_Coronavirus.96172.aspx
Brambilla, IMarseglia, GLThe Pediatric Infectious Disease JournalCOVID-19 in the Pediatric Population Admitted to a Tertiary Referral Hospitap in Northern Italy: Preliminary Clinical Data12 May 2020ItalyEurope17Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/COVID_19_in_the_Pediatric_Population_Admitted_to_a.96177.aspx
Brambilla, I.Ciprandi, G.Obesity: A research journalSpecial Issues for COVID‐19 in Children and Adolescents12 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22878
Meslin, PZemouri, NThe Pediatric Infectious Disease JournalCoronavirus Disease 2019 in Newborns and Very Young Infants a Series of Six Patients in France12 May 2020FranceEurope6Clinical - Clinical Featureshttps://journals.lww.com/pidj/Fulltext/2020/07000/Coronavirus_Disease_2019_in_Newborns_and_Very.33.aspx
Cai, XLi, WFront. PediatrClinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children12 May 2020ChinaAsiaClinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00258/full
Shekerdemian, LSBurns, JPJAMA PediatricsCharacteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units11 May 2020USA & CanadaNorth America48Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766037

This is a cross-sectional study of children admitted to 46 PICUs in North America. 48 children were admitted during the collection period (March 14 to April 3 2020). All had confirmed COVID-19 infection on PCR from a nasal swab.

Most patients presented with respiratory symptoms, but there were other presentations – three with DKA, and one with vaso-occlusive crisis (sickle cell). 86% of these patients had at least one comorbidity. 69% were severely or critically ill on admission, and 25% needed vasoactive drugs. 81% of patients needed respiratory support that exceeded their baseline.

61% had a range of therapies, including Hydroxychloroquine, Azithromycin, Remdisivir, and Tocilizumab. These were used as single agents or in combination with other therapies.

The overall mortality rate was 4.2% (both patients who died had pre-existing comorbidities and developed multisystem organ failure). 32% were still hospitalised at the time of publication (including one patient still receiving ECMO). 65% had been discharged.

This study reinforces what is known about the decreased burden of disease from COVID-19 in children compared with adults. Critically ill children had a less severe course of illness and better hospital outcomes than in adults. Children commonly had medically complex comorbidities. Overall the mortality is much lower in children (4.2%) than has been reported in adults (50-62%).

Chao, JMedar, SJ. Pediatr.Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City 11 May 2020USNorth America46Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30580-1/pdf
Wehl, G..Rauchenzauner, MKlin PadiatrCo-infection of SARS CoV-2 and influenza A in a Pediatric Patient in Germany.11 May 2020GermanyEurope1Clinical - Clinical Featureshttps://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1163-7385
Oberweis, MGarcia, IPediatr. Infect. Dis. J.Pediatric Life-Threatening Coronavirus Disease 2019 With Myocarditis11 May 2020LuxembourgEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Pediatric_Life_Threatening_Coronavirus_Disease.96160.aspx

In this case report from Luxembourg, the authors describe an 8yo boy of African ethinicity with COVID-19 complicated by myocarditis. Presenting features included fever, cough, fatigue and cervical adenopathy associated with painful erythematous swelling of the skin. Following admission, the patient developed renal failure and refractory hypotension necessitating ICU admission. CRP (151mg/L), ferritin (2869ng/mL), D-dimer and IL-6 were all elevated. Echocardiography demonstrated myocarditis with biventricular dysfunction and troponin was elevated. SARS-CoV-2 infection was confirmed on RT-PCR of nasopharyngeal swab and stool; serology (IgA and IgG) was also positive.

IVIG and tocilizumab (anti-IL-6 monoclonal antibody) were given along with supportive care including enoxaparin and inotropes. The patient made a full recovery with resolution of changes on repeat cardiac imaging and was discharged home on day 10.

This case, likely submitted prior to the description of PIMS-TS / MIS-C, fits with the definition for these syndromes. The myocarditis, refractory hypotension, overlap with features of Kawasaki Disease, laboratory findings suggestive of cytokine storm as well as the patient's African ethnicity are all in keeping with recent reports from UK, Europe and the US. The authors postulate that the "cardiac injury could be due to disproportionate host immune response to SARS-CoV2" and describe a rapid clinical response following administration of tocilizumab.

With emerging reports of PIMS-TS / MIS-C, our understanding of the pathophysiology of this condition will increase. At this stage the role of immunomodulatory agents remain uncertain in PIMS-TS / MIS-C; discussion with paediatric ID clinicians on a case by case basis is recommended.

Zhang, NZheng, XTransl PediatrAnalysis and suggestions for the preview and triage screening of children with suspected COVID-19 outside the epidemic area of Hubei Province10 May 2020ChinaAsia36Clinical - Clinical Features http://dx.doi.org/10.21037/tp.2020.03.08
Andina, D.Torello, A.Paediatric DermatologyChilblains in children in the setting of COVID-19 pandemic09 May 2020SpainEurope22Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14215
Locatelli, ASena, PJ Eur Acad Dermatol VenereolHistologic features of long lasting chilblain‐like lesions in a pediatric COVID‐19 patient09 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16617

This retrospective single case report describes clinical and pathological signs of chilblain-like lesions whilst the patient was asymptomatic. He did not have any signs of autoimmune conditions including on histological examination. The lesions persisted for several weeks whilst he remained positive for SARS-CoV-2 on nasopharyngeal swab. The authors highlight young people with this sign could be carriers of the virus.

A 16-year-old male patient attended Papa Giovanni XXIII Hospital, Italy. His nasopharyngeal swab was positive for SARS-CoV-2. His mother was admitted to hospital for SARS-CoV-2 management following his presentation.

Clinical features: Diarrhoea and dysgeusia were experienced 3 days prior to the onset of skin lesions described as “multiple asymptomatic erythematous oedematous partially eroded macules and plaques on dorsal aspects of the fingers”. A lesion was also noted on second toe.

Radiology: None discussed.

Bloods: "Routine bloods autoimmunity, cryoglobulins, viral serologies all negative or within normal limits"

Treatments: None

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: Histopathological examination demonstrated oedema of the papillary dermis, superficial and deep lymphocytic infiltrate in the perivascular and strong peri-eccrine pattern. Images are provided.

Diercks, GRKwolek, CJInternational Journal of Pediatric OtorhinolaryngologyAsymptomatic COVID-19 infection in a child with nasal foreign body08 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205643/pdf/main.pdf
Fu, BFu, XMed Clin (Barc)Clinical characteristics of 11 asymptomatic patients with COVID-1908 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205640/pdf/main.pdf
Ma, Y.Zhang, Z.Microbes and InfectionCharacteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China07 May 2020ChinaAsia10Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204664/pdf/main.pdf
Zhang, YSun, BCell Mol ImmunolProtective humoral immunity in SARS-CoV-2 infected pediatric patients07 May 2020China Asia6Clinical - Clinical Featureshttps://www.nature.com/articles/s41423-020-0438-3

This is a study looking at the immune responses of 6 children with Sars-CoV-2 infection and comparing it to controls, in hospitals in China, in “areas other than Wuhan”. The clinical characteristics of the children were described previously (Cai et al Clin. Infect. Dis. 2020). All six children had positive respiratory samples RT PCR positive for Sars-Cov-2. All had a mild respiratory illness, needing no supportive treatment.

It is somewhat difficult to interpret exactly what immunological tests were done on which child from the study report. However, flow cytometry analysis analysing T and B cells was performed on 4 of the positive patients and was compared to five uninfected controls, admitted to the same hospital for non Sars-CoV-2 related reasons. There was no significant difference in lymphocyte count, or percentage of CD3+, CD4+, and CD8+ T cells between positive or control groups. The percentage of IgG+ in total B cells was higher, though not significantly, between groups but the percentage of IgG+ memory B cells was significantly higher in infected group.

The authors used Nucleocapsid protein and receptor binding domain of spike protein (spike-RBD) of SARS-COV-2 as antigen. All 6 infected children were tested for antigen specific antibodies, with 5 of 6 children producing antigen specific antibodies between 2 – 17 days post infection (it is unclear whether these were serial samples, or opportunistic sampling, therefore exact time of production of antigen specific antibodies is unclear). The team report that most of the IgM antibody for spike RBD Sars-CoV-2 was undetectable shortly after disease onset, suggesting class switching occurred within one week of virus exposure.

The team went on to select select serum from one patient with high concentration of spike RBD protein, and demonstrated in vitro it could block the receptor binding between spikeprotein and ACE2 protein, which is considered a vital pathway for Sars-CoV-2 to infect.

Authors conclude that the efficient humoral immune response might explain why the majority of children infected with SARS-CoV-2 had milder symptoms and recovered more easily than adults.

Papa, AVarrassi, GPain TherImages in Practice: Painful Cutaneous Vasculitis in a SARS-Cov-2 IgG-Positive Child06 May 2020ItalyEurope1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s40122-020-00174-4.pdf
Ma, H.Shao, J.BMC MedicineA single-center, retrospective study of COVID-19 features in children: a descriptive investigation06 May 2020ChinaAsia158Clinical - Clinical Featureshttps://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-020-01596-9
Zhang, BZhang SJ InfectionChildren hospitalized for coronavirus disease 2019 (COVID-19): A multicenter retrospective descriptive study06 May 2020ChinaAsia46Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204760/pdf/main.pdf
Wang, YSun, DPediatr Infect Dis JThe Risk of Children Hospitalized With Severe COVID-19 in Wuhan06 May 2020ChinaAsia43Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32384397
Colonna, C. Gelmetti, C.Paediatric DermatologyChilblains-like lesions in children following suspected Covid-19 infection06 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14210
Li, J.Song, S.Q.The Brazilian Journal of INFECTIOUS DISEASEAn infant with a mild SARS-CoV-2 infection detected only by anal swabs: a case report06 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S141386702030043X
Xiong, X.Tam, P.Med archivesAre COVID-19 infected children with gastrointestinal symptoms different from those without symptoms? A comparative study of the clinical characteristics and epidemiological trend of 244 pediatric cases from Wuhan05 May 2020ChinaAsia244Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.04.29.20084244v1
Lu, YDu, HPed Infectious Disease JSymptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan05 May 2020ChinaAsia110Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Symptomatic_Infection_is_Associated_with_Prolonged.96181.aspx

This retrospective study analysed demographic, clinical, laboratory, radiological and therapeutic data from the electronic medical records of 110 children hospitalised with “mild/ordinary” COVID-19 (classified as per the National Health Commission of People’s Republic of China National Recommendations for Diagnosis and Treatment of COVID-19, 7th edition) at Wuhan Children’s Hospital in Hubei, China between 30th January and 10th March 2020. Inclusion criteria: throat or nasopharyngeal swabs RT-PCR SARS-CoV-2 positive and patient discharged from hospital after recovery (an initial cohort of 127 children was reduced to 110 after exclusion of 2 critical cases and 15 children in whom the onset of disease could not be accurately determined).

Study design: Timings of onset of illness, most recent exposure (presumably to SARS-CoV-2-confirmed or symptomatic contacts, although this isn’t specified), diagnosis and discharge from hospital were recorded. Patients were discharged only once they had two consecutive RT-PCR SARS-CoV-2 negative swab results (separated by at least 24 hours). The authors calculated the duration of viral shedding for (a) symptomatic patients (81/110, 74%) as time from onset of illness to discharge and for (b) asymptomatic patients (29/110, 26%) as time from date of most recent exposure OR abnormal chest radiological imaging (reason for imaging not specified in these asymptomatic patients) to discharge. This definition of duration of viral shedding, with starting point presumably in most cases a retrospective parent-reported start of symptoms or exposure to an infectious contact, and end point two negative swabs leading to discharge from hospital, makes interpreting the duration figures problematic. Viral shedding in urine and faeces was not measured.

Clinical features: Median age of the 110 children was 6 years (IQR 2-9); 59/110 male (54%), 51/110 female (46%). Symptoms included: cough and dyspnoea 57/110 (52%), fever 56/110 (51%), GI (including diarrhoea, vomiting, poor feeding, anorexia, abdominal pain) 26/110 (24%), rhinorrhoea 10/110 (9%).Radiology: 64/103 (62%) had unspecified chest imaging reported as demonstrating pneumonia (55/75 symptomatic (73%) and 9/28 asymptomatic (32%)).

Bloods: Leucocytes < 4.0 x 109/L in 6/110 (5%) (all 6 were symptomatic). Leucocytes > 10.5 x 109/L in 12/110 (11%) (9 symptomatic & 3 asymptomatic). Lymphocyte ranges not specified. Haemoglobin < 110 g/L in 13/110 (12%) (all 13 symptomatic). Fibrinogen < 2.0 g/L in 34/90 (38%) (20 symptomatic & 14 asymptomatic). Hs-CRP > 3.0 mg/L in 21/110 (19%) (18 symptomatic & 3 asymptomatic). Procalcitonin > 0.05 ng/mL in 52/110 (47%) (43 symptomatic & 9 asymptomatic). AST > 50.0 U/L in 19/110 (17%) (all 19 symptomatic).

Treatment: None of the patients required oxygen therapy. All of them received antiviral therapy, mostly commonly nebulised interferon-. According to the data table 22/110 received Chinese medicine therapy, although no details are given and it’s not clear if this was pre-hospitalisation. Median duration of hospital stay was 10 days (IQR 8-13).

Conclusions: The median duration of viral shedding using the definitions above was 15 days overall (IQR 11-20 days, range 5-37 days): 17 days (IQR 12-23) in symptomatic patients and 11 days (IQR 9-13) in asymptomatic patients. Symptomatic infection, fever, pneumonia and lymphocyte counts < 2.0 x 109/L were reported to be associated with prolonged duration of shedding.

Garcia-Lara, G.Ruiz-Villaverde, R.Dermatologic TherapyChilblain-like lesions in pediatrics dermatological outpatients during the COVID-19 outbreak 05 May 2020SpainEurope27Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13516
Merza, MAbdulah, D.Diabetes Metab SyndrCOVID-19 outbreak in Iraqi Kurdistan: The first report characterizing epidemiological, clinical, laboratory, and radiological findings of the disease05 May 2020Iraqi KurdistanMiddle East4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199697/
Hong-Rui, C.Wan-Xin, C.The Pediatric Infectious Disease Journal:A CASE OF CHILDHOOD COVID-19 INFECTION WITH PLEURAL EFFUSION COMPLICATED BY POSSIBLE SECONDARY MYCOPLASMA PNEUMONIAE INFECTION05 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_CASE_OF_CHILDHOOD_COVID_19_INFECTION_WITH.96183.aspx
Peng, HXu, HJ Clin VirologyCoronavirus disease 2019 in children: Characteristics, antimicrobial treatment, and outcomes04 May 2020China Asia75Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204737/table/tbl0010/
Rahmanzade, RHashemian, SA A PractRespiratory Distress in Postanesthesia Care Unit: First Presentation of Coronavirus Disease 2019 in a 17-Year-Old Girl: A Case Report04 May 2020IranAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227797/pdf/acc-14-e01227.pdf
Morey-Olive, MGarcia-Patos, VAnales de pediatriaCutaneous manifestations in the current pandemic of coronavirus infection disease (COVID 2019)04 May 2020SpainEurope2Clinical - Clinical Featureshttps://www.analesdepediatria.org/en-cutaneous-manifestations-in-current-pandemic-avance-S2341287920300673
Nirenberg, M.Herrera, MDMRJ Am Podiatr Med Assoc.Foot Manifestations in a COVID-19 Positive Patient, A case study04 May 2020SpainEuropeClinical - Clinical Featureshttps://www.japmaonline.org/doi/pdf/10.7547/20-088
Zheng, ZLiu, JJ Cent South Univ (Med Sci)Chest CT findings and clinical features of coronavirus disease 2019 in children03 May 2020ChinaAsia9Clinical - Clinical Featureshttp://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202003236.pdf
Sun, JWang, YJ Infect Dev CtriesDifferent outcome of COVID-19 in members of a family03 May 2020ChinaAsia1Clinical - Clinical Featureshttps://jidc.org/index.php/journal/article/download/12792/2248
Steinberger, SLittle, B PAm J RoentgenolCT Features of Coronavirus Disease (COVID-19) in 30 Pediatric Patients 01 May 2020ChinaAsia30Clinical - Clinical Featureshttps://www.ajronline.org/doi/10.2214/AJR.20.23145
Qiu, LLuo, XPediatr Infect DisA Typical Case of Critically Ill Infant of Coronavirus Disease 2019 With Persistent Reduction of T Lymphocytes01 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_Typical_Case_of_Critically_Ill_Infant_of.96189.aspx
Tsao, HFearon, DPediatricsThrombocytopenia (ITP) in a SARS-CoV-2 Positive Pediatric Patient01 May 2020USANorth America1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/05/19/peds.2020-1419.full.pdf

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2.

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications.

A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Zhu, XCiu, LVirusResCo-infection with respiratory pathogens among COVID-2019 cases30 Apr 2020China Asia11Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0168170220303531
Yu, X.Fu, C.Transboundary and Emerging diseasesEpidemiological and clinical characteristics of 333 confirmed cases with coronavirus disease 2019 in Shanghai, China29 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/tbed.13604
Casas, CGarcia-Doval, IBr J DermatologyClassification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases29 Apr 2020spainEurope0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19163

This article from a team in Spain aimed to classify cutaneous manifestations of COVID-19 and relate them to other clinical findings.

From 3rd of April 2020 to 16th of April 2020 they collected 429 cases but excluded 54 leaving a sample of 375 patients. A standardised questionnaire was used, photographs were taken and the questionnaires and photographs were independently reviewed by 4 dermatologists.

Data was collected by Spanish dermatologists from across the country most of whom had been redeployed from their usual dermatology posts.

Patients with an eruption of recent onset (previous 2 weeks) and no clear explanation, plus suspected or confirmed COVID-19 were included.They describe 5 cutaneous manifestations.

Acral areas of Erythema-oedema with some vesicles or pustules: 19% of cases. These were more likely in children.

Other vesicular eruptions: 9%. May also affect the limbs and have a haemorrhagic content, and become larger or diffuse.

3 Urticarial lesions: 19%. Mostly distributed in the trunk or disperse. A few cases were palmar.

Other maculopapular: 47%. Some showed perifollicular distribution and varying degrees of scaling, Some had been described as similar to pityriasis rosea.Livedo or necrosis: 6% Strengths of this study are the large number of patients recruited and that four dermatologists independently reviewed the images. It adds to the understanding of skin manifestations of COVID-19, which may give additional information when trying to make a clinical diagnosis of COVID-19 if other symptoms are non-specific, also the cutaneous manifestations may persist for some time once other symptoms have resolved.

A weakness is the authors did not specify the age of the patients involved so the usefulness for paediatric patients is limited. Also, in some areas, diagnosis of COVID-19 infection could only be made clinically, based on symptoms as the ability to test patients was limited during the height of the pandemic.

Chacon-Aguilar, R.Perez-Moneo, B.An Padiatric (Engl Ed)COVID-19: Fever syndrome and neurological symptoms in a neonate27 Apr 2020SpainEurope1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183976/
Nathan, NCorvol, HLancetAtypical presentation of COVID-19 in young infants27 Apr 2020FranceEurope5Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30980-6/fulltext

This correspondence in the Lancet describes the clinical features of 5 infants with COVID-19 who were admitted to a Paris hospital during the first week after imposed population quarantine in France (from 17th March 2020). At this time at Trousseau Hospital, children needing admission with fever or respiratory symptoms (or both) were admitted to a dedicated SARS-CoV-2 infection unit: during this week 14 infants under the age of 3 months were admitted and of these 5 out of 14 were confirmed SARS-CoV-2 positive on nasopharyngeal swabs.

Age/gender of infants: All 5 of these previously healthy infants with COVID-19 were boys; ages ranged from 1.6 to 2.7 months (median 2.1). All of their parents had mild signs of viral infection (including fever, cough, rhinitis), which could have been indicative of undiagnosed COVID-19.Clinical features at presentation: 5/5 fever (range 37.4 to 38.5 C), 4/5 neurological signs (drowsiness/hypotonia/abnormal “moaning” cry), 4/5 mottled skin, 4/5 runny nose, 4/5 cough, 0/5 dyspnoea, 5/5 normal SpO2, 0/5 digestive symptoms.

Investigations: FBC, CRP & procalcitonin largely unremarkable, with the exception of lymphopaenia in 2/5. Lumbar punctures in 4/5 babies with abnormal neurology reported normal (including negative for RT-PCR SARS-CoV-2). Chest X-rays performed in 4/5 essentially normal.

Outcomes: All 5 showed rapid clinical improvement and received no drugs other than paracetamol. Inpatient stays ranged from 1 to 3 days and duration of fever ranged from 1 to 5 days (max 39C). The infants were followed up for 2 weeks post-discharge with a daily phone call from a paediatrician using a standardised questionnaire.

Conclusion: This encouraging report of a small cohort of SARS-CoV-2 positive infants under the age of 3 months presenting Atypical presentation of COVID-19 in young infantswith fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.

Piccolo, VBassi, AJournal of the European Academy of Dermatology and VenereologyChillblain-like lesions during COVID-19 pandemic: a preliminary study on 63 patients24 Apr 2020ItalyEurope63Clinical - Clinical Featureshttps://doi.org/10.1111/jdv.16526

This is a report of chilblain like lesions observed during the COVID-19 pandemic, collected through a survey issued to Italian dermatologists and Paediatricians. This is a preliminary report as data collection still ongoing.

Importantly – very few patients in this cohort were tested for COVID-19 (11/63) and only 2 of these patients were positive. It is therefore difficult to extrapolate these findings to paediatric COVID-19 specifically, but is worth being aware of.

63 patients have been reported on with a median age of 14 years (IQR 12 – 16yrs) with feet alone being bar far the most commonly affected area (85/7%) followed by feet and hands together (7%). In uploaded pictures from 54 patients, erythematous-oedematous lesions were most common (31/54) followed by blistering lesions (23/54) and pain and itch were common, although a quarter of lesions were “asymptomatic”. Median time of onset of rash to diagnosis was 10 days. The lesions were generally stable and no other cutaneous signs observed. GI symptoms were the most common co-existing (11.1%) with surprisingly low levels of respiratory symptoms (7.9%).

This is basically a description of a common skin manifestation which coincided with COVID-19, and looked like it could be infectious in origin. Few patients tested, and even fewer positive. An interesting series worth bearing in mind given increasing reports of skin manifestation of COVID-19.

Racalcati, SFantini, FJ Eur Acad Dermatol VenereolAcral cutaneous lesions in the time of COVID-1924 Apr 2020ItalyEurope11Clinical - Clinical Featureshttps://doi.org/10.1111/JDV.16533

This pre-print Letter to the Editor reports on a series of unusual dermatological manifestations presenting to the Dermatologic Unit in Alessandro Manzoni Hospital, Italy in March and April 2020. The authors observed 14 cases, of which 11 were children with a mean age of 14.4 years and a range of 13-18 years. Of the 14 cases, 6 (43%) were male. 3 pairs of cases were siblings.

None of the cases had systemic symptoms (other than mild itch in 3 cases), there was no association with cold exposure, co-morbidities or drug intake, and there was no family history of COVID-19 related symptoms. 3 cases reported cough and fever 3 weeks prior to the onset of the lesions.

The authors believe that these dermatological findings are related to COVID-19 due to the rapid outbreak and clustering of these unusual skin lesions occurring at the same time as the COVID-19 outbreak. In support of this they report multiple similar cases being described from other areas affected by the pandemic. They hypothesise that the skin lesions may represent late manifestations of COVID-19 infection in young, healthy subjects, possibly due to an immunologic response targeting the cutaneous vessels. They accept that this hypothesis cannot be tested until a reliable serological test for antibody response to COVID-19 has been developed.

Clinical features: Acral eruption of erythemato-violaceous papules and macules, with possible bullous evolution or digital swelling. Lesions were found on the feet in 8 cases, hands in 4 cases, and on both sites in 2 cases. 2 children developed erythemato-papular targetoid lesions on the hands and elbows after a few days.

Histology: Lesions on fingers showed diffuse dense lymphoid infiltrate of the superficial and deep dermis, with a prevalent perivascular pattern and signs of endothelial activation. Targetoid lesions on elbows showed mild superficial perivascular dermatitis.

Bloods: Normal FBC, CRP, LDH and D-dimer. Serology was negative for EBV, CMV, Coxsackie and Parvovirus B19.

Outcomes: In all cases the lesions resolved without treatment after 2-4 weeks. It is worth noting that this study is limited both by the small number of cases, but more particularly by the lack of evidence linking these skin lesions with a proven COVID-19 infection.Piccolo et al (Clinical)

Landa, NAguirre, TInternational Journal of DermatologyChillblain-like lesions on feet and hands during the COVID-19 pandemic24 Apr 2020SpainEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ijd.14937
Wu, PNie, SGraefes Arch Clin Exp OphthalmolA child confirmed COVID-19 with only symptoms of conjunctivitis and eyelid dermatitis24 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00417-020-04708-6
Zhang, BZhang SJ InfectPositive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19)23 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30233-4/fulltext

In this case series from Dongguan, China, three normally fit & well children aged 14y, 13y and 10m were followed up after positive throat swab for SARS-CoV-2. All three had a subsequent negative throat swab within approximately 7 days, and fully recovered, however 7-9 days later all three had rectal swabs which were positive. These findings raise the question of whether apparently well COVID-19 patients continue to carry and possibly shed the virus. If this was found to be the case in larger and more comprehensive studies, there may be an argument for introduction of strategies to increase avoidance of transmission via the faecal-oral route.

Huang, LZhou, JClin ImagInitial CT imaging characters of an imported family cluster of COVID-1923 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175903/#!po=31.2500
Kan, MJGreenhow, TLJ Ped Inf Dis SocFever without a source in a young infant due to SARS-CoV-222 Apr 2020United States North America1Clinical - Clinical Featureshttps://doi.org/10.1093/jpids/piaa044
Carrabba, GLocatelli, MLancetNeurosurgery in an infant with COVID-1922 Apr 2020Italy Europe1Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30927-2/fulltext
Genovese, GMarzano, AVPediatr DermatolVaricella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?21 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14201

This single case report describes an 8 year old girl presenting on a hospital in Milan, Lombardy region, Italy, on 21 March 2020 with a painless, non-pruritic papulovesicular rash on the trunk developing 3 days after onset of a mild cough. The rash was predominantly papular with some vesicles with crusting, similar in appearance to chickenpox. Limbs, face, genitalia and mucous membranes were spared. She developed a mild fever 5 days after the onset of the rash, and tested positive for SARS-CoV-2. She had bloods including FBC, renal function, liver function and CRP, all of which were normal with the exception of a mild thrombocytopenia with platelets of 105 x 109/L, which subsequently normalised. The rash lasted 7 days, by which time systemic symptoms had resolved. The young girl had a history of varicella infection a year previously.

The authors quote other case reports of cutaneous manifestations associated with COVID-19: petechial rash, widespread urticaria and varicella-like rash predominantly involving the trunk. Although unable to confirm that the rash was definitely associated with COVID-19, they feel it is likely given the child’s previous history of varicella infection and lack of pruritis to suggest the lesions were insect bites. They suggest papulovesicular eruptions be included in the spectrum of exanthems possibly associated with COVID-19.

Li, HXu, QJ Infect The Profile of Peripheral Blood Lymphocyte Subsets and Serum Cytokines in Children With 2019 Novel Coronavirus Pneumonia20 Apr 2020China Asia40Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0163445320302073?via%3Dihub

This was a retrospective observational study, studying lymphocyte subsets and serum cytokines of 40 children admitted with 2019-nCoV pneumonia to Wuhan Children’s Hospital between 24 January and 22 February 2020. These were compared against the lymphocyte subsets and serum cytokines of 16 children admitted with RSV pneumonia to the same hospital between 10 December 2019 and 22 February 2020. Study authors report they could not compare 2019-nCoV pneumonia to healthy controls, as the city was in lockdown.

It is not described how these patients were selected from all patients admitted with 2019-nCoV pneumonia, and RSV pneumonia, and what proportion the included patients were of the total admitted patients with these conditions.

There were 40 children with 2019-nCoV pneumonia, diagnosed by real time PCR. The mean age was 5.07 years (4.71 SD). 23 were male, with 17 females. All 40 children had a CT performed, 16 had unilateral changes, 26 had bilateral changes, and 1 had no changes. Severity was classed as needing ICU admission, only 1 out of 40 was classed as “severe”.

There were 16 children with RSV pneumonia included with mean age of 1.36 years (0.85 SD). 10 were male, 6 were female. All had CT chest, with 3 unilateral changes, 12 bilateral changes, and 1 with no changes. 2 out of 16 required were classified as severe and needed ICU admission.

Lymphocyte subsets were drawn within first 3 days of admission. Those treated with glucocorticoids (3 2019-nCoV and 4 with RSV pneumonia) had them taken before steroids were administered. They compared mean and % between patient groups. Mean CD3+ CD8+ are higher in 2019-nCoV patients; mean 933N/µL(SD 421) than RSV patients mean 675 N/µL (SD 426) (p = 0.044), CD3+ CD8+ % were also significantly higher in 2019-nCoV pneumonia patients. IL10 levels were significantly lower in children with 2019-nCoV pneumonia, though exact figures were not given. The child with severe 2019-nCoV had serial lymphocyte subsets. The authors concluded that immune responses could play a significant role in the disease and influence the severity of response.

The limitations of the study discussed were the small numbers, the very few patients with severe illness and the lack of a normal control. The authors did not comment on the significant age differences between the groups, and how these patients were selected.

Richardson, SDavidson, KJAMA networkPresenting Characteristics, Comorbidities and Outcomes among 5700 patients hospitalized with COVID-19 in the New York City area20 Apr 2020USANorth America34Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2765184

This is a paper from New York, USA, looking at the presenting characteristics, comorbidities, and outcomes of 5700 patients who were hospitalized with Covid-19. These were patients who were admitted to one of 12 Northwell Health acute care hospitals between 01/03/2020 and 04/04/2020. Clinical outcomes were monitored until 04/04/2020. All patients who were sufficiently medically ill to require hospital admission with confirmed severe acute respiratory syndrome coronavirus 2 infection by positive result on PCR testing of an NPA were included. The median age of patients was 63 years (IQR 52-75), 39.7% were female.

At presentations, 30.7% of patients had a temperature of over 380C. 20% had oxygen saturations of less than 90%. 43.1% of patients were considered tachycardic with a heart rate of over 100.

The majority of patients white cell count and differentials were within normal range. The mean white blood cell count was 7 (IQR 5.2-9.5). Neutrophil count 5.3 (IQR 3.7-7.7), however some patients were mildly lymphopenic, median 0.88 (IQR 0.6-1.2). Most patients had a low CRP, the mean result was 16 (IQR 6.4-26.9). Most patients had a raised ferritin, the mean result was 798 (IQR 411-1515), with 15-400 being considered normal range. Of note lactate dehydrogenase was tested in 70% of the patients and was significantly raised in most patients, the mean being 404 (IQR 300-551) with the normal considered to be 50-242.

A venous lactate was recorded in 44% of patients and all results were normal- <2. The most common comorbidities were hypertension (56.6%), obesity (41.7%) and diabetes (33.8%).

At the study end point 2634 patients had been discharged or had died during hospitalisation. Of these 14.2% were treated in ICU, 12.2% of them received mechanical ventilation, and 21% of these patients died. At the end point of the study of those patients who had received mechanical ventilation 3.3% were discharged alive, 24.5% died, 72.2% were still in hospital. There were no deaths in the under 18 age group (34 patients).

Of the patients who died, those with diabetes were more likely to have received mechanical ventilation or care in the ICU compared to those who did not have diabetes. Interestingly of those who died, those with hypertension were less likely to have received invasive mechanical ventilation than those without hypertension.

As most patients were still in the hospital at the endo point of the study (53.8%) this biases rates toward including patients who died early in their hospital course. The researchers point out that as these patients complete their hospital course, reported mortality rates will decline.

This study was slightly limited by the fact that the data was collected from the electronic heath record database and not the medical notes, from which a greater level of detail may have been established, however it was using this method that allowed for such a large number of patients to have been included and reviewed over a relatively short space of time. It is also limited by the fact that the study population only included patients from within the New York metropolitan area which may underrepresent some ethnic minorities.

Li, HXu, JJournal of Medical VirologyPositive result of SARS-CoV-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu, China20 Apr 2020ChinaAsia0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25905
Du, AZhang, ZInfectionClinical characteristics of COVID-19 in children compared with adults in Shandong Province, China16 Apr 2020ChinaAsia14Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs15010-020-01427-2
Xing, YXing, QJ InfecDynamics of faecal SARS-CoV-2 in infected children during the convalescent phase16 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30177-8/fulltext
Jiang, SYu, XClin Chem Lab MedCoinfection of SARS-CoV-2 and multiple respiratory pathogens in children16 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://www.degruyter.com/view/journals/cclm/ahead-of-print/article-10.1515-cclm-2020-0434/article-10.1515-cclm-2020-0434.xml
See, K CIbrahim Hinternational journal of infectious diseasesCOVID-19: Four paediatric cases in Malaysia15 Apr 2020malaysia Asia4Clinical - Clinical Featureshttps://www.ijidonline.com/article/S1201-9712(20)30181-8/fulltext
Shi, BXu, HClin PediatrSevere pneumonia due to SARS-CoV-2 and respiratory syncytial virus infection: a case report15 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820920016?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&#articleCitationDownloadContainer
Chen, JHuang, AGenes Dis.The clinical and immunological features of pediatric COVID-19 patients in China14 Apr 2020ChinaAsia12Clinical - Clinical Featureshttps://reader.elsevier.com/reader/sd/pii/S2352304220300507?token=631DD2FAEE11F02D80D1CC96D2AB2621AA7960348DA5FFDD2FAB802D188A0726E724273D5014403A376291F4BD637C50

This early study from Chongqing, China describes the features of 12 children diagnosed with COVID-19. All had a mild course of illness. CT imaging was abnormal in 10 of 12 with patchy ground glass opacity the most common finding. Lymphopenia was present in 2 children.

The authors also compare the "immune profile" (including lymphocyte counts, immunoglobulins, complement, CRP and IL6 levels) of the 12 children with a group of 20 adults patients. Aside from a lower CRP in children (mean 11.5 vs 23.3mg/L) and expected age-related differences in absolute lymphocyte numbers, there were no significant differences between the groups.

liu, J.Lu, B.JMVDetection of SARS‐CoV‐2 by RT‐PCR in anal from patients who have recovered from coronavirus disease 201914 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25875
Shen, LLan, JJournal of InfectionClinical and laboratory-derived parameters of 199 hospitalized patients with coronavirus disease 2019 in Xiangyang, Hubei Province, China10 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.038
Wang, H.Lu, XiaoxiaPediatric Infectious Disease JournalRehospiatlization of a recovered coronavirus disease 19 (COVID-19) child with positive nucleic acid detection09 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/onlinefirst/Rehospitalization_of_a_Recovered_Coronavirus.96214.aspx
Lazerrini, MTrobia, GLancet Child and Adolescent HealthDelayed access of provision of care in Italy resulting from fear of COVID-1909 Apr 2020ItalyEurope12Clinical - Clinical Featureshttps://doi.org/10.1016/S2352-4642(20)30108-5

This is a report of case studies during the COVID-19 pandemic in Italy of children whose presentations were thought to have been delayed due to parental fears of coming to the hospital. They report from 5 hospitals between March 1st and March 27th 2020, where paediatric presentations were reduced between 73–88%.

During this period, in the week of March 23rd to 27th 12 children are identified whose parents reported avoiding accessing hospital due to concerns over SARS-CoV-2 infection . 6 of these were admitted to PICU and there were 4 deaths. The cases include 2 children with DKA, 2 with acute leukaemia, 2 children with cerebral palsy and complex needs, 1 with pneumonia and febrile convulsions, 1 with pyelonephritis, 1 with pyloric stenosis, 1 with a Wilm’s tumour, 1 with vomiting and hypoglycaemia and 1 with a congenital syndrome on dialysis.

This case series highlights the concerns of many paediatricians that more deaths will be seen in children from collateral damage born from the COVID-19 response, than will die of COVID-19. Delayed presentations is a major concern around the world currently, and whilst these cases certainly raise concerns, evidence is needed to ascertain the true presence and extent of this problem.

Zhu, CZhu, LPediatric PulmonologyClinical characteristics of a case series of children with coronavirus disease 201908 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24767

This is a case series of ten paediatrics patients aged 1 – 17 years with confirmed Covid 19. These cases were retrospectively selected from 3 hospitals in Jiangsu, a coastal province approx 700 km east of Wuhan. Cases were collect from 24th January 2020 to 22nd February 2020. All cases were confirmed by RT-PCR anal or throat swabs. 70% of children presented with symptoms, and 30% were asymptomatic, but were screened due to contact with confirmed family member.

The most common symptoms on presentation were fever (40%), cough, (20%) and headache (20%). There was no report of whether children had underlying conditions. All children had a CT chest completed. Half of the cohort had CT changes. There were 2 cases of bilateral pneumonia, and 3 cases of unilateral pneumonia, 2 of which were in asymptomatic patients. Bloods were unremarkable, one child aged 1 year had Lymphocytosis, all others had normal lymphocyte counts. CRP was not raised in any child. Only one patient in the cohort required oxygen, and there were no ICU admissions. Five children were treated with antiviral medication including lopinavir/ritonavir (n=4) interferon α‐2b (n = 4), and oseltamivir (n = 1).

Of note, 5 children were still in hospital at the end of the case series.

Yuan, JLiu, LClinical Infectious DiseasesPCR assays turned positive in 25 discharged COVID-19 patients08 Apr 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa398
Shen, QZhou, ZPediatric PulmonologyNovel coronavirus infection in children outside of Wuhan, China07 Apr 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24762

This retrospective study examines the clinical characteristics of children admitted to Public Health centre of Changsha, Hunan, China. There were 9 children admitted during the study period 08/01/2019 and 19/02/2020 who tested positive for COVID-19. All had a confirmed contact case with COVID-19. Median age was 8 years, with a minimum age 1 year and oldest was 12 years. Children were predominantly female (6/9, 66%). There was no information provided about co-morbidities.Clinical features: 2/9 were asymptomatic, 1/9 had cough, 4/9 had fever, 1/9 had sore throat and 2/9 had diarrhoea.

Radiology: 2 patients had chest CT that were described as ground glass opacities. No further information was provided about the indications.

Bloods: 1/9 had lymphocytosis in whom other infectious causes were excluded. 1/9 had raised CRP, 4/9 raised ESR, 1/9 raised LDH, 2/9 had raised AST with 0/9 ALT abnormalities. All abnormalities were mild.

Treatments: All (9/9) children were treated10/2.5 mg/kg lopinavir/ritonavir twice daily, orally. 5/9 children received 10 mg/kg azithromycin once a day. One child received meprednisone and immune globulin therapy for febrile convulsion. No additional information regarding treatments were provided.All children required oxygen therapy. None required intensive care or mechanical ventilation.Outcomes: At the end of data collection 3/9 remained under hospital care and were positive for COVID-19. The remainder (6/9) were discharged from hospital. The time spent in hospital varied between 11 and 22 days (median 13.5 IQR 10.75-14 days).

Other salient features: 6/9 children were RT-PCR negative at discharge. The time between initial contact and a negative test varied between 9 and 20 days (median 13.5 IQR 10.75-14 days).

All averages were calculated by the reviewer from the data provided within the article.

Lei, PJiao, JJournal of X-ray Science and TechnologyClinical and computed tomographic (CT) images characteristics in the patients with COVID-19 infection: what should radiologists need to know?07 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://content.iospress.com/articles/journal-of-x-ray-science-and-technology/xst200670
Han, YFang, YJournal of Medical VirologyA comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults06 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1002/jmv.25835

This retrospective study compares the clinical characteristics of 25 adults and 7 children with acute respiratory disease confirmed as COVID-19. Cases were retrospectively identified from patients admitted to Xian Eighth Hospital in Shaanxi, China, between 31st January and 16th February 2020. The mean age of the children was 1.3 years with a range of 2 months to 13 years, and 4 (57%) were male. None had any co-morbidities.

Clinical features: 5/7 (71%) children had cough, 3/7 (43%) had shortness of breath, 5/7 (71%) had fever, 1/7 (14%) had sore throat and 4/7 (57%) had diarrhoea and/or vomiting.

Radiology: 5/7 (71%) children had “positive findings suggestive of pneumonia” reported on CXR and/or CT. Examples of these findings were ground glass opacities and segmental consolidation in bilateral lung fields, particularly peripherally.

Bloods: No children had a low lymphocyte count (<0.8). Raised lymphocyte counts were not mentioned but raised WCC was reported in 2/7 (29%) children. 2/7 (29%) had a raised CRP (>10). 4/7 (57%) had a raised AST (>50) or ALT (>37). 5/7 (71%) had increased Brain Natriuretic Peptide (>125). 4/7 (57%) had a raised CK Isoenzyme (>30).

Outcomes: All 7 cases in children were classified as mild and recovered within 1-2 weeks. None of the children were admitted to intensive care and none died.Comparison of clinical characteristics in adults and children: Children were more likely than adults to have diarrhoea and/or vomiting (57% vs. 8%, p=0.012). Adults more frequently had a reduced WCC, compared to a raised WCC in children, and raised CK isoenzyme was less common in adults.

Graselli, GPasenti, AJAMABaseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy06 Apr 2020ItalyEurope4Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2764365

This is a retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the regional ICU coordinator of the Lombardy ICU Network, and treated at one of the ICUs of the 72 hospitals in the network. Patients were recruited between 20/02/2020 and 18/03/2020 with follow-up on 25/03/2020. Data was collected via telephone. Of the nearly 1600 patients referred for ICU admission, only 4 were between 0 and 20 years of age, with a median age of 16 and interquartile range of 14 to 19 years of age. Three of the four patients (75%) were male and three of the four had comorbidities (specific details not given).

Two required mechanical ventilation. It’s important to note that the patients in this study were those admitted to ICU and not patients on medical wards, in the ED or in the community so the high percentage of ventilated patients in this study is not a reflection of the other patients in the region with SARS-CoV-2. These two patients had relatively low oxygen requirements with an FiO2 of 30% and 50%; relatively low PEEPs of 5 and 14 mmHg; and favourable PaO2/FiO2 ratios of 195 and 323, placing these two patients in the mild to moderate ARDS severity scores (for more information on PaO2/FiO2 ratios have a look at the LITFL explanation at https://litfl. com/pao2-fio2-ratio/). None of the four patients in the 0-20 year old category received ECMO. Information on disposition was only available for two of the four patients. None of these patients died. Two remained on ICU on 25/03/2020 at time of follow-up.What can we take from this study? As the study recruited patients admitted to ICU, the numbers of adolescent patients in this case series is low at only four, with an age range of 16 to 19. The data was collected retrospectively via telephone making it difficult to draw robust conclusions. However, we can see that compared to the older groups of patients in the study, ventilation requirements were lower. Three of the four adolescent patients had comorbidities, which might suggest that children and adolescents without comorbidities in the Lombardy region were less severely unwell and did not require ICU admission.

Lai, WLiu, JPediatr RadiolComputed tomography of the lungs in novel corona virus (COVID-19) infection06 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04664-7
Canarutto, DBarera, GPediatric PulmonologyCOVID-19 infection in a paucisymptomatic infant: raising the index of suspicion in epidemic settings06 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24754

This early single case report from Milan, Italy describes an infant with mild a mild case of COVID-19 who recovered without need for intervention. His father, the implied household index, had an upper airway infection with conjunctivitis without confirmatory testing.

Patient: 32 day old boy, presented to hospital symptomatic

Clinical Features: Cough, fever, rhinitis

Radiology: CXR normal

Bloods: reactive lymphocytes on film, monocytosis (1400/L) and neutrpenia (900/uL), CRP normal

Outcomes: Resolution of fever by day 3 of hospitalisation, full recovery without need for supportive therapy. Breast feeding maintained.

Lin, LShan, HGutGastrointestinal symptoms of 95 cases with SARS-CoV-2 infection02 Apr 2020ChinaAsia5Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/04/02/gutjnl-2020-321013
Xing, YXing, QJournal of Microbiology, Immunology and Infection.Prolonged viral shedding in feces of pediatric patients with coronavirus disease 201928 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://dx.doi.org/10.1016%2Fj.jmii.2020.03.021
Yin XLi HRadiology of Infectious Diseases A mild type of childhood COVID-19 - a case report27 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jrid.2020.03.004
Qui, HLancet: Infectious DiseasesClinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study25 Mar 2020ChinaAsia36Clinical - Clinical Featureshttps://doi.org/10.1016/S1473-3099(20)30198-5

Qui and colleagues retrospectively identified 36 children with an EMR diagnosis of COVID-19, during the period Jan 17 through March 1st, at three hospitals in Zhejiang, China, a province 900km to the east of Wuhan. Diagnosis was made by COVID-19 RT PCR for all patients presenting with fever, cough and radiographic presentation, or if there was a history of exposure to an infected individual.

For the mild cohort, 28% of patients were asymptomatic, with moderate cases more likely to have fever of 38oC or higher (47%), cough (24%), vomiting or diarrhoea (10%) or headache (10%). More than half (53%) of patients had ground-glass opacities on CT scan, meeting the case definition for Moderate illness. Key laboratory values of note include lymphopaenia, leukocytopaenia and increased procalcitonin as all associated with moderate illness. No patients in this cohort were hypoxaemic as a result of their pneumonia.

The authors also draw comparisons between adults and children with COVID-19 (less severe illness, less likely to have abnormal investigations), as well as comparing the clinical features and severity of COVID-19 with SARS (milder symptoms and severity) and H1N1 influenza (fewer symptoms, more frequent pneumonia) in children. Wisely, Qui & colleagues note the high rate of findings that are not clinically obvious, and the high proportion of asymptomatic cases make for very challenging case identification in the absence of clear epidemiologic information. “This finding suggests a dangerous situation if community-acquired infections occur.”

Su, LGai, ZEmerging Microbes and InfectionsThe different clinical characteristics of corona virus disease cases between children and their families in China - the character of children with COVID-1925 Mar 2020Asia9Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/22221751.2020.1744483

This study from the Jinan Infectious Disease Hospital retrospectively reviewed cases of nucleic acid-positive SARS-CoV-2 patients between 24th January to 24th February 2020 (detected using the (ORF1ab/N) nucleic acid detection kit by Bio-germ, Shanghai, China). Nine children and members of their family totalling 14 adults were included. Note that two family members missed enrollment as they were at another hospital. Of the 9 children, 6 were female (66%). The age group ranged from 11 months to 9 years and 9 months old (mean age 4.5 years). For eight of the nine children, there was history of their parents having travelled frequently, being in contact with someone from Wuhan or having worked or visited Wuhan. Of note, five of the discharged children were readmitted to hospital because their stool showed positive results in SARS-CoV-2 PCR.

Clinical Features (children): 3 of the 9 children had fever (33%) and one had cough (11.2%). Imaging (children): On chest x-ray and CT, two children had findings consistent with bronchitis (22.2%), one had bronchial pneumonia (11.1%) and a further one had pulmonary consolidation and ground glass opacity. From the two example images included,, findings appear to be bilateral but this was not specified in the body of the text. Bloods (children): 8 of 9 children (88.9%) had normal or decreased white blood cell counts. Six children (66.7%) had increased CK-MB. ALT, AST. All children had a normal CRP, PCT, ESR and IL-6. Clinical Features (adults): Of the 14 adults, 8 (57.1%) had fever, five had cough (35.7%), three had chest tightness or pain (21.4%), a further three had fatigue (21.4%) and one reported a sore throat (7.1%). Imaging (adults): Ten (71.4%) had abnormal imaging mainly pulmonary consolidation, with 7 (50%) having nodular shadow and 7 (50%) having ground glass opacities. Bloods (adults): Four (28.6%) had reduced whice cell count with seven (50%) having lymphocytopaenia.

Zheng, FJin, RCurrent Medical ScienceClinical characteristics of children with coronavirus disease 2019 in Hubei, China24 Mar 2020ChinaAsia25Clinical - Clinical Featureshttps://doi.org/10.1007/s11596-020-2172-6

This is a retrospective case series of 25 children <14 years of age hospitalised with COVID-19 from 10 hospitals across the Hubei province between February 1st and February 10th 2020. It is unclear how the cases were ascertained. 14/25 were male (54%) and the median age was 3yrs (IQR 2-9yrs). Most patients were <3 years (40%). 2 patients had a background of repaired congenital heart disease (both infants), although we have no more detail than this. Both of these children went on to develop critical illness.Clinical features: 13/25 (52%) had fever, 11/25 (44%) had cough, 3/25 (12%) had diarrhoea, and 2/25 (8%) had nasal congestion, vomiting, breathlessness or abdominal pain.

Bloods: Inflammatory markers were not particularly raised, with a median CRP of 14.5mg/L (IQR 0.93 - 25). 10/25 (40%) patients had lymphopenia.

Radiology: CT chest was normal in 8/24 (32%) with unilateral involvement in 5/24 (20%) and bilateral in 12/24 (48%). Changes typically showed patchy shadows. Younger children appeared more likely to have bilateral lung findings than older children.

Co-infection: Other organisms identified included Mycoplasma pneumoniae (3/25, 12%), Influenza B (2/25, 8%) and one of the 2 critically ill children had Enterobacter aerogenes.

Lou, XTian, YJournal of Paediatrics and Child HealthThree children who recovered from novel coronavirus 2019 pneumonia22 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://doi.org/10.1111/jpc.14871

This is a case series of 3 children diagnosed with COVID-19 and admitted in the Zhengzhou University Children’s hospital in Henan Province, China (dates not provided). They were 2 sisters aged 6 and 8yrs, and a 6m old infant. The children were all infected by a family member, although the family of the 6m infant had no link to Wuhan.

Clinical features: All 3 had a fever, 2 had nasal congestion and rhinitis alongside fatigue, diarrhoea, and headache. The 6yr old girl had a cough.

Radiology: All 3 patients had CT scans with bilateral infiltrates

Bloods: Not reported

Outcomes: No children required intensive care/intubation or had any severe complications. All have been discharged. The 2 sisters were treated with nebulized interferon.

Liu HLan WJournal of InfectionClinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children21 Mar 2020ChinaAsia4Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.007

This study is a review of CT imaging findings in children and pregnant women in a hospital in the Hubei Province. Four children with confirmed COVID-19 infection were included in the study. The bottom line is that pulmonary CT changes in children were mild, with either focal ground glass opacification or focal consolidation. Although CT has been reported as a useful screening tool in adults with suspected COVID-19 infection, the CT changes of the four children were non-specific; the authors conclude that exposure history and clinical symptoms are more helpful for screening in swab-negative children than CT. 41 pregnant women with either laboratory-confirmed or clinically-diagnosed COVID-19 infection were included in the study. All pregnant women had mild courses of their COVID-19 illnesses. Six of the 16 laboratory-confirmed pregnant women and 10 of the 25 clinically diagnosed pregnant women delivered during the study period. There were no cases of vertically transmitted COVID-19 in the neonates born to these pregnant women.

Case 1: 5 year old female with fever, cough and fatigue. No lymphadenopathy. Bloods: low WCC with raised lymphocytes and decreased neutrophil ratio. Normal CRP. CT: normal. Follow-up CT 9 days later remained normal.

Case 2: 11 month old male with fever and cough. No lymphadenopathy Bloods: normal WCC with raised lymphocyte count and decreased neutrophil ratio. Normal CRP. CT chest: single consolidation without peripheral predominance (unlike reported findings in adults).

Case 3: 9 year old female with fever but no cough. No lymphadenopathy. Bloods: normal WCC, low lymphocytes and normal neutrophil ratio. Normal CRP. CT chest: single ground glass opacity without peripheral predominance (unlike reported findings in adults).

Case 4: 2 month old male with cough but no fever. No lymphadenopathy. This infant was coinfected with RSV. Bloods: normal WCC with normal lymphocytes and normal neutrophil ratio. CRP raised (does not say how high). CT chest: multiple focal consolidations and pleural effusion. This infant’s CT findings were more severe than the other three children, thought to be due to coinfection with RSV.

Lu, XWong, GWKNEJMSARS-CoV-2 infection in children18 Mar 2020ChinaAsia171Clinical - Clinical Featureshttps://www.nejm.org/doi/full/10.1056/NEJMc2005073

This retrospective study examines the clinical characteristics of children with confirmed COVID-19 diagnosed at Wuhan Children’s hospital. There were 1391 children tested between Jan 28th and Feb 26th 2020 due to known contact with a case of COVID-19, of these 171 were confirmed to have SARSCoV-2. Median age was 6.7yrs, and there was a relatively even spread amongst age groups. Children were predominantly male (104/171, 60.8%).

Clinical features: 83/171 had cough, 79/171 had pharyngeal inflammation (sore throat), 71/171 had fever. 15/171 had diarrhoea and 13/171 had rhinorrhoea. 49/171 were tachypnoeic on admission and 72/171 were tachycardia. Only 4/171 had Oxygen saturations <92% during hospitalisation. 0/31 infants <1yr were asymptomatic in this cohort, with rates of asymptomatic infection increasing with age. There were higher rates of pneumonia in infants (25/6), but the definition of this is unclear. We also have no information regarding co-infection with other viruses or bacteria.

Radiology: Not delineated into CXR or CT, but descriptions sound like CT findings. The most common was bilateral ground glass opacity (56/171) followed by unilateral patchy shadowing (32/171) and bilateral patchy shadowing (21/171). There were several children with radiographic pneumonia who were asymptomatic.

Bloods: The supplementary appendix contains lab results. Only 6/171 patients had lymphopaenia, the vast majority were in normal range (Med 2.9×109/L, IQR 2.2 – 4.4). CRP was elevated (>10mg/L) in 33/171 (Med 4, IQR 1.3 – 8) of which 27/33 had pneumonia.

Outcomes: 3 patients required ITU admission and intubation. All 3 had comorbidities, including hydronephrosis, leukaemia and intussusception. The child with intussusception suffered multiorgan failure and died after 4 weeks. The cause of death is not clear from the report. As of writing 149 patients had been discharged with 21 stable in the general wards.

Cui, YZha, YJournal of Infectious DiseasesA 55-day-old female infant infected with 2019 novel coronavirus disease: presenting with pneumonia, liver injury, and heart damage17 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa113/5807961

This is a case report of a 55 day old with SARS-CoV-2 who was admitted to hospital in China on February 2, 2020. She was treated with inhaled intereron-alpha-1b, amoxicillin, reduced glutathione, ursodeoxycholic acid, and traditional Chinese medicine lotus qingwen. The child was initially well, although her respiratory status worsened on day 2-6, and she required supplemental oxygen via nasal cannulae. Anal swabs on day 11 and 13 were positive on day 11-13 despite negative pharyngeal swabs.Note is made in the title of this study that the infant sustained liver injury and heart damage. This is on the basis of marginally elevated liver tranaminases and cardiac troponin measurements, for which it is unclear why the tests were performed. There is no indication of any clinical compromise demonstrated. It should be noted that a significant proportion of the child’s care (including investigations) would not be considered standard practice in UK/US/Aus paediatric medicine.

Zhang, CZhou, XMedRxIVClinical characteristics of 34 children with coronavirus disease-2019 in the West of China: a multiple-center case series16 Mar 2020ChinaAsia34Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.12.20034686v1

A pre-print, the information should be treated with caution until it has undergone peer review.This is a further retrospective case study looking at 34 children with confirmed COVID-19 between Jan 1st and Feb 25th 2020 in 4 hospitals in Western China. They were aged 1 month to 12 years.

Clinical features: The most common symptom was fever (26/34) followed by cough (20/34), followed by vomiting (4/34) and diarrhoea (4/34). A significant number had co-infections (16/34) including Mycoplasma pneumoniae (9/34), influenza A or B (12/34) and 2/34 were mononucleosis. One child had a nephroblastoma and one had asthma. The median incubation period was 10 days (IQR 7.75 – 25.25) and median 3 days (IQ 2 – 4) from admission to fever resolution

Bloods: Lymphocytosis was most common (17/34). CRP was not significantly elevated (median 7.56ml/L, IQR 1.21 – 15.13), but was >5 for 20/34, and procalcitonin was not significantly elevated either (0.6, 0.03 – 0.07)

Radiography: On chest CT 14/34 had patchy shadows bilaterally, 14/34 unilaterally, and 6 had normal CT chest.

Ji, LJian, RWorld Journal of PediatricsClinical features of pediatric patients with COVID-19: a report of two family cluster cases16 Mar 2020ChinaAsia2Clinical - Clinical Featureshttps://dx.doi.org/10.1007/s12519-020-00356-2

This is a review of two confirmed paediatric cases of COVID-19 (both from oropharyngeal swabs) from two family clusters with recent travel to Wuhan. One child presented with fever and the other with diarrhoea.

Case one: 15-year-old boy presenting with a one-day history of fever. Clinical features: Temperature 37.9oC, pharyngeal congestion. Normal lung auscultation. Laboratory findings: mildly elevated white cell count at 11.82 x109/L, predominantly neutrophils (67.3%) and 25.7% lymphocytes. His CRP was mildly elevated at 35 mg/L. Radiological findings: normal unenhanced CT chest. Outcome: Symptomatic treatment. Symptoms disappeared after two days. Family information: both parents also tested positive for SARSCoV2.

Case two: 9-year-old boy presented with mild diarrhoea but no cough and no fever. Normal examination. Laboratory findings: normal white cell count and normal CRP. Radiological findings: normal unenhanced CT chest. Outcome. Treated with oral probiotic and symptoms disappeared after 2 days. Family information: Family members had negative COVID-19 swabs but were symptomatic. His mother presented with fever and cough with bilateral peripheral ground glass opacifications on CT chest. The child’s father and two-year old sister had normal CT chests but had mild symptoms consistent with COVID-19: his father had a cough for four days and his twoyear-old sister had a transient two-day low-grade fever.

Xu, YGong, SNature MedicineCharacteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding13 Mar 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1038/s41591-020-0817-4

This study presents the results of widespread screening for COVID-19 in Guangzhou in China. 745 children were screened of which 10 were positive for COVID-19. Their ages ranged from 2 months to 15 years.

Clinical features: 6/10 had a fever over 38oC. 5/10 had a cough. 4/10 had a sore throat. 2/10 had rhinorrhoea and 2/10 had diarrhoea.

Radiography: 7/10 had coarse lung markings on CXR with no pneumonia, and 3/10 were normal. CT scans revealed ground glass or patchy opacities in 5/10.Bloods: Basically normal in all cases

They made note that rectal swabs were frequently positive and that these swabs were positive for a longer duration than nasal swabs. The authors suggest on this basis that faecal-oral transmission may be possible, however this is very uncertain and will require further research to elucidate.

Xing, YXing, QmedRxivProlonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase13 March 2020ChinaAsia3Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.11.20033159v1

A pre-print, the information should be treated again with caution until it has undergone peer review.

This study of 3 paediatric patients with COVID-19 from Qingdao, China (aged 1.5, 5 and 6 years) all had fevers and none were severe. All children had elevated lymphocytes (>4.4 x 109/L) and 2 of 3 had abnormalities on chest CT (consolidation in one and ground glass changes in the other). The primary point made in the paper is that whilst respiratory swabs were negative within 2 weeks after children became afebrile, stool remained positive for over 4 weeks.

Liu, WLiu, YNEJMDetection of COVID-19 in children in early January 2020 in Wuhan, China12 Mar 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1056/NEJMc2003717

This letter to the editor describes a case series from Tongji hospital in Wuhan, China, taken from a cohort of 366 hospitalized children between January 7th and 15th 2020. 6 children were PCR Positive for COVID-19. Of the 6 patients, age range 1-7 years. All had fever >39oC, cough and 4/6 had vomiting. All had lymphocytopenia, with 4/6 leukopenia and 3/6 with neutropenia. One child required an ICU admission, receiving pooled donor IVIG. The median recovery time was 7.5 days. Authors surmise COVID-19 occurs in children with some moderate-severe episodes of illness.

Li, WLi, SPediatric RadiologyChest computed tomography in children with COVID-19 respiratory infection11 Mar 2020ChinaAsia5Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04656-7

This study describes five children with confirmed COVID-19 who had CT chest scans in a large tertiary level hospital in China. Three of the five children had patchy ground-glass opacities on their CT scans but these changes were less severe than those seen in infected adults. The treatment is not detailed in the paper, so presented as published in this summary.

Case 1: 17 month old asymptomatic male. Bloods: CRP 9.4, WCC 9.2. Radiology: CT chest performed on day 4 showed patchy ground glass opacities. Repeat CT on day 9 after treatment had normalised (antiviral, anti-infective, immunoglobulin, interferon and Lianhua qingwen granules). No CXR.

Case 2: 10 month old asymptomatic female. Bloods: CRP 0.9, WCC 14.8. Radiology: Day 2 scan: normal. Not repeated. No CXR.

Case 3: 3 year old male with coryza, productive cough, sore throat and fever after 3 days. Bloods: CRP 0.7, WCC 15.0. Radiology: Day 9 CT showed patchy ground-glass opacities. Repeat CT on day 16 had normalised after treatment (antiviral, anti-infective, immunoglobulin). No CXR.

Case 4: 4 year old asymptomatic male. Bloods: CRP 0.2, WCC 6.6. Radiology: Day 2 CT chest showed patchy ground-glass opacities. Repeat CT on day 7 had normalised after treatment (montelukast, immunoglobulin). No CXR.

Case 5: 6 year old asymptomatic male. Bloods: CRP 0.6, WCC 5.3. Radiology:

Day 3 CT was normal. No CXR.

Xu, R.Hu, XQuantit Imag Med and SurgCT imaging of one extended family cluster of corona virus disease 2019 (COVID-19) including adolescent patients and "silent infection" 10 Mar 2020China Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136726/
Bahar, BDelaney, MJ Peds Kinetics of viral clearance and antibody production across age groups in children with severe acute respiratory syndrome coronavirus 2 infection09 Mar 2020United StatesNorth America641Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31114-8/fulltext

This is a retrospective study of SARS-CoV-2 viral clearance and antibody production in children. Children with who were tested with a nasopharyngeal SARS-CoV-2 RT-PCR test from March to June 2020 at Children’s National Hospital Washington, US were included.

Overall, there were 641 positive RT-PCR tests in 592 patients (median of 1 test per patient, max 6 tests) and 5777 negative tests (median of 1 test per patient, max 15 tests). 68 patients had more than 1 RT-PCR test. Of the 238 serological tests done, 69 were positive in a total of 58 patients (median of 1 test per patient).

The median duration of RT-PCR positivity was 19.5 days. Of note, children aged 6-15 years had a longer duration of RT-PCR positivity compared with older children (16-22 years) (median 32 vs 18 days). The median time to achieve positive serology was 18 days, however, to reach sufficient levels of neutralising antibodies was 36 days. IgG class antibodies against the S1 and S2 glycoproteins were detected in blood samples of children prior to viral clearance.

This study provides further insight into the kinetics viral clearance and the antibody response in children infected with SARS-CoV-2. The prolonged period of RT-PCR positivity is consistent with other studies in children and adults. Importantly, it is unknown whether this period of PCR positivity correlates with ongoing shedding of viable virus particles capable of transmission. Unfortunately, this study did not include details of symptoms associated with the laboratory results.

Xia, WHu, DPediatric PulmonologyClinical and CT features in pediatric patients with COVID-19 infection: different points from adults05 Mar 2020ChinaAsia20Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24718

A case series of 20 paediatric patients with COVID-19 infection identified with COVID-19 NAT on pharyngeal swabs from Wuhan Children’s Hospital. It reviews the clinical information and co-infections.

Clinical features: two thirds had a clear contact history. Incubation 24hrs28 days of life. 13/20 had a cough, 12/20 had a fever. Bloods: 11/20 had (N) CRP, i.e. less than 3mg/L and 80% had PCT >0.05.

Radiology: On CT: Subpleural findings were seen in all 20 patients. 50% had bilateral findings, with a further 6/20 with unilateral findings. Consolidation with a halo in 50% of cases, considered as atypical signs in paediatric patien. Chloral hydrate was the primary sedative for CTs These were predominantly mild cases in the paediatric patients, with CXR adding little diagnostically. An early chest CT exam seemed to be necessary. 9/20 had coinfection, most commonly with mycoplasma (4/9) – although the ‘flu B,’flu A or RSV accounted for almost all of the remainder

Despite this, the physical chest symptoms were mild, with retraction in one case, and another case with cyanosis.

The average length of stay 12.9 days. Some patients were managed on the basis of their CT alone. These are similar to those seen in adults.

Lan, L.Xu, H. Korean J Radiol Early CT Findings of Coronavirus Disease 2019 (COVID-19) in Asymptomatic Children: A Single-Center Experience.04 Mar 2020China Asia4Clinical - Clinical Featureshttps://kjronline.org/Synapse/Data/PDFData/0068KJR/kjr-21-919.pdf
Zhu, YFeng, SJournal of Infection Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)03 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.033
Dong YJiang ZPediatrics Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China01 Mar 2020ChinaAsia2143Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/03/16/peds.2020-0702/tab-figures-data?versioned=true

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Kai-qian, KThoon, KCClinical Infectious DiseasesA well infant with coronavirus disease 2019 with high viral load28 Feb 2020SingaporeAsia1Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa201

This was a case report of a single 6-month-old with a positive nasopharyngeal swab until D16 of admission to hospital. There had been household transmission. There was a positive NPA with rt-PCR on D1 of admission although the child was asymptomatic – daily swabs remained positive until D17. The child was febrile once during the course of admission although they remained asymptomatic. Blood and stool tests were positive on D2.

They had essentially normal investigations except for a neutropenia.

Cai, JZeng, MClinical Infectious DIseasesA case series of children with 2019 novel coronavirus infection: clinical and epidemiological features28 Feb 2020ChinaAsia10Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa198/5766430

This retrospective study examines 10 children diagnosed with confirmed COVID-19 between 19th Jan and 3rd February 2020 at the Children’s hospital in Shanghai. The age range is from 3 months to 11 years. None had comorbidities. There were no severe cases.

Clinical features: The assumed incubation period (time from exposure to index case to developing symptoms) was between 2 – 10 days, but median (and mode) 7 days. With regard to symptoms, 7/10 had fever >38oC, 6/10 had a cough, 4/10 had a sore throat, 3/10 had nasal congestion, 2/10 had rhinorrhea and 2/10 were sneezing.

Radiology: The chest x-ray was normal in 6/10. The rest had unilateral opacities.

Bloods: Lymphocyte counts were normal in 9/10, raised in one case. CRP ranged from 0.5mg/L to 35mg/L but was <10 for 7/10. Procalcitonin was normal (<0.25) in all children. 2 patients had a mild elevation of ALT (100U/L) or AST (142U/L and 51U/L) Detection of SARS-CoV-2: Virus was found in NP/throat swabs in all patients, and the duration of shedding ranged from 6-22 days (Median 12 days). Stool shedding was prolonged, over 30 days in one patient. No urine was positive, and no serum positive.

Chen, CWang, FLancet pre-print serverCoronavirus disease-19 among children outside Wuhan, China25 Feb 2020ChinaAsia31Clinical - Clinical Featureshttp://dx.doi.org/10.2139/ssrn.3546071

A pre-print, the information should be treated with caution until it has undergone peer review. This is a prospective case series of 31 paediatric cases of COVID-19 diagnosed at the Shenzen Third Peoples hospital between Jan 16th and Feb 19th 2020. This made up 7.9% of all cases diagnosed in Shenzen. They were all confirmed by PCR. None had been exposed to the seafood market in WUhan. The patients received nebulised interferon and, IV ribavirin or oral lopinovir/ritonavir. The median age was 6.75, with most patients (41.9%) aged 5-9. Followed by 0-4yrs (32.2%) and 10-14yrs (19.4%). 41.9% were male.Clinical features: 12/31 Children were asymptomatic. Fever was observed in 14/31, Cough in 13/41, Sore throat in 2/31, Rhinorrhoea in 22/31 and diarrhoea in 2/31. Median duration of fever was 2 days, with a range of 1–9 days. Bloods: Lymphopaenia was not observed. Lymphocytosis occurred in 17/31 patients. CRP was elevated in 4/31 patients. Radiology: On admission 64.5% of CT were normal, with 25% having unilateral pneumonia and 9.7% having bilateral. During hospitalization one child developed a unilateral pneumonia whose radiography was initially normal. Outcome: 23 children had been discharged at the time of writing, and the remainder were well and afebrile.

Xu, XWLi, LJBMJClinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: a retrospective case series19 Feb 2020ChinaAsia2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pubmed/32075786

This study looks at a group of 62 patients with COVID-19 in a province outside of Wuhan (Hubei). 2 of these were children, aged 10 and 11. There is a lot of clinical data in the paper but it is not broken down by age, so we cannot make any inference on behalf of the paediatric patients.

Wei, MLiu, YJAMANovel coronavirus infection in hospitalized infants under 1 year of age in China14 Feb 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1001/jama.2020.2131

This is a case series of, from Dec 8 2019 to Feb 6 2020, from China of 9 infants – all of whom had been hospitalised.

Clinical presentation: 4/9 fever, 2/9 mild URTI symptoms, 1/9 were asymptomatic. All had family members that were COVID-19 positive. There were no severe complications or ICU admissions.

Parri, NMasi, SPediatrics COVID-19 in 17 Italian Pediatric Emergency Departments09 Jan 2020ItalyEurope170Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/09/21/peds.2020-1235

This is a retrospective review of 170 children with confirmed SARS-CoV-2 who presented to Italian emergency departments between March and May 2020. Children in this cohort had a median age of 45 months and 38 (22%) had a comorbidity. Interestingly, under half (70; 41%) had a family member with confirmed SARS-CoV-2, while 21 (12%) had travelled to areas with documented community transmission. Seven (4%) children were infected from an unknown source.

Similar to other cohort studies, the most common symptoms at presentation were fever (48%), cough (43%), decreased feeding (35%) and rhinorrhoea (20%). Of the 13 children (8%) who required respiratory support, 6 had a pre-existing comorbidity. 17% of children who were SARS-CoV-2 positive were asymptomatic.

A chest X-ray was done in 62 children (36%) and showed unilateral patchy infiltrate with ground-glass changes in 20 (32%) and pneumonia in 14 (32%). Chest CT was done in 3 children and 2 had interstitial abnormalities. Point-of-care lung ultrasound was used in 13 (8%) children as an alternative to other imaging modalities, and as an adjunct in 2 children. Of these, 11 (84%) had sonographic features of interstitial disease and 5 showed an additional consolidation.

Three children in this series met criteria for MIS-C. All were febrile with elevated inflammatory markers and received intravenous immunoglobulin and steroids.

This retrospective cohort study is comparable to other similar studies describing cohorts in China, Europe and the United States. Of note, this series included a larger proportion of children <1 year of age and who had only mild symptoms or were completely asymptomatic, likely explained due to differences in testing criteria between countries. The utility of point-of-care ultrasound was demonstrated for diagnosing more severe disease without exposing children to radiation.

Brisca, GMoscatelli, AActa PaediatrClinical course of COVID‐19 in children with pre‐existing medical conditions21 12 2020ItalyEurope37Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15730

This is a short report of a study (the authors call it a prospective study) of the clinical course of 37 children with pre-existing medical conditions who were diagnosed with COVID-19 after they presented at the children’s hospital in Genoa, Italy. This is a subset of the total 167 children who presented between 21st March and 15th November 2020, the other 130 having no identified pre-existing condition. Data was extracted from their electronic record.

The data is presented in a table in the supplementary information. Generally, the mild course but diverse clinical features of COVID-19 in children was seen.

• 10 of the children had known respiratory disease (9 asthma) but there was a diverse range of other pre-existing conditions

• 13 were admitted to HDU, 16 to a general paediatric ward and 8 did not require admission. None required ICU

• 30(81%) of the children had no respiratory symptoms and only 2 required oxygen support

The authors state that although the risk of severe COVID-19 was low in their cohort, children with pre-existing conditions need to be carefully assessed and monitored. They note that further data is required to define management guidelines for high-risk children.

The children in this study presented over an 8-month period and there is no reference to the fact that knowledge of the course and treatment of COVID-19 in children increased during that period and the authors references are all from the earlier period of the pandemic.

Tsankov, BJacobson, KIntnl J of Inf DisSevere COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis.20 Nov 2020WorldwideInternational285014Clinical - Comorbiditieshttps://www.ijidonline.com/article/S1201-9712(20)32475-9/fulltext

This systematic review and meta-analysis, published on 20th November 2020, of 42 studies (totalling 275,661 children without comorbidities and 9,353 children with comorbidities), investigated the effects of paediatric comorbidities on COVID-19 severity.

Study selection: The authors of this review, who are based in Canada (mainly at BC Children’s Hospital in Vancouver), searched PubMed, Medline and Embase databases for articles published between 1st January and 5th October 2020 about SARS-CoV-2 infection in paediatric patients (defined as under 21 years of age), in accordance with PRISMA recommendations. An initial 13,310 articles were screened: of the remaining 808 assessed for eligibility, 98 articles in English had paediatric study participants with pre-existing comorbidities and COVID-19 for which clear outcomes were reported. After literature grading 86 were analysed, of which only 42 studies had paediatric case-control participants without comorbidities with either severe COVID-19 and/or COVID-19-associated mortality. 5 studies only examined children who died from COVID-19 and were therefore only included in the mortality analysis. Studies were from the USA 18/42 (43%), China 4/42 (10%), Italy 4/42 (10%), Spain 4/42 (10%), France 3/42 (7%), UK 2/42 (5%), Iran 2/42 (5%), Austria 1/42 (2%), Brazil 1/42 (2%), India 1/42 (2%), Turkey 1/42 (2%), Uruguay 1/42 (2%). Extracted data included disease severity, PICU admission and mortality. Severe COVID-19 was defined as any SARS-CoV-2 infection requiring supplemental help to normal breathing and/or PICU admission.

Study patient characteristics: From the 42 articles 285,014 paediatric patients with laboratory-confirmed SARS-CoV-2 infection were identified, of which 9,353 (3.3%) had at least one underlying comorbidity. Data on gender was available for 280,999 patients: 50.7% female, 49.9% male. Age category data was only available in 362 children. The comorbidities break down as follows: chronic respiratory 49%, immune 8.1%, cardiovascular 6.6%, metabolic 5.9%, obesity 5.4%, neurological 2.3%, renal 1.5%, haematological 1%, cancer 0.9%, hepatobiliary 0.8%, allergy 0.5%, GI 0.3%, other 17.4%.

Relative risk of paediatric comorbidities on severe COVID-19: Severe COVID-19 and/or PICU admission in paediatric patients with SARS-CoV-2 infection: with comorbidities 481/9,353 (5.1%) versus without comorbidities 579/275,661 (0.21%). Relative risk of severe COVID-19 and/or PICU admission among children with comorbidities relative to those without: 1.79 (95% CI 1.27–2.51; 𝜒2=602.31 (P < 0.001), I2=94%) (37/42 studies included in this analysis since 5 studies only examined COVID-19-associated deaths). 7 studies had a higher risk ratio of severe COVID-19 among those without comorbidities versus those with. Individual exclusion of each of the 37 studies from the analysis didn’t significantly influence the risk ratio in either direction.

Relative risk of paediatric comorbidities on mortality associated with COVID-19 infection: 19/42 articles reported children who died with COVID-19. Across these 19 articles, only 77/274,647 (0.03%) paediatric patients without comorbidities died across 8 studies versus 134/8,960 (1.5%) with comorbidities across 15 studies. Relative risk of mortality among paediatric patients with comorbidities and COVID-19 relative to those without: 2.81 (95% CI 1.31–6.02; 𝜒2 = 97.85 (P < 0.001); I2 = 82%). In only 5 of the studies did children with comorbidities have a lower risk of mortality during the course of COVID-19. Again, subsequent sensitivity analysis confirmed that no one article significantly affected the relative risk ratio.

Relative risk of obesity on severe COVID-19: Defined as BMI greater than or equal to the 95th percentile for children of the same age and sex. Analysis performed only on the 6 studies including case-control participants. Relative risk of severe COVID-19 in children with obesity relative to children without comorbidities: 2.87 (95% CI 1.16–7.07; 𝜒2 = 7.81 (P = 0.17); I2 = 36%).

Limitations identified by authors: There will be variation in PICU admission criteria across the studies and there may be selection bias of PICU admissions in favour of children with underlying conditions. There is a high degree of study heterogeneity and many studies were of small sample size. The meta-analysis was not able to capture the relative risk that comorbidities other than obesity contribute to severe COVID-19, because of the sub-population heterogeneity of comorbidities, which limits the ability to draw accurate comparisons between the studies. Testing of asymptomatic and pauci-symptomatic children is very limited, so mild cases among children with comorbidities are likely to be underrepresented.

Conclusions: Children with comorbidities have a higher risk of severe COVID-19 and associated mortality than children without underlying disease. Childhood obesity was shown to be associated with a more severe course of disease.

Nepogodiev, DBSJFavourable perioperative outcomes for children with SARS‐CoV‐219 Oct 2020United KingdomInternational88Clinical - Comorbiditieshttps://bjssjournals.onlinelibrary.wiley.com/doi/10.1002/bjs.12038

To better understand the surgical risks for children with confirmed SARS-CoV-2, CovidSurg, a multicentre, observational, international cohort study summarised observations of paediatric SARSCoV-2 surgical patients whose diagnosis had been made from 7 days before to 30 days after surgery and in whom surgery was carried out between 1st January and April 30, 2020. On the ground surgical interventions for children were commonly being delayed or cancelled during the foregone Covid-19 pandemic wave due to concerns for risk of nosocomial SARS-CoV-2 infections, concern for perioperative complications and constrained resources for routine surgery. The authors concerns expanded to include health complications when children’s surgical treatments were delayed or cancelled.

Fifty-two hospitals in 21 countries participated. Assessed were 5,388 patients, of whom 88 were children were under 16 years of age, 56 (63.6%). Diagnosis of SARS-CoV-2 was preoperative was in 48(56%) of the children.The majority (89%) of the children required emergency surgery. The distribution of the disease conditions included benign conditions (81%), trauma (11%) and cancer (8%). There was one death (1/88) in the 30 day post-operative period, low compared to confirmed SARSCoV-2 adult post-operative mortality of 23.8% referred to in this research letter. Pulmonary complications (pneumonia/acute respiratory syndrome or unexpected post-operative ventilation problem) occurred in 12 of the 88 (13.6%) children, also considered low compared to adult pulmonary complications of 51.2% in confirmed SARS-CoV-2 post-operative adults reported in the research letter.

This research letter informs but it probably only begins asking the question whether less restrictive surgical rationing policies should be considered for children. The authors’ call for further studies toward answering the question raised is supported. Due to the likelihood of the influence of age and other likely confounders in the adult perioperative SARS-CoV-2 confirmed patients referred to by the authors in the research letter, observation of matched cohorts of perioperative paediatric surgical patients with confirmed SARS-CoV-2 and those without may be a further worthwhile scenario to explore

Kabesch Msingle authorPed Allergy ImmunologyShielding against SARS‐Cov‐2 infection is not justified in children with severe asthma05 Aug 2020EuropeEurope0Clinical - Comorbiditieshttps://doi.org/10.1111/pai.13327

In the UK, severe asthma was one of the diagnoses which mandated ‘shielding’, i.e. remaining at home at all times, during the lockdown, for children and adults. Some doubted whether this was necessary. This brief report suggests that the doubters were right. Using a database which was originally designed to monitor the use of biologic treatments in severe asthma, the author surveyed 37 major asthma centres in 25 European countries. None of the centres were aware of any symptomatic COVID-19 case from March-July 2020 in any of the roughly 1000 children included.

So was this because shielding prevented it? No, because they compared the 4 countries with strict shielding policies (including the UK) with the others where precautions for asthmatics were the same as everyone else. There was no difference.They conclude that shielding is unnecessary, even in the most severe asthmatics.

Wilkes, MRapaport RJ of PediatricsSevere COVID-19 in Children and Young Adults.23 Jun 2020USANorth America10Clinical - Comorbiditieshttps://www.jpeds.com/article/S0022-3476(20)30764-2/pdf
Kulkarni, RKJadhav, TIndian Journal of PaediatricsFatal Covid-19 in a Malnourished Child with Megaloblastic Anemia17 Jun 2020IndiaAsia1Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297666/
Yuksel, MAriKan, CEur J Gastroenterol HepatolImmune monitoring of a child with autoimmune hepatitis and type 1 diabetes during COVID-19 infection16 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://journals.lww.com/eurojgh/Abstract/9000/Immune_monitoring_of_a_child_with_autoimmune.97545.aspx
Akcabelen, Y. M.Yarali, N.Pediatr Blood Cancer: e28443.COVID‐19 in a child with severe aplastic anemia15 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28443?af=R
Cesaro, S.Petris, MGPaediatr Blood CancerScreening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy15 Jun 2020ItalyEurope282Clinical - Comorbiditieshttps://doi.org/10.1002/pbc.28466

Observational study of nasopharyngeal presence of SARS-CoV-2 in a cohort of 282 paediatric oncology patient presenting for scheduled care at 14 specialist centres in Italy between 20/02/20 and 19/04/20. Median age for oncology cases (n=247) was 7 years (range 0-17.9) and for stem cell transplant (SCT) patients (n=35) was 9.6 years (range 0.3-17.6). 10/334 swabs from the oncology group were +ve and 0/56 from the SCT group. Only 2/10 NPS +ve patients had any symptoms (both "mild fever").

Chemotherapy was paused for all NPS +ve patients until 2 clear swabs were obtained 24 hours apart. No adverse outcomes were recorded up to the study end but follow up was only reported up to 30/04/20. This study demonstrates that paediatric oncology patients can remain asymtomatic whilst carrying SARS-CoV-2 in the nasopharynx, and recover spontaneously, without any apparent increased rate of adverse outcomes. Researchers raise the question of whether routine chemotherapy needs to be paused for asymptomatic NP carriage of SARS-CoV-2 but present no evidence for the safety of this course of action.

Flores, VLenica A, CAnn Hematol.SARS-CoV-2 infection in children with febrile neutropenia12 Jun 2020MexicoSouth America3Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289627/

This letter to Annals of Hematology offers a brief description of three children with ALL who presented with febrile illness and were found to be SARS-CoV2 PCR positive. The letter is of note as sadly one of the children died during this illness following cardiac arrest; the authors offer the paper to highlight the occurrence of SARS CoV2 in febrile neutropenic patients; however it prompts further analysis of those cases of severe infection in the context of immunosuppression.

The patients were identified at a centre in Mexico however the time period is not known. The three patients were aged 4yrs, 8yrs and 9yrs. All had ALL, two receiving consolidation chemotherapy and one on immunosuppression with mycophenolate and prednisolone. The latter patient had undergone HSCT for ALL, the time since HSCT was not provided, however this patient was admitted from the community suggesting she wasn’t in the immediate post-transplant period. All patients developed neutropenia either at time of fever or quickly following it and similarly evolved to have ‘respiratory symptoms’. All had negative blood cultures however results of other virology is not provided. Over-all pre-covid health status is not provided within the letter and this might be helpful in understanding the severity of symptoms in the patient who died.

The child who died was 8 years old and presented with febrile neutropenia, they were on mycophenolate and prednisolone following HSCT for ALL. The child quickly developed respiratory distress and required invasive mechanical ventilation; a heamodynamic deterioration led to cardiac arrest and resuscitation measures failed.

The distinguishing features of this child was her immunosuppression and history of HSCT, she was also more profoundly lymphopenic and thrombocytopenic. All other laboratory values were variable between all three patients. Further information on her overall cardiorespiratory status pre-SARS-CoV-2 would be helpful to understand her vulnerabilities and to guide management of children presenting with similar comorbidities in the future.

Gine, CLopez, MJ Laparoendosc Adv Surg Tech A .Thoracoscopic Bullectomy for Persistent Air Leak in a 14-Year-Old Child With COVID-19 Bilateral Pulmonary Disease11 Jun 2020SpainEurope1Clinical - Comorbiditieshttps://www.liebertpub.com/doi/abs/10.1089/lap.2020.0289
Anurathapan, U.Hongeng, S.Bone Marrow Transplantation; www.nature.com/bmt/Hematopoietic stem cell transplantation from an infected SARS-CoV2 donor sibling11 Jun 2020ThailandAsia2Clinical - Comorbiditieshttps://www.nature.com/articles/s41409-020-0969-3
Du, HGao, YAllergyClinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status10 Jun 2020ChinaAsia183Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1111/all.14452
Sabatino, JDi Salvo, GJ Clin MedCOVID-19 and Congenital Heart Disease: Results from a Nationwide Survey08 Jun 2020ItalyEurope4Clinical - Comorbiditieshttps://www.mdpi.com/2077-0383/9/6/1774
Alloway, B. C.Hardy, G.Radiology Case reports Suspected case of COVID-19-associated pancreatitis in a child.06 Jun 2020USANorth America1Clinical - Comorbiditieshttps://reader.elsevier.com/reader/sd/pii/S1930043320302569?token=2F2186726A3F368F41FAC9F6CCCAB2CE9CB00D44308E9ADA898D0795CFDBF9CC12EE79807C3C0390C107B51CF81D49EA
Wahlster, LSankaran, VG Pediatr Blood CancerCOVID-19 presenting with autoimmune hemolytic anemia in the setting of underlying immune dysregulation.03 Jun 2020USANorth America1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28382?af=R
Tennuri, UMiyatani, HClinics (Sao Paulo)Low Incidence of COVID-19 in Children and Adolescent Post-Liver Transplant at a Latin American Reference Center03 Jun 2020BrazilSouth America6Clinical - Comorbiditieshttps://www.scielo.br/pdf/clin/v75/1807-5932-clin-75-e1986.pdf
Mirzaree, SMMVossough, ARadiologyFocal Cerebral Arteriopathy in a COVID-19 Pediatric Patient 02 Jun 2020IranMiddle East1Clinical - Comorbiditieshttps://pubs.rsna.org/doi/pdf/10.1148/radiol.2020202197
Harman KGupta ALancetEthnicity and COVID-19 in children with comorbidities28 May 2020UKEurope12Clinical - Comorbidities https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30167-X/fulltext

Between 25 February 2020 and 28 April 2020, 12h children aged 0 to 16 years with confirmed COVID-19 who required admission to hospital were prospectively identified at Kings College Hospital London. 5 of these had known comorbidities (identified here as Group A) and 7 had no known comorbidities (Group B).

Age: Median age of Group A was 7.1yrs (range 0.2-15.3 with 2 <1 yr) and Group B was 4.8yrs (range 0-15.4).

Gender: 40% (n=2) in Group A and 71% (n=5) in Group B are male gender.

Ethnicity: 80% (n=4) in Group A and 71% (n=5) in Group B were from a black, Asian and minority ethnic (BAME) group.

Comorbidities: In Group A pre-existing comorbidities included cerebral palsy, prematurity, Wilsons disease, and dilated cardiomyopathy.

Clinical features: Most common symptoms on admission in group A and B respectively were fever (60%, n 3/5 and 86% n 6/7) and tachypnoea (60% n 3/5 and 71% n5/7). Liver dysfunction was observed in 4/5 patients in Group A but 2 had underlying liver conditions including one with Wilsons disease who has since had a liver transplant.

Radiology: In Group A radiological evidence of new infiltrates was seen in 50% (n2/4) of patients in Group A who had an x-ray because of clinical indication.

Bloods: In Group A 3 /5 patients had lymphopenia and thrombocytopenia, 3 /4 had raised CRP, 4/5 had liver dysfunction but 2 of these had underlying liver disease, 1/5 had renal dysfunction. None had symptoms that would be compatible with multisystem inflammatory syndrome. No blood data given for Group B.

Outcome: Median length of stay in hospital for Group A was 20 days (range 7-84 days) with 1child with liver transplant still an inpatient on 20th May 2020. For Group B the median stay was 3 days ( range 1-8 days); 1 admitted to hospital for safeguarding concerns and another was a neonate with vertical transmission of Covid-19.

Other salient feature: During this period 2288 adults were admitted to Kings College Hospital so children only formed 0.5% of total admissions. in Group A all children received antibiotics, 1 remdesivir and 1 hydroxychloroquine.

This case study presents data on 12 children with COVID-19 (5 of whom had comorbidities) admitted to Kings College Hospital London during 25th Feb-28th April 2020.

It is noteworthy that 75% of the total children admitted with Covid-19 and 80% of 5 children who had comorbidities were from a black, Asian, and minority (BAME) communities. Even keeping in mind that in Inner London 39% of the population is BAME, this data suggests that ethnicity in children may be an independent risk factor for severe disease. Conclusion is that Children from BAME communities particularly if they have comorbidities, may be at greater risk of severe disease from COVID-19. This is particularly significant given the ongoing investigation into the increased rates of severe COVID-19 infection in adults from BAME backgrounds.

This is a relatively new observation in children and although the numbers are very small, justifies considering this paper to be important.

Ferrari, ABalduzzi, APediatr Blood CancerChildren with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy26 May 2020ItalyEurope286Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28410

This Letter to the Editor describes the findings of 6 paediatric haematology and oncology centres in Lombardy during the 8 weeks after the COVID-19 pandemic began in Italy. Between 20th February 2020 and 15th April 2020 286 patients were tested for COVID-19 when accessing services at these centres: 74 were symptomatic, 25 had close contact with a diagnosed case and 187 were tested for screening purposes. Of these, 21 cases tested positive for COVID-19, with a median age of 6 years (range 1-17 years) and 48% were male.

Of the 21 cases 10 had leukaemia, 5 had soft tissue or bone sarcoma, 2 had lymphoma, two had hepatoblastoma, 1 had a CNS tumour and 1 had colon carcinoma. 15 patients were currently receiving treatment while 6 had completed treatment and were receiving follow up.

Clinical features: 1 patient (who had existing neurological respiratory impairment) developed aspiration pneumonia requiring respiratory support, and 1 developed atypical bilateral pneumonia with mild symptoms.

Outcomes: There were no deaths related to COVID-19 infection. Cancer treatment was modified in 10 cases (delaying chemotherapy, reducing drug doses and postponing surgery).

The authors observe that despite the overwhelming rate of COVID-19 in the general population in the region at the time, relatively few paediatric cancer patients were symptomatic, or tested positive for the virus, and that severe illness was rare. They suggest that these results may indicate that paediatric anti-cancer treatments could continue without major adjustments, especially as alterations may reduce their efficacy.

Of note, these centres experienced a reduction in newly diagnosed cancer cases to 55% of the expected rate, which may reflect delayed access to healthcare services.

Issitt, RWSebire, NJmedRxivCoronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population25 May 2020UKEurope166Clinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.05.20.20107904v1

A retrospective cohort study published by Great Ormond Street Hospital (GOSH), London, UK suggested children who are defined as vulnerable in the COVID-19 pandemic era do not appear to be at significantly increased risk of being admitted to hospital with COVID-19. In addition, the vulnerable group have similar outcomes to those who are COVID-19 negative. However, the authors do identify children undergoing chemotherapy or radiotherapy are ‘over-represented’ in the vulnerable group. Data was collected from the institution’s electronic health record system. The inclusion criteria were any patient admitted between 01/03/2020 and 15/05/2020 who was admitted with features suggestive of COVID-19 based on the attending clinician’s interpretation, of undefined grade, including fever, cough and “systemic symptoms”. Children were defined as COVID-19 positive by a positive PCR test for nucleic acid in respiratory or blood specimens performed at the referring or presenting hospital or a documented positive familial test. Patients were classified as vulnerable if they fulfilled the high risk shielded list from NHS digital or the institutions local policy that was not provided. Due to the nature of the specialist paediatric services the population of children were highly selected.

166 children fulfilled the criteria; 65 (38.7%) were COVID positive and 101 (60.8%) were negative. The average age for COVID positive group was 9 years [IQR 0.9-14] with 38 (58.5%) males. This compared to the COVID-19 negative group with an average age of 1 year [0.1-5.75], 58 (55.4%) male. The COVID-19 positive patients were significantly older (p<0.001). Differences in ethnicity frequency was statistically significant for Asian ethnicity: 12 (8.5%) COVID-19 positive compared to 6 (5.9%) in the COVID-19 negative group (p=0.02).

The number of vulnerable children who were COVID-19 positive totalled 31 (47.7%) compared to 73 who were COVID-19 negative (72.3%), demonstrating a lower number of vulnerable children were positive for COVID-19, (p=0.002).

Clinical features: Breakdown of symptoms were not provided

Radiology: N/A

Bloods (For those COVID-19 positive):

ALT 41.5 U/L [IQR 29-74], Albumin 32 g/L [IQR 27-36], AntiDNAse 310U/mL [80.8-402], AntiStreptolysin O 285 IU/mL [134-384], AST 70 U/L [43-100], CRP 28 mg/L [10-74], CK 63.5 U/L [35-214], Creatinine 23 umol/L [14-46], D-dimer 1876 ug/L [1043-3618], Ferritin 788 ug/L [445-1863], Fibrinogen 3.65 g/L [2.4-4.8], Interleukin-6 50 pg/ml [50-152], Interleukin-10 50pg/mL, LDH 848 U/L [654-1136], BNP 3550 pg/ml [626-6992], Lymphocytes 1.44 X10^9/L [0.64-2.49], Neutrophils 3.90X10^9/L [1.46-8.6], WBC 8X10^9/L [3.38-13.2], Troponin I 54 ng/L [13-157], Prothrombin time 12 seconds [11.3-13], bilirubin 6 umol/L [3-10], Triglycerides 2.48 mmol/L [1.65-3.56].

The results highlight the difference in results between the COVID positive and negative groups but do not define further differences between vulnerable and non-vulnerable groups. These include a statistically higher average CRP (p=0.002, fibrinogen (p<0.001), albumin (p0.02) neutrophil (p<0.001) and white blood cell count (p<0.001) and a lower LDH (p=0.002),

Treatments: Patient were treated following national or speciality specific guidance. No further information was provided.

Outcomes: Mortality for those who were COVID-19 was 1 (1.5%) who was in the vulnerable group. Additional comments described the primary focus of treatment was aspiration pneumonia. This compared to 4 (4%) in the non-COVID-9 group, all of whom were in the vulnerable group. The difference in mortality rates was not statistically significant.

There was no difference in the proportion of vulnerable patients based on their COVID-19 status: 61% of vulnerable patients who were COVID-19 positive compared to 64.3% who were negative, (p = 0.84). Overall, comparing all patients, a significantly lower proportion of COVID-19 positive patients required mechanical ventilation (27.7%) than COVID-19 negative patients (57.4%), (p<0.001). The individual number of patients were not provided.

The average ICU length of stay for those with COVID-19 was 4 days [2.4-10.6]. For those in the vulnerable subgroup the average was 11 days [3.7-15.1]. The significance of the difference between the vulnerable and non-vulnerable group was not described. However, vulnerable non-COVID-19 patients had a 6 [2.8-12.2] day stay in ICU. The difference between vulnerable COVID-19 positive and negative groups demonstrated no significance (p=0.3).

The average total hospital stay for vulnerable patients with COVID-19 was 16.2 days [3.8-20.8]. This compared to vulnerable COVID-19 negative patient were in hospital for 12.3 days [5.2-19.8]. The difference in duration was not significant (p=0.94).

Other salient features: Breaking down conditions that comprises vulnerable children there was a significant increased number of children with cancer undergoing active chemotherapy or radiotherapy who were admitted to hospital with symptoms and COVID-19 positive status compared to with symptoms but COVID-19 negative [7 VS 3 (p=0.01)]. There was no statistical differences between the COVID-19 positive and negative categories with on the national transplant, transplant medication, haematological cancer, respiratory and rare genetic, metabolic and autoimmune conditions lists or local severe respiratory conditions, rare diseases immunosuppressive therapies and other potential factors lists.

Barsoum, ZSN Comprehensive Clinical MedicinePediatric Asthma & Coronavirus (COVID-19)-Clinical Presentation in an Asthmatic Child—Case Report19 May 2020Northern IrelandEurope1Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s42399-020-00310-3.pdf
Hains, DKrammer, FJAMAAsymptomatic Seroconversion of Immunoglobulins to SARS-CoV-2 in a Pediatric Dialysis Unit14 May 2020USANorth America3Clinical - Comorbiditieshttps://jamanetwork.com/journals/jama/fullarticle/2766215
Boulad, FBouvier, NJAMA Oncol.COVID-19 in Children With Cancer in New York City13 May 2020USNorth America20Clinical - Comorbiditieshttps://jamanetwork.com/journals/jamaoncology/fullarticle/2766112

This research letter reports the results of SARS-CoV-2 screening of patients and caregivers from one of the largest paediatric cancer centres in the US (Memorial Sloan Kettering Cancer Center, New York) in a region with very high levels of community SARS-CoV-2 transmission.

From March 10th to April 12th 2020, inpatients and outpatients with either symptoms of or exposure to SARS-CoV-2 infection underwent RT-PCR testing. Asymptomatic patients were also tested prior to admission, deep sedation and or myelosuppressive chemotherapy, as were caregivers of children being admitted.

Overall 11% (20/178) of paediatric patients returned a positive SARS-CoV-2 result; including 29.3% in the symptomatic / exposed group and 2.5% in the asymptomatic group. In contrast 14.7% (10/76) of asymptomatic caregivers were positive. Despite close contact, 5 of the 10 children of caregivers with SARS-CoV-2 were uninfected.Only 1 of the 20 paediatric patients required hospitalisation for COVID-19 symptoms, without need for critical care.

This data provides reassurance that children with cancer may not be more vulnerable to complications of SARS-CoV-2 infection compared to other children. The lack of specific clinical detail in this report limits the ability to draw more definitive conclusions regarding risk.

The lower rate of asymptomatic carriage in children relative to their caregivers provides further evidence that children, including paediatric cancer patients, may be less susceptible to SARS-CoV-2 infection compared with adults.Clearly infection control strategies must consider the risk of nosocomial spread from infected caregivers as well as paediatric patients, particularly in areas with high levels of community transmission.

Marlais, MTullus KLancet Child Adolesc HealthThe severity of COVID-19 in children on immunosuppressive medication13 May 2020Multi-countryMulti-region18Clinical - Comorbiditieshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30145-0.pdf
Bush, R.Upadhyay, K.Am J TransplantMild COVID-19 in a Pediatric Renal Transplant Recipient13 May 2020USANorth America1Clinical - Comorbiditieshttps://pubmed.ncbi.nlm.nih.gov/32406181/
Zhao, YGao, GPediatr Infect Dis JFIRST CASE OF CORONAVIRUS DISEASE 2019 IN CHILDHOOD LEUKEMIA IN CHINA12 May 2020ChinaAsia1Clinical - Comorbiditieshttps://journals.lww.com/pidj/Abstract/9000/FIRST_CASE_OF_CORONAVIRUS_DISEASE_2019_IN.96166.aspx
Angelletti, AForno, RClin TransplantRisk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study12 May 2020ItalyEurope64Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ctr.13889

Giannina Gaslini Children’s Hospital, Italy undertook this prospective observational study of patients, who received a kidney transplant between January 2010 and March 2020, with stable graft function and were taking chronic immunosuppressant therapy. They were interviewed weekly between 24th February and 12th April 2020 for 7 weeks, using a 12-point structure questionnaire contained in the appendix, to evaluate the health status of themselves and their cohabitants. The data for adults and children were combined presenting a median age of 20 (2-30) years. The demographics were reported as a combined total; 93 were male.

2 patients, an adult (information not included) and 1 girl aged 13, had co-habitants who were positive for SARS-CoV-2. The 13-year-old had a kidney transplant aged 9 years old. At the time of study, she was taking a combination of steroid, calcineurin inhibitor (CNI and mycophenolate mofetil (MMF) and had investigations including a white cell count and haemoglobin within normal limits.

She tested negative for SARS-CoV-2 using a nasopharyngeal swab (test not declared) and did not develop any symptoms in the subsequent 21 days, declared as the incubation period. Anti-SARS-CoV-2 antibodies were also negative at an undefined time point.

Clinical features: No patients developed any clinical symptoms.

Radiology: None discussed.

Bloods: None discussed for patients who were positive for SARS-CoV-2.

Treatments: None.

Outcomes: None.

Other salient features: The authors recommend avoiding altering the immunosuppressive therapy in young transplant recipients who do not have symptoms of SARS-CoV-2 including those who are exposed to positive close contact. Despite observing a relatively large population of kidney transplant recipients, a small number, 2 (1 child) were exposed to SARS-CoV-2, upon which has the conclusions are based.

Koczulla, RAKneidinger, NAmerican Journal of TransplantationSARS-CoV-2 infection in two patients following recent lung transplantation12 May 2020GermanyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.15998
Blanchon, SRochat, IPediatr PulmonolCOVID-19: A Message of Hope From a Young Girl With Severe Cystic Fibrosis11 May 2020SwitzerlandEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24812
Brenner, EUngaro RGastroenterologyCorticosteroids but not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Pateitns with Inflammatory Bowel Disease: Results from an International Registry. 08 May 2020USANorth America30Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0016508520306557

This is a pre-proof article and therefore has not yet undergone final editing and review.This is an article from America (Carolina) aiming to characterise the clinical course of COVID-19 on patients with inflammatory bowel disease (IBD) and evaluate the association between demographics, clinical characteristics and immunosuppressant treatments of COVID-19 outcomes.

The authors created a surveillance database and healthcare providers were encouraged to voluntarily report all cases of Polymerase Chain Reaction (PCR)-confirmed COVID-19 patients with IBD. A website was developed to enable international contributions. Contributors were asked to report cases a minimum of 7 days from symptom onset and after sufficient time had passed to observe disease course through to resolution of acute illness or death.

525 patients from 33 countries were reported. 7% had severe COVID-19, 31% were hospitalised, 3% of patients died. The median age of patient was 41 years (from 5 to 90). The majority of patients had Crohns Disease (59.4%) and IBD disease activity was classed as remission in 58.9% of cases. The most common class of treatment was TNF antagonist therapy (43.4% of patients).

63.5% of patients had no comorbidities other than IBD. Most patients who died had other co-morbidities. Only 3 paediatric patients (10% of paediatric cases) required hospitalization. After controlling for all other covariates use of systemic corticosteroids and ASA/sulfasalazine use were strongly associated with more serious outcomes after infection with COVID-19 but there was no significant association seen between TNF antagonist use and adverse outcomes.

The authors observed an age-standardized mortality ration of approximately 1.5-1.9 as compared to the general populations of China, Italy and the U.S.

They state it is reassuring that the most commonly used treatment- TNF antagonists- appears not to lead to increased adverse outcome for patients infected with COVID-19.

This study has strength in that it includes data from many countries although how comparable that data can be between countries is debatable. The authors did not look at dosing regimens or what was done in terms of continuing or postponing treatment which may well have varied from one country to another. There may also be some bias towards patients who were unwell enough to present to hospital, there may have been other patients who were infected but not unwell enough to require hospital treatment/testing for COVID-19 who would not have been included in this study population.

de Rojas, TPerez-Martinez, APediatric Blood and CancerCOVID-19 Infection in children and adolescents with cancer in Madrid08 May 2020Italy Europe15Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28397
Andre, NGandemer, VPediatr Blood CancerCOVID-19 in pediatric oncology from French pediatric oncology and hematology centers: High risk of severe forms?08 May 2020FranceEurope33Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28392
Morand, AFabre AArchives de PediatrieChild with liver transplant recovers from COVID-19 infection. A case report. 06 May 2020franceEurope1Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0929693X2030110X

This a case report form France of a 2-and-a-half-year-old girl who recovered from COVID-19 infection, 5 months after a liver transplant; she had co-infection with Epstein-Barr virus (EBV).

The child had received a living donor transplant (father) as she had developed portal hypertension post Kasai portoentemrostoy performed at 53 days of age for biliary atresia.

She had been discharged home 20 days post procedure on tacrolimus immunosuppression therapy and had no immunization against EBV before transplantation.

On day 96 post transplant she was found to have primary EBV infection linked to the transplant- her father was EBV positive- but was asymptomatic of this.

The first developed rhinitis which developed into a fever, cough and tachypnoea. In the few days before this her mother had been hospitalized with pneumonia and found to be COVID-19 positive on nasopharyngeal swab. On day three of the illness the child was referred to hospital where she was found to be positive for COVID-19 on NPA.

On admission she was tachypnoeic with no other signs of respiratory distress, her CRP was low (3). A chest CT showed focal alveolar condensation of the ligula and a stable mediastinal enlargement. Her liver function tests had deteriorated (GGT and AST). An US of the liver showed aggravation of the transplanted biliary tract stenosis and an elevated EBV blood viral load. She was managed symptomatically, and she did not receive any COVID-19 specific treatment.

She recovered from COVID-19 infection despite the high level of immunosuppression caused by her tacrolimus treatment. NPA test samples became negative on day 11. The authors report they reduced the dose of tacrolimus but do not state at which point in the illness nor for how long. They do not state how long it took for her LFTs to return to previous levels nor if there were any consequences of the raised EBV viral load.

The authors suggest liver transplantation is not associated with COVID-19 symptom severity development even when there is high level immunosuppression on tacrolimus. Moreover COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.

It is difficult to draw conclusions based on one case study. Particularly as other studies have shown the severity of COVID-19 is increased when present with other co-morbidities. This particular patient, due to the nature of her original liver insult and the fact that she is a young patient, did not have other co-morbidities, this is often not the case for other patients who have required a liver transplantation.

Michelena, XMarsal, S.Med archivesIncidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs05 May 2020SpainEuropeClinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.04.30.20086090v1.full.pdf
Sieni, EFavre, CBritish Journal of HaematologyFavourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression05 May 2020ItalyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16781

This retrospective single case report discusses the progression and treatment of a child with high risk acute myeloid leukaemia having undertaken the third chemotherapy cycle of the induction phase following AIEOP LAM 2013 protocol.

13-month-old female patient attended routine clinic at Myers Hospital, Florence, Italy following completion of the chemotherapy. Routine investigations revealed a low white cell count, haemoglobin and platelet count which necessitated admission for transfusions. The need for admission was the initial reason for testing for SARS-CoV-2. RT-PCR was performed for nasal and pharyngeal swabs. Faecal PCR testing was also positive.

Clinical features: Fever starting on day 3 (the combination of fever and low WCC suggested neutropenic sepsis), vomiting and diarrhoea with negative stool culture.

Radiology: CXR on day 3 showed bilateral reticular markings. A repeat prior to discharge demonstrated “no significant modification from baseline”.

Bloods: Day 0 showed low WCC (80/mmc), haemoglobin (7.9g/dL) and platelet (5000/mmc) count. The elevated CRP was highest at day 5 (7.2mg/dL) and normalised by day 10 (<0.5mg/dL). Additional laboratory investigations included LDH which was highest by day 13 (401 IU/L) and ferratin maximally raised on day 9 (3000 mg/mL). Immunoglobulins were low throughout the illness. On day 3 the results were: IgG 258 mg/dL, IgA 18.7 mg/dL, IgM 7 mg/dL. IL-1β, IL-6, IL-10, TNFα and cardiac enzymes were normal.

Blood microbiology was negative.

Additional laboratory investigations, including cytokines (IL-1β, IL-6, IL-10 and TNFα) and cardiac enzymes, were normal; lactate dehydrogenase slightly increased (up to 401 IU/L at day 13), whereas ferritin values showed moderate elevation from day 9

Treatments: Treatment for neutropenic sepsis with piperacillin-tazobactam and fluconazole was commenced on day 3 due to fever. Hydroxychloroquine day 3-11. On day 4 lopinavir/ritonavir stopping day 12

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: There was a undetectable viral plasma load by day 16, however nasal swab for SARS-CoV-2 remained positive beyond discharge at day 26. There is no data to suggest a negative test to publication date.

It is unclear if the low WCC, anaemia and thrombocytopenia requiring transfusion was due to the chemotherapy, underlying acute myeloid leukaemia or COVID-19 infection, however, on discharge these values had normalised and were maintained by day 26.

Summary: This case describes a high-risk young patient with acute myeloid leukaemia undergoing chemotherapy presenting with febrile neutropenia. Whilst the symptoms were initially vague, subsequent investigations suggested the underlying cause was SARS-CoV-2. Early anti-viral treatments were commenced. Given the patient’s immunosuppression the authors discuss fears regarding seroconversion, viral dissemination and inflammatory responses which did not occur.

Melgosa, MPerez-Beltran, VPed NephrolSARS-CoV-2 infection in Spanish children with chronic kidney pathologies01 May 2020Spain Europe16Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s00467-020-04597-1.pdf
Odièvre, MCorvol, HAm J HematologyDramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome01 May 2020FranceEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1002/ajh.25855

The authors of this case study are based at two hospitals in Paris; in this correspondence they describe the treatment of a 16 year old girl with homozygous sickle cell disease (SCD) admitted to ICU with acute chest syndrome (ACS) and pulmonary emboli complicating COVID-19 pneumonia, in particular the use of Tocilizumab, a humanised anti-IL-6 monoclonal antibody (usual indications include use as immunosuppressant therapy in rheumatoid arthritis and giant cell arteritis in adults and juvenile idiopathic arthritis in children).

Course of SCD prior to admission: The patient had a history of recurrent vaso-occlusive crises and abnormal transcranial dopplers between the ages of 5 and 11 years old, necessitating treatment with exchange transfusions. At 11 years of age she was commenced on daily hydroxyurea with resolution of vaso-occlusive events. She had no history of ACS or pulmonary hypertension; respiratory function and chest radiography were previously normal.

Presentation with COVID-19-19: She presented with isolated fever, with nasophyaryngeal swabs subsequently confirmed as RT-PCR SARS-CoV-2 positive. 7 days later she developed acute chest pain associated with respiratory distress (SpO2 85%).

Radiology: CT pulmonary angiogram (CTPA) showed bilateral pulmonary emboli and bilateral consolidation with right-sided halo sign.

Treatment in ICU: Included non-invasive ventilation, anticoagulation and red cell exchange transfusion followed by simple transfusion (lowest Hb 64 g/L). Based on recent experience in adult SCD patients with COVID-19 disease she also received a single infusion of Tocilizumab (8 mg/kg). The authors report rapid clinical improvement after Tocilizumab with repeat CTPA 5 days later showing complete resolution of pulmonary emboli and consolidation on the right and decrease on the left. She was discharged from hospital 11 days after admission to continue oral anticoagulation for 6 weeks.

Conclusions: Inflammatory cytokines such as IL-6 and TNF- are elevated in COVID-19. COVID-19 pneumonia can cause ACS in SCD patients; there have been several recent reports of successful treatment using Tocilizumab.

Inci Yildirim, ATurkmen Karaagac, AIndian PediatricsCOVID-19 in a Young Girl with Restrictive Cardiomyopathy and Chronic Lung Disease30 Apr 2020TurkeyWestern Asia, Southeastern Europe1Clinical - Comorbiditieshttps://www.indianpediatrics.net/june2020/577.pdf
Russell M.Reardon LThe Journal of Heart and Lung TransplantationCOVID-19 in a paediatric heart transplant recipient: Emergence of donor-specific antibodies 29 Apr 2020UKEurope1Clinical - Comorbidities https://www.jhltonline.org/article/S1053-2498(20)31532-1/fulltext

This is a case report of a 3 year old child who had received a heart transplant at 11 months of age for congenital dilated cardiomyopathy.

Her post-transplant course had been unremarkable except for persistent Ebstein Barr Virus (EBV) viremia. She was on tacrolimus monotherapy.

Her initial symptoms were productive cough with rhinorrhea and nasal congestion, she was not tested for COVID-19 at this point as she had no Centres for Disease Control risk factors for infection and testing was not widely available.

A week later a follow-up telehealth visit was performed and there was improvement in symptoms.Surveillance blood tests demonstrated the following de novo Class II donor specific antibodies: DQ4, DR8 and DQA1*04.

One week later the patient was scheduled for routine admission for intravenous immunoglobulin administration, because of the history of cough had a nasal swab sent for reverse transcriptase polymerase chain reaction testing for COVID-19. Other than an intermittent wet cough she was well, and her observations were within normal limits. She received the immunoglobulin infusion overnight. The next morning the nasal swab was reported as positive for COVID-19 infection.

The patient remained well without symptoms of respiratory distress. Repeat COVID-19 nasal polymerase chain reaction testing was planned for 2 weeks with IVIG administration repeated every month for 2 more months. The authors report that although the patient tolerated IVIG administration with concurrent COVID-19 infection without any notable reaction they would be hesitant to attempt more aggressive forms of desensitisation with active infection until more clinical knowledge of COVID-19 is available.

Climent, F. J.Pérez-Martínez, ARev Esp Cardiol (Engl Ed). Fatal outcome of COVID-19 disease in a 5-month infant with comorbidities27 Apr 2020SpainEurope12Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183979/pdf/main.pdf
Schwierzeck, VKampmeier, SClin Infect DisFirst reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit27 Apr 2020GermanyEurope13Clinical - Comorbiditieshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa491/5825509

This paper presents the results of an outbreak investigation following a member of staff on a paediatric dialysis unit developing confirmed COVID-19. Detailed contact tracing was carried out and found that 48 cases in total were involved - this included 13 patients, 28 healthcare workers and seven 'accompanying persons'. Of note, of the 3 traced who children tested positive for SARS-CoV-2, only one had symptoms; given these children's high-risk status, their asymptomatic presentations are noteable. The paper discusses hygiene measures put in place to avoid further spread.

Chen, YHuang, KDiabetes CareClinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication24 Apr 2020ChinaAsia3Clinical - Comorbiditieshttps://care.diabetesjournals.org/content/early/2020/05/13/dc20-0660
Poli, PBadolato, RJ. Cyst FibrosAsymptomatic case of COVID-19 in an infant with cystic fibrosis14 Apr 2020ItalyEurope1Clinical - Comorbiditieshttps://www.cysticfibrosisjournal.com/article/S1569-1993(20)30096-5/fulltext#%20

This is the first case report of confirmed SARS-CoV-2 infection in a child with cystic fibrosis. The 1 month-old, from Italy, was diagnosed with CF on newborn screening. SARS-CoV-2 infection was confirmed on nasopharyngeal swab PCR as part of contact tracing following exposure to COVID-19 through his grandfather.

The infant remained asymptomatic throughout follow up and did not require hospital admission.This is one of a limited number of reports of SARS-CoV-2 infection in people with CF. A better understanding of the course of illness in this group will likely emerge with data from ongoing collaborative studies.

Hrusak, OSchrappe, MEur J CancerFlash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment07 Apr 2020International (first author from Czechia)International9Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141482/

This is the report of a data from an international survey of paediatric haematology and oncology clinicians to assess the frequency and severity of SARS-CoV-2 infection amongst children with cancer. The survey, conducted from 16th-17th March 2020, had over 35 respondents from 25 countries. Of an estimated 10,000 patients at risk and over 200 tested, 9 children were positive for SARS-CoV-2. Clinical details are provided for 8 cases, 6 of whom had solid tumours and 2 with acute lymphoblastic leukaemia. 7 had mild or asymptomatic disease, 1 patient required low flow oxygen. Fever was the presenting symptom in 6 patients and one patient also had diarrhoea. All 7 patients with outcome data available made a full recovery.

The interpretation of these data is clearly limited by the study design as well as the relatively early stage of the pandemic during which the survey was conducted. Notwithstanding these limitations, the absence of severe COVID-19 cases in this report provides some early reassurance. More detailed clinical studies are needed to draw firm conclusions about the risk of severe disease in children receiving chemotherapy.

Balduzzi, ABiondi, ALancet pre-print serverLessons after the early management of the COVID-19 outbreak in a pediatric transplant and hemato-oncology center embedded within a COVID-19 dedicated hospital in Lombardia, Italy02 Apr 2020ItalyEurope5Clinical - Comorbiditieshttps://dx.doi.org/10.2139/ssrn.3559560

This report from a paediatric haematology unit in Lombardia, Italy, includes the Italian experience of COVID-19 in children with malignancy so far. At their particular unit, they have had no children with malignancy test positive for COVID-19 (they admit this is dependent on testing criteria, requiring hospitalisation at their institute). They are aware of 5 cases of paediatric cancer patients who have had COVID-19 and have all suffered a mild course, with 3 managed at home and 2 in hospital.

This small case series provides further reassurance for at risk paediatric populations.

Lagana, SMLefkowitch, JHArchives of Pathology & Laboratory MedicineCOVID-19 associated hepatitis complicating recent living donor liver transplantation02 Apr 2020USANorth America1Clinical - Comorbiditieshttps://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2020-0186-SA

This retrospective single case report examines the histopathological features of liver associated COVID-19 in a child admitted to Columbia University Medical Centre, USA. The female child, 6 months old, was admitted for a liver transplant for treatment of biliary atresia. COVID-19 was diagnosed in the donor on post-operative day 2 and confirmed in the patient day 4 post-operatively. The type of test used was not described.

Clinical features: Increased work of breathing requiring CPAP, fever and diarrhoea were developed on post-operative day 4.

Radiology: CXR on post-operative day 4 was described as “no significant changes compared to prior exam with only patchy areas of atelectasis in irregularly aerated lungs”. CXR on day 6 demonstrated “patchy lung opacities bilaterally, mildly increased in the right upper lobe and left lung base”. Bloods: Deranged LFTs exacerbated from baseline on post-operative day 1: AST (maximum 908U/L from 163U/L), ALT (maximum 980U/L from 215U/L), GGT (maximum 473U/L from 174U/L), ALP (maximum 578U/L from 388U/L).

Treatments: Treated with hydroxychloroquine from day 4 post-operative. She required CPAP for an undefined time period. Undefined immunosuppressant treatment was provided for acute transplant rejection, however liver enzymes worsened when commenced.

Outcomes: Remains on a hospital ward without supplemental oxygen.

A liver biopsy was performed on post-operative day 7 demonstrating portal tract expansion through a mixed inflammatory infiltrate which consisted of lymphocytes, rare plasma cells, and interspersed eosinophils, lymphocytic cholangitis, reactive changes in the interlobular bile ducts and mild portal venulitis. These were interpreted as acute cellular rejection.

Other findings of moderate acute hepatitis including an “azonal pattern of clusters of apoptotic hepatocytes” and singly dispersed apoptotic hepatocytes. Other features of interest include large fragments of cytoplasmic debris described as “crumbling” hepatocytes, few mitotic figures, regions of Kupffer cell prominence with sinusoidal and central vein endotheliitis. The authors commented that the extent of hepatocyte apoptosis and large clusters were unusual and not a usual feature of acute cellular rejection (ACR). Central endotheliitis may also be a feature of COVID-19 hepatitis, with the presence of more Kupffer cells and less plasma cells than ACR.

Summary: COVID-19 hepatitis likely presents as a moderate acute hepatitis with prominent clusters of “crumbling” apoptotic hepatocytes. Other features may be lymphohistiocytic inflammation of sinusoidal and central vein endothelium, with the presence of more Kupffer and less plasma cells when compared to ACR.

Turner, DRussel, RJournal of Pediatric Gastroenterology and NutritionCOVID-19 and paediatric inflammatory bowel diseases31 Mar 2020InternationalInternational8Clinical - Comorbiditieshttps://doi.org/10.1097/MPG.0000000000002729

This article outlines the experience from Asia and Europe so far of children with inflammatory bowel disease given the COVID-19 pandemic. This is of particular interest because many of these children receive immunosuppression as part of their treatment, and so could be considered high risk for complications of the disease.

It appears to have been routine practice to suspend treatment for IBD during the outbreak of COVID-19, which resulted in a large number of relapses. No children with IBD contracted COVID-19 in China in the period covered by the survey.

In South Korea treatment for IBD was not suspended. They also have had no cases of COVID-19 in children with IBD.

In the PORTO IBD group of ESPGHAN (covering Europe, some centres in Canada and Israel) treatment was not suspended in 31/32 centres. 7 children with IBD, who were on immunosuppression, had COVID-19. They all suffered a mild illness with no flare of their IBD. There is an additional child case from an international IBD database identified who also experiences mild symptoms (no hospitalisation required).

This survey provides further reassurance that treatment with immunosuppression does not appear to significantly increase the risk of severe disease from COVID-19 in children.

D'Antiga, LLiver transplantationCoronaviruses and immunosuppressed patients: the facts during the third epidemic20 Mar 2020ItalyEurope3Clinical - Comorbiditieshttps://doi.org/10.1002/lt.25756

This letter is from a liver transplant centre in Lombardy, Italy, reporting their experience of patients (including children) with immunosuppression and COVID-19. They have had 3 children post liver transplant test positive for SARS-CoV-2, and none have developed clinical pulmonary disease. They believe due to the widespread nature of infection that many other of their patients may also be infected, but not developed clinically apparent disease.

This provides the first official reports of vulnerable paediatric populations with COVID-19, which so far does not appear to be any more severe than the rest of the population in that age bracket. Further data is awaited.

Weisberg, SFarber, DNat ImmunolDistinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.5 Nov 2020USANorth America47Clinical - PIMS-TShttps://doi.org/10.1038/s41590-020-00826-9

This study, published online on 5th November 2020, investigates the SARS-CoV-2 antibody response and its protective capacity in 32 adult and 47 paediatric patients seen at New York-Presbyterian/Columbia University Irving Medical Center hospital and the Morgan Stanley Children’s Hospital of New York during the height of the COVID-19 pandemic in New York City from March to June 2020. Children with SARS-CoV-2 infection are often asymptomatic and rarely have severe respiratory symptoms, but may very rarely present with multisystem inflammatory syndrome in children (MIS-C), typically 2-4 weeks after infection with SARS-CoV-2. Adults are more likely to experience respiratory symptoms of varying severity, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (particularly in older adults and those with comorbidities such as diabetes). The authors aimed to investigate the immune response after SARS-Co-2 infection in adults and children with a range of clinical presentations, by analysing antibodies specific for the major SARS-CoV-2 antigens, including the S protein (which binds the cellular receptor for viral entry) and the N protein (necessary for viral replication). They also analysed the neutralising activity of these antibodies in blocking viral infection, which correlates with their protective capacity (only a small fraction of antibodies raised against viral antigens will have neutralising activity).

Study population: There were 4 patient cohorts in the study (2 adult and 2 paediatric, one each of mild and severe disease in each age group) totalling 79 individuals, defined as having been SARS-CoV-2-infected based on symptoms, positive PCR and/or serology:

1. 19/79 (24%) adult convalescent plasma donors (CPDs): recovered from mild COVID-19 respiratory disease without hospitalisation and recruited from the community via web tool as part of convalescent plasma trial (telephone screening to determine eligibility as plasma donors), median age 45 yrs (range 28-69), 10/19 (53%) male, ethnicity: 53% white, 32% Asian, 11% Pacific Islander, 5% Hispanic/Latin American, 5% other/unknown. Median time from onset of symptoms consistent with COVID-19 to sampling during outpatient donation of blood: 24 days (IQR 19-37).

2. 13/79 (16%) adults hospitalised with severe COVID-19 ARDS (COVID-ARDS): median age 62 yrs (range 19-84), male 11/13 (85%), ethnicity: 31% Hispanic/Latin American, 23% Black/African American, 15% white, 38% other/unknown. Co-morbidities: diabetes 4/13 (31%), hypertension 4/13 (31%), current/former smoker 3/13 (23%), COPD 2/13 (15%), chronic neurological disease/dementia 1/13 (8%). Median time from onset of respiratory/COVID-19 symptoms to sampling (after diagnosis of ARDS requiring intubation and admission to ICU): 16 days (IQR 14-21). 30-day in-hospital mortality 6/13 (46%), 4 patients remained hospitalised.

3. 16/79 (20%) children hospitalised with MIS-C (paediatric MIS-C): median age 11 yrs (range 4-17), male 7/16 (44%), ethnicity: 44% Black/African American, 44% white, 25% Hispanic/Latin American, 6% other/unknown. Asthma 4/16 (25%) (no other co-morbidities). Median time after onset of symptoms of MIS-C to sampling on admission to PICU: 6 days (IQR 4-7). 30-day in-hospital mortality 0%, 1/16 (6%) developed respiratory failure/ARDS.

4. 31/79 (39%) children infected with SARS-CoV-2 who didn’t develop MIS-C (paediatric non-MIS-C): median age 11 yrs (range 3-18), male 17/31 (55%), ethnicity: 48% white, 42% Hispanic/Latin American, 13% Black/Latin American, 23% other/unknown. Co-morbidities: asthma 1/31 (3%), chronic kidney disease 1, hypertension 1. Clinical presentation: surgical 9/31 (29%), COVID-19 symptoms 7/31 (23%), psychiatric 4/31 (13%), trauma 3/31 (10%), fever (non-COVID) 2/31 (6%), other 6/31 (19%). Asymptomatic 15/31 (48%). Median time from symptom onset or from confirmed COVID-19 exposure (reportable data for 16 individuals) to sampling during clinical care (including routine screening for admission and procedures): 29 days (IQR 17-44). 30-day in-hospital mortality 0%, 1/31 (3%) developed respiratory failure/ARDS. These samples were obtained from the Columbia University Biobank after screening for appropriate age and exclusion of confounders such as immune deficiency, malignancy and genetic abnormality.

SARS-CoV-2 specific antibodies for each cohort: Blood samples were collected from all 4 cohorts during the same 60 day time window. Levels of antibodies to SARS-CoV-2 S (spike) and N (nucleocapsid) proteins were measured in patient plasma samples (and in a negative control pre-pandemic plasma) using serial dilutions in an indirect ELISA assay to detect anti-S IgG, anti-S IgM, anti-S IgA and anti-N IgG. Detailed results and graphs are reported in the article, together with statistical comparisons between cohorts. Anti-S antibodies were present as IgM (primary response), IgG (prominent in serum) and IgA (prominent in secretions) classes in adult CPDs and COVID-ARDS, with significantly higher concentration in COVID-ARDS patients for all classes. By contrast, anti-S antibody titres and isotype predominance in both paediatric cohorts (MISC-C and non-MIS-C) were similar to each other and to the adult CPDs, showing predominant anti-S IgG, low titres of anti-S IgM (similar to the negative control) and variable titres of anti-S IgA antibodies. The specificity of anti-S IgG for SARS-CoV-2 S protein compared to other coronavirus strains was assessed using a cell-based ELISA: plasma IgG from subject samples (but not pre-pandemic control plasma) bound SARS-CoV-2 protein and the common circulating D614G S protein variant, but did not significantly bind S protein from SARS-CoV-1 or MERS coronaviruses. Anti-N IgG titres were significantly lower in both paediatric cohorts compared to the two adult cohorts. The low titres of anti-N IgG in children were similar in MIS-C and non-MIS-C cohorts. The higher titres of anti-N IgG in adults were similar in CPDs and COVID-ARDS cohorts, suggesting that production of anti-N antibody is age- but not symptom-dependent.

Effect of age on antibodies in each cohort: No significant correlation between age and anti-S IgG in adults or paediatric MIS-C cohort; modest but significant negative correlation between age and anti-S IgG in paediatric non-MIS-C cohort (younger children having higher anti-S titres than teens). Significant correlation between age and anti-N IgG in adult CPDs (younger adults having lower anti-N titres than older adults). Both paediatric cohorts had low anti-N titres across all ages.

Effect of time post-symptom onset on antibodies in each cohort: Significant correlation between anti-S IgG titres and increased time post-symptom onset for both paediatric cohorts and the adult COVID-ARDS cohort, suggesting an evolving response over time. No correlation between anti-S IgM and time post-symptom onset in any cohort.

Neutralising activity of antibodies in each cohort: A pseudovirus assay was used to measure neutralising activity. Both paediatric cohorts exhibited significantly lower neutralising activity than the two adults cohorts, with no difference between MIS-C and non-MIS-C cohorts. Plasma from adult COVID-ARDS patients showed the highest neutralising activity. No correlation between age and neutralising activity in either adult cohort. Significant decline of neutralising activity with age in the paediatric non-MIS-C cohort, similar to the decrease in anti-S IgG observed during the teenage years. Neutralising activity within each cohort did not correlate with time post-symptom onset except in the adult COVID-ARDS cohort. 10/16 (62.5%) MIS-C patients maintained the same anti-S IgG titres and neutralising activity when followed up 2-4 weeks post hospital discharge based on paired analysis, suggesting that lower levels of functional antibody responses in paediatric SARS-CoV-2 infection compared to adults is age-associated and not related to infection course.

Additional analysis to better define how antibody responses relate to age and disease severity: Multivariable linear regression analysis was performed to control for the effects of demographic and clinical covariates. Consistent with the grouped analysis, analysis of all paediatric and adult data showed that the paediatric age group was a significant predictor of lower SARS-CoV-2 neutralising activity, anti-S IgM and anti-N IgG, independent of time post-symptom onset, clinical syndrome or sex. ARDS was a significant independent predictor of higher neutralising activity, anti-S IgG and anti-S IgM.

Observations: Self-selection bias may apply to the CPDs cohort, since they volunteered via the internet to be plasma donors. Timing of onset of symptoms was subjective and the paediatric non-MIS-C cohort included 48% asymptomatic patients whose symptom onset to sampling time interval was calculated based on days since confirmed COVID-19 exposure (with reportable data for only half the cohort). The paediatric MIS-C cohort symptom onset to sampling time interval is based on onset of MIS-C symptoms, not potential initial COVID-19 symptoms or COVID-19 exposure. Samples from COVID-ARDS and MIS-C patients were obtained within 24-36 hours of being admitted to ICU/PICU or intubated for respiratory failure; this was not always before the initiation of therapeutic interventions. Treatments received by the 13 COVID-ARDS patients included: convalescent plasma 4/13 (31%) (1/13 sampled post-treatment), hydrocortisone 6/13 (46%) (1/13 sampled post-treatment), methylprednisolone 9/13 (69%) (8/13 sampled post-treatment), monoclonal antibodies 7/13 (54%) (6/13 sampled post-treatment), remdesevir 6/13 (40%) (2/13 sampled post-treatment). 16 MIS-C patients: hydrocortisone 3/16 (19%) (3/13 sampled post-treatment), intravenous immunoglobulin 14/16 (88%) (6/16 sampled post-treatment), methylprednisolone 15/16 (94%) (10/16 sampled post-treatment), monoclonal antibodies 3/16 (1/16 sampled post-treatment), remdesevir 1/16 (1/16 sampled post-treatment). 31 non-MISC-C patients: intravenous immunoglobulin 2/31 (6%) (both sampled before treatment), methylprednisolone 1/31 (3%) (1/31 sampled post-treatment), remdesevir 1/31 (3%) (1/31 sampled post-treatment).

Conclusions: This study demonstrates quantitative and qualitative differences between children and adults in the anti-SARS-CoV-2-specific antibody response in both mild and severe disease. The anti-SARS-CoV-2 antibody response in children was found to be predominantly anti-S IgG antibodies, with low neutralising activity compared to adults. Children with and without MIS-C had similar antibody profiles (suggesting that the adaptive immune response is not in itself associated with MIS-C pathogenesis), in contrast to the adult cohorts, where those with the most severe disease had higher abundance, breadth and neutralising activity of anti-SARS-CoV-2 antibodies compared to adults who recovered from mild disease. Anti-N antibody titres were low in children compared to adults, which is consistent with a milder course of infection in children (release of N proteins requires lysis of virally infected cells). This effect was also seen in the adult CPDs cohort, where anti-N antibodies increased with age, consistent with an increase in severe and prolonged disease in older adults. Testing platforms using anti-N IgG to identify previous infection may have decreased sensitivity in children, since children were shown to predominantly generate IgG antibodies specific for the S protein, but not the N protein. Age was the major factor distinguishing antibody profiles (independent of sex, disease severity and time post-symptom onset). The authors note the opportunity to study primary immune responses across all ages afforded by the sudden and widespread emergence of SARS-CoV-2 as a new pathogen; the majority of primary exposures to common viral respiratory pathogens occur in infancy and childhood, so that virus-specific immune memory is established by adulthood, and therefore differences between primary immune responses in children and adults are currently unknown. The authors postulate that the reduced functional adaptive antibody response in children compared to adults may be due to efficient immune-mediated viral clearance resulting in fewer respiratory symptoms and less severe disease. Children may have more naïve T cells available to respond to new pathogens or more recently acquired T cell memory to related coronaviruses due to more recent and frequent respiratory illnesses. Defining the nature of the antibody response to SARS-CoV-2 infection as a function of age and disease severity will improve age-targeted screening and protection in the form of therapeutics and vaccines.

García-Salido, AGonzález Cortés, RCrit Care 24(1): 666Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain26 Nov 2020SpainEurope74Clinical - PIMS-TShttps://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03332-4

Multicentre registry-based study of 74 children admitted to 47 PICUs in Spain with SARS-CoV-2-related disease, from 01/03-15/06/20, comparing cases with a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) with non-MIS-C cases. MIS-C cases were more likely to be older, to not to have any prior medical condition, to present with fever, fatigue, GI symptoms and to develop cardiac dysfunction and shock, and to need vasoactive drugs, antibiotics and immunomodulatory drugs than were non-MIS-C cases. They had lower lymphocyte counts and LDH levels but higher neutrophil counts and pro-calcitonin and CRP levels. They were less likely to present with cough, respiratory distress or rhinorrhoea, to need non-invasive or mechanical ventilation, or blood product support. All 3 deaths were in non-MIS-c cases with significant underlying medical conditions. Whereas non-MIS-C cases were admitted reasonably regularly throughout the 1st pandemic wave, MIS-C admissions showed a delayed peak compared to national case numbers. MIS-C cases were more likely to have negative PCR for SARS-CoV-2 than non-MIS-C cases, though many had other immunological evidence of infection. The authors point out that the findings of this study are only applicable to PICU populations and do not reflect the full spectrum of MIS-C disease, since milder cases will not have been admitted to a PICU.

Anderson, EHensley, SJPIDSSARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-1902 Dec 2020USANorth America29Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa161
Lucio Verdoni, MD Lorenzo D'Antiga, MDThe LancetAn outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study 13th May 2020ItalyEurope10Clinical - PIMS-TShttps://doi.org/10.1016/S0140-6736(20)31103-X

This is the second published manuscript on the increase in a Kawaski-like illness (now termed PIMS-TS) during the SARS-CoV-2 pandemic.

This is a retrospective study of children with a diagnosis of Kawasaki Disease (KD) in the Bergamo province of Italy, an area which was significantly affected by SARS-CoV-2. Overall, 10 children were diagnosed with KD during the pandemic (Feb 18 to April 20,2020), compared with 19 children prior to the pandemic (Jan 1 2015 to Feb 17 2020). Interestingly, 8 of 10 children were positive for SARS-CoV-2 IgG, IgM or both.

The two groups of children were compared, and those with KD during the SARS-CoV-2 pandemic were found to be older, have a higher rate of KD and were more likely to present with KD shock syndrome or Macrophage Activation Syndrome. Overall, there was a 30 fold increased incidence of a KD-like illness during the pandemic.

Prieto, LMBlazquez, DClin Microbiol Infect Cardiovascular magnetic resonance imaging in children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and heart dysfunction10 Oct 2020SpainEurope5Clinical - PIMS-TShttps://doi.org/10.1016/j.cmi.2020.10.005

The authors (from the Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid) describe their recent experience with five patients affected by PIMS-TS from April 28 to May 11, 2020. The exact mechanisms of how SARS-CoV-2 causes this transient myocardial dysfunction in children with PIMS-TS are not well understood. Cardiovascular magnetic resonance imaging (CMRI) has become the diagnostic tool of choice for patients with evidence for acute non-ischemic myocardial injury, including myocarditis in the last decade. CMRI allows for targeting several features of myocardial injury: inflammatory hyperemia and edema, necrosis/scar, contractile dysfunction and pericardial effusion. CMRI is also a predictor of functional and clinical recovery. They state CMRI allows for a robust assessment of the extent of injury and dysfunction in clinically acute scenarios of myocardial injury but the diagnostic value of echocardiography for myocardial injury is limited by the fact that many patients with less severe disease have a normal echocardiogram and the highly variable echocardiographic findings lack specificity.

Presenting features and investigations

All were previously healthy children, with a median age of 7 years old of varying racial backgrounds, [interquartile range (IQR), 5-12 years]. They presented at admission with fever, tachycardia and hypotension. The median white cell count was 9100 cells/mm3 and the median lymphocyte count was 1700 cells/mm3. Other ancillary tests revealed elevated cardiac biomarkers [median troponin T was 66.6 ng/l (IQR: 3.2-75.2) and NT-proBNP of 14,407 pg/ml (IQR: 3988–16,150)], and markedly increased inflammatory biomarkers like C-reactive protein and procalcitonin [10.2 mg/dl (IQR: 9.4-26.9) and 10.5 ng/ml (IQR: 3.4-14.8), respectively]. The median ferritin was 421 μg/l (IQR: 369-639) and the median interleukin 6 was 63.5 pg/ml (IQR: 27.2-216.2). The echocardiography revealed mild to moderate heart dysfunction in all of the patients. All of them had a positive serology against SARS-CoV-2 (Ig anti receptor-binding domain) and met criteria for PIMS-TS according to UK, WHO and CDC definitions. Z-score for coronary artery diameters were also standardly assessed.

Treatment

Patients received IVIG, and in three cases steroids were added because of persistent fever 48 hours after IVIG administration.

Outcome

They were all discharged home with total recovery of the heart function.

A cardiovascular magnetic resonance imaging (CMRI) was performed after discharge [median day after admission: +16, (range 9-17)]. The protocol performed included steady-state free precession cine 2D sequences (short axis, 4, 3 and 2 Chamber views); study of edema (Inversion Recovery sequence in short axis), hyperemia and capillary leak (early gadolinium enhancement) and myocyte necrosis and fibrosis (late gadolinium enhancement). Both ventricles had normal function and no edema or abnormalities in early and late gadolinium enhancement were observed in any cases.

Conclusions

CMRI did not show any myocardial damage in this small series of patients with PIMS-TS. CMRI is considered a highly sensitive technique to evaluate myocardial injury. Although the number of patients in this series was small, the authors felt that heart dysfunction did not seem secondary to myocardial viral injury in these children. They put forward an alternative hypothesis that the exaggerated inflammatory response observed in these children with PIMS-TS could be the cause of the heart dysfunction. The rapid recovery of the heart function after immunomodulatory treatment and the absence of myocardial abnormalities in CMRI support this hypothesis. They conclude that further studies to further elucidate the cause of myocardial dysfunction in children with multisystem inflammatory syndrome related to COVID-19 are warranted.

Minocha, PSingh, RClinical PediatricsCardiac Findings in Pediatric Patients With Multisystem Inflammatory Syndrome in Children Associated With COVID-1925 Sep 2020USANorth America33Clinical - PIMS-TShttps://doi.org/10.1177/0009922820961771

Methods: The authors retrospectively reviewed the clinical course and cardiac testing results in paediatric patients hospitalized with Multisystem Inflammatory Syndrome in Children (MIS-C) at 2 large hospital systems in the New York City metropolitan area over 3 months between March 1st and June 8th 2020. A standardized pathway was used to evaluate suspected cases of MIS-C and patients with acute respiratory COVID-19 infection were excluded.

Data on patient demographics, clinical course, testing results, treatment, and outcomes was collected. Patients were assessed for prior COVID-19 exposures and COVID-19 infections. All patients were tested with SARS-CoV-2 nasopharyngeal (RT-PCR) on admission. After introduction of SARS-CoV-2 serological testing on May 12, 2020, all patients with MIS-C received SARS-CoV-2 IgG (immunoglobulin G) antibody testing on admission.

For this study, MIS-C patients with positive cardiac testing were defined as having an abnormality of one or more of the following on admission: electrocardiogram (ECG), serum troponin, brain natriuretic peptide (BNP), and/or echocardiogram (echo). Left ventricular (LV) systolic function was calculated by 5/6 area length method and LV dysfunction was defined as a LV ejection fraction (LVEF) <55%.LV diastolic function was assessed by E/A wave ratios of mitral valve inflow Doppler interrogation, tissue Doppler imaging, and/or strain analysis. The classification of coronary artery dilation, aneurysm size, and Kawasaki disease were based on the 2017 American Heart Association statement. Appropriate ethical approval of the study was gained.

Results: 33 patients (median age 2.8 years) were in the study cohort There was a male predominance (58%) with Hispanics constituting the largest ethnic group (36%). Comorbidities included obesity (21%) and asthma (15%). Median duration of symptoms prior to admission was 5 days (IQR: 3-6 days). The most common symptoms were fevers (100%), rash (58%), conjunctivitis (36%), and diarrhea (36%). Three (9%) patients met the criteria for Kawasaki disease, while 10 (30%) patients met the criteria for atypical Kawasaki disease. SARS-CoV-2 RT-PCR testing was positive in 11 (33%) patients. Of the 23 patients who underwent SARS-CoV-2 IgG antibody testing, 14 (61%) were IgG positive. Inflammatory markers on admission were elevated with a median C-reactive protein (CRP) of 85 mg/L (IQR: 33-196 mg/L), median D-dimer of 649 ng/mL (IQR: 362-1093 ng/mL), and median ferritin of 206 ng/mL (IQR: 105-633 ng/mL)

24 (73%) had at least one abnormality in cardiac testing: abnormal electrocardiogram (48%), elevated brain natriuretic peptide (43%), abnormal echocardiogram (30%), and/or elevated troponin (21%).

The most common ECG changes seen were T wave (24%) and ST segment abnormalities (18%). Prolonged QTc was seen in 3 (9%) patients.

All 4 patients with LV dysfunction had normal systolic function on follow-up echos (LVEF = 66%, IQR = 64% to 69%). The median time to documented normalization of LV function was 2 days (IQR = 1.5-8.5 days). Mitral valve insufficiency and dilation of the LMCA all normalized on follow-up echos within 2 weeks of hospitalization. ST segment and T-wave abnormalities resolved on follow-up ECGs.

On univariate testing, BNP >100 pg/mL (P = .012) and CRP >50 mg/L (P = .023) were associated with an abnormal echo. There was no statistically significant association between D-dimer (P = .26), ferritin (P = .45), troponin (P = .20), or EKG findings (P = 1.0) with an abnormal echo.

Treatment: Eleven (33%) patients required ICU-level care. Most patients were treated with intravenous immunoglobulin (IVIG; 72%) and glucocorticoids (55%). Median hospital length of stay was 4 days (IQR: 3-6 days). All patients have been discharged except for one critically ill patient with a history of persistent fevers despite IVIG, glucocorticoids, and Anakinra (interleukin-1 receptor antagonist). Patients were sent home on low-dose aspirin (3-5 mg/kg/day) that was stopped after a normal echo at 6 weeks post-MIS-C diagnosis. Electrocardiogram and echocardiogram abnormalities all resolved by the 2-week outpatient follow-up cardiology visit.

Limitations of study: As a rare disease, the numbers of patients in this study is relatively small. This was a retrospective review and there was no standardization of care provided. The demographics both younger age and Hispanic preponderance may have affected the results. With its broad case definition, there may have been misclassification of patients with MIS-C who may have had these other diagnoses. Not all patients received SARS-CoV-2 antibody testing in this study due to the novel nature of this disease during our study period.

Comment: The authors conclude that there is a spectrum of cardiac disease in MIS-C and that not all patients are as severely affected as suggested previously. Obesity and Asthma were comorbidities in a significant proportion of patients. While 73% of pediatric patients with MIS-C had evidence of abnormal cardiac testing on hospital admission in the study, all cardiac testing was normal by outpatient hospital discharge follow-up. They also state that cardiac screening tests should be performed in all patients diagnosed with MIS-C given the high rate of abnormal cardiac findings in their study cohort.

Pang, JBreuer, JPediatricsSARS-CoV-2 Polymorphisms and Multisystem Inflammatory Syndrome in Children (MIS-C)01 Sep 2020United Kingdom Europe13Clinical - PIMS-TShttps://pediatrics.aappublications.org/content/early/2020/09/07/peds.2020-019844
Godfred-Cato, SBelay, EMorb Mortal Wkly Rep COVID-19–Associated Multisystem Inflammatory Syndrome in Children — United States, March–July 202007 Aug 2020United StatesNorth America570Clinical - PIMS-TShttps://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6932e2-H.pdf

On May 14th 2020, the CDC (Centre of Disease Dontrol) In the United states issued an alert on Multisystem Inflammatory Syndrome in Children, and asked clinicians to report any suspected cases to local and state health departments.

As of 29 July 2020, a total of 570 MIS-C patients with onset dates from March 2 to July 18, 2020, had been reported from 40 state health departments, the District of Columbia, and New York City. The median patient age was 8 years (range = 2 weeks–20 years); 55.4% were male, 40.5% were Hispanic or Latino (Hispanic), 33.1% were non-Hispanic black (black), and 13.2% non-Hispanic white (white). Obesity was the most commonly reported underlying medical condition, occurring in 30.5% of Hispanic, 27.5% of black, and 6.6% of white MIS-C patients. 364 (63.9%) of patients needed ICU care, and 10 children (1.8%) died.

Latent class analysis (LCA), a statistical modelling technique that can divide cases into groups by underlying similarities, was used to identify and describe differing manifestations in patients who met the MIS-C case definition. Indicator variables used in the analysis were presence or absence of SARS-CoV-2–positive test results by PCR or serology, shock, pneumonia, and involvement of organ systems.

This analysis divided the cohort of patients into three groups.

Class 1: 203 (35.6%) patients. Median age 9 years. These patients had the highest number of involved organ systems. Of this group, 99 (48.8%) had involvement of six or more organ systems; most commonly cardiovascular (100.0%) and gastrointestinal (97.5%). Compared with other Classes they had significantly more shock/abdominal pain/myocarditis/lymphopenia and markedly raised inflammatory markers. Coronary artery dilatation and aneurysm rate was 21.1%. 10 (4.9%) met full criteria for Kawasaki disease. 98% had positive Sars COV2 positive serology with/without positive PCR. 1 child from this group died (case fatality rate 0.5%)

Class 2: 169 (29.6%) patients. Median age 10 years. In this group, 129 (76.3%) had respiratory system involvement. These patients were significantly more likely to have cough, shortness, ARDS. Coronary artery dilatation and aneurysm rate 15.8%. 5 children (3%) met full criteria for Kawasaki disease. Most of this group (84%) had Sars CoV2 positive PCR without positive serology. This suggested Class 2 had severe acute Covid 19 disease. Nine children in this group died, giving the highest case fatality 5.8%

Class 3: 198 (34.7%) patients. Median age 6 years (significantly younger). This group had the highest prevalence of rash (62.6%), and mucocutaneous lesions (44.9%). Prevalence of coronary artery aneurysm and dilatations was 18.2%. 6.6% met criteria for complete Kawasaki disease. This group had the lowest prevalence of underlying medical conditions, organ system involvement, complications (e.g., shock, myocarditis), and markers of inflammation and cardiac damage. 63.1% had positive SARS-CoV-2 serology only and 33.8% had both serologic confirmation and positive RT-PCR results. None of these children died.

Comparison with UK report of PIMS-TS;The association of Covid 19 with an inflammatory syndrome has been reported in many countries across Europe following on from the peak outbreaks in the respective countries. In the UK, Whittaker et al, in JAMA in June, published a cohort of 58 children who met the criteria for PIMS-TS. These 58 children were reported as one group; however they were stratified by shock, Kawasaki disease, Kawasaki clinical criteria, coronary artery aneurysm, and prevalence of Sars CoV 2 infection (PCR or serology). Though direct comparison across the groups is somewhat difficult, some similarities and differences are apparent.

CDC Class 1 with shock abdominal pain and a somewhat older age group at presentation, with markedly raised inflammatory markers, is seen also in the UK group. The prevalence of abdominal symptoms is significantly higher in those where KD disease or clinical criteria is not met.

Similarly CDC Class 3 group of younger children with increase prevalence of mucocutaneous lesions, and rash were younger, and lower prevalence of shock is seen in the UK cohort when stratified.

CDC Class 2 with 76.3% respiratory involvement is not really reflected in the UK cohort, with respiratory symptoms only present in 26% of the total group, without wide variation when the UK group is stratified. It appears that this CDC Class 2 may be representative of acute severe Covid infection, which was not incorporated UK PIMS-TS cohort.

Coronary artery dilation and aneurysm was higher across all CDC classes compared with UK cohort prevalence of 14%.

Jhaveri SStern KJpeds Longitudinal Echocardiographic Assessment of Coronary Arteries and Left Ventricular Function Following Multisystem Inflammatory Syndrome in Children (MIS-C)02 Aug 2020United StatesNorth America15Clinical - PIMS-TShttps://www.jpeds.com/article/S0022-3476(20)30984-7/pdf
Diorio, CBassiri, HJCIMultisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-230 Jul 2020USANorth America20Clinical - PIMS-TShttps://www.jci.org/articles/view/140970#sd

According to the authors this is a prospective report comparing life threatening complications of SARS-CoV-2 in children.

Children admitted to the Children's hospital of Philadelphia between April 3rd and May 15th 2020 were prospectively screened and enrolled if there was evidence of past or present SARS-CoV-2 infection. After enrolment the children were categorised by clinical presentation as MIS-C, severe COVID-19 or minimal COVID-19.

Data collected included demographics, co-morbid conditions, sources of co-infection, treatments used and many laboratory investigations particularly looking for organ dysfunction and inflammatory markers.

26 children were enrolled, there was only sufficient data on 20. Of these 6 met the criteria for MIS-C (and 2 of these also met criteria for Kawasaki Disease), 9 severe COVID-19 and 5 minimal COVID-19. All 6 MIS-C patients had been previously healthy and were younger than the other groups. 8 of the 9 severe COVID-19 had pre-existing conditions and all 5 of the minimal COVID-19 had other infections or pre-existing conditions which were the reason for admission. Ethnicity showed no significant differences between the groups. Among the wealth of analyses, only TNF+IL-10 significantly distinguished between MIS-C and severe COVID-19 (p=0.036). Data also supports an infective aetiology for MIS-C.

This is a small study from early in the pandemic (enrolment was started before CDC alert on MIS-C in USA). Various hypotheses are mentioned but not statistically proven. The authors themselves state "We believe these results can inform hypotheses for future studies when larger cohorts are available and we would caution against broad generalisation of these results until such work is complete.

Lee, PYSon, MBFJ Clin Invest 2020Distinct clinical and immunological features of SARS-COV-2- induced multisystem inflammatory syndrome in children23 Jul 2020USANorth America28Clinical - PIMS-TShttps://www.jci.org/articles/view/141113

28 children with MIS-C and evidence of SARS-CoV-2 were identified at a tertiary referral unit in Boston, USA, between March and June 2020. Age range, 1 month–17 years; median, 9 years. 57% male. Statistically significant over-representation of black and Hispanic cases. 50% had pre-existing medical conditions. Comprehensive data is given on the clinical and immunological features, treatment and outcomes.

The pattern of MIS-C showed a clear distinction from both Kawasaki disease and Macrophage Activation Syndrome. Respiratory features were mild compared to adult MIS (none mechanically ventilated, 25% non-invasive support, 14% supplemental O2 only) but other organ systems were similarly affected (GI 54%, conjunctivitis 57%, rash 36%, low platelets 64%, low lymphocytes 75%, raised D-dimers 96%, acute kidney injury 21%, L ventricular dysfunction 39%). 61% required ICU admission, 54% due to hypotension/shock, but none developed ARDS. Intravenous immunoglobulin (71%), corticosteroids (61%), remdesivir (25%), anakrina (18%) and hydroxychloroquine (1 case) were given as immunomodulatory treatments, with clinical improvement in all cases. There were no deaths.

To, KKwan, MDiagnostic Microbiology and Infectious DiseaseFalse-positive SARS-CoV-2 serology in 3 children with Kawasaki disease17 Jul 2020ChinaAsia3Clinical - PIMS-TShttps://doi.org/10.1016/j.diagmicrobio.2020.115141

This retrospective case study of three children with typical Kawasaki disease reports the discrepancy between positive tests for SARS-CoV-2 anti-NP or anti-RBD IgG, and subsequent microneutralization assays which were negative in all three.

Clinical features: The study took place in Hong Kong, China. Three children were identified as having typical Kawasaki disease between January and April 2020. Two were aged 3 months and one was aged 6 months; two were girls and one a boy. None reported any epidemiological links to individuals with COVID-19 or any travel history in areas with COVID-19 outbreaks.

All three had fever, conjunctivitis, a maculopapular rash, cracked or erythematous lips and rhinorrhea. Two had in addition a cough and one had cervical lymphadenopathy. Two had abnormal echocardiograms (perivascular echogenicity and non-tapering coronary arteries) and one had a normal echocardiogram.

Each patient tested negative for SARS-CoV-2 and other common respiratory pathogens in nasopharyngeal aspirate polymerase chain reaction (PCR).

Bloods: One patient tested positive for SARS-CoV-2 anti-RBD and anti-NP IgG after 60 days; a second patient tested positive for SARS-CoV-2 anti-RBD and anti-NP IgG after 87 days; and the third patient tested positive for only SARS-CoV-2 anti-RBD IgG after 90 days.

All three patients subsequently tested negative for SARS-CoV-2 neutralising antibodies by microneutralization assay (a titre ≥10 was considered positive).

Outcomes: All three were treated with intravenous immunoglobulin and high dose aspirin (30–50 mg/kg per day), followed by low dose aspirin (3–5mg/kg per day) for 8 weeks. All made a full recovery including normal echocardiograms.

Comment: The authors speculate that the false-positive SARS-CoV-2 IgG could be due to cross-reactive antibodies triggered by Kawasaki Disease or triggered by other coronaviruses. They discount the possibility that the results were related to the administration of IVIG, which had been obtained from healthy Hong Kong blood donors months before its use, and long before the first case of COVID-19 was diagnosed in Hong Kong in late January 2020.

There needs to be caution in investigating pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), in the light of these results, The authors recommend patients with positive SARS-CoV-2 serology but negative PCR should be further tested by microneutralization assay for the presence of neutralizing antibodies.

Davies, PRamnarayan, PLancetIntensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study09 Jul 2020UKEurope78Clinical - PIMS-TShttps://doi.org/10.1016/S2352-4642(20)30215-7

This multicentre observational study examines 78 children with PIMS-TS, admitted to 21 of the 23 PICUs in the UK between April 1 and May 10, 2020. The study team analysed routinely collected de-identified data submitted by clinicians from the individual PICUs.

The median age of patients was 11 years (IQR 8–14). There were 52 male patients (67%) and 61 patients (78%) were from ethnic minority backgrounds.

Clinical features: Common presenting features were fever in 78 (100%), shock in 68 (87%), abdominal pain in 48 (62%), vomiting in 49 (63%) and diarrhoea in 50 (64%). Rash was seen in 35 (45%) and conjunctivitis in 23 (29%).

Bloods: Of 35 patients tested for SARS-CoV-2 IgG serology, 33 were positive, and one of the two negative serology patients was PCR positive. 32 patients were PCR negative, with unknown serology and without a known COVID-19 contact. Over the first 4 days of admission there was a reduction in C-reactive protein (from a median of 264 mg/L on day 1 to 96 mg/L on day 4) and ferritin (1042 μg/L to 757 μg/L), whereas the lymphocyte count increased to more than 1·0 × 109 cells per L by day 3.

Outcomes: 36 (46%) patients were invasively ventilated and 65 (83%) needed vasoactive infusions; 57 (73%) received steroids, 59 (76%) received intravenous immunoglobulin, and 17 (22%) received biologic therapies. 28 (36%) had evidence of coronary artery abnormalities (18 aneurysms and ten echogenicity). Three children needed extracorporeal membrane oxygenation, and two children died.

During the study period, the rate of PICU admissions for PIMS-TS was at least 11-fold higher than historical trends for similar inflammatory conditions. Using these data and extrapolating from international child sero-prevalence data (Spain ~3% of children being infected, equivalent to 456,000 children in the UK) this would result in a conservative estimate of the risk of a child infected with SARS-CoV-2 subsequently being admitted to PICU with PIMS-TS as just under 2 per 10,000 infections.

Dufort, EZucker, H NEJMMultisystem Inflammatory Syndrome in Children in New York State29 Jun 2020USANorth America99Clinical - PIMS-TShttps://www.nejm.org/doi/full/10.1056/NEJMoa2021756?query=featured_coronavirus

This is a case series of 99 children (<21 years of age) from New York State with multisystem inflammatory syndrome in children (MIS-C). Of note some of these cases have been reported in small series (Cheung et al JAMA 2020). New York State Department of Health required hospitals that provide paediatric medical or surgical care to report potential cases of Kawasaki’s disease, toxic shock syndrome, or myocarditis or who were suspected to have MIS-C among persons younger than 21 years of age admitted since March 1, 2020, through the NYSDOH Health Emergency Response Data System. The clinical and laboratory characteristics of these reports were studied. Between March 1 and May 10 2020 191 cases were reported of which 95 met the criteria for MIS-C and 4 further were suspected.

Case definition: Confirmed cases were defined by the presence of both clinical and laboratory criteria. Suspected cases had clinical and epidemiological criteria. Clinical criteria were children <21 years of age with fever and needing hospitalisation with either; 1 or more of hypotension or shock, features of severe cardiac illness, or other severe organ failure. Or 2 or more of; maculopapular rash, non-purulent conjunctivitis, mucocutaneous inflammatory signs or acute GI symptoms with an absence of other cause.

Laboratory criteria: 1. General Criteria; Two or more of raised inflammatory markers and 2. Either positive SARS CoV2 RNA at time of presentation or within 4 weeks or detection of specific antibody.

Epidemiological criteria: In 6 weeks prior to exposure close contact with a person with confirmed or clinically consistent Sars CoV2 infection or travel to or resident in an area with ongoing community transmission.

Baseline characteristics: 53 (54%) were male. Age range was 0-5 years (31%), 6 to 12 year (42%) and 13 to 20 years (26%). 78 patients had data on race with 29 (37%) were white, 31 (40%) were black, 4 (5%) were Asian, and 14 (18%) were of other races. 36 patients had a preexisting condition, 29 had obesity. 24 (24%) had a Covid-19–compatible illness a median of 21 days (interquartile range, 10 to 31) before hospitalization, 38 (38%) had exposure to a person with confirmed Covid-19, and 22 (22%) had direct contact with a person who had clinical Covid 19.

Symptoms : Described in detail in the study. Prevalence of dermatologic symptoms was highest among children 0 to 5 years of age, and the prevalence of myocarditis (diagnoses and clinical) was highest among the adolescents.

Treatment : Of 99 patients, 79 were treated in ICU. 69 had IVIG, 63 received systemic glucocorticoids, 48 received both systemic glucocorticoids and IVIG. 9 patients had coronary aneurysm

Outcome : As of May 15, a total of 76 patients (77%) had been discharged and 21 (21%) were still hospitalised. Unfortunately 2 patients died in the hospital. Both were intubated and ventilated, once received ECMO. Neither received IVIG, systemic glucocorticoids, or immunomodulators.p

Feldstein, LRRandolph, AGNEJMMultiststem Inflammatory Syndrome in U.S. Children and Adolescents29 Jun 2020USANorth America186Clinical - PIMS-TShttps://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.nejm.org%2Fdoi%2Ffull%2F10.1056%2FNEJMoa2021680&data=01%7C01%7CA.Munro%40soton.ac.uk%7C44a8f00e84024fc3091408d81ce42e9c%7C4a5378f929f44d3ebe89669d03ada9d8%7C0&sdata=bQRL8Sx61R5%2FkQST67%2FVl9CZj8puJPfyKJCftB6Q9ec%3D&reserved=0

This retrospective and prospective multi-centre cohort study from 53 participating hospitals in 26 states looked at 234 patients under 21 years of age that met criteria for multi system inflammatory syndrome in children (MIS-C), between March 15 and May 20th

The median age of the patients was 8.3years old and 62% (115) were male. Fifty one patients (27%) had an underlying medical condition. In terms of confirmation of SARS_CoV-2 infection - 70% were positive for RT-PCR and/or antibody testing. Of a small subgroup of 14 patients with Covid-19 symptoms before MIS-C, the median time between Covid-19 symptom to MIS-C was 25 days (6-51 days).

Criteria for MIS-C were based on CDC guidelines (in brief, requiring hospitalisation, at least two systems involved, fever of at least 24 hours and either lab confirmed SARS_CoV-2 infection (via RT-PCR or antibody testing) or an epidemiological link to a person with Covid-19 within 4 weeks before onset of symptoms).

Although MIS-C criteria was at least 2 system involvement, 71% had involvement of four organ systems or more. The most frequent systems in order were gastrointestinal (92%) followed by cardiovascular (80%), haematological (76%) and respiratory (70%). Blood changes observed included lymphocytopaenia in 80% of patients, and an elevated CRP in 91%.

Looking at similarity and overlap with Kawasaki disease, 40% of patients had either fever for at least 5 days and 4-5 of Kawasaki's disease-like features or 2-3 Kawasaki's disease-like features with additional lab or echocardiographic findings. Common symptoms similar to Kawasaki disease bilateral conjunctival infection in 103 (55%), oral mucosal changes in 78 (42%), peripheral extremity change in 69 (37%), rash in 110 (59%), cervical lymphadenoapthy (>1.5cm diameter) in 18 (10%). Differences between MIS-C and Kawasaki's disease groups include an older age group and a different cardiovascular involvement (more likely myocardial dysfunction) in MIS-C patients.

The majority of patients required ICU admission (n=148, 80%) with one in five patients needing invasive mechanical ventilation. Eight patients received ECMO support. Treatment included IVIG in 77% and systemic glucocorticoids in 49%. There were four deaths (two of which had received ECMO). At the time of writing the paper, 70% of patients had fully recovered with 28% still in hospital.

Felstein, LRandolph, ANEJMMultisystem Inflammatory Syndrome in U.S. Children and Adolescents29 Jun 2020USANorth AmericaClinical - PIMS-TShttps://www.nejm.org/doi/full/10.1056/NEJMoa2021680
Hameed, SJogeesvaran, K HRadiologySpectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19.25 Jun 2020UKEurope35Clinical - PIMS-TShttps://pubs.rsna.org/doi/10.1148/radiol.2020202543
Riollano-Cruz, MPaniz-Mondolfi, AJ Med VirolMultisystem Inflammatory Syndrome in Children (MIS‐C) Related to COVID‐19: A New York City Experience25 Jun 2020USANorth America15Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26224

This retrospective case series describes 15 patients presenting to Mount Sinai Hospital in New York between 24th April and 19th June 2020. Patients were identified by presentation to hospital with clinical features meeting the criteria for MIS-C (known in the UK as PIMS-TS) as defined by the Centers for Disease Control and Prevention Emergency Preparedness and Response, and the New York City Health Department. The mean age of the 15 patients was 12 years, with a range of 3 to 20 years. 11 patients (73%) were male, and 10 patients (66%) identified as Hispanic or Latino.

Clinical features: All patients had a fever at admission and 13/15 (87%) had gastrointestinal symptoms including abdominal pain, vomiting and diarrhoea. Respiratory symptoms were far less common, with cough or sore throat only occurring in 3/15 (20%) of cases. Other features at admission included rash in 7/15 (47%), conjunctivitis in 4/15 (27%) and swollen hands and feet in 4/15 (27%).

COVID-19 status: 7/15 (47%) tested positive for SARS-CoV-2 from a nasopharygeal or respiratory specimen during admission, and 2/15 (13%) had a positive test in the month prior to admission. 15/15 (100%) of patients were positive for COVID-19 antibodies.

Radiology: CXR at admission showed non-specific findings in 7/15 (47%), reactive airway disease in 4/15 (27%), pleural effusions in 4/15 (27%) and were normal in 3/15 (20%). Echocardiogram was abnormal in 12/15 (80%): 4/15 (27%) had reduced LV function, 3/15 (20%) had reduced biventricular function and 3/15 (20%) had coronary artery abnormalities.

Bloods: 13/15 patient (87%) presented with lymphopenia, and 14/15 (93%) had elevated fibrinogen. During admission 15/15 cases (100%) had a raised CRP and D-dimer, 14/15 (93%) had a raised ESR and 13/15 (87%) had a raised ferritin. IL-6 and IL-8 were elevated in 15/15 patients (100%) whereas 0/15 (0%) had an elevated IL-1 (which tends to be raised in Kawasaki disease).

Treatment: 15/15 patients (100%) received prophylactic enoxaparin until 2 weeks post-discharge. 12/15 patients (80%) received tocilizumab (anti-IL-6 antibody), 12 (80%) were given IVIG, 3 (20%) received steroids, 2 (13%) initially received Anakinra (IL-1 receptor antagonist),and 2 (13%) patients were treated with Remdesivir. Outcomes were not analysed according to treatment received.

Outcomes: 14/15 patients (93%) were admitted to PICU. 3 patients (20%) needed mechanical ventilation, another 5 patients (33%) required non-invasive ventilation, and 8 patients (53%) needed inotropic support. At the time of publication 13 patients had been discharged, 1 was still an inpatient and 1 had died.

Chiu, J. S., Samuels-Kalow, MPediatr Cardiol. Kawasaki Disease Features and Myocarditis in a Patient with COVID-1915 Jun 2020USANorth America1Clinical - PIMS-TShttps://link.springer.com/article/10.1007/s00246-020-02393-0
Capone, CDavidson, KJ. PediatrCharacteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection14 Jun 2020USNorth America33Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293762/

This is a single-centre retrospective case series of 33 sequentially hospitalized febrile paediatric patients with CDC case definition for Multisystem Inflammatory Disease of Childhood (MIS-C) and WHO criteria for Multisystem Inflammatory Syndrome (MIS) admitted to Cohen Children's Medical Center, Queens, NY from April 17, 2020 through May 13, 2020. All cases were positive for SARS-CoV-2 by detection of serum antibodies or nucleic acid from a nasopharyngeal specimen. Patients with COVID-like lower respiratory tract involvement were excluded. The peak of hospitalizations occurred approximately five weeks after the peak of hospitalizations with acute COVID-19. Patients were predominantly male (20, 61%) and non-Hispanic (24, 73%) with a median age of 8.6 years (IQR 5.5-12.6). Most patients were previously healthy but a higher proportion were overweight (2,6%) or obese (12, 39%) compared with the regional childhood obesity rate of 18%. 

Patients presented with a median of 4 days (IQR 3-5) of fever and almost all (32, 97%) had gastrointestinal symptoms (including diarrhoea, vomiting and abdominal pain) as well as other organ system involvement. 21 (64%) patients fulfilled complete criteria for KD and most patients with complete KD criteria, had shock (16, 76%). 

All patients had negative blood cultures and multiplex nucleic acid amplification test for multiple respiratory pathogens except 1 patient in whom influenza virus detected. 26 (79%) patients needed intensive care and 6 (18%) required mechanical ventilation. 58% had myocardial dysfunction and 76% required vasoactive medications. Coronary artery aneurysm was identified in 5 (15%) and dilation was detected in 3 (9%) patients.

All patients were treated with IVIG, 88% received aspirin, and 70% were given a corticosteroid and 42% were given Enoxaparin. 24% of patients exhibited a partial response to these treatments and received a biologic modifying medication (Anakinra, Tocilizumab, Infliximab). Most patients demonstrated rapid clinical improvement. No patients died. Median length of hospital stay was 4 days (IQR 4, 8). At hospital discharge, mild cardiac dysfunction was still present in 9 of 19 patients. This case series shares similarities with smaller international case series reported as Kawasaki-like disease and hyperinflammatory shock syndrome. In all these studies, most patients had antibodies against SARS-COV2 virus, suggestive of a post-infectious, immunologically mediated pathophysiology. The authors suggest that the latent period between the peak of paediatric cases of COVID-19 and MIS-C suggests that MIS-C has a post-infectious, possibly immunologically mediated pathogenesis.

Despite clinical similarities with KD, differences include the predominance of gastrointestinal symptoms, an older age range (8.6 year in MIS-C patients compared with a median age of 2.5 years for patients with KD), markedly elevated inflammatory markers, higher proportion of patients with shock and/or impaired cardiac function (76%) than in other KD studies (less than 3% shock reported), and the lack of thrombotic events in the case series patients. This suggests that MIS-C may be a syndrome distinct from KD. Acute COVID-19 with "cytokine storm" further complicates differentiation of these presentations.  

Further study is needed to shed light on the pathophysiology, treatment options, and outcomes of MIS-C.

Foong Ng, KTang, JWTJournal of Medical VirologyCOVID-19 Multisystem Inflammatory Syndrome in Three Teenagers with Confirmed SARS-CoV-2 Infection13 Jun 2020UKEurope3Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26206
Kaushik, SMedar, SJ PediatricsMultisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection: A Multi-institutional Study from New York City13 Jun 2020USANorth America33Clinical - PIMS-TShttps://www.jpeds.com/action/showPdf?pii=S0022-3476%2820%2930747-2

This retrospective observational study details clinical characteristics, therapies and outcomes of a multicentre cohort of 33 children with Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 admitted to PICUs at 3 tertiary care children’s hospitals in New York City between 23 April and 23 May 2020.Study design: Patients aged 1 month to 21 years admitted to 3 NYC PICUs (at Children’s Hospital at Montefiore, Mount Sinai Kravis Children’s Hospital and Jacobi Medical Center) with confirmed SARS-CoV-2 infection (positive nasopharyngeal swab RT-PCR or antibody assay) meeting criteria for MIS-C (US CDC case definition, formalised on 14 May 2020, used: age < 21 yrs presenting with fever, laboratory evidence of inflammation and evidence of clinically severe illness requiring hospitalisation, with 2 organ involvement, plus no alternative plausible diagnosis, plus positive for current/recent SARS-CoV-2 infection or COVID-19 exposure within 4 wks prior to onset of symptoms). During the study period there were additional suspected patients with similar presentations and management without confirmed SARS-CoV-2 infection/exposure who were excluded; only cases with confirmed infection by RT-PCR/antibody assay were included.

Study population: 33 children met the inclusion criteria at the 3 centres. Median age 10 years (IQR 6-13), 20/33 male (61%), median BMI 18.6 kg/m2 (IQR 15.9-22.9), 2/33 obese (6%, BMI > 30 kg/m2). 15/33 Hispanic/Latino (45%), 13/33 black (39%), 3/33 white (9%), 1/33 Asian (3%), 1/33 other (3%). 16/33 comorbidities (48%) (most common comorbidity was asthma). 8/33 (24%) had had contact with an ill person, 5/33 (15%) had had contact with a confirmed COVID-19 case.

Clinical features: Fever 31/33 (94%), mucocutaneous involvement 7/33 (21%), conjunctivitis 12/33 (36%), rash 14/33 (42%), abdominal pain 21/33 (64%), nausea/vomiting 23/33 (70%), diarrhoea 16/33 (48%), dyspnoea 11/33 (33%), dizziness 3/33 (9%). Duration of symptoms prior to admission 4.5 days (IQR 3-6). 21/33 (64%) were hypotensive on admission.

Admission blood results: Medians (IQR in brackets): WBC 11,000/L (8450-14,400), lymphocytes 1,100/L (600-1,300), CRP 250 mg/L (156-302), ESR 53 mm/hr (28-77), procalcitonin 5.4 ng/mL (1.8-16.7), ferritin 568 ng/mL (340-954), fibrinogen 627 mg/dL (455-782), D-dimer 3.7 g/mL FEU (2.4-5.1), BNP 388 pg/mL (75-1086), pro-BNP 4328 pg/mL (2117-13370), troponin T 0.08 ng/mL (0.02-0.17), IL-6 200 pg/mL (56.4-330), IL-8 41.7 pg/mL (25.1-54.4), creatinine 0.6 mg/dL (0.4-1.1).

CXRs: Cardiomegaly 10/33 (30%), focal or bilateral pulmonary opacities 11/33 (33%).

Echocardiograms: Performed in 32/33 (97%). Pericardial effusion 15/32 (47%), median LVEF 47% (IQR 40-53). LVEF < 30% 4/32 (13%), LVEF 30-50% 17/32 (53%), LVEF > 50% 11/32 (34%). 24/32 had a second echocardiogram prior to discharge: of those with initial LVEF < 50%, 20/21 (95%) had recovery of ventricular function with normal EF. Median pre-discharge LVEF 58% (IQR 55-62). A detailed table is supplied for the 21 patients with LVEF < 50%, including BNP/troponin levels, drug treatment by patient and the 8/21 who had prominent coronary arteries on echo.

Treatment in PICU: 18/33 received IVIg (55%), 17/33 corticosteroids (52%), 12/33 tocilizumab (35%), 7/33 remdesivir (21%), 4/33 Anakinra (12%), convalescent plasma therapy 1/33 (3%), 17/33 vasopressor/inotropes (52%) (median duration of vasopressor use 72 hrs (IQR 48-110), norepinephrine most commonly used agent), 8/33 aspirin (24%), 21/33 diuretics (64%). Anticoagulation was used in all patients: prophylactic dose enoxaparin 5/33 (15%),therapeutic dose enoxaparin 27/33 (82%), therapeutic dose unfractionated heparin 1/33 (3%). Empiric antibiotic coverage for < 48 hrs in 14/33 (42%) and > 48 hrs in 15/33 (45%). 5/33 (15%) required invasive mechanical ventilation. 2/33 (6%) required mechanical circulatory support: 1 ECMO (5-yr-old) and 1 intra-aortic balloon pump (20-yr-old).

Outcomes: 32/33 (97%) patients were discharged home with median PICU stay of 4.7 days (IQR 4-8) and hospital stay of 7.8 days (IQR 6-10). 1/33 (3%) died (ischaemic brain infarction with subarachnoid haemorrhage on day 6 of ECMO).The authors conclude that rapid, complete clinical and myocardial recovery was almost universal in their study. They hypothesise that this novel COVID-19 MIS-C is predominantly an antibody-mediated or other immune cell-mediated cytokine storm, with some contribution from direct myocardial injury. They note the lower morbidity in their cohort relative to recent European studies

Schnapp, AMolho-Pessach, VJ Eur Acad Dermatol VenereolIntroductory histopathologic findings may shed light on COVID19 pediatric hyperinflammatory shock syndrome13 Jun 2020IsraelMiddle East1Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16749
Ramcharan, TChikermane, APediatr Cardiol.Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital12 Jun 2020UKEurope15Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289638/

This retrospective case-series on the cardiac manifestations of PIMS-TS from a UK Paediatric Centre (Birmingham); reinforces and highlights some of the clinical features reported elsewhere.

15 patients meeting the definition of PIMS-TS were identified over one month, between 10th of April and 9th of May, at Birmingham Women’s and Children’s NHS Foundation Trust. Patient demographics were consistent with other larger reports; patient age 8.8yrs (IQR 6.4-11.2years); which the authors highlight is older than the average age of children affected by Kawasaki’s disease in the UK and consistent with previous literature on PIMS-TS. Furthermore; this cohort were predominantly male (11/15 (73%) and all (100%) were from African/Afro-Caribbean, South Asian, mixed or other minority ethnic groups; the authors highlight that this is disproportionate to the ethnic demographics of children within the region.

The paper focuses on cardiac investigations and highlights that all patients in this cohort had evidence of cardiac involvement. 60% (9/15) had ECG abnormalities;

primarily T-wave abnormalities; 93% (14/15) had coronary artery abnormalities on echo. Coronary abnormalities were detailed as ‘prominent’, ‘dilated’ or ‘aneurysmal’. Aneurysms were seen in only one patient. Left ventricular dysfunction was evidenced in 80% and this was reflected in the needs for cardiovascular support (necessary in 10/15 (67%) of patients and an equal number requiring PICU admission).

Reassuringly all patients survived and were discharged after a median hospital stay of 12 days (IQR 9-13days). In the 12 patients who had completed their first clinic review (1 week following discharge), all had stable cardiac function and no new coronary changes.

Pouletty, AMelki, IAnn Rheum Dis Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort11 Jun 2020FranceEurope16Clinical - PIMS-TShttps://ard.bmj.com/content/annrheumdis/early/2020/06/11/annrheumdis-2020-217960.full.pdf

This is a retrospective clinical case series, comprising 16 children from the Paris region, France, who were reported to two national networks of children with rare auto-immune and rheumatologic disorders between 7 and 30 April 2020. Median age was 10 years (IQR (4.7 to 12.5)) and sex-ratio was 1. Four children were overweight and 2 had asthma.

SaRs-CoV-2 was detected in either nasopharyngeal secretion or stool samples in 11 cases (69%), while the remaining five cases included in the series had close exposure to a SARS-CoV-2 PCR-positive individual.

Ten patients (62%) had Kawasaki Disease, defined by persistent fever over 5 days associated with at least four of the five following criteria: conjunctivitis, lymphadenopathy, skin rash, red and cracked lips, inflammation of hands and feet; whilst the remaining 6 were described as having “incomplete” Kawasaki Disease.

Clinical features: Cough and dyspnoea occurred in 2 (12%) and anosmia in 1 (6%), whereas 13 (81%) had gastrointestinal signs. Neurological signs (headache or aseptic meningitis) occurred in 9 (56%). Thirteen (81%) had skin rash, 11 (68%) had erythema/oedema of hands and feet, 15 (94%) had conjunctivitis, 14 (87%) had dry cracked lips and 6 (37%) had cervical lymphadenopathy.

Eleven (69%) children developed haemodynamic failure and 9 (56%) developed acute renal failure. 7 patients (44%) developed Kawasaki shock syndrome.

Laboratory investigations: Inflammatory biomarkers were highly elevated in all patients, with median C-reactive protein (CRP) 207mg/L (IQR 162 to 236). Ferritin (median 1067 μg/L (IQR 272 to 1709)) was abnormal in 12 of 14 tested patients, and highly elevated (>500μg/L) in 50% of cases. Myocardial enzymes were elevated in 11 patients.

Imaging: Only 5 (31%) children had an abnormal chest X-ray. Eleven (69%) had an abnormal cardiac ultrasound, including coronary artery dilatation and signs of myocarditis or pericarditis.Treatment: Fifteen patients (94%) were treated with intravenous immunoglobulin. Additional treatments included steroids in 3 (19%) and aspirin in 15 (94%). Seven children (44%) were admitted to ICU.

Outcome: Median duration of symptoms from onset until abatement of fever was 9 days (IQR 8 to 13). No patient died. All made a recovery, but two have persistent mild cardiac dysfunction due to myocarditis.

This paper makes an important contribution to the clinical literature about Paediatric Multisystem Inflammatory Syndrome temporally associated with COVID-19.

The authors compared their patients to an historical series of 220 French children diagnosed with Kawasaki disease between 2005 and 2020. The children in the historical series were significantly younger and had significantly higher platelet and lymphocyte counts. Importantly, the patients reported in the present study had a significantly higher frequency of cardiac complications than children in the historical series.

The authors also attempted to subdivide the small cohort into a severe and non-severe group, but the comparison does not appear to serve a useful purpose.

Blondiaux EDucou le Pointe HRadiologyCardiac MRI of Children with Multisystem Inflammatory Syndrome (MIS-C) Associated with COVID-19: Case Series09 Jun 2020FranceEurope4Clinical - PIMS-TShttps://pubs.rsna.org/doi/10.1148/radiol.2020202288

The authors describe 4 children who developed MIS-C who required admission to PICU because they had developed myocarditis and signs of cardiogenic and/or septic shock syndrome. One required mechanical ventilation. All 4 recovered.

Mean age was 9year (range 6-12years), and cardiac features developed <1 week after onset of covid-19 symptoms of abdominal pain and rash. 3 of the 4 had chelitis or conjunctivitis. None had experienced any respiratory symptoms.

Nasopharyngeal swabs and respiratory and stool samples were all negative for covid-19 using RT-PCR. All 4 had positive IgG to covid-19 and one also had positive IgM antibody. The clinical and laboratory findings and treatment given are tabulated, and a further table gives the cardiac MRI findings with images. MRI was undertaken during the acute phase in 3 and recovery phase in the 4th patient. The main MRI finding was of cardiac hyperaemia and oedema, without evidence of fibrosis. There were no coronary artery abnormalities.

The authors contrast the diffuse myocardial findings of MIS-C in children with the cardiac effects of covid-19 in adults, in whom it causes focal myocardial fibrosis/necrosis. They highlight that their findings point to inflammatory infiltration of the interstitial myocardium similar to that seen in Kawasaki disease. They suggest that this points to an inflammatory immune response to an antigen rather than to viral infiltration. The timescale of peak inflammatory response at 10 days after onset of symptoms and resolution by 20 days is also similar Kawaski disease. In contrast to Kawasaki disease, MISC-C affects an older age group and was not associated with arterial changes in this series.

Cheung, EMilner, JJAMAMultisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City08 Jun 2020USANorth America17Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2767207?appId=scweb

This is a case series of 17 children, admitted to a hospital in New York city, between April 18th and May 5th 2020 with features of Multisystem Inflammatory Syndrome Related to COVID-19.

Patients included in this series were i. less than 21 years old, ii. presented with a clinical syndrome characterized by prolonged fever, systemic inflammation, shock, end-organ dysfunction, or symptoms reminiscent of Kawasaki Disease or Toxic Shock Syndrome and iii. had evidence of recent (SARS-CoV-2) infection. The baseline characteristics of these children were; median age 8 years (1.8-16), 8 were male (47%); 12 were classified white (70.1%), 4 black (23.5%), 1 Asian (5.9%).

Presentation: All had fever, with median duration of 5 days. 14/17 had GI symptoms. Mucocutaneous findings were common (12 rash, 11 conjunctivitis, 9 lip redness/swelling). 3 were hypoxic at presentation, and 13 had shock. 8 met criteria for KD and 5 for incomplete KD.Investigations: 8 patients tested positive for SARS-CoV-2 by RT-PCR and 9 by serology.

Xrays: 14 had abnormal chest radiograph findings, most commonly bilateral, interstitial opacities.

Bloods: mean values for a wide variety of investigations shown in paper in table 2. Mainly group were lymphopenic with raised ferritin, d dimers, clotting times, and troponin. Cardiac: ECG of 16 patients showed nonspecific ST/T-wave abnormalities in 10 and attenuated QRS voltage in 1. Dysrhythmias were noted in 3. Admission echos showed normal to mildly decreased left ventricular function in 11, or moderate or more ventricular dysfunction in 6. All patients had normal coronary arteries by measurement, though coronary arteries were described as prominent or echogenic in 7. However one patient (aged 4 years) developed a medium-sized aneurysm (z score, 5.2) of the left anterior descending coronary artery. This patient presented with fever, diarrhea, and shock, with no additional features of KD.Treatment: 15/17 patients were admitted to PICU; vasoactive support was required in 10. Treatment was varied, 14 received steroids (either methylprednisone or hydrocortisone, prednisolone numbers of each not given). 13/17 received IVIG including 3 patients who did not receive steroids and 8 who met criteria for KD. One patient received tocilizumab.

Outcome: All patients discharged home with no fatalities.

Comparison with other PIMS TS cohorts:

Reports of hyperinflammatory syndrome in children during the Sars CoV2 outbreak has been reported in France, Italy, UK and US. (see https://dontforgetthebubbles.com/pims-ts/) This cohort used the CDC definition, which is broadly similar to RCPCH and WHO, though in the US paediatrics < 21 years of age.

Like the other cohorts, the age range is older than typically seen in Kawasaki Disease. Fever and GI symptoms are very common. Mucocutaneous signs were also common. Children presented very unwell, with many needing PICU care (88% in this study). Treatment used included IVIG and steroids.

Unlike other cohorts where black ethnicity was pronounced, 70% of this cohort was classified as white. It would be useful to know the demographic breakdown of the local paediatric population who attend this hospital.

Whittaker, ELevin, MJAMAClinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-208 Jun 2020UKEurope58Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2767209

This paper provides a detailed description of the clinical and laboratory features of 58 children diagnosed with PIMS-TS from 8 hospitals in England between March 23rd and May 16th 2020. All children fulfilling the UK, WHO or CDC criteria for PIMS-TS / MIS-C were included; evidence of SARS-CoV-2 infection was not required for inclusion. Features of this group were compared with previous data from children with Kawasaki Disease (KD), KD shock syndrome (KDSS) and toxic shock syndrome (TSS).

Of the 58 patients, 45 (78%) had evidence of SARS-CoV-2 infection (RT-PCR (15) and or IgG (40)). 33 (57%) were female. 22 (38%) were of black race, 18 (31%) asian. The majority were previously well; only 7 had co-morbidities (3 with asthma, 1 epilepsy, 1 neuro-disability, 1 sickle cell trait, 1 alopecia)

All patients had fever (range 3-19 days). Gastrointestinal symptoms were common (abdominal pain (53%), diarrhoea (52%), vomiting (45%)) whilst respiratory symptoms were relatively uncommon (21%) and 15 (26%) had headache. 

Only 13 (22%) of patients fulfilled criteria for KD; 8 (14%) had coronary artery aneurysm, 26 (45%) conjunctival injection, 30 (52%) rash, 17 (29%) mucous membrane changes, 9 (16%) lymphadenopathy, and 9 (16%) swollen hands and feet. Half of patients developed shock. Laboratory findings were consistent with marked inflammation (mean CRP 229 mg/L (IQR 156-338), ferritin 610 μg/L (359-1280), fibrinogen 5.7 g/L (4.4-7), D-dimer 3578 ng/mL (2085-8235)) with neutrophilia (13 x 10^9 (10-19)). Evidence of myocardial injury was common with troponin elevated in 34/50 (68%) and NT ProBNP in 24/29 (83%). Low haemaglobin (92 g/L (83-103)), lymphocyte (0.8 x 10^9 (0.5-1.5) and platelet levels (151 x 10^9 (104-210)) were also observed. 

Half of patients were admitted to a critical care unit; 25 (43%) requiring mechanical ventilation, 27 (47%) inotropes and 3 (5%) ECMO. A range of treatments were given including IVIG (71%), steroids (64%), anakinra (5%) and infliximab (14%). 13 (22%) recovered without immunomodulatory treatment, whilst 60% received >/= 2 and  16% >/= 3 agents. To the last date of follow up only one child had passed away. p

The authors suggest three clinical patterns of PIMS-TS based on the patients included in this series:   (1) persistent fever and elevated inflammatory markers (without KD, shock or organ failure) - 23 patients here  (2) fever and shock, often with myocardial dysfunction - 29 patients   (3) children fulfilling criteria for KD - 7 patients (13 if aneurysm included in criteria). 

Compared with children with KD, KDSS and TSS, children with PIMS-TS were older (median age 9 (IQR 5.7-14)) with higher CRP and lower haemaglobin. Compared with those with KD and KDSS, PIMS-TS patients in this series had higher neutrophil count, ferritin and troponin with lower platelet and lymphocyte counts. Compared with pre-COVID-KD cases children with PIMS-TS KD were older and had higher markers of inflammation and myocardial injury. 

This is the most detailed clinical report of PIMS-TS to date. The findings here demonstrate a syndrome with a wide spectrum of signs, symptoms and severity with some overlap with KD, KDSS and TSS. PIMS-TS is characterised by marked inflammation with myocardial dysfunction and often shock necessitating ICU admission for inotropic support, mechanical ventilation and, in a small number of patients, ECMO. Treatment with immunomodulatory agents similar to those used in KD has been employed and only one death had occurred at the time of the report. Differences in clinical and laboratory profile compared with KD, KDSS and TSS, suggests= that PIMS-TS is a unique entity, potentially arising from a maladaptive acquired immune response to SARS-CoV-2 infection. 

Toubiana, JAllali, SBMJKawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study03 Jun 2020FranceEurope21Clinical - PIMS-TShttps://www.bmj.com/content/369/bmj.m2094

This cohort study looks at a cluster of patients diagnosed with Kawasakis disease at a hospital in Paris between April 27th and May 11th. During this time they admitted 21 children with a diagnosis of Kawasakis or incomplete Kawasakis, with a median age of 7.9yr and 12/21 female.

Clinical features: All children presented with persistent fever and with initial GI symptoms (vomiting and diarrhoea) with over half fulfilling complete KD criteria (11/21, 52%). The majority were irritable (12/21, 57%) and myocarditis was common (16/21, 76%). Coronary artery dilation was seen in 5/21 (24%) but no aneurysms seen. 8/18 who had chest imaging had lung changes.Bloods: Inflammatory markers were significantly raised, with a median CRP of 253, PCT 22.5 and IL-6 170. Interestingly mean platelet count was 499 (but up to 838). Median troponin 282 and D dimer 4025 (up to 19330). Ferritin not reported.

COVID-19 status: 8/21 tested positive on swab and 19/21 had positive serology Treatment: All were given IVIg, following which 5/21 still had fever 36hrs afterwards. They were given a second dose of IVIg and steroids. 15/21 required inotropic support and 11/21 required intubation/ventilation.

Outcomes: Median length of stay was 8 days (rage 5 – 17). There were no deaths.Three subsequent studies have confirmed very similar presentations of this hyperinflammatory syndrome (PIMS-TS) in children, with initial abdominal pain, fever, diarrhoea and vomiting, progressing to a picture similar to Kawasakis disease but with a significant number developing shock and significant cardiac involvement.

Grimaud, MOualha, MAnnals of Intensive careAcute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children.01 Jun 2020FranceEurope20Clinical - PIMS-TS https://annalsofintensivecare.springeropen.com/track/pdf/10.1186/s13613-020-00690-8

This is a retrospective observational study of 20 children who were admitted to paediatric intensive care units across four academic tertiary centres in Paris, four weeks after the start of French lockdown. None of the children had existing co-morbidities nor a history of symptomatic COVID-19 infection.

All patients were less than 18 years old and presented with hypotensive shock and acute myocarditis.

All children had the same presenting complaint- severe abdominal pain, vomiting and fever, for an average of 6 days previously (1-10). On admission to PCIU all children had a raised CRP, (median 251) and procalcitonin, (median 46). p

All children had myocarditis, defined as: elevated troponin, ST segment elevation or depression on ECG and regional wall motion abnormalities with decreased left ventricular function on ECHO. Pericardial effusion was found in four children. All children but one required inotropic support for a median of 3 days (1-7). Eight children required mechanical ventilation for 1-7 days.

Fourteen children had transient acute renal failure but none required renal replacement therapy.

SARS-CoV-2 PCR and serology were positive for 10 and 15 children respectively. One child had a negative PCR and serology but typical SARS-CoV-2 chest CT scan changes. No other bacterial or viral infections were identified.

All children had at least one feature of Kawasaki disease along with a fever, skin rash (10), conjunctivitis (6), cheilitis (5), adenitis (2).

All children received intravenous immunoglobulin within 48hrs of admission and 18 were afebrile thereafter. Two children also received corticosteroids, the reason for this additional therapy is not documented in the article.

All children survived and were afebrile with a full left ventricular function recovery at the time of discharge from PICU.

Wolfler, AndreaZuccotti, GianvincenzoLancet Child Adolescent Health 2020Acute myocardial injury: a novel pattern in children with Covid-19 01 Jun 2020ItalyEurope9Clinical - PIMS-TShttps://doi.org/10.1016/s2352-4642(20)30168-1
Greene, ASinert, RAJEMToxic shock-like syndrome and COVID-19: A case report of multisysteminflammatory syndrome in children (MIS-C)31 May 2020USANorth America1Clinical - PIMS-TShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274960/pdf/main.pdf
Miller, JMargolis, KGastroeneterologyGastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (MIS-C) that is related to COVID-19 a single center experience of 44 cases30 May 2020USANorth America44Clinical - PIMS-TShttps://www.gastrojournal.org/article/S0016-5085(20)34753-3/pdf

A retrospective case study of gastrointestinal symptoms in children with PIMS-TS (the authors call MIS-C). 44 children (age range 7months -20years, 20male), were identified with MIS-C between 18 April 2020 and 22 May 2020. The diagnostic criteria for MIS-C were not given. Gastrointestinal symptoms were present in 84.1% of children, all were febrile and 31/40 (70.5%) had a skin rash.

Importantly 13/44 (29.5%) of children had presented previously with only symptoms of different milder GI conditions.

22/44 50% children had cardiac dysfunction, 22/44 50% had shock requiring treatment with vasopressors, 13/44 29.5% had neurological symptoms, 11/44 25% needed supplemental O2, and 7/44 had acute kidney injury.

Investigations showed markedly elevated inflammatory markers in all and half the children had elevated transaminases. GI imaging was undertaken in 15, 10/12 children had abnormal ultrasounds and 2/3 abnormal CT/MR

The authors conclude that PIMS-TS (MIS-C) should be considered in children with prominent GI symptoms and a history of Covid-19 infection. They also suggest long term follow up may be warranted for IBD surveillance.

Choitos, KJohn, AJ Pediat Inf Dis SocMultisystem Inflammatory Syndrome in Children during the COVID-19 pandemic: a case series26 May 2020AmericaNorth America8Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa069
Chang, AHicar, MmedRxivKawasaki Disease serum responses against SARS-CoV-2.26 May 2020United StatesNorth America14Clinical - PIMS-TShttps://www.medrxiv.org/content/10.1101/2020.05.24.20111732v1
Labe, PMahe, EJ Eur Acad Dermatol VenereolErythema multiforme and Kawasaki disease associated with COVID-19 infection in children26 May 2020FranceEurope2Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16666

This is a retrospective case-series from the United Kingdom of children with neurological symptoms, identified from a larger cohort (n = 55) of SARS-CoV-2 positive children. Of the 55 children, 27 had features of paediatric multisystem inflammatory syndrome (PIMS-TS) and of these, 4 had neurological symptoms.

Clinical Features: The four children had a median age of 12 years (range 8-15 years) and interestingly, two children were of South Asian ethnicity and two of Afro-Caribbean ethnicity. Of the neurological symptoms reported, encephalopathy (4/4), headache (3/4) and brainstem signs such as dysarthria or dysphagia (2/4) were most common. Peripheral nervous system involvement was present in all patients and included proximal muscle weakness (4/4) and decreased reflexes (2/2). Neurological symptoms occurred alongside a range of systemic symptoms but were part of the initial presentation in 2 children.

Investigations: The four children had a range of investigations, including a lumbar puncture (2/4), EEG (3/4), EMG (3/4), MRI (4/4). The CSF was acellular and SARS-CoV2 negative, mild excess of slow activity was seen on EEG, and EMG showed mild myopathic and neuropathic changes. Interestingly, MRI findings were consistent in all four children, and included signal changes in the splenium of the corpus callosum. Three of the four children also had T2 hyperintense lesions associated with restricted diffusion.

Treatments: Therapeutics given varied. Three children received treatment for PIMS-TS more broadly, including methylprednisolone (2/4), dexamethasone (2/4), IVIG (2/4), anakinra (2/4), and rituximab (1/4).

Outcome: At the time of follow-up (median 18 days, range 11-13 days), 2 patients remain in hospital and have residual lower limb weakness and require a wheelchair to mobilise, and 2 patients have been discharged ambulating without support.

Overall, this paper provides a thorough description of neurological features associated with SARS-CoV-2 infection in the setting of multisystem inflammation.

Waltuch, TGill, PAm J Emerg MedFeatures of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department23 May 2020North AmericaNorth America4Clinical - PIMS-TShttps://www.ajemjournal.com/article/S0735-6757(20)30403-4/fulltext#t0005
Acharyya, BDas, DIndian Pediatr Novel Coronavirus Mimicking Kawasaki Disease in an Infant22 May 2020IndiaAsia1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00184.pdf
Deza Leon, MAsmar, BJPIDSCOVID-19–Associated Pediatric Multisystem Inflammatory Syndrome22 May 2020USANorth America1Clinical - PIMS-TShttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa061/5842067

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Leon, MAsmar, BPIDSCOVID-19 Associated Pediatric Multi-System Inflammatory Syndrome22 May 2020USANorth America1Clinical - PIMS-TShttps://doi.org/10.1093/jpids/piaa061

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Tullie, LCurry, JThe Lancet. Child & adolescent healthGastrointestinal features in children with COVID-19: an observation of varied presentation in eight children19 May 2020EnglandEurope8Clinical - PIMS-TShttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30165-6/fulltext#articleInformation

This is a case series of eight children referred to a single UK centre with symptoms of atypical appendicitis before rapid deterioration requiring hospitalisation and, in some cases, intensive care support. All were found to have evidence of terminal ileitis on imaging and did not require surgical intervention. Although the term is not used by the authors, all children in this case series appear to meet the case definition for Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS). 4/8 children were PCR positive for Covid-19 on initial testing, increasing to 5/8 on repeat testing. Antibody testing is not reported.

Authors highlight the importance of imaging prior to surgery in suspected appendicitis during the COVID-19 pandemic. CT is superior to ultrasound in demonstrating a non-inflamed appendix.

Of note, 6 out of 8 were from Black or Asian ethnic group, this is in keeping with the increased rates of PIMS-TS reported among these ethnic groups. The weight of patients is not reported.

Clinical features: All patients presented with fever, abdominal pain, diarrhoea, and vomiting. All but one child had significantly raised CRP. Four patients developed multi-system inflammatory response with shock and required intensive care support, including one child with myocarditis who required ECMO.

Radiological features: Abdominal imaging demonstrated lymphadenopathy and presence of inflammatory fat throughout the mesentery, with thickening of the terminal ileum.Treatment: Four children were treated with IVIG and steroids for ‘atypical Kawasaki disease’, although two of these children did not have features of Kawasaki disease. All patients were treated with IV antibiotics and fluids.

Outcomes: At the time of writing 2 children had been discharged and the remainder were still hospitalised. There were no deaths.

Study period: 25 Apr 2020 to 2 May 2020

Age range: 4-16yr, mean: 10.6yr

This case series highlights that Covid-19, or PIMS-TS, may mimic appendicitis in children, due to inflammation of the terminal ileum. It is important to investigate appropriately to prevent unnecessary surgery on these children.

Licciardi,FMontin, DPediatricsSAR-Cov2-Induced Kawasaki -Like Hperinflamatory Syndrome: A novel Covid Phenotype in Children19 May 2020ItalyEurope2Clinical - PIMS-TShttps://pediatrics.aappublications.org/content/pediatrics/early/2020/05/19/peds.2020-1711.full.pdf
Belhadjer, ZWacker, JCirculationAcute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic17 May 2020France and SwitzerlandEurope35Clinical - PIMS-TShttps://onlinelibrary.wiley.com/doi/abs/10.1111/ctr.13889

A multi-centred retrospective case series studied the early outcomes for children admitted to intensive care for cardiogenic shock, left ventricular dysfunction and severe inflammatory state. The study involved 14 centres in France and Switzerland. The inclusion criteria were admission between 22nd March and 30th April 2020 with fever (>38.5°C), cardiogenic shock or left ventricular dysfunction (left ventricular ejection fraction<50% in the presence of an inflammatory state (CRP> 100 mg/mL).

In summary, left ventricular systolic dysfunction was present in all patients who experienced a low systolic blood pressure. The authors contrast this to Kawasaki disease, in which diastolic dysfunction predominates and only a third of patients experience left ventricular systolic dysfunction.

The authors suggest the rapid resolution of systolic dysfunction in conjunction with a mild to moderate troponin rise implies the mechanism of cardiac impairment associated with SARS-CoV2 in the paediatric population differs to that seen in the adult population. Due to the high BNP levels present in the case series a mechanism of myocardial oedema or stunning is suggested. Very high levels of Interleukin-6 were also seen and may be related to vasoplegia. It was hypothesised these significantly raised results could be caused by stretched cardiomyocytes and cardiac fibroblasts in conjunction with macrophage activation. However, further research would be required to determine the immune mechanisms involved and potentially guide treatment choices.

35 patients were included with a median age of 10 years (IQR 2-16 years), 18 were male. 31 patients were confirmed SARS-CoV2 positive by either a nasopharyngeal RT-PCR, faecal RT-PCR, tracheal swab, or serology using Chemiluminescent Microplate Immunoassay-CMIA technique. 2 other patients were SARS-CoV2 negative, however, had CT chest appearances consistent with SARS-CoV2 changes.

10 of the patients had an identified co-morbidity: 3 (8.5%) had asthma, 1 (3%) had lupus and 6 (17%) were overweight with a BMI greater than 25. There was no data regarding ethnic origin included.

Clinical features: 35 (100%) had fever, 35 (100%) Asthenia, GI symptoms 29 (83%), rhinorrhoea 15 (43%), respiratory distress 23 (65%), adenopathy 21 (60%), rash 20 (57%), meningism 11 (31%), chest pain 6 (71%), cardiogenic shock 28 (80%), ventricular arrhythmia 1 (3%). A large proportion of the patients had shock with low systemic blood pressure with limited information.

Radiology: 2 patients had CT chest appearances “typical” for those with SARS-CoV2.Bloods: CRP 241 mg/mL (IQR150-311) mg/mL, Troponin I 347 (IQR 186-1267) ng/L (normal <26ng/L), Creatinine Kinase 174 U/L (IQR 110-510), NT-proBNP 41484 pg/mL (IQR 35811-52475) (normal <300 pg/mL), BNP 5743 pg/mL (IQR 2648-11909) normal <100 pg/mL), D-Dimer 5284 ng/ml (IQR 4069-9095), Procalcitonin 36 ng/ml (IQR 8-99), WCC 16 X 10^3/L (IQR 12-23), Neutrophil count 13 X 10^3/L (IQR 8-19), Interleukin 6 135 pg/mL (IQR 87-175) (normal <8.5 pg/mL)

Treatments: All patients required intensive care management with 10 (28%) needing V-A ECMO for an average of 4.5 days (range 3-6), 28 (80%) needing inotropic medication, 22 (62%) invasive ventilation and 11 (32%) non-invasive ventilation.

25 (71%) were given intravenous immune globulin with 1 (3%) patient given repeated IVIG due to persistent fever 48 hours after the first dose. 12 (34%) received intravenous steroids, dose unclear, due to grading them high-risk with symptoms similar to an incomplete form of Kawasaki disease and 3 patients received interleukin 1 receptor antagonist (anakinra) due to a persistent severe inflammatory state. 23 patients received therapeutic heparin.

Outcomes: No patients died. All 10 patients requiring V-A ECMO were weaned off successfully. The average hospital stay was 8 days (IQR 8-14) with ICU duration of 7 days (3.7-10 days). At the time of publication 7 (20%) patients remained as an inpatient or had residual left ventricular dysfunction.

Complete recovery of left ventricular function, [left ventricular ejection fraction > 60% at day 7] was seen in 25 patients (71%) by an average of 2 days after admission. 5 (14%) had residual mild to moderate left ventricular systolic dysfunction with a left ventricular ejection fraction greater than 45%. This was measured on the last follow up, an average of 12 days after admission.

Other investigations were undertaken to assess cardiac function.

ECG: 1 patient (3%) had ST elevation on ECG.

Echocardiography results: 10 (29%) of patients had an ejection fraction below 30% on admission whilst 25 (71%) had an ejection fraction between 30 and 50%. Global hypokinesis was seen in 31 (89%) with an additional 3 (9%) patients had segmental wall hypokinesis. 1 (3%) patient had Takotsubo syndrome presentation with akinesis of the apical segment Pericardial effusions were diagnosed in 3 (9%) patients.

Coronary artery dilatation, defined as Z-score >2 adjusted for body temperature, was present in 6 patients (17%): 5 patients (14%) had dilatation of the left main stem and 1 (3%) had dilatation of the right coronary artery. Right ventricular function was normal, and no thrombi were seen. No coronary aneurysms have been seen, however, ongoing follow up is planned. Data was not presented regarding SARS-CoV2 antibodies, however, within the discussion it was noted that those who were serologically positive for SARS-CoV2 already had IgG antibodies suggesting the patients included within the study had contact with the virus “more than 3 weeks before admission”.

Pain, CHedrich, CLancet RheumatolNovel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms15 May 2020United Kingdom Europe1Clinical - PIMS-TShttps://www.thelancet.com/action/showPdf?pii=S2665-9913%2820%2930137-5

This is a case report from Alder Hey Childrens Hospital, Liverpool of previously health 14 year old patient fitting criteria for PIM-TS, successfully treated with Anakinra.

Initial presentation : This patient initially presented with a a 3-day history of fever, abdominal pain, nausea, and vomiting, and no respiratory symptoms. A previous history of mild respiratory symptoms 3 weeks earlier was reported. On initial presentation patient had fever 38.1, was cardiovascularly stable, no respiratory distress, but had a tense abdomen with guarding in right upper and lower quadrant. Initial investigations conducted showed; bloods - lymphopenia (0·14 × 109 cells/L), CRP of 242mg/per L, urine – sterile pyuria (30cells), radiology – normal CXR, normal abdominal ultrasound. Nasopharyngeal Sars CoV2 PCR – sent (subsequently negative). A provisional diagnose of acute appendicitis was made, and patient started on Piperacillin-tazobactam.

Deterioration : Within 24 hours of admission, patient became visually more unwell, was tachycardic, had increased dyspnoea and cough, and developed a widespread maculopapular rash. Further investigations showed; Radiology – Ct chest, showed typical findings of SARS-CoV-2. Bloods showed; lymphopenia, anaemia, thrombocytopenia, raised CRP and Ferritin, raised serum interleukin (IL)-6 (1098 pg/mL [normal range<7]), coagulopathy with raised D Dimers and prolonged PR and APTT, raised increased liver enzymes, hypertriglyceridaemia, ANA negative, raised APL (anticardiolipin IgG 25·5 U/mL [normal range <20] and antiβ2-glycoprotein IgG 28·8 U/mL [normal range <20]) were positive, and low complement levels (C3 0·09 g/L [normal range 0·90–1·88], C4 0·12 g/L [normal range 0·18–0·42]). Patient also developed mild polyarticular arthritis.

Treatment and ongoing care : Initial oxygen requirement (8 L/min), finally escalating to CPAP ventilation support. IV Bolus for hypertension. Anti-inflammatory treatment with recombinant IL-1 receptor antagonist (Anakinra) was started after multidisciplinary discussion. It was commenced at 4 mg/kg per day s/c but increased to 8 mg/kg per day after 36 hours because patient required inotropic support for hypotension and rising lactate (6 mmol/L). Because of cardiovascular involvement (borderline LV systolic dysfunction, aortic regurgitation, progressive left coronary dilatation, enzyme leak with troponin-T 45 ng/L), aspirin was started (2 mg/kg) for its antithrombotic effects. Patient did not show additional clinical features of Kawasaki disease, and upon discussion IVIG nor corticosteroids were not given.

Outcome : SARS-CoV-2 IgG became positive (borderline day 6, positive day 11). In temporal relation with anakinra treatment, the patient’s respiratory status stabilised and clinical and laboratory variables returned to normal.

Cabrero-Hernandez, MSerrano-Gonzalez, APediatr Infect Dis JSevere SARS-CoV-2 Infection in Children With Suspected Acute Abdomen: A Case Series From a Tertiary Hospital in Spain10 May 2020SpainEurope5Clinical - PIMS-TShttps://journals.lww.com/pidj/Abstract/9000/Severe_SARS_CoV_2_Infection_in_Children_With.96141.aspx
Balasubramanian, SRamanan, AIndian PediatrHyper-inflammatory Syndrome in a Child With COVID-19 Treated Successfully With Intravenous Immunoglobulin and Tocilizumab10 May 2020IndiaAsia1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00180.pdf
Rivera-Figueroa, ESimpson. SIndian PediatrIncomplete Kawasaki Disease in a Child With Covid-1909 May 2020USANorth America1Clinical - PIMS-TShttps://www.indianpediatrics.net/COVID29.03.2020/CCL-00179.pdf
Riphagen, STheocharis, PLancet Hyperinflammatory shock in children during COVID-19 pandemic01 May 2020LondonEurope8Clinical - PIMS-TShttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31094-1/fulltext

This is the first case series to describe a cluster of children presenting with hyperinflammatory shock during the COVID-19 pandemic.

Eight children aged 4 to 14 years were identified by a paediatric retrieval service based in London in mid-April 2020. Interestingly, of the 8 children, 7 had weights >75th centile. Notably 6 were of Afro-Caribbean descent and 2 were Asian, with no Caucasian children in this cohort. 5/8 were boys. 4 children had exposure to family members with COVID-19.

The clinical presentation was similar to Kawasaki disease, with unrelenting fever, rash, conjunctivitis, peripheral oedema, and extremity pain, in addition to gastrointestinal symptoms. All children developed warm, vasoplegic shock and required inotropic support. Seven children required mechanical ventilation.

Small pleural, pericardial and ascitic effusions, also consistent with a diffuse inflammatory process were also observed. Vascular involvement was demonstrated with echo-bright coronary arteries seen in all children, with a giant coronary aneurysm in one patient. One child died from a large cerebrovascular infarct. Myocardial enzymes were significantly elevated.

A range of investigations were done in all children, and despite this no causative pathogen was identified. Adenovirus and enterovirus were isolated in one child. Four children had known exposures to SARS-CoV-2 in family members, but only two tested positive for SARS-CoV-2 (1 was positive only postmortem).

In addition to other supportive therapies, all children received IVIG and broad-spectrum antibiotics (ceftriaxone, clindamycin). Six children have been given aspirin. This clinical presentation may represent a new phenomenon associated with SARS-CoV-2 infection in children and has remarkable similarities to Kawasaki Disease. Following publication of this case series, Evelina London Children’s Hospital has managed >20 similar cases in children. Ten of these children were SARS-CoV-2 antibody positive (unclear which antibody or which test was used).

These findings have garnered particular interest due to the fact that children have otherwise been relatively spared from severe disease due to COVID-19, and here both the temporal association and high proportion of children with seemingly positive serology suggests a possible association with this hyperinflammatory syndrome. Anecdotally, clusters have also been noted in the USA (particularly NYC) and some centres in Spain and Italy. Reports are conspicuously absent from Asia, most notable as Kawasakis disease is more common amongst this population normally. Even more striking is the gross overrepresention of children with an Afro-Carribean background, which given current investigations into the increased incidence of severe adult disease in these communities seems even more pertinent.

As so little is currently known about “garden variety” Kawasakis, it will make defining this disease and its associated with COVID-19 that bit more difficult, but studies are currently ongoing to assess the nature and mechanism of this disease (https://www.diamonds2020.eu/). For now, this cohort doesn’t change the management of childhood COVID-19, nor does it change the management of hyperinflammatory shock or Kawasakis – although the RCPCH have produced excellent guidance for suggested investigations and processes to include these patients in ongoing research.

Jones, VMathew, RHospital PediatricsCOVID-19 and Kawasaki Disease: Novel virus and novel case07 Apr 2020AmericaNorth America1Clinical - PIMS-TShttps://hosppeds.aappublications.org/content/hosppeds/early/2020/04/06/hpeds.2020-0123.full.pdf

This is a case study from the USA of a 6m old child who presented with fever and fussiness with no history of respiratory symptoms. They had unremarkable flu swab and urine MC&S, diagnosed viral illness. She subsequently developed an erythematous non-pruritic and blotchy rash.

On day 4 of fever she presented with the rash, still no significant respiratory symptoms. She was tachycardic, irritable, had limbic sparing conjunctivitis and dry cracked lips with no lymphadenopathy and no extremity skin changes. She had normal platelets with high CRP (133mg/L). Chest x-ray showed faint opacity in the left lung, and respiratory PC negative. No unwell contacts, no travel.

She was admitted with suspected Kawasakis, and due to fever and CXR was swabbed for SARS-CoV-2. Upon arrival to the paeds ward she met all Kawasakis criteria and was treated with IVIG and aspirin. Normal Echo. Just before discharge her SARS-CoV-2 test returned positive.This case is highly pertinent given current media headlines about a collection of cases in the UK of a Kawasaki like syndrome, some testing positive for COVID-19 and some negative. This case seems a bit different, as the child had “barn door” classic Kawasaki syndrome, and had an otherwise unremarkable course.

Further details regarding these cases from London (and possibly elsewhere) will be needed to determine a link between COVID-19 and a systemic inflammatory response syndrome. 3 things are particularly interesting.

Kawasakis disease has been theorised to be triggered by viral infections. One could imagine if this is the case, then COVID-19 could also trigger a similar syndromeIt is well documented that some adults experience a systemic inflammatory response to COVID-19 (including cytokine storm) and whilst children generally suffer a much milder course, it seems within reason that a subset of children may develop a similar illnessReports from a paper in 2005 suggested a link between human coronaviruses in Kawasakis disease. A case control study found significantly higher rates of coronavirus in children with Kawasakis (72.7%) than a matched control group without Kawasakis (4.2%) The meaning of all this is still unclear – it doesn’t change the management of Kawasakis disease or COVID-19, but presents interesting research questions which can be addressed in the coming months.

Miron, ODavidovitch, NArch Dis Child.COVID-19 infections following physical school reopening.7 Dec 2020USANorth AmericaEpidemiology - Disease Burdenhttps://adc.bmj.com/content/early/2020/12/06/archdischild-2020-321018

This letter, published in Archives of Disease in Childhood on 7th December 2020, describes an analysis of COVID-19 incidence in Florida, USA, at ages 6-13 years (elementary school) and 14-17 years (high school) relative to school reopening in August-September 2020 (most schools in the USA were closed in March-April 2020 because of the COVID-19 pandemic). The analysis compares counties in Florida with physical learning in schools (in-person teaching) to those with remote learning; there were 3 counties with remote learning: Broward, Miami-Dade and Palm Beach (which are grouped together in south-eastern Florida on the coast). There are 67 counties in Florida (numbers of schools and pupils in the 3 remote learning counties and 64 physical learning counties are not supplied).

Collection of data: The authors, who are based in Boston, USA, and Israel, used a Florida database to extract COVID-19 incidence by county for the two age bands (6-13 and 14-17 years), using a 7-day moving average; these incidence figures were matched with each county’s date of school reopening (day 0), looking at the period from 10 days before reopening to 20 days after reopening. Rates were aggregated for counties with physical learning and for those with remote learning in order to compare trends.

Florida counties teaching physically: For ages 6-13 years, COVID-19 incidence decreased slightly from day -10 to day 4 (-0.5% daily change), to an incidence of 11 daily cases/100,000 at day 4 (95% CI 9.9-12), followed by a slight increase from day 4 to 12.8/100,000 at day 20 (95% CI 11.7-13.9). For ages 14-17 years, incidence decreased more steeply from day -10 to day 1 (-3.2% daily change), to an incidence of 16.1/100,00 at day 1 (95% CI 14.4-17.9) followed by an increase from day 1 of 1.4% daily change to an incidence of 20.5/100,000 on day 20 (95% CI 18.5-22.5).

Florida counties teaching remotely: For ages 6-13 years, COVID-19 incidence decreased from day -10 to day 4 (-5.6% daily change) followed by no significant trend up or down to day 20. For ages 14-17 years, incidence decreased from day -10 to day 6 (-4.3% daily change) followed by no significant trend up or down to day 20. The slope for both age groups in counties teaching remotely was significantly different from the slope in counties teaching physically.

Conclusions and limitations: The authors conclude that physical reopening of schools was followed by increased COVID-19 incidence at school ages over the first 20 days, especially in high schools. The 3 counties with remote learning did not have increased incidence; the authors note that this may also relate to their lower COVID-19 rates before school reopening, their public mask mandate and gathering limit or their socio-economic differences. A limitation noted is that some parents opted not to send their children to physical learning. A possible confounder for increased infections with physical learning could be that it enabled parents to go to work, which might increase infections in children.

Lee, EReilly, KJAMA Netw OpenRace/Ethnicity Among Children With COVID-19-Associated Multisystem Inflammatory Syndrome.30 11 2020USANorth America223Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.30280

The authors seek to gather the data “to contextualise the racial/ethnic distribution of MIS-C cases” as a higher proportion are reported to be in Black and Hispanic children.

It is a short but number/statistics heavy article

Population based cohort study: the method of identifying cases is described

Cases of MIS-C reported in New York City between 1st March and 30th June 2020 with a Median age of 7y. 22.4% had an underlying condition mostly asthma or obesity. Only 8.5% reported COVID-19 like illness in previous 4 weeks. 78.5% had lab evidence of COVID-19 infection, current or past.

34.4% of children were Black compared with 22.2% NY population and 19.9% COVID-19 admissions and 29.8% Hispanic compared with 35.6% NY population and 40% COVID-19 admissions. Compared to White children, MIS-C had a higher incidence in Black (IRR 3.2, 95%CI 2.0-4.9) and Hispanic (IRR 1.7, 95%CI1.1-2.7). No significant difference in IRR rates between White, Asian or Pacific Islander. Black and Hispanic children also had a higher COVID-19 admission rate compared to White children

Conclusions

There is a higher burden of MIS-C amongst Black and Hispanic children but it is unclear whether this is distinct phenomenon or because of the increased COVID-19 rates in Black and Hispanic communities. Ethnicity data is missing for 36 (16.5%) of these MIS-C cases and the authors report that it is mostly missing for confirmed, non-hospitalised and non-fatal COVID-19 cases in NYC which limits the possible analyses.

Bailey, LCForrest CBJAMA PedsAssessment of 135 794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States23 Nov 2020.USANorth America135794Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/10.1001/jamapediatrics.2020.5052

This study used the PEDSNet system to gather data on SARS-CoV-2 PCR testing on a large population of children and young people (CYP) throughout the US. PEDSNet includes 7 major children’s hospitals, and covers about 3% of the US child population. Data from 135 800 people under 25 years old who were tested between 1st January and 8th September were reported. There was no mass population testing, so the results reflect availability and access to tests, and local testing policies, as much as genuine disease prevalence. Paediatric care in the US can continue until young people are in their twenties.

They made some interesting observations: 290 per 10 000 population were tested, although this varied between centres (range 155-395). Overall 4% of those tested were positive, a much lower rate than that found in adults. Of the 5370 test-positive patients, 7% were hospitalised for Covid-related symptoms, and of these 28% required intensive care. Eight died (0.2% of test-positives).

CYP of non-white ethnicity were both less likely to be tested (odds ratios 0.6-0.7), and more likely to test positive: black CYP were nearly 3 times more likely to test positive (OR 2.66) and Hispanics nearly 4 times (OR 3.75). Older age increased likelihoods of testing positive (OR for 5-11 year-olds 1.25; for 18-24 year-olds 3.51). In the States, patients can be categorised according to whether their healthcare is commercially funded or publicly funded, as a proxy for deprivation: perhaps unsurprisingly, children relying on public funding were more likely to test positive (OR 1.43).

They also looked at pre-existing conditions, grouped together by systems: amongst others, malignant, haematological, cardiac, gastrointestinal, endocrine (types 1 and 2 diabetes) and mental health disorders all increased the risk of testing positive; curiously, however, the risk was reduced in respiratory disorders including asthma.

As a side issue, they tried to look at incidence of multisystem inflammatory syndrome in children, MIS-C (also known as paediatric inflammatory multisystem syndrome), thought to be associated with Covid-19. There was no diagnostic code for this new condition from which they could identify cases, so they looked for cases of Kawasaki Disease (KD), which it closely resembles, over the same time period: they found a 40% fall in incidence compared to the same period in 2018 and 2019. This might represent a genuine fall in incidence, but anyway it seems unlikely that clinicians are classifying MIS-C as KD.

This tells us little about true population prevalence of the virus, as many children with mild or no symptoms would never have been tested. But it does repeat the findings seen elsewhere: although they are less vulnerable generally, the stark social and ethnic differences seen in adults apply to children as well.

Roarty, CWaterfield, TLancet Infect DisKinetics and seroprevalence of SARS-CoV-2 antibodies in children 19 Nov 2020United KingdomEurope849Epidemiology - Disease Burdenhttps://doi.org/10.1016/S1473-3099(20)30884-7
Oved, KLustig, Yj.eclinmMulti-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation19 Nov 2020IsrealMiddle East688Epidemiology - Disease Burdenhttps://doi.org/10.1016/j.eclinm.2020.100651

Background; An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. They validated the performance of six commercially available automated IgG/total antibody serology products for SARS-CoV-2 and one ELISA format: Roche Cobas Total Ig (Roche), Abbott SARS-CoV-2 IgG (Abbott), BioMerieux VIDAS IgG (VIDAS IgG), Beckman Coulter Access IgG (Beckman), Siemens ADVIA IgG (Siemens), Diasorin Liaison IgG (Diasorin) and the RBD ELISA assay of Mt. Sinai (ELISA). Previous studies have been limited in the number of assays compared and the power and heterogeneity of the samples used, including small cohorts, lack of psadiatric samples, gender biases, and disease severity biases.

Methods; The diagnostic laboratories of all four Health Maintenance Organizations (HMOs) in Israel – Clalit, Maccabi, Leumit and Meuhedet and the Central Virology Laboratory of the Ministry of Health, participated in the study which was designed and executed during March-July 2020. Each lab obtained and tested serum samples from different cohorts of non-SARS-CoV-2 and SARS-CoV-2 patients collected from all regions in Israel. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed.

Results; Immunoassays’ sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (<15%) prevalence scenarios.

Specificity in children; Protective immunity in children might partially be due to cross-reactive immunity to past Coronavirus strains, the study specifically investigated the specificity in children and adolescents under 20 years (688 samples which compose 28.7% of our SARS-CoV-2 negative cohort). Results show that specificity in children and adolescents were similar to those overall: Abbott 99.7% (642/644: CI 98.9–99.9), Diasorin 98.0% (633/646: CI 96.6–98.8), Vidas VIDAS IgG 97.4% (330/339: CI 95.0–98.6), Roche 100% (367/367: CI 99.0–100.0), ELISA 98.6% (351/356: CI 96.8–99.4), Beckman 100% (12/12: CI 73.5–100.0) and Siemens 100% (20/20: CI 83.2–100.0).

No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies.

All patients were described as seronegative non-responders if they were tested with 4 or more independent assays and remained negative across all tests. The study found the proportion of this subpopulation to be 4.7% of the symptomatic PCR positive patients with blood collection 14 or more days after the positive PCR result. In patients who were negative in 3 or more different assays, the proportion increased to 6.5%.

The seronegative subpopulation was compared with seropositive patients to search for potential unique characteristics, but found no clear differences in age, hospitalization, disease severity, time from positive PCR and gender, although numbers are too small to rule out such differences. This measurement represents the first population-wide estimate using multiple commercially available tests and different antigens to quantify the proportion of seronegative non-responding patients at risk for re-infection.

Conclusions; The commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The study finds no decrease in antibody titers in the first 8 weeks in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The ~5% who were seronegative non-responders, using multiple assays in a population-wide manner, represents the proportion of patients that may be at risk for re-infection.

Therefore their impact on herd immunity or the healthcare system is expected to be limited; yet, these individuals are at increased risk for re-infection. The assay of choice for epidemiological assessments and diagnosis should be determined separately in each country and be based on the prevalence of SARS-CoV-2.

Seronegative non-responders are also expected at a certain proportion after immunization and the proportion of vaccine non-responders was traditionally higher than the natural disease itself. The study estimates that the proportion of vaccination failure in the Israeli population may be higher than 5% regardless of the vaccine identity.

Somekh, ISomekh, EClin Infect DisReopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.18 Jan 2021IsraelAsiaEpidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab035/6103916

This study, published on 18th January 2021, investigates the effects on the dynamics of SARS-CoV-2 infections in Israel of the reopening of schools and the easing of social distancing restrictions between March and July 2020.

Background: Israel’s schools were closed from 14 March 2020 as part of efforts to control the spread of COVID-19 (which included a complete lockdown from 25 March to 19 April). The peak of infections was at the end of March 2020 and schools were partially reopened on 3 May (for children in grades 1-3 and 11-12, with separate groups attending at different times on different days) and then completely reopened on 17 May for all day in-person learning (with social distancing and masks for children over 7 years of age, but no cohorting). When schools reopened, there was low incidence of SARS-CoV-2 infections in all age groups. On 20 May there was a partial easing of social distancing in the community, with the opening of synagogues and beaches to the public, followed by further easing on 12 June, when gatherings of up to 250 people at social events were permitted. The end of the academic year was 19 June for high school students (grades 7-12) and 30 June for elementary school students (grades 1-6).

Collection of data: Using data sources including the Israeli Center for Diseases Control, Ministry of Health and Israel Central Bureau of Statistics, the authors examined the nationwide weekly incidence, prevalence, numbers of SARS-Co-2 PCR tests, their positivity, COVID-19 hospitalisations and deaths, for 5 age groups: 0-9 years, 10-19 years, 20-39 years, 40-59 years and 60+ years. Incidence rates were adjusted for number of PCR tests: for each age group, incidence rate (weekly number of new cases/100,000 population in this age group) was multiplied by the proportion of this age group in the general population to the proportion of samples obtained from individuals in this age group. Patients classified as moderately and severely ill were included in hospitalisations data, to avoid bias from changing definitions of severity over the course of the pandemic and to exclude mildly ill patients who might have been hospitalised for quarantine, rather than medical reasons. Weekly data were used to avoid incidental daily fluctuations.

Temporal trends: The effects over time on the parameters examined of schools reopening in May, the easing of social restrictions such as permitted large scale gatherings from 12 June and then schools closing for the end of term in late June were investigated. Data on COVID-19 incidence, prevalence and PCR test positivity rates from the week prior to the implementation of the measure being analysed were compared to data at 14-20 days and 21-27 days after the implemented measure. For hospitalisations and mortality, the data at 14-27 days and 21-34 days respectively were analysed and compared with that prior to the implemented measure. The lag period of 21-34 days between possible exposure and mortality was based on an average of 17 days between symptoms and death, plus an additional 4-6 days for a child who was infected in school to infect an adult, extended to 34 days to allow for several rounds of infection.

Incidence, adjusted incidence and prevalence after school reopening: Incidence rates, adjusted incidence rates (adjusted for the number of PCR tests in each age group) and prevalence of SARS-CoV-2 infection gradually increased following complete school opening in both paediatric/adolescent age groups and the three adult age groups.

Increase in PCR testing following school reopening: During this period, the number of PCR tests performed also increased for all age groups, but particularly for the 0-9 and 10-19 years age groups. Weekly SARS-CoV-2 samples tested: 0-9 yrs 2133 17-23 May vs 15081 7-13 June (7.1-fold increase); 10-19 yrs 2073 17-23 May vs 16952 7-13 June (8.2-fold increase); 20-59 yrs 17917 17-23 May vs 45564 7-13 June (2.5-fold increase); 60+ yrs 10090 17-23 May vs 15889 7-13 June (1.6-fold increase).

Positivity rates of PCR tests following school reopening: Following complete school opening on 17 May, positivity rates increased gradually for the adult age groups, but not for paediatric/adolescent age groups, when comparing rates the week prior to schools reopening (10-16 May) with 14-20 days after (31 May – 6 June) and 21-27 days after (7-13 June). 0-9 yrs: 14/1950 (0.7%) samples positive 1-7 days prior to complete school reopening followed by 78/9853 (0.8%) positive 14-20 days after reopening and 158/15081 (1.0%) positive 21-27 days after reopening; RR (relative ratio) of 1.1 [95% CI 0.63-1.94] and 1.46 [0.85-2.51] respectively (compared to prior to reopening). 10-19 yrs: 33/2092 (1.6%) positive 1-7 days prior to reopening followed by 168/16431 (1.0%) 14-20 days after and 250/16952 (1.5%) 21-27 days after; RR of 0.65 [0.45-0.94] and 0.93 [0.65-1.34]. 20-39 yrs: 49/11169 (0.4%) positive 1-7 days prior to reopening followed by 229/19884 (1.2%) 14-20 days after and 396/26779 (1.5%) 21-27 days after; RR of 2.62 [1.93-3.57] and 3.37 [2.51-4.53]. 40-59 yrs: 32/9311 (0.3%) positive 1-7 days prior to reopening followed by 167/15626 (1.1%) 14-20 days after and 276/17568 (1.6%) 21-27 days after; RR of 3.1 [2.13-4.5] and 4.72 [3.26-6.83]. 60+ yrs: 35/13762 (0.3%) positive 1-7 days prior to reopening, followed by 64/14739 (0.4%) 14-20 days after and 111/15889 (0.7%) 21-27 days after; RR of 1.7 [1.13-2.58] and 2.75 [1.88-4.01].

Single cluster of COVID-19 in a high school in Jerusalem: There was a single peak of a high rate of SARS-CoV-2 infections in 10-19 year olds at the end of May 2020, related to a high school in Jerusalem (see Stein-Kamir et al, A large COVID-19 outbreak in a high school 10 days after schools’ reopening, Israel, May 2020, Eurosurveillance, published 23 June 2020), which resulted in a 6% sample positivity during 24-30 May in that age group. This outbreak has been postulated to be linked to the temporary lifting of restrictions requiring face masks in school due to a heat wave from 19 to 22 May. During the following 2 weeks, the positivity rate in 10-19 year olds reduced to 1.0% (31 May – 6 June) and 1.5% (7-13 June).

Adjusted incidence rate ratios (aIRRs) following school reopening: aIRRs were calculated by comparing incidence (adjusted for the number of PCR tests performed) 14-20 and 21-27 days after complete school reopening to adjusted incidence during the week prior to reopening. The adjusted incidence rate increased in all age groups, but mostly in adults. The largest increase 14-20 days after reopening was in 40-59 yrs (aIRR 6.22 [3.6-10.7]), followed by 20-39 yrs (aIRR 5.25 [3.5-7.8]). The smallest increase was in 0-9 yrs (aIRR 2.2 [1.6-3.1])and 10-19 yrs (aIRR 1.3 [0.9-1.8]), with 60+ yrs having an aIRR of 3.42 [1.8-6.7] 14-20 days after reopening. Higher aIRRs in adults compared to children were also seen 21-27 days after school reopening: 0-9 yrs aIRR 3.51 [2.5-4.9], 10-19 yrs aIRR 2.25 [1.7-3.0], 20-39 yrs aIRR 8.13 [5.5-12.0], 40-59 yrs 11.1 [6.5-18.7], 60+ yrs 6.73 [3.5-12.4].

Trends after schools closed in June at end of academic year: Incidence, prevalence, number of samples tested and their positivity all increased for all age groups at the end of term (this also coincided with the relaxation of social restrictions in the community). The highest increases in these parameters following the end of term were in 10-19 yr olds.

Positivity rates of PCR tests following easing of social restrictions: Following partial easing of social restrictions on 20 May, rates of test positivity were initially similar to those of school reopening, but after restrictions on large scale gatherings were lifted on 12 June, increased positivity rates were seen in all age groups. 0-9 yrs: 0.8% samples positive 1-7 days prior to permitted large events (5-11 June), followed by 2.3% 14-20 days after (26 June – 2 July) and 3.1% 21-27 days after (3-9 July); RR 2.77 and 3.64 respectively. 10-19 years: 1.1% 1-7 days prior, 5.5% 14-20 and 6.7% 21-27 days after; RR 5.13 and 6.25. 20-39 yrs: 1.2% 1-7 days prior, 5.2% 14-20 and 6.1% 21-27 days after; RR 4.31 and 5.07. 40-59 yrs: 1.3% 1-7 days prior, 4.4% 14-20 and 5.0% 21-27 days after; RR 3.34 and 3.84. 60+ yrs: 0.7% 1-7 days prior, 2.7% 14-20 days and 3.3% 21-27 days after; RR 3.99 and 4.86.

aIRRs following permitted large scale social gatherings: Adjusted incidence rates increased after large events of up to 250 people were permitted on 12 June in all age groups. 0-9 yrs: aIRR 3.11 14-20 days and 5.6 21-27 days after, compared to 1-7 days prior to lifting of restrictions on large scale gatherings. 10-19 yrs: aIRR 5.77 14-20 days and 9.6 21-27 days after. 20-39 yrs: aIRR 4.85 14-20 days and 7.8 21-27 days after. 40-59 yrs: aIRR 3.8 14-20 days and 5.99 21-27 days after. 60+ yrs: aIRR 4.5 14-20 days and 7.52 21-27 days after.

Hospitalisations and mortality following schools reopening: Weekly hospitalisations and deaths of COVID-19 patients did not increase following partial and complete school reopening. This lack of increased mortality was seen even up to 49 days after school reopening. However, the weekly deaths due to COVID-19 significantly increased following the end of the academic year. Risk ratios were 15.2 [5.5-41.9] 28-34 days after high school term ended and 17.2 [6.3-47.3] 28-34 days after elementary school term ended.

Hospitalisations and mortality following easing of social restrictions: No significant increases in SARS-CoV-2-related hospitalisations and deaths were seen following partial easing of social restrictions on 20 May. However, a significant increase in hospitalisations (risk ratio: 3.95 [3.2-4.8]) and deaths (risk ratio: 4 [1.9-8.3]) occurred at 21-27 days and 28-34 days, respectively, following permission to attend large scale events on 12 June. There were no deaths amongst SARS-CoV-2 infected children during the study period.

Conclusions: This national data from Israel suggests that the reopening of schools in May 2020 had a limited effect on the SARS-CoV-2 infection rate in children and adults and that it was not a major contributor to SARS-CoV-2-related mortality. It also suggests that the easing of restrictions on large scale gatherings may have been related to a resurgence of cases and associated increased mortality. The analysis adjusted for the number of PCR tests performed at different time periods in different age groups; this is important given the high proportion of asymptomatic and mildly symptomatic cases of SARS-CoV-2.

Somekh, ISomekh, EClin Infect DisReopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.18 Jan 2021IsraelAsiaEpidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab035/6103916
de Gier, BHahne, SEuro Surveill Occupation- and age-associated risk of SARS-CoV-2 test positivity, the Netherlands, June to October 202017 Dec 2020NetherlandsEurope000000000000000Epidemiology - Disease Burdenhttps://doi.org/10.2807/1560-7917.ES.2020.25.50.2001884

This is a comprehensive survey of all PCR tests for SARS-CoV-2 in all ages in the Netherlands, covering 5 months of the pandemic. Data gathering there is centralised, and unlike some other national surveys, they recorded information on occupations.

The situation in the Netherlands was very similar to the UK, both in terms of Covid-19 prevalence and preventative measures taken by government. Much of this survey concerns occupational groups in adults and is of limited interest to paediatricians. Also there are many missing data and possible biases. However some findings are worth noting.

As elsewhere, they found that the proportion of children tested who proved positive was much lower than that seen in adults. This changed later in the year, but only because national policy changed to deliberately not testing children under 13 years with only mild symptoms, to conserve testing resources for adults. Educators did not appear to be at especially high risk.

They observed that positivity rates were lower in healthcare workers and school staff, compared to other occupations involving close personal contact (e.g. hairdressers). They explain this by suggesting that they were better at using PPE, or that they were more likely to ask for a test even when they had symptoms not due to Covid-19; although not stated, it is also possible that they had enhanced immunity due to prior exposure to other corona viruses. This study could not address this question.

Vos E R Avan der Klis F R MJ Epidemiol Community HealthNationwide seroprevalence of SARS-CoV-2 and identification of risk factors in the general population of the Netherlands during the first epidemic wave10 Nov 2020NetherlandsEurope586Epidemiology - Disease Burdenhttps://jech.bmj.com/content/early/2020/11/28/jech-2020-215678

The authors motivated by lack of scope of Covid-2 prevalence in populations aimed to detect SARS-CoV-2 serum antibodies in the general population of the Netherlands and also identify risk factors for seropositivity amidst the first COVID-19 epidemic wave. The Netherlands first case had been confirmed on 27 February 2020 and interventions to suppress the virus were implemented on March 16 commenced to relax on 1st June 2020.

The authors employed a previously (2016-2017) created two stage cluster-designed nationwide sero-survey population sample (Pienter-3 created to gain insights into protection from vaccine preventable diseases by vaccination offered by the Netherlands National Immunisation Programme) and an adjuncted enhanced random sample among the Orthodox-Reformed Protestant populations described to live a socio-demographically clustered life-style to launch the Pienter-Corona or PICO study.

Subjects (n=6,100 of 7,600 Pienter-3 population sample) aged 2-90 years completed an online questionnaire in which they provided information including sociodemographic characteristics, COVID-19-related symptoms, comorbidities, medication use and behavioural factors and who in addition self-collected 0.3ml microtainer samples.

Half the subjects (n=3207, 53% of the 6100 invited from the 7,600 Pienter-3 candidate baseline) responded, 2,637 from the national survey (NS) and 570 from the low vaccination coverage (LVC) municipalities including the Orthodox -Reformed Protestants sociodemographic community. Using microtainers subjects aged 2 years to 90years self-collected 0.3ml size blood samples and sent them to the laboratory where sera was assayed for SARSCoV-2 spike S1-specific IgG antibodies on 3,100 subjects (less than 5% of subjects lost to follow through) and the titre cut-off concentration for seropositivity was set at 2.37 AU/mL applied.

Analyses were conducted in SAS v.9.4 (SAS Institute Inc., USA) and R v.3.6. The authors accepted P values of <0.05 to be statistically significant. Sociodemographic characteristics and COVID-19-related symptoms (general, respiratory, and gastrointestinal) that had developed since onset of the epidemic were stratified by sample (NS vs LVC), or sex, respectively, and described for seropositive and seronegative participants. Differences were tested via Pearson’s χ², or Fisher’s exact test. Differences in geometric mean concentration between reported symptoms in seropositive subjects were determined and tested by the Mann-Whitney U-test.

Adult (18-90 years) SARS-CoV-2 seropositivity was 2.8%. Seropositivity among the 586 (18.9%) children aged 2-17 years was 1.7%, ranging from <1% at 2y to 3% at 17y.This was considered low compared to seropositivity rate of 5.3% among 226 young adults aged 18-24 years and compared to the whole adult study cohort. Half (56%) the parents of participants were reported to have had daily contact with patients, clients and/or children in their normal profession or volunteer work. The children were not further separately stratified.

This study showed a low SARS-CoV-2 seropositivity in children aged 2-17 years despite the exposure of their parents in work including in the caring professions. However, this study has mostly described common risk factors for infection and so sero-positivity as it pertains to adults even in the low vaccination coverage communities notable the Orthodox Reformed Protestant communities. In addition the extent to which infection may occur but fail to stimulate and manifest antibody response in an individual including in children remains an unknown, and so one can ask if that factor could pull back Covid-2 infection prevalence estimates? That antibody production might be suppressed in an individual adult or child on immunosuppressant would be on the radar of most clinicians but immunosuppression although met with often is an exception not the norm.

It is likely the particularly high rates of seropositivity among young adults are due to contact patterns during this period. Lower rates in children may be a reflection of both reduced susceptibility and reduced contacts due to school closure. More seropositivity prevalence studies would be warranted in the child population while deployment of vaccine against Covid-2 is still to come.

Wang, MChen, WJ. Paediatr. Child HealthEpidemiological characteristics and transmission dynamics of paediatric cases with coronavirus disease 2019 in Hubei province, China08 12 2020ChinaAsia1386Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1111/jpc.15287

In this study, the epidemiological characteristics of children and adults with suspected and confirmed SARS-CoV-2 infection in Hubei province, China are compared. Cases from 8th December 2019 and 7th March 2020 were identified from the National Infectious Diseases Surveillance System. Due to limitation in PCR testing availability early in the pandemic, "clinically diagnosed" cases with consistent symptoms, imaging and an epidemiological link were included.

A total of 1369 paediatric cases were identified, including 384 clinically diagnosed cases and 985 laboratory confirmed cases. Median age was 9yo (IQR 3-14yo). Most cases were mild (50.1%) or moderate (30.9%). Compared with adults (total 68,541 cases), children were more likely to be asymptomatic (15.4% vs 2.9%) and less likely to have severe or critical illness (3.6% vs 18.6%).

The paediatric epidemiological curve peaked 19 days later than that of adults (11th February vs 23rd January). The reduction in transmission occurred concurrent with the isolation of Wuhan City from neighbouring regions (23rd January) and prior to the implementation of a province-wide stay-at-home order(16th February). Compared with adults, children were more likely to have a contact history with a confimred case (44.5% vs 22.4%) or a link with a known cluster (22.0% vs 12.5%).

This study has several limitations including the inclusion of non-laboratory confirmed cases, the likely incomplete case ascertainment given early testing limitations and missing data on some variables in a significant proportion of cases. Notwithstanding this, the milder clinical course and higher proportion of asymptomatic cases in children is consistent with data elsewhere, although the absolute proportion of asymptomatic cases here is likely an underestimate. The demonstrated lag in the paediatric epidemiological curve may not be immediately generalisable to other settings given the unique circumstances in Hubei with potential occupational exposure in adults at the very start of the pandemic together with the timing coinciding with the school holiday period. The findings here do highlight the importance of household exposure in paediatric SARS-CoV-2 infections, consistent with data from contact tracing studies elsewhere.

Maltezou, HTsolia, MPediatr Infect Dis JChildren and Adolescents With SARS-CoV-2 Infection: Epidemiology, Clinical Course and Viral Loads01 DEC 2020GreeceEurope203Epidemiology - Disease Burdenhttps://doi.org/10.1097/inf.0000000000002899

This is a retrospective study of data from a national registry of SARS-CoV-2 cases which analysed within-family transmission and examined the viral loads of affected children in Greece between February 26th and June 30th 2020.

Analysis; 203 SARS-CoV-2-infected children were identified (median age 11y, range 6 days - 18.4y). 111 (54.7%) had an asymptomatic infection. Of the 92 children with symptomatic disease 24 (26.1%) were hospitalised. One child with an underlying neuromuscular disorder had a severe illness. All the other children made full recoveries and there were no deaths.

Virologic investigation was by RT-PCR of respiratory samples. Viral loads were categorised using PCR amplification cycle threshold (Ct) values as high, moderate, low or negative (Ct <25, 25–30, >30, or >38 respectively).

Transmission from a household member accounted for 132 (74.2%) of the 178 paediatric cases with SARS-CoV-2 infection. The median attack rate was 40% (range 11.1%–100%) per family. An adult was the first case of infection in the families of 125 (66.8%) children with SARS-CoV-2 infection. 62 children (33.2%) were identified as the first case of infection in their families. Child-to-child infection occurred in only one case. In only one family was there evidence of transmission from a paediatric case (a 16-year-old) to an adult.

Of 164 children for whom Ct values were available, 46 (28.1%) had a high, 44 (26.8%) a moderate and 74 (45.1%) a low viral load. Viral load did not differ significantly between children of different ages, sex, underlying condition, fever and hospitalisation.

The authors concluded that adults played the key role in the introduction and spread of SARS-CoV-2 infection in families.

Szépfalusi, ZFrischer, TPediatr Allergy ImmunolLessons from low seroprevalence of SARS-CoV-2 antibodies in schoolchildren: a cross-sectional study 29 JAN 2021AustriaEurope2069Epidemiology - Disease Burdenhttps://doi.org/10.1111/pai.13459

This was a cross-sectional study of the prevalence of SARS-CoV-2 antibodies and virus RNA in children and young people (CYP), combined with contact tracing and symptom reporting from Austria between 18 May to 2 July 2020.

Analysis

The study enrolled 2069 children and young people (52.4% female) between the ages of 5 and 21 years (median 13, IQR 10-15) in Vienna. Oropharyngeal and nasopharyngeal samples were analysed for SARS-CoV-2 by real-time PCR. SARS-CoV-2-specific antibodies were identified in blood by ELISA testing. Questionnaires about gender, age, symptoms of SARS-CoV-2 infection and contact with infected individuals were administered on the day of screening.

SARS-CoV-2 RNA was detected in 2 CYP by RT-PCR (1 pair of siblings, 0.1%). 26 CYP (1.3%) tested positive for specific antibodies. Seroprevalence was higher in children older than 10 years and peaked at the age of 13. Seropositivity was associated with a history of mild clinical symptoms in 14 CYP (53.8%), while the remainder had no symptoms.

Contact tracing of seropositive individuals revealed 16 CYP had been in contact with confirmed COVID-19 cases: 7 from within their families and 9 from outside the family – all of these were intergenerational contacts.

A significantly larger probability of seropositivity (n=11, 42%, p<0.001) was found in CYP whose family members had been in contact with a suspected COVID-19-case. 6.3% of CYP who had been in contact with a suspected SARS-CoV-2 case showed a seropositive result as compared to 0.8% of children with no such contact.

The authors conclude that the rate of infection with SARS-CoV-2 was low in schoolchildren and was associated with mild or no symptoms. Spread of virus was far more likely to occur between intergenerational contacts than among siblings in the same household.

Kociolek, LPollock, NJ Clin MicrobiologyComparison of upper respiratory viral load distributions in asymptomatic and symptomatic children diagnosed with SARS-CoV-2 infection in pediatric hospital testing programs.22 Oct 2020USA, CanadaNorth America817Epidemiology - Disease Burdenhttps://jcm.asm.org/content/early/2020/10/22/JCM.02593-20

This study, published online on 22nd October 2020, analyses SARS-CoV-2 viral load data in asymptomatic and symptomatic infected children (aged 0-17 years) tested by 9 children’s hospitals in the USA and Canada from March to July 2020. The article contributes to what is known about upper respiratory viral burden and risk factors in SARS-CoV-2 infected children and to the search for clarification of the role of infected children with and without COVID-19 symptoms in the transmission of SARS-CoV-2.

Study population: Medical charts at 8 children’s hospitals across the USA (in Boston, Los Angeles, Wisconsin, Chicago, Washington, Colorado, Texas and Atlanta) and Canada (Toronto) were retrospectively reviewed for patients testing positive for SARS-CoV-2 by nasopharyngeal or oropharyngeal sampling, blinded to PCR cycle threshold (Ct) values (which are inversely related to viral loads). Clinical data collected for each patient at the time of testing included age, sex, race, ethnicity, presence or absence of immunocompromise and diabetes. Only the first positive test for each patient was included.

The primary reasons for testing asymptomatic (ASx) patients (n=339) were coded in 3 categories: surveillance (contact tracing or broad community surveillance), pre-operative/aerosol generating procedure or hospital admission screening. These patients had no symptoms nor clinical suspicion of COVID-19 at the time of testing (other than potential contact status). Data were collected on known contacts and their timing ( 2 wks/> 2 wks prior to testing or unknown) and whether any symptoms of COVID-19 developed within 5 days after the positive test.

Symptomatic (Sx) patients (n=478) were required to have 2 or more symptoms consistent with COVID-19 (cough, fever/chills, shortness of breath, sore throat, abdominal pain, diarrhoea, fatigue, myalgia, new loss of sense of taste or smell, headache, congestion/rhinorrhoea, nausea/vomiting, rash, conjunctivitis) at the time of testing and were tested due to clinical suspicion of COVID-19.

Within each institution, each asymptomatic patient was matched with up to 2 symptomatic patients by age bracket (0-4 yrs, 5-9 yrs, 10-13 yrs, 14-17 yrs) and date of testing (as close as possible, minimum within 30 days). They were required to have been tested with the same sample type (either nasopharyngeal or oropharyngeal).

The testing assay used (12 different assays were used across the 9 institutions) and Ct values obtained (averaged for assays with more than one target) were recorded for each positive test. Ct values are assay-dependent: to standardise Ct data across the multiple assays used in the different institutions adjusted Ct values were calculated using a centering technique, whereby each institution calculated the median/IQR for Ct values for all positive symptomatic patients (or a representative subset) tested with each assay over the study period, to obtain an institutional symptomatic median; the difference between individual Ct values and this calculated institutional median are reported as adjusted Ct values, which are aggregated in this study. Each institution also reported a viral load (VL) estimate (copies/mL sample) for each Ct value, based on data from internal validation studies, the manufacturer or package inserts.

Demographics of study population: ASx: male 178/339 (52.5%), female 161/339 (47.5%); Sx: male 248/478 (51.9%), female 230/478 (48.1%). Age of ASx patients: 0-4 yrs 118/339 (34.8%), 5-9 yrs 79/339 (23.3%), 10-13 yrs 69/339 (20.4%), 14-17 yrs 73/339 (21.5%); age of Sx patients: 0-4 yrs 197/478 (41.2%), 5-9 yrs 97/478 (20.3%), 10-13 yrs 75/478 (15.7%), 14-17 yrs 109/478 (22.8%).

Co-morbidities recorded in study population: ASx with immunocompromise 35/339 (10.3%); Sx with immunocompromise 16/478 (3.3%). ASx with diabetes 9/339 (2.7%); Sx with diabetes 10/478 (2.1%).

Adjusted Ct values/estimated VLs in ASx and Sx patients: ASx median adjusted Ct value 8.6 (IQR 2.5 to 12.2) versus Sx median adjusted Ct value -1.7 (IQR -6.0 to 4.8) (p<0.0001), i.e. 10.3 cycles higher in ASx children. ASx median estimated VL 2.0 x 103 copies/mL (IQR 162 to 1.7 x 105) versus Sx median estimated VL 1.3 x 107 copies/mL (IQR 5.6 x 104 to 3.8 x 108) (p<0.0001), i.e. viral load 3-4 logs lower in ASx children.

Adjusted Ct values/estimated VLs in ASx and Sx patients by age, sex, ethnicity and race: For each of the four age brackets, differences of similar magnitude with p<0.0001 were observed for both adjusted Ct and estimated VL; these differences narrowed with increasing age (ages 0-4 yrs 11.95 cycle difference; 5-9 yrs 10.32; 10-13 yrs 9.78; 14-17 yrs 8.49), correlating with progressively decreasing median estimated VL in the symptomatic group within each age bracket (ages 0-4 yrs ASx 1.28 x 103 vs Sx 5.33 x 107; 5-9 yrs ASx 1.74 x 103 vs Sx 1.36 x 107; ages 10-13 yrs ASx 4.26 x 103 vs Sx 5.58 x 106; 14-17 yrs ASx 2.43 x 103 vs Sx 2.52 x 106 copies/mL). These differences were consistent across all institutions and were not affected by sex, ethnicity or race.

Adjusted Ct values/estimated VLs in ASx patients by co-morbidities, reason for testing, timing of contacts, subsequent development of symptoms: Odds ratios were calculated to assess the estimated risk of having a Ct value in the lowest quartile (or viral load in the highest quartile) within the asymptomatic Ct value distribution. There was a higher estimated risk of having a Ct value in the lowest quartile for ASx children with diabetes (OR 6.5, p=0.01), recent contact with a COVID-19 case (OR 2.3, p=0.02) and testing for surveillance (OR 2.7, p=0.05) than for ASx children without these risk factors, while immunocompromise, sex, race and ethnicity had no effect. Similar results were obtained for these risk factors in ASx children using estimated VLs. Pre-symptomatic children (those who developed symptoms within 5 days after testing) trended towards higher median VLs (7.7 x 104 copies/mL) versus non-pre-symptomatic children (1.4 x 104), although this difference was not statistically significant.

Conclusions: In this study combining SARS-CoV-2 PCR test results from 9 North American paediatric institutions from March to July 2020, infected children across all ages from 0 to 17 years without symptoms had higher Ct values and lower estimated viral loads than children with symptoms matched by age bracket and test date range. Differences in viral burden were consistent across all 9 collaborating institutions, despite the fact that they used different SARS-CoV-2 test assays and were at different stages of the pandemic over the study period. There was overlap between viral load distributions in asymptomatic and symptomatic children in all age brackets, but asymptomatic children with diabetes, recent contact with a COVID-19 case and those tested for surveillance purposes (rather than pre-procedure or pre-admission) had a higher estimated risk of being in the highest viral load quartile. The authors note that in the pre-procedure and pre-admission screening groups, almost all viral loads were probably below the limits of detection of available rapid antigen tests. The question of interest is that of the potential for disease transmission by asymptomatic individuals; correlation of viral load with ability to recover virus in culture, often used as a surrogate for infectivity, is challenging, and inability to recover replicating virus in culture does not necessarily preclude transmissibility. Additional research is needed to determine the extent to which individuals of any age are able to transmit infection at low viral loads.

Limitations identified by authors: The symptomatic population in this study may have been slightly biased towards more severe disease by requiring that each patient have a minimum of 2 symptoms (this was to maximise the chances that symptoms were truly caused by SARS-CoV-2). The asymptomatic population in this study may not be representative of recently infected asymptomatic children; the asymptomatic children analysed here may be biased towards lower viral loads due to a higher frequency of infections remote in time picked up on screening testing. The pre-symptomatic children in this study had a slightly higher median viral load than those who did not develop symptoms, but their viral loads were still relatively low. Data about contacts or subsequent symptoms were not available for many asymptomatic children in the study. Further investigation to define the peak viral load in asymptomatic and pre-symptomatic children is needed. However, even in the asymptomatic surveillance sub-cohort with highest viral loads, median viral loads were still significantly lower than in the symptomatic cohort.

Buonsenso, DValentini, PmedRxivSARS-CoV-2 infections in Italian schools: preliminary findings after one month of school opening during the second wave of the pandemic11 Oct 2020ItalyEurope1059Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.10.10.20210328v1

This article is a pre-print and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

This study about SARS-CoV-2 cases in Italian schools from the opening of schools in September to 5th October 2020 was posted on medRxiv on 11th October 2020.

Methodology: The authors (who are based in Rome) used an open access, online dataset developed on 14th September 2020 by two PhD students. They monitor media news about SARS-CoV-2 infections in Italian schools on a daily basis, using internet searches, institutional websites and other news reports. For each relevant news report, the spreadsheet records date, region, province, city, school name, type of school, number of SARS-CoV-2 positive cases within the school, numbers of students/teachers/others, type of quarantine activated after notification of a positive case, whether the school was closed, number of secondary positive cases and reference to the news reports. The article includes a map of Italy showing the location of cases reported. The dataset is ongoing (the first entry is for 3rd September 2020, with data analysed for this article to 5th October 2020). Most Italian schools opened on 14th September 2020. The article states that more than 8 million students attend school in Italy (7,599,259 for national schools and 866,805 for peer schools (undefined) for 2019-20).

Results: As of 5th October 2020, the dataset records 1350 SARS-CoV-2 cases in Italian schools, comprising 1059/1350 (78.4%) students, 145/1350 (10.7%) teachers and 146/1350 (10.8%) other school members. The 146 other school members are divided in the tables supplied into 52/146 “others” and 94/146 “missing”. The cases involved 1212 Italian schools (1.9% out of a total 65,104 schools).

Cases by type of school: Nurseries/kindergardens 236/1350 (17.5%), elementary (primary) schools 300/1350 (22.2%), middle (lower secondary) schools 208/1350 (15.4%), high (upper secondary) schools 452/1350 (33.5%), peer schools 55/1350 (4.1%), school type unavailable 99/1350 (7.3%).

Students as proportion of cases in each type of school: Nurseries/kindergardens 171/236 (72.5%), elementary schools 230/300 (76.7%), middle schools 177/208 (85.1%), high schools 384/452 (85.0%), peer schools 28/55 (50.9%) (plus 69 student cases out of the 99 cases with school type unavailable).

Numbers of cases in each school: With the exception of peer schools, only 1 case of SARS-CoV-2 was reported in more than 90% of reports, and only in 1 high school was there a cluster of more than 10 cases. Breakdown by type of school for reports of numbers of cases in a school: nurseries/kindergardens with 1 case 218/236 (92.4%), 2-5 cases 10/236 (4.2%), 6-10 cases 0%, > 10 cases 0%, details missing 8/236 (3.3%); elementary schools with 1 case 280/300 (93.3%), 2-5 cases 17/300 (5.7%), 6-10 cases 2/300 (0.7%), > 10 cases 0%, details missing 1/300 (0.3%); middle schools with 1 case 198/208 (95.2%), 2-5 cases 5/208 (2.4%), 6-10 cases 1/208 (0.5%), > 10 cases 0%, details missing 4/208 (2.0%); high schools with 1 case 419/452 (92.7%), 2-5 cases 25/452 (5.5%), 6-10 cases 2/452 (0.4%), > 10 cases 1/452 (0.2%), details missing 5/452 (1.1%); peer schools with 1 case 47/55 (85.5%), 2-5 cases 3/55 (5.5%), 6-10 cases 0%, > 10 cases 0%, details missing 5/55 (9.1%) (plus 99/1350 cases with school type unavailable).

School closures after 1 or more positive cases identified: 192 schools were closed (14.2% of schools with 1 or more cases), by school type: nurseries/kindergardens 51/236 (21.6%), elementary schools 38/300 (12.7%), middle schools 23/208 (11.1%), high schools 49/452 (10.8%), peer schools 21/55 (21.6%).

Limitations of study: This dataset is based on news available on the internet with no further investigation to verify reliability of reports. The breakdown of cases between students, teachers and other school members includes 94 cases (7%) where it wasn’t possible to identify which category they belonged to. School type was unavailable for 99 cases (7%).

Leeb, RTLozier MCenters for Disease Control and Prevention Morbidity and Mortality Weekly Report (MMWR)COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 202002 Oct 2020USANorth America277285Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6939e2.htm

This paper describes the trends in COVID infection in school age children in the USA. There are about 56 million kids in school there (age 5-17). They all went back to school in Sept, but the analysis is only for the 277,285 cases in 5-17 years olds from March 1st to Sept 19 (so not really capturing the effect of going back to school).

Confirmed cases included in this report had a positive real-time reverse transcription–polymerase chain reaction (RT-PCR) test result for SARS-CoV-2. This means that may be underreporting the impact of the disease on children as children not tested not included. Weekly incidence in 12-17y roughly twice children age 5-11 (37.4 cases per 100,000 v 19.0). Of the 277,285, 101,503 (37%) in children aged 5–11 years and 175,782 (63%) in adolescents aged 12–17 years. Data is an aggregate of the cases and deaths reported. These data do not include cases where no sex or age was included in the reports aggregated – so may be an underestimate.

Underlying conditions were more common among school-aged children with severe outcomes related to COVID-19: among school-aged children who were hospitalized, admitted to an intensive care unit (ICU), or who died, 16%, 27%, and 28%, respectively, had at least one underlying medical condition. Among school-aged children with COVID-19, at least one underlying condition was reported for 7,738 (3%), including approximately 3% of adolescents and 2% of younger children.

Among those with an underlying condition, chronic lung disease, including asthma, was most commonly reported (55%), followed by disability*** (9%), immunosuppressive conditions (7%), diabetes (6%), psychological conditions (6%), cardiovascular disease (5%), and severe obesity (4%)

BUT Underlying conditions were based on pre-defined categories on the reporting form and were skewed to adult problems – hypertension, severe obesity based on a BMI >40, cardiovascular disease – there was an disability (including neurological) option, and “other” – but nothing for CF, or renal transplant, or DMD – so again I do wonder about underreporting of underlying conditions specific to childhood.

This report contains a lot of US national testing capacity data – showing oscillations in the amount of tests requested. Adolescents (12-17) had more tests than the younger children (5-11). Percentage positivity also reported for US nationally and regionally.

Other interesting facts from these data: Among school-aged children with laboratory-confirmed COVID-19, 58% reported at least one symptom, 5% reported no symptoms, and information on symptoms was missing or unknown for 37%. Overall, 3,240 (1.2%) school-aged children with COVID-19 were hospitalized, including 404 (0.1%) who required ICU admission. Fifty-one (<0.01%) school age children died of COVID-19

Among school-aged children with complete information on race/ethnicity who were hospitalized (2,473 [76%]) or admitted to an ICU (321 [80%]), Hispanic ethnicity was most commonly reported (45%and 43%, respectively), followed by Black (24% and 28%, respectively) and White (22% and 17%, respectively) races

Conclusion: these are high quality data that provide an idea of the minimum harm that COVID has caused for school age children in the USA. The table is especially The mortality is low, and I wonder how accurate the capturing of underlying conditions is based on the reported methodology. Provides a baseline for measuring national trends and comparing nations. And may help unravel the impact of return to school as these data are not included here.

Kuchar, EKubiak, JEur J Clin Microbiol Infect DisChildren were less frequently infected with SARS-CoV-2 than adults during 2020 COVID-19 pandemic in Warsaw, Poland28 Sep 2020PolandEurope904Epidemiology - Disease Burdenhttps://doi.org/10.1007/s10096-020-04038-9

Question: Were children in Warsaw, Poland affected less frequently and less severely than adults with COVID-19 during the 2020 pandemic?

Methods: Subjects were children, from 1 month to 18 years old, and adults, over 18 years old. Patients were enrolled from 2 hospitals in Warsaw during March and May 2020. The Adults and Children groups were each divided into asymptomatic and symptomatic subgroups.

Symptoms: fever, respiratory tract infection syndromes, gastrointestinal symptoms, dyspnoea, cough, chest pain, and seizures were included in the symptomatic groups.

Asymptomatic group: made up of two groups: (1) asymptomatic children who underwent screening for SARS-CoV-2 at the admission for planned hospitalization unrelated to COVID-19, (2) asymptomatic legal guardians of the asymptomatic children and medical staff involved in contact tracing.

All participants were tested by rtPCR for SARS-CoV-2 on NP/OP swabs. Some were also tested for additional respiratory viruses

Results: Symptomatic children (n = 459), Symptomatic adults (n = 1774), Asymptomatic children (n = 445), Asymptomatic adults (n = 239) Total number of children was 904 and adults = 2013

Symptomatic: SARS-CoV-2 in Symptomatic Children: 3.26% (15/459) ,SARS-CoV-2 in Symptomatic Adults: 5.58% (99/1774), p = 0.0448

Asymptomatic: SARS-CoV-2 in Asymptomatic Children 0% (0/445), SARS-CoV-2 in Asymptomatic Adults: 0.83% (2/239), p value = 0.0533

Other respiratory viruses in symptomatic children:, RSV positive: 17.14% (6/35) (p = 0.0002), Influenza A: 8.16% (4/49), Influenza B: 2.04% (1/49), No cases of co-infection with SARS-CoV-2

Authors’ conclusion on the analysis of their key outcome was that there was a difference between the proportions infected in children and adults. Children were more likely to be infected with RSV or influenza A/B than with SARS-CoV-2.

Commentary: There was only weak statistical evidence for a difference between adults and children in likelihood of COVID-19 infection given that a p value of 0.0448 approximates to 0.05, the threshold defined by the authors for “significance”. The secondary aim was a comparison of symptomatology between adults and children, but no data were supplied.

The sources of bias in this study are of concern: sampling bias may be likely in the population studied: are the children admitted to these hospitals, representative of the general population in Warsaw? Parents may have kept COVID-19 positive mildly symptomatic children at home. Were the infections acquired in hospital or in the community? Were all hospitals attendances screened for COVID-19 on admission? There was no information on the selection criteria of the subgroup of symptomatic paediatric patients who were tested for other respiratory viruses. The only reasonable conclusion of this study, assuming no bias in the selection of patients who were tested for other respiratory viruses is that: during the COVD-19 2020 epidemic in the months of March through to May, in symptomatic children admitted to 2 hospitals in Warsaw, RSV and Influenza A or B were more likely to be isolated than SARS-CoV-2, from throat or naso-pharyngeal swabs.

Ulyte, AKriemler, SmedRxivVariation in SARS-CoV-2 seroprevalence in school-children across districts, schools and classes18 Sep 2020SwitzerlandEurope2585Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.09.18.20191254v1

This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

This cross-sectional analysis of baseline measurements of a Swiss longitudinal cohort study of 2585 children aged 6-16 years in 55 randomly selected schools in the canton of Zurich (population 1.5 million) was posted on medRxiv on 18th September 2020. Schools in Switzerland were closed for 2 months (16th March to 10th May 2020) because of the COVID-19 pandemic; there was an initial partial re-opening for 4 weeks (e.g. teaching in half-classes, restricting larger group activities) and then on 7th June 2020 regular teaching resumed. This analysis presents SARS-CoV-2 seroprevalence measured in this cohort of school children between 16th June and 9th July 2020.

Study design: This large prospective school-based study (Ciao Corona, described in an article posted on medRxiv on 2nd September 2020) aims to follow SARS-CoV-2 seroprevalence and symptoms, in addition to sociodemographic and lifestyle factors, of a cohort of enrolled school children (and their parents and school staff) in the canton of Zurich (which includes both urban and rural settings and an ethically diverse population) from June 2020 to April 2021, to assess SARS-CoV-2 prevalence, transmission routes, clustering, temporal trends, asymptomatic cases, risk factors and duration of immunity. The study is part of a research programme across Switzerland (Corona Immunitas, www.corona-immunitas.ch) investigating SARS-CoV-2 immunity across the country.

Children aged 5 to 16 years attending primary and secondary schools in the canton of Zurich were enrolled from 16th June to 9th July 2020, with collection of venous blood samples for SARS-CoV-2 serological testing planned in 3 phases: June/July 2020 (baseline estimate of seroprevalence after lockdown and subsequent re-opening of schools, reported in this article), October/November 2020 (after summer break and 3 months of school) and March/April 2021 (after the winter season). Primary schools (public and private) were selected randomly and the nearest secondary school matched with each, with a predetermined target number of schools to enrol for each of the 12 districts of the canton, depending on district size (initial target was 29 primary and 29 secondary schools). Within the schools, children were invited to participate from randomly selected classes within lower (grades 1-2, ages 6 to 9 years), middle (grades 4-5, ages 9 to 13 years) and upper (grades 7-8, ages 12 to 16 years) levels of schools (grades 3, 6 and 9 were excluded as follow-up would be compromised for students changing school after the summer break). Exclusions included small school size and suspected or confirmed SARS-CoV-2 infection during testing. Serological testing of parents and school personnel will also take place during the course of the study. Questionnaires completed for enrolled children (by their parents) and by parents living in the same household and all school personnel of participating schools assess symptoms and tests, health, preventative behaviour, lifestyle and quality of life over the course of the study.

Study population: 55 out of 156 invited primary and secondary schools agreed to participate and 2585 children (1337/2585 (52%) girls, median age 11 yrs, range 6-16 yrs) were enrolled in randomly selected classes in the participating schools. Mean participation rate across classes was 45% (range 5% to 94%). Participation rate by school level: 754/2585 (29%) lower, 899/2585 (35%) middle, 932/2585 (36%) upper. [Participation bias is a factor to consider at the school and individual level.]M

SARS-CoV-2 seroprevalence findings: Venous blood samples were collected from 2484/2585 (96%) enrolled children (1276/2484 (51%) girls, median age 11 yrs, age range 6-16 yrs). At the University of Zurich an in-house binding assay based on the Luminex technology was used to analyse IgG, IgM and IgA antibodies against 4 SARS-CoV-2 targets (receptor binding domain, spike proteins S1 and S2 and the nucleocapsid protein), yielding 12 different measurements: samples were defined as SARS-CoV-2 seropositive if at least 2 of the 12 parameters were above cut-off values established against pre-pandemic plasma (sensitivity 93.3% and specificity 99.6%). Bayesian hierarchical modelling was used to estimate seroprevalence, accounting for the sensitivity and specificity of the antibody test, the hierarchical structure of the cohort and adjustment for population-level grade level and geographical district.

74 children had SARS-CoV-2 antibodies, resulting in an overall weighted seroprevalence of 2.8% (95% credible interval 1.6-4.1%) and a range from 1.0% to 4.5% in different districts, with 3.8% (1.9-6.1%) in grades 1-2 (6-9 yr olds), 2.5% (1.1-4.2%) in grades 4-5 (9-13 yr olds) and 1.5% (0.5-3.0%) in grades 7-8 (12-16 yr olds). Girls 2.8% (1.6-4.1%), boys 2.7% (1.5-4.0%). At least one seropositive child was found in 36/55 (65%) of tested schools: 24% of all classes (regardless of participation rate) had at least one seropositive child; 34% (43/128) of classes with 5 children and 50% of the class tested had at least one seropositive child (with a maximum of 3 cases per class in this participation rate bracket); 45% of classes with 15 children and 60% of the class tested had at least one case.

Comparison with adult seroprevalence: To compare seroprevalence estimates in children and adults, data from a random sample (in the same region in June-July 2020) of 577 adults taking part in the Corona Immunitas research programme was used: this uses the SenASTrIS test to detect IgG and IgA binding to the entire trimeric S protein of SARS-CoV-2 (98.3% sensitivity and 98.4% specificity for IgG and IgA combined). For comparability, 1717 children’s blood samples from the Ciao Corona study were also analysed with the SenASTrIS test.

Seroprevalence of children (measured using the Corona Immunitas test of IgG and IgA combined) was very similar to that of the adult sample (3.1%, 95% CI 1.4-5.4% versus 3.3%, 95% CI 1.4-5.5%).

Comparison with PCR-confirmed cases: Based on the cumulative incidence of SARS-CoV-2 RT-PCR-confirmed cases by the end of June (0.03% for children and 0.24% for adults, using official statistics for the canton of Zurich), the authors calculate “total infections” (using seropositivity) to be 89 times PCR-confirmed cases in children and 12 times PCR-confirmed cases in adults.

Symptom questionnaire: Baseline online questionnaires were completed for 2259/2585 (87%) children. 73% of children reported any SARS-CoV-2 compatible symptoms between January and June 2020 (from most frequently reported to least: runny nose, cough, headache, sore throat, fever, fatigue, muscle soreness, diarrhoea, nausea, loss of appetite, upset stomach, shortness of breath, anosmia): none of the symptoms were more frequent in seropositive than seronegative children.

Conclusion: The authors reported variation in SARS-CoV-2 seroprevalence in 6 to 16 year olds across districts, schools and classes in this study of randomly sampled schools and classes in the canton of Zurich, Switzerland in June/July 2020, reflecting SARS-CoV-2 infection in this cohort of school children in the 4 months to approximately end of May 2020 (allowing for an estimated time interval for production of antibodies), which included 2 months of school closure and a month of “mild” population lockdown. They reported no indication of clustering of SARS-CoV-2 seropositive cases within schools or major transmission within schools. Although no outbreaks were reported in schools in the region at the time of testing, seropositive cases were detected in more than half of tested schools and a third of tested classes (for classes with a participation rate of 5 children and 50% tested). The vast majority of classes with cases had only a single case. Overall estimated seroprevalence was the same in children and adults (approximately 3%), but only approximately 1 in 90 cases in children had been previously confirmed by PCR testing, compared to 1 in 12 cases in adults. The authors suggest that these differences might be explained by the non-specific nature of symptoms in children versus adults and differences in testing indications. Differences in asymptomatic case rates are presumably also relevant. When seroprevalence across school levels was compared, there was a trend of higher seroprevalence in younger children (3.8% for 6-9 year olds versus 1.5% for 12-16 year olds). The reporting of COVID-19-compatible symptoms during the 6 month period prior to enrolment was extremely common in the cohort and not specific to seropositive children.

Gabriel, MFernández-Cañadas Morillo, APediatr Infect Dis JMaternal, Perinatal and Neonatal Outcomes With COVID-19: A Multicenter Study of 242 Pregnancies and Their 248 Infant Newborns During Their First Month of Life11 Sep 2020SpainEurope235Epidemiology - Disease Burdenhttps://journals.lww.com/pidj/Abstract/9000/Maternal,_Perinatal_and_Neonatal_Outcomes_With.96042.aspx

Spain has been one of the worst-hit countries in Europe with regard to Coronavirus-19 infection, having recorded more than half a million cases and currently declaring a 10% test positivity rate – more than twice that of France and four times that of the UK. It is important, therefore, to have reliable data which help understand the impact the infection is having on pregnancy outcomes in that country.

This paper reports a multicentre observational study with the aim, first, of documenting the symptoms and perinatal outcomes for women who were diagnosed as having contracted Covid-19 infection during the third trimester of pregnancy and, second, of tracking the progress of their babies during the first month of life. The study was conducted in 16 Spanish university hospitals by the newly-formed Neo-COVID-19 Research Group. The hospitals involved are not listed but the majority of the members of the research group are based in Madrid with others in Barcelona, Girona, Santiago de Compostela and Valladolid, all in northern Spain. The study took place over an 11-week period from March 13 to May 31, 2020.

The study design is reported to be descriptive and prospective except for the first week of the study, for which data were collected retrospectively. Full details of case ascertainment are not given but all of the included women were positive either for SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction (RT-PCR) testing of nasopharyngeal (NP) and/or oropharyngeal (OP) swab samples (92.1%), or had positive serological testing during labour for IgG using ELISA assays (7.8%) – 2.4% were also positive for IgM. Clinical data and information for the 242 mothers were collected from the medical records; perinatal data for the 248 babies were collected from the hospital medical records. Follow up information for 235 babies (94.7%) was acquired at one month, when the parents were contacted to determine details of hospitalisation or emergency medical consultations.

With regard to symptoms, 40.5% of the pregnant women were asymptomatic; it is not clear why these mothers were tested. The commonest recorded symptoms were coughing (33%) and fever (29.7%); anosmia occurred in 16.1%, ageusia in 9.1% and dyspnoea in 15.7%. 19% were admitted to hospital because of Covid-19-related illness and 2.7% deteriorated sufficiently to require admission to intensive care. One patient died as a result of a massive thromboembolic event.

Delivery was by caesarean section (CS) in 26%; clinical deterioration was the indication for the CS in 2.4%. This represented an increased risk of CS for all infected women; the calculated OR was 2.15 (95% CI: 1.09;4.25, p=0.027). The source of the comparator data for the OR is not given but the inference must be that standard caesarean section rates are much lower in Spain than those currently in the UK.

Thirty-six (14.5%) of the deliveries were preterm and 58.3% of these were late preterm; only 4 (1.6% of all babies) were born at less than 32 weeks gestation. The risk of preterm delivery was higher for infants whose mothers had been admitted because of their Covid-19 infection - OR 2.95 (95%CI: 1.37;6.41, p=0.006). The authors concluded that the prematurity rate was higher than for non-Covid pregnancies.

Of the 115 babies (46.3%) admitted to a neonatal unit the reason for admission for 87 (75.6%) was organisational in that that their mothers were being nursed in a Covid-19 area, rather than a maternity ward. 11.3% were admitted to a NICU - 10.4% required respiratory support and 1.2% were mechanically ventilated. One infant, who was test negative, developed hypoxic ischaemic encephalopathy (HIE). There were no deaths. At the time of discharge 40.4% were exclusively breast feeding and another 38.4% were having some breast feeds; the rates at one month were 40.4% and 35.7% respectively.

RT-PCR testing was performed on NP or OP samples in 230 (92.7%) of the babies at a median age of 3 hours (IQR 2-15) - it was not performed on the other 7.2% because their mothers were RT-PCR negative during labour. The tests were positive in 11 (4.4%), two of the babies having been delivered by CS; six of the eleven had been allowed skin-to-skin contact with their mothers and four had been born to mothers who were RT-PCR positive during delivery; all of these babies tested negative on re-testing. Two infants who tested negative on a first sample were found to have positive tests on a second; both were asymptomatic and these infants were considered to be false positives. Re-testing for RT-PCR in another 85 showed negative results. The authors concluded that no evidence of vertical transmission had been found.

At the one-month follow-up phone call five babies were reported to have been re-tested for Covid-19 because of either fever or primarily upper respiratory signs and all tested negative. The authors considered that, overall, there had been a slightly higher rate of visits to the emergency ward compared with published data.

Over the past few months there have been a number of studies, including systematic reviews, reporting perinatal outcomes for pregnancies in which the mother tested positive for SARS-CoV-2. For the mothers, there is general agreement among the studies that common symptoms include fever, cough, lethargy and dyspnoea while the frequency of others, such as myalgia, anosmia and ageusia, is more variable. The relevance of caesarean section to clinical deterioration in the mother is uncertain. For other perinatal outcomes, comparison between published studies is more complex. The table below shows the outcomes of the current study and those of a UK cohort review and two systematic reviews.

The disparity reflects not only differences in study design, methodology and timing of infection but also variations between units and between countries in clinical practice. There is also evidence of a risk of iatrogenic preterm birth and caesarean section in Covid-19 pregnancies which affects the inferences which can be drawn from the reported data.3 There seems to be agreement, however, that perinatal mortality rates are low in babies born to mothers who contract Covid-19 in pregnancy and the current paper adds to the evidence that in-utero transmission of SARS-CoV-2 is rare. Other important aspects of the management of Covid-19 pregnancies, such as skin-to-skin contact and breast feeding, will hopefully form the topics for future studies.

Kam, KYung, CmedRxivSARS-CoV-2 Viral RNA Load Dynamics in the Nasopharynx of Infected Children02 Sep 2020SingaporeAsia17Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.08.21.20178574v1

This observational study, posted on medRxiv on 2nd September 2020, measured the daily SARS-CoV-2 viral load in nasopharyngeal samples of 17 infected children at KK Women’s and Children’s Hospital (KKH) in Singapore, in order to analyse the temporal trend of viral load in symptomatic and asymptomatic infected children.

Methodology: KKH (an 830-bed teaching hospital for women and children) is the primary hospital for evaluation and isolation of paediatric COVID-19 cases in Singapore. Data was collected from hospital records of paediatric inpatients presenting to the hospital between 23rd March and 5th April 2020 who were diagnosed as confirmed COVID-19 cases by nasopharyngeal swabs positive for SARS-CoV-2 rRT-PCR E gene assay (using the Corman et al protocol). Most of these children were contacts of confirmed cases in their households. Nasopharyngeal swabs were taken daily from every confirmed case. Confirmed cases were discharged from hospital once they had 2 negative swab results on consecutive days. Age, gender and cycle threshold (Ct) values of all nasopharyngeal swabs for each confirmed case were recorded. Ct values are inversely correlated with viral load. A Ct of 45 was considered undetectable. All first-time positive results for each patient were confirmed by a second different PCR assay.

Measurement of viral load over time: Ct values were reported in relation to: 1. day of onset of illness for symptomatic patients and 2. day of diagnosis for asymptomatic patients. Average Ct values were calculated for each day of illness (symptomatic patients) or diagnosis (asymptomatic patients). These were plotted graphically to compare average Ct trends on each day of illness/diagnosis for the 2 groups. Since it is difficult to ascertain the exact day of infection in both symptomatic and asymptomatic children, a second analysis was performed in order to mitigate bias in timing of detection between the two groups, using an estimated day of infection for each case. This was during the early part of the pandemic in Singapore with detailed contact tracing and testing and most children in this study were likely to have been infected by a household confirmed case: the date of symptom onset for the index household COVID-19 case was used as the estimated day of infection (for cases where this information was unavailable, the average duration for cases where the information was available was used).

Clinical features of confirmed cases: 17 children with nasopharyngeal swabs positive for SARS-CoV-2 were cared for as inpatients at the hospital during this two week period. Median age was 7.7 years (range 0.3 to 15.8 years). Gender of cases is not stated. The cohort included Chinese, Malay, Indian and Eurasian ethnicities. 10/17 (58.8%) were symptomatic. All symptomatic children had a mild upper respiratory tract illness (no pneumonia or complications) with symptoms resolved by day 5 of illness. All asymptomatic children remained well with no symptoms until discharge.

Mean duration of viral shedding: Combined group 16 days (range 3-29 days) with symptomatic children 17 days and asymptomatic children 14 days (not statistically significant, p=0.48). In the second analysis, using estimated day of infection to adjust for bias in timing of detection, the durations of viral shedding for the two groups were similar. The longest duration of viral shedding was 30 days in a previously symptomatic child.

Viral loads in confirmed cases: Higher on day 7 of illness for symptomatic children (mean Ct 28.6) than asymptomatic children (mean Ct 36.7) (95% CI = 1.9 to 14.3, p=0.02). Peak viral loads occurred around days 2-3 of illness (symptomatic)/diagnosis (asymptomatic). In the second analysis, using estimated day of infection to adjust for bias in timing of detection, the viral loads remained higher in symptomatic versus asymptomatic children.

Conclusions: In this study (of a small sample of paediatric COVID-19 inpatients in a Singaporean hospital with mild illness or asymptomatic in isolation after a positive test) the symptomatic SARS-CoV-2-infected children had higher viral loads in the nasopharynx than the asymptomatic children. The authors suggest that this may indicate that symptomatic children may be more likely to transmit SARS-CoV-2 than asymptomatic children. They also suggest that pre-symptomatic transmission is probable, since peak SARS-CoV-2 viral loads occurred early at around 2-3 days post-symptom onset. Around 60% of infected children were symptomatic and around 40% asymptomatic. The majority of cases had detectable virus on day 7 of illness/diagnosis.

Sola, A MChan, D KJAMA PediatrPrevalence of SARS-CoV-2 Infection in Children Without Symptoms of Coronavirus Disease 201925 Aug 2020USNorth America33041Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2769878

An epidemiological study of asymptomatic Covid-19 in children across 28 centres in the US from 29/05/2020 to 09/07/2020. Asymptomatic children presenting to the ENT team (for surgery, clinic or planned admissions) were screened for Covid-19. It is noted that they may have had symptoms attributed to their underlying conditions that overlap with Covid-19 symptoms, but that there was not clinical suspicion of Covid-19.

Covid-19 weekly incidence data for the whole population was then obtained for the geographical areas of the hospitals from Johns Hopkins for the same time period and compared with the paediatric asymptomatic screening results.

Results: 250 of 33 041 children (age range, 0-18 years) without symptoms were positive for Covid-19 (on PCR testing). Prevalence varied from 0% to 2.2% between areas, with a pooled prevalence of 0.65% (95% CI, 0.47%-0.83%, with significant heterogeneity).

The whole population weekly Covid-19 incidence for each area was strongly correlated to the paediatric asymptomatic prevalence for that area.

Conclusions: Asymptomatic carriage of Covid-19 in children was found to be low but with significant heterogeneity of results according to centre. It was strongly correlated with the whole population incidence of Covid-19 in that area.

Wood, JJohn, CCureusPrevalence of Asymptomatic SARS-CoV-2 Infection in Children and Adults in Marion County, Indiana16 Aug 2020USANorth America119Epidemiology - Disease Burdenhttps://www.cureus.com/articles/35775-prevalence-of-asymptomatic-sars-cov-2-infection-in-children-and-adults-in-marion-county-indiana
Ladhani, SNRamsay, ME ADCCOVID-19 in children: analysis of the first pandemic peak in England12 Aug 2020UKEurope35200Epidemiology - Disease Burdenhttps://adc.bmj.com/content/early/2020/07/28/archdischild-2020-320042

Ladhani et al have provided epidemiological insight into COVID-19 between the dates of 16 January to 3 May 2020 in children compared to adults in England by reporting data from both Public Health England surveillance and Patient Demographic Service fatality data.

Their data adds to the growing evidence bank of the limited role played by children in the pandemic: only 1% of all cases of COVID-19 in England in the first four months of the pandemic were in the under 16 age group.

During the study period nearly half a million people in England were tested for SARS-CoV-2. Twenty-four percent of tests were positive but only 1.1% (1,408) of the positive cases were children.

35,200 children were swabbed, but only 4% were positive. The highest rates of SARS-CoV-2 were found in infants, particularly those under 3 months. This was a much lower percentage than adults who were swabbed, who tested positive in 19.1 – 34.9% of adults and older ages (the highest rates being in the over 80s).

When the data for people presenting in the community with an acute respiratory infection was analysed it demonstrated a very low percentage of children (only 2.8%) positive for SARS-CoV-2 contrasting with much higher rates in adults, reaching nearly 50% in the over 80s.

During the 3 and a half months of the study, 8 children with SARS-CoV-2 died (0.3%), 4 of whom had multiple comorbidities. The other 4 children died of other causes, with SARS-CoV-2 reported as an incidental or indirect contributor to death. Overall, despite fears that the national ‘Stay at Home’ message would lead to delayed presentations to emergency departments and potentially avoidable fatalities, there was no increase in excess deaths in children, even though excess deaths were reported in other age groups.

The findings from this study are consistent with data from other countries: children make up only a very small percentage of COVID-19, with a low case-fatality rate. Contrary to some assertions the data cannot inform us regarding children's involvement in transmission

Kim, LGarg, SMMWR Morb Mortal Wkly RepHospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-Confirmed COVID-19 - COVID-NET, 14 States, March 1-July 25, 202007 Aug 2020USANorth America576Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6932e3.htm

This report was posted as a Morbidity and Mortality Weekly Report Early Release on 7th August 2020 on the US Centers for Disease Control and Prevention (CDC) website (https://www.cdc.gov/mmwr). Most COVID-19 cases in children under 18 years of age are asymptomatic or mild; here data is presented about more severe cases in children hospitalised with COVID-19 between 1st March and 25th July 2020 in 14 US states.

Background: The COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) is a population-based surveillance system which collects data on laboratory-confirmed COVID-19 hospitalisations in 99 counties of 14 states in the USA (California, Connecticut, Colorado, Georgia, Iowa, Maryland, Michigan, Minnesota, New Mexico, New York, Ohio, Oregon, Tennessee, Utah) representing all 10 US Department of Health and Human Services Regions. COVID-NET surveillance includes COVID-19-associated hospitalisations among residents in a predefined surveillance catchment area who had a positive SARS-CoV-2 molecular test (ordered at the discretion of the treating health care provider) during hospitalisation or up to 14 days before admission. Trained surveillance officers perform medical chart abstractions for all identified cases.

Study design: 576 patients < 18 years of age hospitalised with COVID-19 were reported to COVID-NET from 1st March to 25th July 2020. 208/576 (36%) had complete medical chart reviews. This report is a descriptive analysis of the available data for these inpatients with a positive SARS-CoV-2 test up to 14 days before or during admission to hospital. Only those hospitalisations with complete medical chart review where patients were discharged alive or died during hospitalisation were included for clinical intervention, treatment and outcome figures. Weekly and cumulative COVID-19–associated hospitalisation rates were also calculated: numerator = number of catchment area residents hospitalised with COVID-19 / denominator = National Center for Health Statistics vintage 2019 bridged-race postcensal population estimates.

Age of children hospitalised with COVID-19: Median age was 8 years (IQR 9 months to 15 yrs). Breakdown: under 3 months: 108/576 (18.8%), 3-5 months 20/576 (3.5%), 6-11 months 29/576 (5.0%), 12-23 months 31/576 (5.4%), 2-4 yrs 50/576 (8.7%), 5-11 yrs 97/576 (16.8%), 12-17 yrs 241/597 (41.8%).

Gender of children hospitalised with COVID-19: Male 292/576 (50.7%), female 284/576 (49.3%). Breakdown by age: 0-2 yrs 56% male/44% female; 2-4 yrs 50% male/50% female; 5-17 yrs 48% male/52% female.

Race/ethnicity of children hospitalised with COVID-19: Information about race/ethnicity was reported for 526/576 (91.3%) patients. Hispanic/Latino 241/526 (45.8%), non-Hispanic black 156/526 (29.7%), non-Hispanic white 74/526 (14.1%), non-Hispanic Asian or Pacific Islander 24/526 (4.6%), non-Hispanic American Indian/Alaska Native 4/526 (0.8%), multiple races 3/526 (0.6%), unknown 24/526 (4.6%).

Underlying medical conditions in children hospitalised with COVID-19: Information about underlying medical conditions was available for 222/576 (38.5%) patients. One or more underlying medical conditions 94/222 (42.3%), obesity (defined as body mass index (kg/m2) 95th percentile for age and sex based on CDC growth charts among children aged 2 yrs; not evaluated for children < 2 yrs) 42/111 (37.8%), chronic lung disease 40/222 (18.0%) (including 30 asthma), prematurity (< 37 weeks, data collected only for children < 2 yrs) 10/65 (15.4%), neurologic disorder 31/222 (14.0%), immunocompromised 12/222 (5.4%), feeding tube dependent 12/222 (5.4%), chronic metabolic disease 10/222 (4.5%) (including 6 diabetes mellitus), blood disorders 8/222 (3.6%) (including 6 sickle cell disease), cardiovascular disease 7/222 (3.2%) (including 4 congenital heart disease).

Breakdown of underlying medical conditions by race/ethnicity: Hispanic/Latino 43/94 (45.7%), non-Hispanic Black 28/94 (29.8%), non-Hispanic White 14/94 (14.9%).

Signs and symptoms reported on admission to hospital: Fever/chills 121/224 (54.0%) (commonest in < 2 yrs 50/67 (74.6%)), inability to eat/poor feeding (data collected only in < 2 yrs) 22/67 (32.8%), nausea/vomiting 69/224 (30.8%), cough 66/224 (29.5%), nasal congestion/rhinorrhoea 53/224 (23.7%), shortness of breath/respiratory distress 50/224 (22.3%), abdominal pain 42/224 (18.8%), diarrhoea 27/224 (12.1%). Gastrointestinal symptoms were reported by 42% of hospitalised children overall.

Length of stay in hospital (N=208): Median duration of stay 2.5 days (IQR 1-5 days), similar for all age groups.

Chest radiograph findings (N=67): Infiltrate/consolidation 44/67 (65.7%), bronchopneumonia/pneumonia 14/67 (20.9%), pleural effusion 4/67 (6.0%).

Chest CT findings (N=14): Ground glass opacities 10/14 (71.4%), infiltrate/consolidation 7/14 (50.0%), bronchopneumonia/pneumonia 4/14 (28.6%), pleural effusion 3/14 (21.4%).

COVID-19 investigational treatments: Only 12/208 (5.8%) received these medications, all aged 5-17 yrs (treatment categories not mutually exclusive). Remdesivir 9/208 (4.3%), azithromycin 6/208 (2.9%), hydroxychloroquine 4/208 (1.9%), convalescent plasma 1/208 (0.5%), lopinavir-ritonavir 1/208 (0.5%).

Admission to ICU: 69/208 (33.2%) admitted to ICU. Median length of stay in ICU 2 days (IQR 1-5 days). Breakdown by age: 0-2 yrs 19/61 (31.1%)(median stay 1 day), 2-4 yrs 9/24 (37.5%) (median stay 2 days), 5-17 yrs 41/123 (33.3%) (median stay 3.5 days). The proportion of hospitalised children admitted to ICU (approx. 1 in 3) is similar to the proportion of hospitalised adults admitted to ICU (32.0%) reported to COVID-NET.

Interventions: The highest level of respiratory support needed for each case that required respiratory support were as follows: invasive mechanical ventilation 12/207 (5.8%), BIPAP/CPAP 8/207 (3.9%), high flow nasal cannula 5/207 (2.4%). Administered: systemic steroids 19/208 (9.1%), intravenous immunoglobulin 14/208 (6.7%), vasopressor 10/208 (4.8%). 2 hospitalised children received ECMO. None received renal replacement therapy. Invasive mechanical ventilation was more frequently required in adults (18.6%).

Multisystem inflammatory syndrome in children (MIS-C): From 18th June 2020 onwards, information enabling discharge diagnoses of MIS-C where relevant has been systematically collected by COVID-NET: 9/83 (10.8%) of children with completed medical chart reviews after this date received a diagnosis of MIS-C.

Outcomes in children hospitalised with COVID-19: 1/208 (0.5%) death in hospital (a child with multiple underlying conditions).

Cumulative rate of COVID-19-associated hospitalisation in children (< 18 yrs): 8.0 per 100,000 population from 1st March to 25th July 2020, with highest rate among children < 2 yrs (24.8 per 100,000). Breakdown by race/ethnicity: Hispanic/Latino 16.4 per 100,000; non-Hispanic black 10.5 per 100,000; non-Hispanic white 2.1 per 100,000 (compared to 164.5 per 100,000 among adults).

Limitations of report suggested by authors: Laboratory confirmation of COVID-19 is dependent on clinician-ordered SARS-CoV-2 testing and rates are likely to be underestimates. Hospitalisation rates are preliminary and may change as additional cases are identified during the surveillance period. Approximately 60% of paediatric hospitalisations reported to COVID-NET have not had a medical chart review and the sample may be biased. Data on MIS-C was not collected until 18th June. However, data from COVID-NET is more geographically and racially diverse than single-centre or state-based studies and this report provides useful information about children hospitalised with COVID-19 in the US. Obesity was the most prevalent underlying condition in children hospitalised with COVID-19 in this report and Hispanic/Latino and black children had higher rates of COVID-19-associated hospitalisation than white children.

Bellino, SPezzotti, PediatrCOVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy14 Jul 2020ITALYEurope3836Epidemiology - Disease Burdenhttps://pediatrics.aappublications.org/content/early/2020/07/16/peds.2020-009399

This study used an Italian national case based surveillance system of SARS-CoV-2 infections from February 27th until May 8th 2020. It focuses on the 3,836 paediatric cases (which accounts for 1.8% of the 216,305 total infections).

Cases were divided in severity into asymptomatic, paucisymptomatic, mild (uncomplicated URTI without dyspnoea or abnormal imaging), severe (pneumonia, hypoxia, dyspnoea, tachypnoea requiring hospitalisation) and critical (requiring intensive care).

Rates of infection among children were highest in teenagers and reduced with younger age groups. Adolescents 13-17 years accounted for 40.1% of childhood cases, followed by 7-12 year olds (28.9%), 2-6 year olds (17.2%) and 0-1 (13.8%). Just over half of all cases were male (51.5%)

Of all childhood cases, 13.3% required hospitalisation, however almost half the cases were children under 6 years of age (children <1 year accounted for 36.6%, 2-6 years 12.9%). This was followed by adolescents (13-17yo, 8.9%) and finally 7-12 years olds (8.8%). Children were more likely to have more severe disease if they had pre-existing medical conditions (OR 2.8, 95% CI [1.74-4.48]).

ICU admission occurred in 3.5% of childhood cases, and the highest proportion were children 2-6 years of age (9.5%).  There were four deaths (0.1% of all paediatric cases) - all children who had significant pre-existing underlying medical conditions as follows:

- 5 year old girl who developed SARS-CoV-2 pneumonia on a background of type 2 mucolipidosis with hypertrophic cardiomyopathy, thickened mitral and aortic valves and sleep apnoea- 2 month old boy with William's Syndrome who could not be weaned off ECMO following cardiac surgery for stenosis  and hypoplasia of pulmonary artery and supravalvular aortic stenosis.- 6 month old infant (gender not specified) with an extra renal malignant rhabdoid tumour who developed febrile neutropenia and pneumonia- 6yo girl with heart failure post-operative for a mitral annuloplasty for severe mitral insufficiency and left ventricular dysfunction.

Median time from symptom onset to diagnosis ranged from 3 days in infants to 6 days in adolescents. Symptom onset to hospitalisation also increased with age, from 1 day in infants to 4 days in adolescents. Due to ongoing data collection in the study, only 38.6% of childhood cases had completed recovery, but from available data, there was a median of 29 days from symptom onset to recovery (IQR, 23-37).

The study also looked at paediatric cases within the time frames of the first month of the epidemic, three weeks post peak epidemic and the last three weeks of the study dates. Cases detected in the last period  had lower risk of disease severity (3.5% vs 5.4% in the first month) and a longer time between symptom onset and diagnosis (9 days compared to 3 and 5 days in the prior periods). This may reflects change in testing practices, health care burden and management of cases over time.

When examining the larger data set of 216,305 total infections in the groups of paediatric (<18 years), adult (18-64 years) and elderly (>65 years), children had lower rates of infection, hospitalisation, ICU admission and much fewer deaths.

Over half of paediatric cases (63.4%) were asymptomatic or paucosymptomatic compared to 44% and 27.3% of adults and elderly respectively.  During the study period, 13.3% of children were hospitalised compared to 28.3% of adults and 49.9% of elderly. Severe or critical cases occurred in 4.2% in children, 17.2% adults and 41.1% elderly. Mortality rates were much higher in elderly (25.8%) and adults (5.8%) groups compared to the 4 deaths (0.1% in the paediatric population.

Overall, children had lower rates of SARS-CoV-2 infection and severity than adults and elderly. Within the paediatric population, adolescents were most likely to be infected (40.1% of cases), however the proportion of hospitalisation was higher in infants under 1 year of age (36.6% of cases) and ICU admission was more common in children from 2-6 years of age (9.5% of cases). All four deaths occurred in children 6 years and under who had significant pre-existing medical conditions.

Pollan, MYotti, RLancetPrevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study06 Jul 2020spain Europe6527Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31483-5/fulltext

Introduction; Spain was one of the countries in Europe hit hardest by the Covid 19 pandemic. These are the first wave results from the Seroepidemiological Survey of SARS-CoV-2 Virus Infection in Spain (Encuesta Seroepidemiológica de la Infección por el Virus SARS-CoV-2 en España; ENE-COVID). This is an epidemiological study with an aim to estimate the sero-prevalence of Sars Cov2 in Spain through symptom checking, point of care antibody testing, and serology.

Methods: 35 883 households across Spain were selected through stratified two stage sampling and invited to take part. This is the result of the first wave of sampling which was conducted from April 27 to May 11, 2020. Participants within selected households answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors. “Asymptomatic” was no symptoms, “paucisymptomatic” (1–2 symptoms without anosmia or ageusia), and symptomatic (anosmia or ageusia, or at least three symptoms among fever; chills; severe tiredness; sore throat; cough; shortness of breath; headache; or nausea, vomiting, or diarrhoea). Participants were contacted by phone and then invited to go to local primary care centre for testing or have a home visit. All participants were offered point-of-care antibody test (Orient Gene Biotech COVID-19 IgG/IgM Rapid Test Cassette; Zhejiang Orient GeneBiotech, Zhejiang, China, SARS-CoV-2 spike protein) and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay (SARS-CoV-2 IgG for use with ARCHITECT; Abbott Laboratories, Abbott Park, IL, USA, SARS-CoV-2 nucleoprotein). Sensitivity of the test was deemed any test positive (point of care/ serum), with specificity both tests positive. Of note Spain was under lockdown at the time of this study.

Results: Of 95 699 eligible individuals, 66 805 study participants took part, with 61 075 receiving point of care testing and 51 958 the immunoassay. Overall seroprevalence was 5.0% (CI 4.7–5.4) by the point-of-care test and 4.6% (CI 4.3–5.0) by immunoassay. In 7 provinces in the central part of Spain, including Madrid, seroprevalence was greater than 10% by both methods. Seroprevalence was similar for females and males. Seroprevalence was lower in the oldest age groups (≥85 years) compared with other adults. With regards occupation it was highest in health-care workers, 10.2% (7.9 - 13) than in other occupations these results were supported by the immunoassay.

In those who reported a contact with a confirmed case, seroprevalence was greater in those who had a confirmed case in their household (range 31.4% to 37.4% between the two tests), in their workplace 9.9–10.6%, among their non-cohabitating family members and friends 13.2–13.7%, or among their caregivers and cleaning staff 12.4–13.5%

Symptoms: For both tests seroprevalence was highest in those with a confirmed Sars CoV2 PCR more than 14 days before testing (88·6–90·1%). Among those with a positive test, the proportion of individuals who reported anosmia or three or more symptoms compatible with COVID-19 was 49.1% for the point-of-care test and 54. 2% for the immunoassay. In 32.7% (CI 30.2–35.4) of point-of-care test and 28.5% (CI 25.6–31.6) participants were asymptomatic.

Results in children: 11,422 children (<19 years) had a point of care test, with 6,527 also having an immunoassay. The proportion of paediatric participants having serology was lower than that of adults, though not unsurprising given the need for extra phlebotomy. Overall seroprevalence for those < 19 years was 3·4% (2·9–3·9) for point of care testing, and 6527 3·8% (3·2–4·6) for immunoassay.

Looking at specific age ranges for point-of-care test seroprevalence was < 1 year, 1.1% (0.3–3.5): 1- 4 years 2.1 %(1.3–3.4); 5 – 9 years 3.1% (2.2–4.2); 10-14 years 4.0% (3.1–5.0); and 15 – 19 years, 3.7% (2.9–4.8). The same pattern but slightly higher percentages were seen with immunoassay <1 year 0.0% (0.0–11.9); 1- 5 years 3.5% (1.7–6.8): 5 – 9 years 3.6% (2.3–5.7); 10 – 14 years 4.1% (3.1–5.5); and 15 – 19 years 3.8 (2.8–5.0). This paper did not give data on symptoms separately in age groups.

Conclusion: Population seroprevalence is lower than expected in areas of high endemic SARS-CoV-2, and is lowest in children. Close contact with people, particularly in the same household increases viral transmission. Over 30% of those with seroprevalence were asymptomatic. This highlights the importance of rapid identification and isolation with those with confirmed SARS-CoV-2, however isolation and separation for other household members may not be realistic in poorer or urban areas.

Ooldali, NDanis, KLancet Child Adolescent HealthEmergence of Kawasaki Disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic:a time-series analysis02 Jul 2020FranceEurope10Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30175-9/fulltext#seccestitle140

This study aimed to determine whether the COVID-19 epidemic was associated with an increase in Kawasaki Disease.

Between December 2005 and May 20th 2020, 230 children presenting to this tertiary Paediatric centre in Paris, France were diagnosed with Kawasaki Disease (KD), or incomplete KD, according to diagnostic criteria of American Heart Association. The quasi-Poisson model estimated the median number of KD cases as 1.2 per month but with 2 notable peaks of increased incidence: in December 2009 when there was Influenza A H1N1 epidemic and in April-May 2020. The latter increase in Kawasaki cases started 2 weeks after the peak of the COVID-19 epidemic in Paris.

During April-May 2020, 10 paediatric in-patients were diagnosed with Kawasaki Disease (6 complete) median age 11.8y, 6 males. Symptoms of SARS-CoV-2 are not reported. 8 had a positive SARS-CoV-2 Nasopharyngeal PCR and/or SARS-CoV-2 serology and/or contact with a case: 1 of the other 2, had exposure to a confirmed case. Median CRP 23.6 mg/dl, Lymphocytes 1042 x 109. Radiological findings are not given. 6 of these children were admitted to PICU but all survived.

This group of patients is compared with a cluster in Bergamo in March-April 2020 and to the cluster at this hospital in December 2009 and there were significant differences with the latter.

The authors comment that this study adds to the evidence that suggests viral respiratory infections, including SARS-CoV-2, could be triggers for Kawasaki Disease. It is not stated how many of the 10 children would also meet the criteria for diagnosis of Paediatric Multi-system Inflammatory Syndrome temporally associated with COVID-19 and so adds more to the literature on Kawasaki Disease than that on PIMS-TS.

Gampel, BRoberts, SSPediatr Blood CancerCOVID‐19 disease in New York City pediatric hematology and oncology patients26 Jun 2020USANorth America174Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1002/pbc.28420

This retrospective observational study provides some insight into the impact of COVID-19 on haematology/oncology patients. There were some limitations in the data collection process as testing was performed for different reasons at the two different sites that are considered. However, we see that between 10/03/2020 - 06/04/2020, 19 out of 174 tested children (each of whom had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation) tested positive for COVID-19. Of these, 11 required hospitalisation. Five required PICU and one sadly died.

Method of data collection: All patients 21 years old or younger who underwent clinical laboratory COVID‐19 testing at two New York haem/onc centres were included. All patients had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation. Informed consent was waived.

The two centres tested differently: “MSK tested all symptomatic patients and screened all patients prior to admission, procedures requiring sedation, and planned myelosuppressive chemotherapy. NYP tested only those patients for whom a positive test would alter management, including those who were symptomatic, likely COVID‐19 exposed, or with planned disposition to a chronic care facility.”

Features specific to children:19 out of 174 tested positive. Of these: 68% had fever, 47% had cough and 37% had dyspnea. 11 patients required hospitalisation and 4 patients required supplemental oxygen. 2 patients required mechanical ventilation and a further 3 were also admitted to PICU (all male). 3 patients received ‘COVID-19-directed therapy’ (with hydroxychloroquine and azithromycin) 1 patient died (“a child with sickle cell disease without a significant history of prior complications. Although this patient demonstrated pulmonary disease, his death may have been preceded by an acute cardiac event. Autopsy was refused…”). The authors make note that 64% of COVID+ oncology patients experienced treatment delays, showing the harms to these patients may not come primarily from COVID-19 disease itself

Pagani, GGalli, MmedRxivSeroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA)24 Jun 2020ItalyEurope000Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.06.24.20138875v1

In this brief report of a SARS-CoV-2 serosurvey from Castiglione D'Adda in Italy, the results of a logistic regression model based on the random sampling of 509 subjects from the region (total population 4550) following the peak of transmission in the region are detailed. Prior to this serosurvey testing was limited to severely symptomatic cases.

The exact number of children included is not provided but the age related prevalence was significantly lower in children - 9.1% (0-5yo), 10.1% (5-10yo), 11.2% (10-15yo), 12.5% (15-20yo) - compared with overall seroprevalence of 22.6%.

The methodological details are limited in this report but the data are consistent with serosurvey data from elsewehere in Europe suggesting that children are less susceptible to SARS-CoV-2 infection compared with adults. 

Rha, BLangley,GJ Pediatric Infect DisSARS-CoV-2 Infections in Children - Multi-Center Surveillance, United States, January-March 2020."18 Jun 2020USANorth America4Epidemiology - Disease Burdenhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa075/5859277?searchresult=1
Hua, CFu, JJ Med VirolEpidemiological features and viral shedding in children with SARS-CoV-2 infection15 Jun 2020ChinaAsia43Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26180
Stringhini, SGuessous, IThe LancetSeroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study11 Jun 2020SwitzerlandEurope455Epidemiology - Disease Burdenhttps://doi.org/10.1016/S0140-6736(20)31304-0

Methods: This study takes a representative population sample from Geneva, Switzerland (already identified by a pre-existing health study) and invites them to attend blood tests looking for antibodies against the SARS-CoV-2 virus over time. The purpose is to monitor what proportion of the population are infected and see how it changes during the course of the pandemic (5 weeks in this study). Participants could only attend once, and were invited by email with a telephone follow up. The only exclusion criteria was living in a prison or care home. Antibodies were measured using a commercial assay (ELISA for S1 domain of spike protein IgG). They performed in house validation of the assay using a couple of techniques (the results of the immunofluorescence validation were factored in to the sensitivity analysis of the model used later in the study)

Analysis: The statistical analysis performed was a Bayesian regression which had a random effect for households and factored in age/sex as well as the test performance to extrapolate the sample results on to population estimates of seropositivity. They calculated the relative risk (RR) of age groups having been infected with age 20 – 49yrs as the reference group.

Results: 5492 people were invited and the final analysis included 2766 people (3426 of the rest were non-responders or awaiting an appointment). 455 children participated. Seropositivity in the population increased between weeks 1 and 2 (4.8% to 8.5%), with no statistically significant difference thereafter (final estimate 10.8%).

The most significant result is that of the children<10yrs in the study, only 1/115 children tested positive (although a further 8 had an equivocal result). This made the RR of infection for children <10yrs 0.32 (0.11 – 0.63) compared to adults aged 20 – 49yrs. There was no statistically significant difference between children aged 10 – 19 yrs (OR 0.86, 0.57–1.22). Another important factor was strong association between household contacts (unsurprisingly). This is important, as there were also lower rates of infection seen in the elderly (>65 yrs OR 0.5, 0.28–0.78) but only 3% of these participants had a positive household contact. Of the 123 children aged 5-9yrs, 17% of them had a positive household contact.

This study adds to a growing body of evidence that younger children (particularly those under 10yrs) may be less susceptible to acquiring infection than adults. The RR of 0.3 despite a relatively high proportion having positive household contacts is in contrast to the elderly, whose low infectivity rate may be explained by reduces exposure (additionally, a relatively high number of elderly will have been hospitalised or passed away from infection during the study, meaning they will not be counted in these statistics).

Considerations: Schools were closed for the duration of this study period which will have reduced community exposure of young children. In addition, almost all validation of antibody assays has been in adults so far. There were a notable number of equivocal results in the young children, but the significance of this is unclear. The results are however consistent with the largest seroprevalence study to date, from Spain.

Alvarez-Roman, MTJimenez-Yuste, VHaemophiliaREGISTRY OF PATIENTS WITH CONGENITAL BLEEDING AND COVID-19 IN MADRID10 Jun 2020SpainEurope84Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/hae.14089
Belot, ALevy-Bruhl, DEurosurveillanceSARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 202004 Jun 2020FranceEurope156Epidemiology - Disease Burdenhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.22.2001010#t1

The first epidemiological surveillance study of SARS-CoV-2-related paediatric inflammatory multisystem syndrome (also known as PIMS-TS). Carried out in France (population: 67 million) this was a nationwide study through the French public health agency. 156 cases were reported between 1st March and 17th May 2020 through both prospective and retrospective case identification.

Case definition required one or more of the following symptoms: seritis (serositis), characteristics of macrophage activation syndrome (MAS), myocarditis and/or Kawasaki-like disease (KLD). Cases were divided according to associated Covid status into confirmed, probable or possible CoV and non-CoV. Comparison was undertaken between non-CoV PIMS and CoV PIMS.

Of note, this definition differs marginally from the UK RCPCH definition of PIMS-TS which is a child with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopaenia) and evidence of single or multi-organ dysfunction.

.Age distribution showed a median of 8 years and an interquartile range of 5–11 years. Peak incidence was week of 18th to 27th April, which was 4-5 weeks behind the peak of the Covid-19 epidemic in France.

95 of the 156 reported cases were confirmed or probable Covid, supporting a causal link between Covid-19 infection and PIMS.

CoV-PIMS cases (n=108) compared with non-CoV PIMS cases (n=48) had a higher median age (8 vs 3) and showed higher rates of myocarditis (70% vs 10%), macrophage-activation syndrome (23% vs 2%), seritis (22% vs 10%) and ITU admission (67% vs 8%). Rates of Kawasaki-like disease (KLD) were higher in the non-CoV group (81% vs 61%0) supporting the idea that these are ‘classic’ Kawasaki Disease presentations. In the CoV-PIMS groups 73% required vasopressors, 43% were ventilated and one child died.

This is the first epidemiological surveillance study of PIMS-TS indicating rates across a population. It supports a causal link with Covid following 4-5 weeks behind the clinical illness.

Jie QuanYuan LiClin Inect DisAge-dependent gender differences of COVID-19 in mainland China: comparative study30 May 2020ChinaAsia0Epidemiology - Disease Burdenhttps://doi.org/10.1093/cid/ciaa683
Choe, PKim, NKJIMSelecting coronavirus disease 2019 patients with negligible risk of progression: early experience from non-hospital isolation facility in Korea29 May 2020KoreaAsia0Epidemiology - Disease Burdenhttp://kjim.org/upload/kjim-2020-159.pdf
Bandi, SMahdavinia, MPediatr Allergy ImmunolAfrican American children are at higher risk for COVID-19 infection29 May 2020USANorth America474Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/abs/10.1111/pai.13298
Zheng, XChen, JJ. InfectionCo-infection of SARS-CoV-2 and Influenza virus in Early Stage of the COVID-19 Epidemic in Wuhan, China28 May 2020ChinaAsia1Epidemiology - Disease Burdenhttps://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.journalofinfection.com%2Farticle%2FS0163-4453(20)30319-4%2Fpdf&data=02%7C01%7Cdr98%40leicester.ac.uk%7C1a70a2a944e24723c11108d807052900%7Caebecd6a31d44b0195ce8274afe853d9%7C0%7C0%7C637267066036624572&sdata=sL1i5FVbIszDDJ6an2gzf9kXbJakQIakOv4kzeTtDSw%3D&reserved=0
Yang, LLei, YJ Clin VirolEpidemiological and clinical features of 200 hospitalized patients with corona virus disease 2019 outside Wuhan, China: A descriptive study26 May 2020ChinaAsia3Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250074/pdf/main.pdf
Tao, YMo, XmedRxivPreliminary analysis of scRNA sequencing of children's lung tissues excludes the expression of SARS-CoV-2 entry related genes as the key reason for the milder syndromes of COVID-19 in children25 May 2020ChinaAsia10Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.25.20110890v2

As a pre print, this study should be interpreted with caution whilst awaiting peer review.

Question: do different expression levels of viral-entry associated genes in infection with SARS-CoV-2 in children compared to adults explain milder COVID-19 symptoms seen in children?

What was analysed? RNA and immunohistochemistry of Angiotensin converting enzyme 2 (ACE2), Transmembrane Protease Serine 2 (TMPRSS2). ACE2 interacts with the spike (S) protein of the virus which is then cleaved by TMPRSS2. They also looked at FURIN because a FURIN cleavage site has been identified in the S protein which may act as another pathway for the virus to gain entry.

Comparison: expression level of ACE2, TMPRSS2 AND FURIN in normal lung tissue derived from children and adults.

Methods: For scRNA-seq analysis for gene level expression lung tissue from:

Adults: 8 adult lung transplant donors, age range 20 to 69 years, 2 males and 6 females (5 African American, 1 Asian and 2 White)

Children: areas of normal lung tissue from 4 children requiring lobectomies, aged less than 1 year, 1 male and 3 females with congenital heart abnormalities (Ebstein Anomaly (EA), Tetralogy of Fallot (ToF), AVSD and VSD). Children with EA and ToF also had pulmonary hypoplasia, child with AVSD had pulmonary emphysema and child with VSD had a pulmonary cyst.

Results of scRNA-seq analysis: ACE2 mainly expressed in Alveolar type 2 (AT2) cells in adults and children. TMPRSS2 mainly expressed in AT2, AT1 and club cells in adults and children, FURIN in Endothelial Cells and monocytes in adults; in AT2 and club cells in children. No significant changes were observed in expression levels of ACE2, TMPRSS2 and FURIN between adults and children

For immunohistochemistry analysis for protein level expression lung tissue from: Adults: 10 adults with lung adenocarcinoma, aged between 40 and 79.

Children: 10 children aged between 1 and 15 years with various forms of cancer with lung metastasis.

Results of Immuno-histochemistry analysis: Overall expression levels of ACE2 similar in adults and children. TMPRSS2 and FURIN expression higher in children than in adults (although differences in FURIN not statistically significant

Interpretation: ACE2 receptors found mainly in AT2 cells, confirming that primary target of SARS-CoV-2 is the AT2 cell.

Partial discrepancy between results from scRNA-seq and IHC might be due to: complicated processes downstream of transcription, or semi-quantitative IHC and its limitations in identifying cell types

Conclusion: Comparable levels of expression of ACE2 and other genes in both children and adults suggests that different expression of these viral entry genes is unlikely to be the key reason for the milder symptoms of COVID-19 found in children.

Phaksy, AGabbie, SEMAResponse to "SARS-CoV-2 Testing and Outcomes in the First 30 Days after the first case of COVID-19 at an Australian Children's Hospital23 May 2020UKEurope18Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/abs/10.1111/1742-6723.13560
Buonsenso, DValentini, PLancet Inf DisToward a clinically based classification of disease severity for paediatric COVID-1915 May 2020ItalyEurope0000Epidemiology - Disease Burdenhttps://doi.org/10.1016/S1473-3099(20)30396-0
de Lusignan, SHobs, FLancet Infect DisRisk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study15 May 2020UKEurope23Epidemiology - Disease Burdenhttps://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930371-6

This study examines the demographic and clinical risk factors for testing positive for SARS-CoV-2 amongst patients within a large primary care network in the UK. This included tests done through Public Health England and the UK National Health Service (NHS) between January 28th and April 4th 2020 with clinical and sociodemographic data extracted from patients' primary care medical records.

Overall 587 of 3802 patient tests returned a positive result for SARS-CoV-2. Of children 4.6% (23/499) tested positive compared with 17.1% (564/3303) of adults.

In multivariate logistic regression, adults had significantly higher odds of a positive test compared with children; those aged 40-64 (aOR 5.36, 95% CI 3.28-8.76) and >75 (aOR 5.23, 95% CI 3.00-9.09) were at highest risk.

Male sex (aOR 1.55, 95% CI 1.27-1.89), social deprivation (aOR 2.03, 95% CI 1.51-2.71) and black ethnicity (aOR 4.75, 95% CI 2.65-8.51) were also associated with an increased risk of a positive SARS-CoV -2 test. Of clinical factors, only chronic kidney disease (aOR 1.91, 95% CI 1.31-2.78) and obesity (aOR 1.41, 95% CI 1.04-1.91) were significantly associated with testing positive. Surprisingly active smoking was associated with lower odds of a positive test (aOR 0.49, 95% CI 0.34-0.71) possibly due to presentation confounding (i.e. presence of cough in chronic smokers prompting increased testing in this group).

This is the first study to utilise primary care data to assess risk factors for testing positive for SARS-CoV-2 in the community. The risk factors identified are similar to those associated with severe COVID-19 in hospitalised patients including increased age, male sex and obesity. The higher odds of a positive test in adults compared with children here are consistent with other studies suggesting children are at lower risk of SARS-CoV-2 infection compared with adults.

Deng, XYu, HClin Infect DisCase fatality risk of the first pandemic wave of novel coronavirus disease 2019 (COVID-19) in China15 May 2020ChinaAsia996Epidemiology - Disease Burdenhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa578/5837356
COVID-19 National Incident Room Surveillance TeamCommun Dis IntellCOVID-19, Australia: Epidemiology Report 1515 May 2020AustraliaAustralasia172Epidemiology - Disease Burdenhttps://doi.org/10.33321/cdi.2020.44.43
Yanover, C.Mizrahi, B.Med archivesWhat factors increase the risk of complications in SARS-CoV-2 positive patients? A cohort study in a nationwide Israeli health organization13 May 2020IsraelMiddle East647Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.07.20091652v2.full.pdf+html
Talarico, VRaiola, GActa Biomed .Preliminary Epidemiological Analysis on Children and Adolescents With Novel Coronavirus Disease (2019-nCoV) in a Central Area of Calabria Region11 May 2020ItalyEurope173Epidemiology - Disease Burdenhttps://www.mattioli1885journals.com/index.php/actabiomedica/article/view/9550/8798
Das, AGopalan, SMedrxivEpidemiology of CoVID-19 and predictors of recovery in the Republic of Korea11 May 2020Republic of KoreaAsia202Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2020.05.07.20094094v1.full.pdf+html
Garazzino, SItalian SITIP-SIP Paediatric Infection Study GroupEurosurveillanceMulticentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 202007 May 2020ItalyEurope168Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219028/

This rapid communication reports the preliminary results of an Italian multicentre study involving 11 of 13 exclusively paediatric hospitals and 51 of 390 paediatric units across Italy (mainly in central and northern Italy). Retrospective data collection began on 25 March 2020.

Study design: Data to 10 April 2020 collected by participating physicians and hospitals for all paediatric patients (aged 1 day to 17 years) with at least one RT-PCR SARS-CoV-2 positive nasal/pharyngeal swab AND adequate follow-up considered necessary by the clinician to define the final outcome (usually 2 wks).

Findings: Data collected for 168 children and adolescents with documented COVID-19:

Gender: 94/168 male (55.9%) & 74/168 female (44.1%)

Age: median 2.3 yrs (IQR 0.3-9.6 yrs, range 1 day-17.7 yrs, mean 5 yrs. <1 yr: 66/168 (39.3%), of which 15/168 neonates (6.9%). 1-5 yrs: 38/168 (22.6%). 6-10 yrs: 24/168 (14.3%). 11-17 yrs: 40/168 (23.8%)

Hospitalised: 110/168 (65.1%): <1 yr: 52/66 (78.8%). 1-5 yrs: 24/38 (63.2%). 6-10 yrs: 13/24 (54.2%). 11-17 yrs: 21/40 (52.5%)

Comorbidities: 33/168 (19.6%): chronic lung disease 7, congenital malformations or complex genetic syndromes 14, cancer 4, epilepsy 5, gastrointestinal disorders 2, metabolic disorders 1,immunosuppression 4, immunocompromise 3. The hospitalisation rate was similar between children with comorbidities (23/33, 70%) and those without (87/135, 64%).

Source of infection: Close contact with a COVID-19 infected person outside the family was rarely reported. 113/168 (67.3%) of children had at least one parent who tested positive for SARS-CoV-2 infection. Symptom onset in relatives preceded symptoms in the infected child by 1 to 14 days in 88/113 (77.8%).

Symptoms: 4/168 (2.4%) asymptomatic. Fever (37.5 to 39C) 138/168 (82.1%), cough 82/168 (48.8%), rhinitis 45/168 (26.8%), diarrhoea 22/168 (13.1%), dyspnoea 16/168 (9.5%), pharyngitis 9/168 (5.4%), vomiting 9/168 (5.4%), conjunctivitis 6/168 (3.6%), chest pain 4/168 (2.4%), fatigue 3/168 (1.8%), non-febrile seizures 3/168 (1.8%, all 3 had a known history of epilepsy), febrile seizures 2/168 (1.2%, 1 with a history of febrile seizures and 1 with first episode of febrile seizures as onset of COVID-19).

Blood results: Of the children who had blood tests, 47/121 (38.8%) had CRP > 0.5 mg/dl. Other abnormal findings were rare.

Complications: 33/168 (19.6%) developed complications: interstitial pneumonia 26/168 (15.5%), severe acute respiratory illness 14/168 (8.3%), peripheral vasculitis 1/168 (0.6%)

No child underwent a chest CT scan; pneumonia was assessed using X-ray or ultrasound in 75/168. Co-infection: Documented in 10/168 (5.9%), including 3 RSV, 3 rhinovirus, 2 EBV, 1 influenza A, 1 non-SARS coronavirus infection, 1 Strep pneumoniae.

Treatment: 16/168 (9.5%) required non-invasive oxygen treatment. 2 were admitted to ICU for mechanical ventilation (1 preterm neonate and a 2-month-old with congenital heart disease). 49/168 (29.2%) children (those with more severe illness) received experimental SARS-CoV-2 treatments, including lopinavir/ritonavir, hydroxychloroquine and/or azithromycin/clarithromycin, systemic steroids.All children, including those with comorbidities, recovered fully and there were no sequelae reported at the time of submission. This paediatric data is in contrast to the high number of cases and case-fatality rate seen in adults in Italy. Children comprised a marginal percentage of those hospitalised in Italy with SARS-CoV-2 infection.

Lounis, MElectron J Gen MedA Descriptive Study of the Current Situation of COVID-19 in Algeria06 May 2020AlgeriaAfrica79Epidemiology - Disease Burdenhttps://www.ejgm.co.uk/download/a-descriptive-study-of-the-current-situation-of-covid-19-in-algeria-8287.pdf
Lian, JYang, YWileyEpidemiological, clinical, and virological characteristics of 465 hospitalized cases of coronavirus disease 2019 (COVID‐19) from Zhejiang province in China04 May 2020ChinaAsia3Epidemiology - Disease Burdenhttps://onlinelibrary.wiley.com/doi/10.1111/irv.12758
COVID-19 National Incident Room Surveillance TeamCommun Dis Intell COVID-19, Australia: Epidemiology Report 13 (Reporting Week to 23:59 AEST 26 April 2020)01 May 2020AustraliaInternationalEpidemiology - Disease Burdenhttps://www1.health.gov.au/internet/main/publishing.nsf/Content/1D03BCB527F40C8BCA258503000302EB/$File/epidemiology_report_13_reporting_week_ending_23_59_aest_26_april_2020.pdf
Li, HHe, YFront Med (Lausanne) 7: 190.Age-Dependent Risks of Incidence and Mortality of COVID-19 in Hubei Province and Other Parts of China30 Apr 2020ChinaAsia260Epidemiology - Disease Burdenhttps://www.frontiersin.org/articles/10.3389/fmed.2020.00190/full
Goldstein, ELipsitch, MEurosurveillanceTemporal rise in the proportion of younger adults and older adolescents among coronavirus disease (COVID-19) cases following the introduction of physical distancing measures, Germany, March to April 202030 Apr 2020GermanyEuropeEpidemiology - Disease Burdenhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.17.2000596
Chen, PXu, YJournal of Formosan Medical AssociationEpidemiological and clinical characteristics of 136 cases of COVID-19 in main district of Chongqing29 Apr 2020ChinaAsia4Epidemiology - Disease Burdenhttps://www.sciencedirect.com/science/article/pii/S0929664620301558
Sun, YWang, FJournal of Autoimmunity Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience24 Apr 2020China Asia3Epidemiology - Disease Burdenhttps://www.sciencedirect.com/science/article/pii/S0896841120300895
Nikpouraghdam, MBagheri, MJournal of Clinical VirologyEpidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in iran: A single center study21 Apr 2020IranMiddle East10Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172806/pdf/main.pdf
Wang, PChen, SInt. J. Infect. DisStatistical and network analysis of 1212 COVID-19 patients in Henan, China18 Apr 2020ChinaAsia31Epidemiology - Disease Burdenhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180361/pdf/main.pdf
Lavezzo, ECrisanti, AmedRXivSuppression of COVID-19 outbreak in the municipality of Vo, Italy 17 Apr 2020ItalyEurope468Epidemiology - Disease Burdenhttps://doi.org/10.1101/2020.04.17.20053157

This paper outlines the strategy of a small town in Italy which immediately shutdown for 14 days following their first death from COVID-19 on Feb 21st 2020. They subsequently screened 86% of the population for SARS-CoV-2 using nasopharyngeal swabs, then screened again 2 weeks later (71.5% of the population).

At the start of the lockdown 2.6% (95% CI 2.1 – 3.3%) of the population tested positive, but 0 of 217 children aged 0 – 10 tested positive (0%), and only 3/250 aged 11 – 20 (1.2%) tested positive. By the end of the lockdown, 0/157 (0%) children aged 0 – 10 tested positive, and 2/210 (1%) children aged 11- 20 tested positive. Many of the children aged 0 -10 lived with infected individuals. They also noted >40% of people who tested positive were asymptomatic. They note a significant number of infections appeared to have come from asymptomatic individuals during contact tracing. They also note these asymptomatic individuals never developed symptoms, and had similar viral loads to symptomatic patients (as determined by the cycle threshold from RT-PCR).

This study has relatively small numbers, but again appears to provide evidence for several important features of paediatric infection: primarily that children appear significantly less likely to become infected than adults. It presents evidence for asymptomatic transmission, and against the theory of viral load correlation with symptom burden.

Randhawa A KJerome K RJAMAChanges in SARS-CoV-2 Positivity Rate in Outpatients in Seattle and Washington State, March 1-April 16, 202015 Apr 2020USANorth America909Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2766035
Gujski, MPinkas, JMed Sci MonitEpidemiological Analysis of the First 1389 Cases of COVID-19 in Poland: A Preliminary Report15 Apr 2020PolandEurope231Epidemiology - Disease Burdenhttps://www.medscimonit.com/download/index/idArt/924702
Gudbjartsson, FStefansson, KNEJMSpread of SARS-CoV-2 in the Icelandic Population14 Apr 2020IcelandEurope1412Epidemiology - Disease Burdenhttps://www.nejm.org/doi/full/10.1056/NEJMoa2006100

This study describes the entry and spread of SARS-CoV-2 through Iceland. Importantly, this is the first epidemiological report to include SARS-CoV-2 screening of the general population and likely represents the most complete national epidemiological data published to date.

Study design: This report includes all confirmed SARS-CoV-2 infections in Iceland identified through either: targeted testing (January 31st to March 31st 2020) – 9199 predominantly symptomatic patients with travel to a high risk country or contact with a confirmed case; population screening (March 13th to April 1st 2020) – 13080 volunteers screened from the general population (without high-risk travel or contact with a confirmed case). Most patients in the population screening cohort were asymptomatic, with a minority with predominantly mild URTI symptoms. A subsequent period of random population screening from April 1st-4th excluded children.

SARS-CoV-2 real-time PCR was performed on combined oropharyngeal and nasopharyngeal samples. All confirmed cases were isolated and close contacts placed in quarantine for 14 days.

Key paediatric findings - there is comparative data provided on the 1412 children <10 years of age tested: of 564 children <10 years old tested in the targeted testing cohort, 6.7% (38) were positive – compared with 13.7% of persons >10 years old; of 848 children <10 years old tested in the population screening cohort, 0% (0) were positive – compared with 0.8% of persons >10 years old.

Details on severity of infection, hospitalisation rates and age specific symptom profiles are not included.

Discussion: The first SARS-CoV-2 infection in Iceland was confirmed on 28th February 2020. The dynamics of new cases has transitioned from imported infections initially to ongoing community spread. To date just over 0.5% of the population have had confirmed infection. Whilst physical distancing measures have been put into place including limiting gatherings to a maximum of 20 people, elementary schools have remained open. Iceland has amongst the highest national rates of SARS-CoV-2 testing per capita, with 6% of the population tested as described here. As a result this report provides the most accurate and complete national epidemiological data published to date.

The lower rate of positive tests in childen <10 year olds adds support the hypothesis that children are less susceptible to SARS-CoV-2 infection compared to adults. Similarly the lack of positive tests amongst >800 children screened goes against the theory that the low reported rates of COVID-19 in children are due to a large number of undocumented/asymptomatic paediatric cases. This finding, particularly, has important implications in decision-making around patient flow and isolation in general paediatric care, suggesting that routine testing and isolation of asymptomatic children may be of low yield in similar settings. Clearly a single PCR screening test at one time point has an insufficient negative predictive value to exclude infection. As such, serological studies will be important in providing a clearer picture of the extent of SARS-CoV-2 infection in children.

Conclusion: Children under 10 yo appear to be less likely to develop SARSCoV-2 infection compared with people >10 yo. In settings with moderate levels of SARS-CoV-2 infection (0.5% population with confirmed infection in this setting), screening of asymptomatic children without overseas travel or contact with a known case is of very low yield.

Amira, YWakita, TEmerg Infect DisSevere Acute Respiratory Syndrome Coronavirus 2 Infection among Returnees to Japan from Wuhan, China, 202010 Apr 2020JapanAsia10Epidemiology - Disease Burdenhttps://wwwnc.cdc.gov/eid/article/26/7/20-0994_article
Santacroce, LDel Prete, REJGMCOVID-19 in Italy: An Overview from the First Case to Date08 Apr 2020ItalyEurope1Epidemiology - Disease Burdenhttps://www.ejgm.co.uk/article/covid-19-in-italy-an-overview-from-the-first-case-to-date-7926
Tagarro, AJAMA PedScreening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in Madrid, Spain08 Apr 2020SpainEurope365Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2764394

This is a registry of confirmed COVID-19 cases in Madrid, Spain from March 2 to March 16 – the first 2 weeks of the epidemic in Spain. Children were screened according to recommendations at the time with PCR.

Of 365 children tested, 41 were positive (11.2%), out of the 4695 cases in the Madrid region (0.8%). 16 children (39%) with confirmed COVID had a known contact with a confirmed case. The median age of positive cases was 1 years. 60% required hospitalisation, 9.7% required PICU admission, and 9.7% required respiratory support beyond nasal prongs (including both non-invasive and invasive mechanical ventilation). Of those requiring ICU admission, only 1 (25%) had a comorbidity (recurrent wheeze). There were no deaths. Two patients (5%) had co-infection with influenza B, but it was not clear whether all patients were tested for co-infection.

CDCMMRWCoronavirus Disease 2019 in Children — United States, February 12–April 2, 202006 Apr 2020USANorth America2572Epidemiology - Disease Burdenhttp://dx.doi.org/10.15585/mmwr.mm6914e4

This is the first USA CDC report of COVID-19 looking specifically at children, examining confirmed cases nationally between FEbruary 12th and April 2nd. Due to the extremely disparate nature of public health reporting in the USA, the data quality and availability for this report is highly variable. There is no information as to the basis on which tests were performed, whether for presentation to hospital, symptomology or due to contact tracing. This cohort is therefore likely extremely heterogeneous. Of the nearly 150,000 confirmed cases in the US at this time, 2,572 (1.7%) were in children. New York City had 33% of paediatric cases. The median age was 11y and males account for 57%. Nearly 33% of cases were in children aged 15 – 17yrs, 15% in children <1y, 11% in children ages 1 – 4y and 15% in children 5 – 9y. 91% of cases had xposure to a known COVID-19 case.

Data on signs/symptoms was only available for 11% of cases. Fever, cough OR shortness of breath were present in 73% of cases, with fever in 56%, cough in 54%, shortness of breath in 13%, rhinorrhoea 7.2%, sore throat 24%, vomiting 11% and diarrhoea 13%. They have not reported on “asymptomatic” cases due to incomplete reporting on symptoms.CU admission was documented for 2% of cases. Hospitalisation was most common in infants (62%), with little difference between other age groups in regards to hospitalisation or ICU admission. From low numbers infants id not appear significantly more likely to be admitted to ICU. Underlying conditions were present in 23% of cases, most commonly respiratory (such as asthma), followed by cardiac conditions and immunosuppression. There are 3 deaths reported, but review is ongoing to determine whether COVID-19 was the cause. This patchy data from the US is useful as it closely resembles data from Chinese cohorts of children in regards to low frequency of severity and adverse outcomes. It confirms available data suggesting lower frequency of common symptoms in children as compared to adults.

Bialek, SSauber-Schatz, ECDC + Morb Mortal Wkly RepSevere Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 202018 Mar 2020USAAmerica123Epidemiology - Disease Burdenhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w

Epidemiologic study of reported COVID–19 cases, by age group published by the United States’s CDC for the period, February 12–March 16, 2020. Data includes hospitalization, intensive care unit (ICU) admission, and case–fatality percentages by age, for 2449 patients with confirmed COVID-19 PCR, including 123 cases aged <19 year old. Of which, 1.6-2.5% hospitalisation rate, no ICU admissions, no deaths.

LivingstonBucherLancetCoronavirus Disease 2019 (COVID-19) in Italy17 Mar 2020ItalyEurope250Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2763401

This is a helpful one page summary of data around COVID-19 numbers in Italy as of 15th March 2020.

Of note, there have been 22,512 cases of COVID-19 with 2026 (9%) being health care workers. There have been 1625 deaths (7.2%) of cases in Italy, which is a higher case fatality than rates from China and other countries so far. Below are two of the charts below which depict the age range and severity of COVID-19 infections. From a paediatric perspective, 1.2% of cases have been in patients <18 years old and remarkably there have been 0 deaths under 30yrs of age so far.

Choe, YMedRxIVCoronavirus disease-19: The First 7,755 Cases in the Republic of Korea15 Mar 2020South KoreaAsia480Epidemiology - Disease Burdenhttps://doi.org/10.1101/2020.03.15.20036368

This is a report of the first 7755 patients with confirmed COVID-19 in Korea as of March 13th. It is notable as Korea undertook one of the worlds most intensive strategies to community testing, which may give a better understanding of the proportions of different groups affected who may have had mild or subclinical infection and might otherwise not have been tested.

The finding of significance is that children made up a very small proportion of total cases, with only 75 (1%) under 9 years of age, and 405 (5.2%) aged 10–19 years. There were no deaths in patients under 30 years of age. This suggests not just low severity of infection in children, but a low attack rate with such low cases numbers.

Dong, YTong, SPediatricsEpidemiology of COVID-19 Among Children in China01 Mar 2020ChinaAsia2143Epidemiology - Disease Burdenhttps://pediatrics.aappublications.org/content/early/2020/03/16/peds.2020-0702

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.

This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Wu, ZMcGoogan, JJAMACharacteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China; Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention24 Feb 2020ChinaAsia1400Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jama/fullarticle/2762130

A cornerstone paper outlining the initial epidemiological data from the outbreak (up to February 11th 2020). This paper gave us the first indication of the enormous impact of age on prognosis from the disease. It reports on 72,312 cases (44,672 confirmed and 16,186 suspected). Of these only 1% were aged <9 years (2% <19 years) with no deaths aged under 9 years.

Zimmerman, KBenjamin, DPediatricsIncidence and Secondary Transmission of SARS-CoV-2 Infections in Schools.8 Jan 2021USANorth AmericaEpidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/01/06/peds.2020-048090

This prepublication release, published online on 8th January 2021, reports a study in North Carolina, USA, which examined 11 school districts (with nearly 100,000 students and staff) open for 9 weeks (first quarter of the 2020-21 academic year) of hybrid in-person schooling, looking at within-school secondary transmission of SARS-CoV-2.

Background: North Carolina public schools (pre-kindergarten to grade 12, ages 4 to 18 years) were closed to in-person instruction on 14th March 2020 because of the COVID-19 pandemic. School districts were allowed to re-open for the start of the 2020-21 school year, choosing either remote learning or a “hybrid” model combining in-person and remote learning. The hybrid model generally involved students attending in-person school for 2 days each week (50% attending Monday/Tuesday, 50% attending Thursday/Friday, with Wednesday all-remote learning and cleaning of the school building). Families in school districts offering the hybrid model could choose between hybrid or all-remote learning. Schools in districts choosing the hybrid model were required to implement mitigation strategies (masks, distancing, hand hygiene, daily symptom and temperature monitoring). The ABC Science Collaborative, a programme developed by faculty at Duke University and the University of North Carolina at Chapel Hill to respond to the impact of COVID-19 on schooling, pairs scientists and physicians with school and community leaders to implement public health measures, share lessons learned to keep schools safe and engage in research.

Study population: Of the 115 school districts in North Carolina (100 per county plus 15 city districts), 56/115 participated in the ABC Science Collaborative. 35/56 of these participating districts offered hybrid in-person schooling for at least part of the 9 week study period (15th August to 23rd October 2020) and 21/56 remained all-remote. 17/35 of the districts offering hybrid in-person schooling did so for all 9 weeks (of the 18/35 remaining, about half did so for 4+ weeks). 11/17 of the districts offering hybrid in-person schooling for all 9 weeks were able to report both primary and secondary infections; these 11 were included in the study (9 country districts + 2 city districts). For most of the 9 weeks examined, the rate of SARS-CoV-2 infection was 1-2 cases per 1,000 residents per week across North Carolina; the 11 counties of the school districts studied had slightly higher community-acquired case rates. Around one third of the students opted to continue with remote schooling, even though their schools were offering hybrid in-person schooling (77,446 students in person reported in the 11 school districts versus 117,417 students in 2019, i.e. 66%).

Collection of data: During the first 9 weeks after re-opening, participating school districts provided data to the ABC School Collaborative about SARS-CoV-2 cases and secondary transmission in schools. Case adjudication of within-school transmission was performed via contact tracing by the local health department. Publicly available data was collected for number of staff, student enrolment and demographics. The number of children attending in person was confirmed with each school superintendent.

Primary cases and secondary transmission in schools: Across the 11 school districts over 9 weeks of schooling, 773 community-acquired SARS-CoV-2 cases were documented by molecular testing, but only 32 adjudicated cases of secondary transmission. 6/11 school districts had zero, 2/11 had one and 3/11 had multiple secondary infections. The 32 secondary cases were distributed across types of school as follows: 6/32 pre-kindergarten, 11/32 elementary schools, 6/32 middle schools, 5/32 high schools, 4/32 K-12 schools. There were no cases of child-to-adult within-school transmission (child-to-child and adult-to-child transmission were not reported).

Conclusions and limitations: This study aimed to address a key question for policy makers: is within-school spread of SARS-CoV-2 greater than, equal to, or less than that observed in the broader community? There was considerable community transmission during the 9 week study period in the 11 counties of the participating school districts, reflected in the 773 community-acquired cases seen in schools. Based on the fact that, on average, North Carolina residents with SARS-CoV-2 infected slightly more than one other individual during the study period, if secondary transmission were as common in schools as in the community, the authors anticipated 800-900 secondary infections in schools, but only 32 were documented. The authors note that participation by school districts in the ABC Science Collaborative is voluntary and that studying those school districts which participated and submitted data may select for school districts that are also better at enforcing mitigation measures. Close contacts of cases were quarantined for 14 days; testing was encouraged, but not enforced, so infections amongst these close contacts may have been missed. The incidence of child-to-child or adult-to-child transmission was not analysed because of confidentiality issues. The study setting doesn’t illustrate 100% in-person school attendance, because in-person schooling was combined with remote schooling in the hybrid model (with students attending 2 out of 5 days per week) and approximately one-third of students opted to remain all-remote even in the districts offering hybrid in-person schooling. The breakdown of case numbers between staff and students is not clear (some figures referred to in the text are not available currently online), nor whether cases in schools were identified by symptoms followed by testing, or whether there was any random testing which might pick up asymptomatic or pauci-symptomatic infections.

Zhu, YShort K RClin Infect DisA meta-analysis on the role of children in SARS-CoV-2 in household transmission clusters 6 Dec 2020AustraliaInternational102Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1825/6024998

The main finding in this meta-analysis of household cluster SARS-Cov-2 infection appears to be that children are less likely to be index cases and are may be resilient to infection from a family member. This meta-analysis sought to bring out evidence if it exists of the extent to which children are an important source of transmission for SARS-Cov-2 in households by examining data of prevalence of child index cases of SARS-Cov-2 and appearing child and adult secondary infections.

Between December 1, 2019 and August 24, 2020 the authors captured data on household SARS-Cov-2 clusters from 12 countries around the globe: China, Japan, France, Germany, Italy, USA, Vietnam, Malaysia, Singapore, Morocco, Greece and South Korea. They identified 57 articles out of 1207 as having sufficient and appropriate data: individuals who first developed symptoms in the household and were positive for SARS-Cov-2 (43 articles) and secondary cases who were confirmed SARS-CoV-2 positive household contacts (14 articles).

There were found 213 pooled index case household clusters comprising only 8/213 (3.8%) clusters involving a child index case (n= 8 ages 42days to 17 years, paediatric index cases of which 5 were in clusters from China). There was a total of 611 individuals in the 213 clusters of whom only 102(16. 7%) were children. Resulting secondary cases were 398 of which only 16 (4%) arose from child transmission suggesting two secondary cases per child index case.

Possible confounders were revealed to include if asymptomatic child contacts but SARSCoV-2 positive were index cases when the index case prevalence went up to 39 (18.5%) children; if only clusters in which there had been no travel by the index case were used in the analysis (152 clusters), then a little more, 32 (21%) child index cases were found; and finally if only clusters outside of lockdown period were analysed, only 3% of clusters had a child as an index case.

Cluster numbers were too few for the authors to define the difference in secondary attack rates (SAR) between child index cases and adult index cases. Too few studies in this meta-analysis had provided information on how many SARS-CoV-2 positive cluster members there were and how many negative (5 clusters containing a child index case yielding an SAR of 46.7% with a large SD ( 28.2%) and 22 clusters containing adult index cases, SAR of 65.8% with an equally large SD of 23.3%).

Comparing the SAR from symptomatic index cases to asymptomatic found significantly less transmission from asymptomatic index cases (RR 0.17).

Meta-analysis of SAR to children from adult index cases found a significantly lower SAR than to other adults (RR 0.62)

Although the meta-analysis has shown in the few clusters where there was sufficient information to make the analysis that SAR was lower in child index case clusters compared to adult index SARS-CoV-2 positive clusters, larger cluster samples in which there are more child SARS-CoV-2 positive index cases may be warranted during this period prior to the Covid-19 vaccinations being rolled out population-wide.

Pray, IWestergaard, RMMWR Morb Mortal Wkly RepCOVID-19 Outbreak at an Overnight Summer School Retreat ― Wisconsin, July–August 202030 OCT 2020USANorth America127Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6943a4

This is a study of an outbreak of COVID-19 which occurred at a boys’ faith based overnight summer school retreat in Wisconsin, USA between July 2 and August 11, 2020.

The retreat was attended by 152 people: 127 male students aged 14-17 years; 21 counsellors aged 17-24 years; and 4 staff aged 21-45 years.

A single student, who received a negative SARS-CoV-2 RT-PCR test result <1 week before the retreat and experienced symptoms 1 day after arriving, was the likely source of introduction, resulting in infection of 76% of attendees.

At the retreat, students and counsellors were not required to wear masks or social distance, and students mixed freely. Classes were outdoors with students seated <2 m apart. Teachers wore masks. The sleeping residences for the 127 students were tightly spaced, with shared bathrooms and common areas. Counsellors and staff members resided separately.

Extensive and rapid transmission of SARS-CoV-2 occurred, especially amongst the students, of whom 100 were affected; 15 counsellors and 1 staff member were also affected. 24 attendees had previous positive serologic results. The attack rate in the susceptible attendees who were not positive was 91%.

Confirmed COVID-19 cases were defined by a positive SARS-CoV-2 RT-PCR test result and occurred in 64 of the 127 students (52%); in 14 of the 21 counsellors (67%); and in none of the staff members. Probable cases were defined by an illness meeting clinical criteria for COVID-19 with symptom onset during the retreat and occurred in 36 students (28%), 1 counsellor (5%) and 1 staff member (25%).

Only one person was asymptomatic. The remainder had mild to moderate symptoms. None required admission to hospital and no deaths occurred.

Conclusions

The authors conclude that SARS-CoV-2 can spread rapidly among adolescents and young adults in a setting with inadequate COVID-19 mitigation measures. They observed that of 24 attendees who had documented evidence of antibodies to SARS-CoV-2 before arrival, none tested positive for SARS-CoV-2 RT-PCR at the retreat, suggesting a possible protective effect. The authors recommend that a robust COVID-19 mitigation plan developed in collaboration with public health authorities is important for preventing and containing similar outbreaks at overnight camps and residential schools.

Peaper, DMurray, TPediatr Infect Dis J Severe Acute Respiratory Syndrome Coronavirus 2 Testing in Children in a Large Regional US Health System During the Coronavirus Disease 2019 Pandemic30 Nov 2020 preprintUnited StatesNorth America688Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.95926.aspx

A cross sectional survey undertaken between 1st March 2020 and 26th September 2020 in North Eastern United States of clinical virology results in children. Nearly ¼ million COVID test were done at the testing laboratories during the period of the study of which 6.8% were positive. 23,137 (9.8%) of the tests were done on children (≤18 years of age). Of these 688 children had 734 positive tests (3.2%). The age of the children with a positive test were significantly older 12.0 years (IQR 5.0-16.0) compared to those who were negative 10.0 (IQR 4.0-16.0). This age difference occurred throughout the study period regardless of community prevalence.

After the first positive child case, the positivity rate increased by 3.7% per week, a significantly slower rate than adults 4.3%. The rate of positivity peaked in children at 18% at the end of March, the rate of decline was 1.6% per week slower in children than adults and plateaued at < 1% at the end of June. There was then another much smaller peak towards the end of July.

The increased number of positive children in the later part of the study was because of increased testing rather than an increased positivity rate. After the reopening of schools there was no increase in positivity.

129 children had repeated tests and of these 31 had at least one positive test. For patients with more than 1 positive test the longest interval between initial and last positive test was 104 days, with 64.5% having a repeat positive test ≥ 10 days.

The authors conclude “An increase in pediatric cases documented in the late summer was predominately due to increased access to testing for children. The percent positivity in children did not change in the first 3 weeks after school opened. A subset of children has detectable severe acute respiratory syndrome coronavirus 2 RNA in the upper respiratory tract for weeks after the initial infection.”

Although an interesting paper, as it is based on laboratory data, is not possible to ascertain why the children were being tested nor how the study population reflects the whole paediatric population of the study area.

Hommes F, van Loon W, Thielecke M, et al. SARS-CoV-2 infection, risk perception, behaviour, and preventive measures at schools in Berlin, Germany, during the early post-lockdown phase: A cross-sectional study. medRxiv. December 18th 2020, https://doi.org/10.1101/2020.12.18.20248398

This is a cross-sectional study from Germany between 11th to 19th of June 2020 comprising questionnaires, clinical and laboratory data obtained from 535 students and teachers attending 24 different schools in Berlin. The article is a preprint which has not yet been peer-reviewed.

The investigators selected schools in areas of Berlin with different socio-economic profiles and studied 193 primary school students, 192 secondary school students and 150 school staff. Median ages were 10 years (range 8-13) for primary and 15 (13-18) for secondary students; sex ratio was 1:1. Of the staff, 98 (71%) were female.

Staff and students completed a questionnaire and had their body temperatures measured. SARS-CoV-2 infection was determined by real-time-PCR from oro- and naso-pharyngeal swabs. Anti-SARS-CoV-2-IgG was measured in blood samples.

Only one SARS-CoV-2 infection was detected in the 532 subjects (0.2%): a 16-year-old, afebrile female student who had headache and rhinorrhoea as her sole symptoms. Seven students (1.3%) (median age 14 years, range 9-17), had IgG antibodies to SARS-CoV-2 – three of these were in the same secondary school class. One of them reported loss of smell and taste in the preceding two weeks.

Symptoms of infection (headache, rhinorrhoea, cough and sore throat) on the day of examination were reported by 19% of primary students, 16% of secondary students and 12% of staff. A temperature of ≥37.5oC was detected in 2.3%.

More than 50% of students and staff reported seeing friends less frequently outside of school than before the pandemic. 72.9% of primary and 60.5 % of secondary students reported a low perception of risk of infection, whereas 59.1% of staff reported a high perception of risk. 81% of primary students, 54.7% of secondary students and 76.9% of staff reported that they frequently to always physically distanced at school. 50% of primary students, 35.3% of secondary students and 39.9% of staff reported that they frequently to always wore a facemask at school.

The majority of schools had reduced class sizes at the time of the study. Sports activities were suspended in all primary and the majority of secondary schools. The time spent in online learning varied between different schools: on average 15% (range 0-50%) of teaching was online in primary schools and 50% (range 0-90%) in secondary schools.

The authors conclude that infection prevention and control measures can be successfully implemented in schools (in the region under study).

Yoon, YYae-Jin, KJ Korean Med SciStepwise School Opening and an Impact on the Epidemiology of COVID-19 in the Children30 NOV 2020South KoreaAsia13100Epidemiology - Transmissionhttps://doi.org/10.3346/jkms.2020.35.e414

This is a retrospective study of data derived from a national registry of SARS-CoV-2 cases which examined whether school re-opening led to an increase in the number of paediatric COVID-19 cases in South Korea, conducted between 18 February to 31 July 2020

The first paediatric case of SARS-CoV-2 infection in a child in South Korea occurred on 18 February 2020. In that country, there are two weeks of school in February, and then a two-week-break before the new academic year starts in March. Because of the pandemic, it was decided to delay school re-opening, which eventually took place at one-weekly intervals between 20 May and 8 June 2020, beginning with high school senior students. Online classes had been held from 9 April.

The authors analysed data derived from press-releases given by the Korea Centers for Disease Control and Prevention.

13,000 students and school staff were tested for COVID-19 infection (by SARS-CoV-2 PCR) during the study period. 44 children were found to be positive after schools re-opened. The authors state that there was not an obvious sudden increase in the number of paediatric cases, or in the proportion of paediatric cases amongst all confirmed cases, before and after school re-opening. They do not provide a statistical analysis of these comparisons.

Out of 800 tests at kindergartens (5- to 7-year-olds), six children were positive for SARS-CoV-2 by PCR. There were no cases of transmission between kindergarten children. Out of 3,000 tests at elementary schools (7- to 12-year-olds), 17 children were positive. There was only one case of transmission, between a pupil who infected two fellow pupils. Out of 7,500 tests at middle schools (13- to 15-year-olds) and high schools (16- to 18-year-olds), 21 students were positive. There were no cases of transmission between students at middle school or high schools.

The authors conclude that school re-opening in South Korea did not cause a significant school-related outbreak of COVID-19 infection in children.

Lee, EJHan, MSEmerg Infect Dis 27(1)Absence of SARS-CoV-2 Transmission from Children in Isolation to Guardians, South Korea30 Nov 2020South KoreaAsia12Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/27/1/20-3450_article

Early online release of a research letter from a small study in S Korea between 18/02–07/06/20. There was no transmission of SARS-CoV-2 from child to adult in 12 cases where all care was given by a unique carer whilst a child was in hospital isolation. Seven children were asymptomatic, 4 had fever or respiratory symptoms and 1 had pneumonia. Median age of children was 6 years (range 2months – 1years). Median length of isolation was 17days (range 7-37days). All adults wore PPE of various types and combinations. Ten of 12 had frequent close contacts. The authors report that appropriate use of PPE may protection adult carers of infected children, and may also support the hypothesis that onward transmission from young children to adults is less likely than from infected adults to other adults.

Laxminarayan, RLewnard, JScienceEpidemiology and transmission dynamics of COVID-19 in two Indian states30 09 2020IndiaAsia20000Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/09/29/science.abd7672/tab-article-info

In this large study from India, surveillance, and contact tracing data from two large states (Tamil Nadu and Andhra Pradesh; population 127.8 million) from between 4th March and 1st August 2020 are analysed. Both states implemented rigorous contact tracing from early in the pandemic response with an attempt to follow up all contacts of laboratory confirmed cases, including testing of contacts between 5-14 days after contact with primary case, irrespective of symptoms. The authors aim to describe transmission dynamics and clinical outcomes.

Just over 435,000 cases were identified with over 3 million exposed contacts reached by contact tracers. Age specific incidence was lower in the 0-4y.o. (6.3 per 10,000) and 5-17y.o. (12.7 per 10,000) compared with adults (35.0-45.3 per 10,000). Case fatality rate was lowest in the 5-17 yo age group (0.05%), increasing with advancing age, and was highest in the >85y.o. group (16.6%).

Individual-level epidemiological data was available for 575,071 contacts of 84,965 cases. A mean of 7.3 contacts were tested for each case (IQR 2-9) and 70% of index cases had no positive contacts. The overall secondary attack rate was 7.5%, higher within households (9.0%) compared with in the community (2.6%) and healthcare settings (1.2%); the highest attack rate (79.3%) was among those with high-risk travel exposures (close proximity in shared conveyance for >6 hours).

Assuming test-positive contacts were infected by the index case, the highest probability of transmission was within contact pairs of the same age. This pattern was strongest among children 0-14 years and adults >65 years. Notably children represented a small proportion of index cases (0-4y.o.=1%, 5-17y.o.=6%) and the greatest proportion of contacts who tested positive were exposed to an index case aged 20-44y.o (~50% of index cases).

This represents the largest dataset to date examining the epidemiology of SARS-CoV-2 transmission and clinical outcomes in a low / middle income setting. The under-representation of children amongst detected cases and the low mortality rate in younger individuals is consistent with previous data. Similarly, the high number of index cases with no positive contacts is in keeping with evidence of substantial variation in likelihood of transmission between individuals and the potential important of super-spread. The apparent increased probability of transmission between child case contact pairs should be interpreted with caution given the small proportion of paediatric index cases. Importantly, the lack of temporal data limits the ability to establish directionality of transmission; meaning children classified as case contact pairs may have rather shared a common exposure to another index case. Moreover, the majority of test-positive contacts overall were traced to young adult index cases.

Considered in totality, this study is consistent with data from some high-income settings implicating young adults, rather than children, as major drivers of transmission of SARS-CoV-2.

Pitman-Hunt, CKannikeswaran, NJ Pediatric Infect Dis SocSARS-CoV-2 Transmission in an Urban Community: The Role of Children and Household Contacts27 Nov 2020USANorth America71Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa158/6007439

This was a retrospective study of SARS-CoV-2 household transmissions patterns in an urban US community, and found no evidence of within-household child to adult transmission.

Study design; This study recruited children testing positive for SARS-CoV-2 (via nasal swab) between 12 March and 15 June at the Michigan Children’s Hospital in Detroit. Patient notes were reviewed retrospectively for the existence of a sick household contact, defined as someone living in the same house and who either tested positive for SARS-CoV-2 or who had symptoms (listed as fever, cough, congestion, sore throat or diarrhoea). Participants were followed up by telephone 6 weeks after discharge to identify any subsequently developing sick household contacts.

Cohort; The study included 71 children ranging from less than 1 year to 17 years of age. Median age was 6 years (IQR 0.8-13 years). 58% were female and 85% were African American (where race was recorded). Severity of illness in the studied children varied from asymptomatic to critical, with 55% being asymptomatic or having mild disease, 23% having moderate disease and 23% having severe or critical disease. Interestingly, 83% of participants were hospitalised, which , based on the figures provided, must have included some mild as well as asymptomatic infection (perhaps with incidental SARS-CoV-2 diagnosis).

Results; In 30 of the 71 cases (42%), a sick household contact with earlier illness onset than the index child was identified. In almost all of these households, the contact had a positive test (the contact was diagnosed symptomatically in 5 households). 76% of these sick contacts were parents and 20% were grandparents. In just 2 cases, the sick contact was a sibling, but one of these was an adult sibling. The timing of the child’s illness onset relative to the sick contact ranged from less than a week after to more than 4 weeks after. No further sick contacts were identified at follow up, suggesting that there were no cases of child to adult within-household transmission in this cohort, or at minimum none who developed symptoms.

Summary; This study supports the findings of previous studies that levels of child to adult transmission of SARS-CoV-2 are low. The authors note that less than half of participants had an identified sick household contact, which is at odds with other studies which have found children predominately infected within the household. This may reflect particular factors in what is a deprived urban community, and difficulties adhering to measures designed to limit community transmission. There may also be a degree of under-reporting of sick household contacts, who may have been asymptomatic.

Although a small study looking at a specific population, this is a useful addition to the body of evidence that children are not primary vectors for SARS-CoV-2.

Kriemler, SRadtke, TmedRxivSurveillance of acute SARS-CoV-2 infections in school children and point-prevalence during a time of high community transmission in Switzerland26 Dec 2020SwitzerlandEurope641Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.24.20248558v1

This is a surveillance pilot study conducted in Zurich Switzerland between 01/12/20 – 11/12/20. The aim was to identify the impact and prevalence of asymptomatic and oligosymptomatic children and teachers in the school setting. Participants underwent buccal swabs for a PCR and rapid diagnostic test (RDT) at two separate time points 1 week apart. 641 children and 66 teachers from 14 different primary and secondary schools took part in the surveillance study and underwent testing at least once. 198 children and 5 teachers reported symptoms in the 5 days prior to the testing. There was one child who had a positive PCR test (negative RDT test) at the 1st collection time point. This child had a runny nose and at the second time point reported anosmia but had a negative PCR and RDT swab test at this time point. This gave a point prevalence of 0.2% (CI 0.0%-1.1%). No teacher had a positive PCR test. There were 7 positive RDTs in children (point prevalence 1.1%) and 2 in the teachers (point prevalence 3%). These were repeated at a time interval ranging from 2 hours to 2 days and they were all negative and as were the PCR swabs. These were therefore classified as false positives. The specificity of the RDT was 99.4% in children and 99.5% in teachers.

This study shows that there is a very low point prevalence in school setting where there was widespread testing as part of the surveillance. It was felt therefore that surveillance testing in schools was not efficient and instead testing should be limited to those with symptoms with effective preventative measures in place and a policy of test, track, isolate and quarantine. The false positives of the RDT lead the authors to conclude that further evaluation was required on this method before more widespread use. The study reports that the buccal route of testing was validated on acutely ill adult patients. Given the low point prevalence, beyond what was expected at a time of high community transmission, the validity of the buccal route of testing in children needs to be questioned. It would have been helpful to have had a nasopharyngeal swab alongside the buccal swab to authenticate the results obtained from the buccal swabs. The study does not specify the strain of SARS CoV2 in circulation at the time of the study. Minimal information is given regarding the participant’s background characteristics/ demographics.

In conclusion, the study shows a lower-than-expected prevalence in the school setting from asymptomatic or oligosymptomatic children and teachers. However, the use of buccal swab testing calls into question the internal validity of the results and the unspecified strain of SARS CoV2 reduces the external validity.

Davies, NEdmunds, JmedRxivEstimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England26 12 2020UKEurope0000000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.24.20248822v1

The SARS-CoV-2 variant - VOC 202012/01 - has recently emerged and rapidly outcompeted pre-existing variants in the UK. This variant is defined by 17 mutations, three of which are of particular concern:

• N501Y which has been shown to increase affinity for the ACE2 receptor

• P681H located near the important furin cleavage site in the spike protein and

• a deletion of 2 amino acids at positions 69-70 which has been associated with immune escape in immunocompromised patients and enhanced infectivity in vitro.

The incidence of VOC 202012/01 increased through the November national lockdown and continued to increase through ongoing Tier 3 restrictions. There has been concern that this variant may be more transmissible, and separately that children may be more susceptible to VOC 202012/01 compared with pre-existing strains.

In this study, a two-strain mathematical model of SARS-CoV-2 transmission fitted COVID-19 admissions, bed occupancy, deaths, and SARS-CoV-2 PCR prevalence to the relative frequency of VOC 202012/01 in the three most heavily affected NHS regions (South East, East of England and London).

Four alternative hypotheses were considered to explain the increased spread of VOC 202012/01: increased infectiousness, immune escape, increased susceptibility among children and shorter generation time (time between exposure and infectiousness). The model for increased infectiousness best matched the observed data suggesting transmissibility of the variant was 56% higher than pre-existing variants (95% CI 50-74%). There was no evidence of a higher risk of severe disease or death based on this model.The other models, including modelling increased susceptibility in children to VOC 202012/01 underestimated the relative growth rate of the new variant.

Projection of future transmission using the increased infectiousness model suggested that even with ongoing Tier 4 restrictions from December until the end of January, COVID-19 cases and deaths would continue to rise, peaking in spring 2021. Schools closures in addition to Tier 4 restrictions were modelled by removing all school related contacts and assuming a reduction in transmissibility across age groups following closure. In this model, closing schools and universities until the end of January 2021 did not reduce the overall burden of disease, but did delay the peak of cases potentially allowing time for more widespread population vaccination in the interim. Finally, only an accelerated uptake of vaccination (2 million vaccination per week vs 200,000 per week) in combination with Tier 4 restrictions and school closures was modelled to reduce peak ICU burden below levels seen during the first wave in the UK.

Based on this mathematical modelling, the observed increase in SARS-CoV-2 burden and relative frequency of the VOC 202012/01 variant, is best accounted for by general increased transmissibility of the new variant by an order of around 50%, rather than increased susceptibility of children alone. With the rapid acceleration of SARS-CoV-2 cases in the UK, the addition of school closures to general restrictions (noting the limitations of the model's assumptions) may serve to delay the peak of cases. A concomitant effort to accelerate vaccine delivery will be vital to reduce ongoing transmission and limit the impact on health care systems.

Falk, AHoeg, TMMWR Morb Mortal Wkly RepCOVID-19 Cases and Transmission in 17 K–12 Schools — Wood County, Wisconsin, August 31–November 29, 202026 01 2021USANorth America133Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7004e3.htm#suggestedcitation

This study from the US assessed the transmission of SARS-CoV-2 infection within 17 selected schools in Wood County, Wisconsin between August 31st to November 29th 2020. During the study period, the majority of students attended in-person learning (estimated 12.4% attending virtually) and infection mitigation measures were employed at all schools including mask wearing for all students and teachers, limitations on mixing between classes and between staff. Community transmission of SARS-CoV-2 in Wood County during the study period was high with test positivity ranging from 7% up to 40% from community samples.

All cases occurring in students or staff during the study period were reported. For each case, infection source was determined though case investigation conducted by the public health department or school administration. Contact tracing was carried out with close contacts required to quarantine at home with further investigation undertaken for contacts who experienced symptoms during quarantine. Surveillance testing and routine testing of contacts was not undertaken.

A total of 4,876 students attending in-person (1,529 primary and 3,347 secondary) and 654 staff were included. A total of 191 of cases were reported within schools; 133 student and 58 adults. Incidence in schools was 37% lower than in the surrounding community (3,454 vs 5,466 cases per 100,000 persons). Of 191 cases, only 7 (3.7%) were associated with in-school transmission, all occurring between students; no staff infections were linked to in-school transmission. No transmission between students and staff or between students in separate classrooms was documented. Compliance with mask wearing in classrooms ranged from 92.1% to 97.4% according to teacher survey responses.

This study adds to a growing body of data demonstrating limited transmission of SARS-CoV-2 in schools with a variety of infection mitigation measures. In contrast to a number of these recent papers, the low number of cases of in-school transmission here was observed despite high levels of transmission in the surrounding community. The authors acknowledge that the study did not include surveillance testing of children, and therefore asymptomatic transmission was not assessed, but highlight recent epidemiological data suggesting asymptomatic cases are much less likely to transmit SARS-CoV-2. Notwithstanding this limitation, the results here suggest that keeping schools open, even in the setting of moderate to high community transmission may be possible with minimal in-school SARS-CoV-2 transmission, provided appropriate mitigation strategies are employed.

Sun, KYu, HScienceTransmission heterogeneities, kinetics, and controllability of SARS-CoV-224 11 2020ChinaAsia0000000Epidemiology - Transmissionhttps://doi.org/10.1126/science.abe2424

In this detailed contact tracing study from Hunan, China, granular epidemiological data was collected from laboratory confirmed SARS-CoV-2 infected individuals and their close contacts between January 16th and April 3rd, 2020.

All cases were admitted to dedicated hospitals for isolation regardless of clinical severity. Contacts were quarantined in medical observation facilities and followed up for a minimum of 2 weeks. Prior to February 7th, contacts were tested if they developed symptoms. After February 7th, all contacts were tested (PCR) at least once during quarantine, regardless of symptoms.

Transmission chains were reconstructed, and timing of infection was estimated based on each patient's exposure history. The impact of factors including type and duration of exposure, age of contact, and timing of exposure relative to symptom onset was measured using a mixed effects multiple logistic regression model. The data was further analysed to determine transmission kinetics, infectiousness profile of a typical case and the expected impact of individual and population-based interventions on control of SARS-CoV-2 transmission.

A total of 1178 SARS-CoV-2 infected individuals and their 15,648 close contacts were included. In 210 epidemiological clusters, between 0 and 4 generations of transmission were observed with 80% of secondary infections traced back to 15% of SARS-CoV-2 infected individuals.

In a subset of 14622 contacts of 870 SARS-CoV-2 patients (excluding those with contacts reporting travel history of Wuhan) transmission was higher for household contacts compared with social or community contacts. Transmission in households increased during the lockdown period whilst community contacts decreased concurrently. Longer exposure increased risk by 10% for each additional day of exposure.

Susceptibility in children 0-12y.o. was lower than in adults 26-64y.o. (OR 0.41, 95% CI 0.26 - 0.63) and higher in those >65 y.o. (OR 1.39, 95% CI 1.02 - 1.91). No statistically significant difference was found between index cases 0-25 y.o. compared with adults 26-64 y.o. In a sensitivity analysis of the regression model infectiousness of children 0-12y.o. was lower compared with adults 26-64 y.o. (OR 0.11) but confidence intervals for this estimate were very wide (crossing 1), likely owing to the low number of child index cases.

Using probabilistic reconstruction of infector-infectee pairs, a median serial interval of 5.3 days was determined (time from symptom onset in an infector to symptom onset in the infectee). Serial interval was prolonged for those isolated > 6 days after symptom onset compared to those isolated <2 days from symptoms (median serial interval 1.7 days vs 7.3 days) indicating prompt case isolation restricts transmission to earlier stages of infection. Peak infectiousness was found to occur at time of symptom onset and half of transmission was estimated to occur in the pre-symptomatic period. Modelling of intervention scenarios suggested case isolation and quarantine of contacts alone would be insufficient to interrupt transmission of SARS-CoV-2, highlighting the need for layered interventions including population level measures such as physical distancing and broad adoption of face masks.

This study is amongst the most detailed contact tracing studies of SARS-CoV-2 infection to date, including temporal data on symptom onset and timing of exposure as well as universal testing of contacts for the majority of the study period. The finding of transmission heterogeneity from index cases is consistent with data elsewhere highlighting the importance of super-spreading in SARS-CoV-2 transmission. The lower susceptibility in child contacts is also consistent with other large epidemiological studies, together with the low number of child index cases. The sensitivity analysis hints at reduced infectiousness of children <12y, but with a high degree of uncertainty. With peak infectiousness occurring near the time of symptom onset, this data underlines the need for a combined approach of case isolation and quarantine of contacts together with broader population measures to control SARS-CoV-2 transmission.

Hallal, PVictora, C LancetSARS-CoV-2 antibody prevalence in Brazil : results from two successive nationwide serological household surveys23 Sept 2020BrazilSouth America56190Epidemiology - Transmissionhttps://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30387-9/fulltext

This is a nationwide repeated cross-sectional study with 2 seroprevalence surveys in 133 sentinel cities in Brazil.1st survey was carried out during 14-21 May 2020 (n=25025) and 2nd survey 4-7June (n=31165).

Methods: They randomly selected households and then randomly selected one individual from all household members. Presence of Ab against SARS-CoV-2 was assessed using lateral flow point-of-care test (WONDFO SARS-Cov-2 Antibody Test) using two drops of blood from finger prick samples.

Results: There were 3400 individuals in 1st survey and 4412 in 2nd survey were aged 1-19 yrs. 2/3 were 10-19 yrs; under1 yr age were excluded. 45/3400 (1.3%) in 1st survey and 79/4412 (1.8% ) in 2nd survey were found positive for SARS-CoV-2 antibodies

Prevalence in children in the 1st survey was similar to that of older age groups. In the 2nd survey prevalence was higher in 20 to 59-year olds (around 3%). There was no significant difference between 1-4, 5-9, and 10-19year olds.

Data on children was not provided separately, but for the whole population groups there were geographical differences in prevalence and it was higher in those living in crowded conditions and households with 6 or more people, and indigenous people (6.4%) compared with white people (1.4%). Prevalence in poorer socio-economic quintile was 3.7% compared with 1.7% in the wealthiest quintile.

The authors conclusion are as follows: antibody prevalence was highly heterogeneous by country region with rapid initial escalation in Brazil’s north and north east. Prevalence is strongly associated with indigenous ancestry and low socio-economic status. These population subgroups are unlikely to be protected if the policy responds to the pandemic by the national government continues to downplay scientific evidence.

This is an impressive well carried out population based nationwide study involving over 56,000 individuals who as part of the study had their SARS-CoV -2 antibodies tested as well as information collected on a range of issues including age, gender, ethnicity, socio-economic status and number of people living in a household. This is probably the largest population-based study in geographical scope. It found high prevalence in 11 cities along the Amazon river, with levels that were among the highest ever reported in population-based studies. This finding of high prevalence in tropical region contradicts the view that continents such as Africa might be protected against COVID-19 because of high ambient temperature. Consistent with other large, well conducted sero-prevalence studies, fewer children were found to have SARS-CoV-2 antibodies than adults.

Tönshoff BKräusslich, H-GJAMA PediatrPrevalence of SARS-CoV-2 Infection in Children and Their Parents in Southwest Germany22 Jan 2021GermanyEurope2482Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2775656

Methods: cross-sectional study carried out during lockdown in Baden-Württemberg, a region with the second highest number of cases of COVID-19 (337 cases per 100,000) in Germany. This study aimed to describe the rates of SARS-Cov-2 infections and the seroprevalence of SARS-CoV-2 antibodies in child-parent pairs, using a population-based sample. Children aged 1 to 10 years old and their corresponding parent (no age limit) living in the same household were eligible for this study. Previous laboratory-confirmed SARS-Cov-2 infection diagnosed before enrolment in either, the child or their parent and/or a child history of severe congenital disease or severe congenital malformations were specified as exclusion criteria. Data collection commenced on the 22nd April 2020 and finalised on 15th May 2020. RTC-PCR testing in naso and oropharyngeal swabs was used to detect the SARS-CoV-2 infections. SARS-Cov-2 IgG antibodies were measured using both, a commercial ELISA for the virus S1 protein and an immunofluorescence test. Where negative in both assays, no further testing was undertaken; if results were discordant, confirmation was carried out with a second ELISA, an in-house-Luminex based assay or electrochemiluminescense assay. Study participation was voluntary.

Analysis: Mixed-effect logistic regression models using seropositivity as response were fitted to account with the paired child-parent structure.

Results: 2250-child-parent pairs were enrolled and 2482 were included in the final analysis (2482 children aged between 1 and 10 years, and 2482 corresponding parents aged between 23 and 66 years old).

70/4964 participants were classified as IgG-positive (9/1129 children aged 1 to 5 years [0.8%]; 13/1353 children aged 6 to 10 years [1.0%] and 48/2482 parents [1.9%]), 60 in both assays and 10 were confirmed through a third test. SARS-Cov-2 neutralising antibodies were detected in 66/70 samples.

56 families with at least one parent or child seropositive for SARS-Cov-2 were reported. The most common combination was seropositive parent and seronegative child (34/56), followed by seropositive child-parent pairs (14/56) and seropositive child with seronegative parent (8/56). The estimated seroprevalence in parents was 1.8% (95% CI, 1.2-2.4), 3.6-fold lower in children aged 1 to 5 years old (0.5%[95% CI 0.2-0.9]) and 2.6-fold lower in children aged 6 to 10 years old (0.7% [95% CI 0.4-1.4])

Only 2 participants(0.04%) tested positive for SARS-Cov-2 RT-PCR (1 child and the corresponding parent). They reported mild-symptoms suggestive of COVID-19 several weeks before enrolment and had detectable neutralising antibodies.

No statistically significant differences in seropositivity were found among children attending exceptional child day-care during lockdown compared to those not attending. A history of symptoms suggestive of SARS-Cov-2 coupled with seropositivity was more common in parents than in children.

Considerations: this is a point-seroprevalence study of SARS-Cov-2 antibodies estimated in a large sample size of child-parent pairs, combining at least 2 serological assays to maximise diagnostic accuracy in a setting with low prevalence. An exciting finding of this study lies on the rates of seropositivity in children attending exceptional childcare. While these were not higher than the observed in children not attending exceptional childcare, the result suggests that contact restrictions may not explain the difference in seropositivity between children and adults. It is important to state that this study was carried out during lockdown and the impact of reduced exposure on the seroprevelance of SARS-Cov-2 IgG in children cannot be excluded.

Leidman, ESauber-Schatz, EMMWR Morb Mortal Wkly Rep 70(3): 88-94COVID-19 Trends Among Persons Aged 0–24 Years — United States, March 1–December 12, 2020 22 Jan 2021United States of AmericaNorth America1222033Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7003e1-H.pdf

The study took place between 1st March 2020 and 12th December 2020 across 44 states in the United States of America with 2,871,828 test results in children and young adults analysed. 1,222,033 (42.6%). of the total were in children aged 0-17; 7.4% were age 0-4, 10.9% age 5-10, 7.9% age 11-13 and 16.3% age 14-17. There was no gender difference in the children aged 0-17. For analysis the children were divided into different age groups reflecting their type of education.

Weekly incidence was higher in each successively increasing age group; and was highest during the final week of the review period (the week of 6th December) in all age groups: 99.9 per 100,000 (0–4 years), 131.4 (5–10 years), 180.6 (11–13 years), 255.6 (14–17 years), and 379.3 (18–24 years). Trends in weekly incidence for all age groups aged 0–17 years paralleled those observed among adults since June. The trend in incidence among young adults aged 18–24 years had a distinct and more prominent peak during the week of 6th September.

Weekly SARS-CoV-2 laboratory testing among children, adolescents, and young adults increased 423.3% from 435,434 tests during the week beginning 31st May to 2,278,688 tests during the week beginning 6th December. At their peak during the week of 15th November, tests conducted among children and adolescents aged 0–17 years represented 9.5% of all tests performed, and tests among young adults aged 18–24 years represented 15.3%.

Case data do not indicate that increases in incidence among adults were preceded by increases among preschool- and school-aged children and adolescents. In contrast, incidence among young adults (aged 18–24 years) was higher than that in other age groups throughout the summer and autumn, with peaks in mid-July and early September that preceded increases among other age groups, suggesting that young adults (age 18-24) might contribute more to community transmission than do younger children.

The authors highlight four limitations of their study, testing was often prioritised amongst symptomatic patients, the data for ethnicity and underlying conditions was incomplete, the reporting of laboratory data differed by jurisdiction and might underrepresent the actual volume of laboratory tests performed, and finally, the presented analysis explored case surveillance data for children, adolescents, and young adults; trends in cases among teachers and school staff members were not available because cases are not reported nationally by occupations other than health care workers.

This is an important paper whose conclusion for children are highly significant. In the last paragraph of the papers the authors are very clear saying “CDC recommends that K–12 (Kindergarten to year 12) schools be the last settings to close after all other mitigation measures have been employed and the first to reopen when they can do so safely”

Ulyte, A Kriemler, SmedRxivClustering and longitudinal change in SARS-1 CoV-2 seroprevalence in 2 school-children: prospective cohort study of 55 schools in Switzerland22 dec 2020switzerlandEurope2603Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.19.20248513v1.full.pdf

This article is a pre-print and has not been peer-reviewed.

Introduction: This study was a longitudinal cohort study of school going children in Switzerland across two time measuring SARS-CoV-2 antibodies and symptoms across two time points, June-July (T1) and October-November (T2). Schools were open with preventative measures during both time points. In Autumn 2020, Switzerland experienced one of the highest second waves of Sars-Cov-2 infection in the world at the time.

Methods: Primary schools in Zurich were randomly selected, stratified by region, and matched with the geographically closest secondary school. Of 156 invited schools 55 took part. Classes within participating schools were selected randomly stratified by school level; lower school grade 1-2 attended by 6 to 9-year-olds; middle school grades 4-5 attended by 9 to 13/14 year-olds and upper school grades 7-8 attended by 12 to 16-year-olds. Children were excluded who had active symptoms of SARS-COV2 as this precluded their attendance at school. Clusters within classes were defined as three or more cases of newly seropositive children within a class in autumn (T2) testing. Clustering was compared against stimulated models where independent chance of seropositive testing was assumed. Semi structured interviews with school principals where clustering occurred to further investigate clusters

Infection control measures: Preventative measures were by August varying degrees of; masks for teachers and students over 12 years, tapering of school breaks, distancing rules in class and teacher rooms, no parents on premises. Mandatory masks for adults in schools from October. Mandatory masks for children over 12 years from November. Once an index case was identified in a school children and school personnel were quarantined based on contact-tracing of close contacts. Full classes were quarantined only when two or more infected students were identified within a class.

Results: Estimated SARS-CoV-2 seroprevalence in T1 in children was 2.4%. Seroprevalence in autumn (newly seropositive in T2) in children was 4.5%. T1+T2 seroprevalence (ever positive to covid) per age was lower school 8.5% , middle school 8.0% , and upper school 6.4%. At least one ever seropositive child was detected in 52 out of 55 schools and in 125 out of 275 classes. Clusters of 3 or more newly seropositive children were observed only in 7 classes out of 55 schools. Symptoms between the summer break and November 2020 were reported in 21.8% of seronegative and in 28.7% newly seropositive children (T2).

In T2 SARS-CoV-2 antibodies were not detected after four months for 40% previously seropositive children.

Conclusion: This study demonstrated only minimal clustering of seropositive children between July and November 2020 despite a clear increase in seroprevalence among children during a time of very high community transmission. Clustering occurred within classes rather than across schools. In contrast to some other studies, a higher seroprevalence or clustering of cases in children of older age in the secondary schools was not observed. Authors felt this may be related to mandatory mask wearing in these older children. Authors suggested this study would support keeping schools open even in times of high community prevalence, once preventative measures are in place within schools and communities.

Villaverde, STagarro, AJ Pediatr.Diagnostic Accuracy of the Panbio SARS-CoV-2 Antigen Rapid Test Compared with Rt-Pcr Testing of Nasopharyngeal Samples in the Pediatric Population20 JAN 2020SpainEurope1620Epidemiology - Transmissionhttps://www.jpeds.com/article/S0022-3476(21)00034-2/fulltext

Background: There is currently a gap between the increasing number of patients and the testing capacity of RT-PCR laboratories; rapid antigen tests have emerged as a possible solution. The Panbio Rapid Antigen Test (Panbio Test) is a simple and rapid test that can detect the SARS-COV-2 virus in nasopharyngeal samples (NPS) and is based on lateral immunochromatography. According to the manufacturer’s information, the test has a sensitivity of 93.9% (95%CI: 86.5-97.4%) in the adult population with <7 days of symptoms. Further studies in the adult population have shown a sensitivity closer to 85% in adults with <5 days of symptoms. However, there is a lack of data assessing the accuracy of these rapid antigen tests in the paediatric population.

Method: This retrospective, multicentre study, which was nested in a prospective, observational multicentre study assessed the diagnostic accuracy of the Panbio test against the more globally used RT-PCR in the paediatric population. Paediatric patients aged between 0-16 years who presented to one of seven Spanish Emergency Departments with symptoms compatible with SARS-COV-2 infection of ≤5 days of evolution were included in the study. Patients who had close contact with confirmed COVID-19 patients and were asymptomatic were excluded.

The collection of two nasopharyngeal samples from each patient occurred concurrently by trained nurses. The Panbio test was performed on site with guidance from the manufacturer’s instructions and interpreted by attending clinicians. Whereas the RT-PCR tests were analysed by microbiology specialists from the laboratories in the participating centres. The study achieved the minimum sample size of 1200 patients, calculated with the use of 80% power, for a 5% prevalence of COVID-19 and a 90% sensitivity of the Panbio test. RT-PCR was also used as the gold standard reference. A total of 1620 paediatric patients were recruited between September and October 2020.

Results: Of the 1620 patients tested, 77 tested positive by RT-PCR (4.8%), 38 tested positive by the Panbio Rapid Antigen Test (2.3%) and 35 patients tested positive by both tests (2.1%). Discordant results occurred in 45 antigen test results compared with RT-PCR (2.7%): 3/1543 (0.2%) false-positive antigen tests and 42/77 (54.5%) false-negative test results. There was a significant difference between the two diagnostic results (P value = 1.47 x 10-08). The sensitivity of the Panbio test was 45.5% (95%CI, 34.1-57.2) and the specificity was 99.8% (95%CI, 99.4-99.9). The test also had a positive predictive value (PPV) of 92.5% (95CI, 78.6-97.4) and a negative predictive value (NPV) of 97.3% (95CI, 96.8-97.8). The positive likelihood ratio (PLR) was 233.8 (95%CI, 73.5-743.3) and the negative likelihood ratios (NLR) was 0.54 (95%CI, 0.44-0.67).

Conclusions and Limitations: The aim of this study was to assess whether the Panbio test is effective in identifying SARS-COV-2 in the paediatric population; and whether it can be used as an alternative to the expensive and slow RT-PCR test. Although the manufacturers state a high sensitivity of the Panbio test in the adult population, this study found that the Panbio test had a relatively low sensitivity in the paediatric population (45.5%, 95%CI, 34.1-57.2). The low sensitivity meant a high proportion of false-negative results (54.5%) which would result in the spread of the infection increasing if contagious patients are not accurately identified and isolated. Regardless of the low sensitivity and NLR, the use of the Panbio test as a primary screening tool may be viable due to the low cost, speed of results and high PLR. However, clinicians should be made aware of the actual accuracy of the test and whether other methods of diagnosis are required.

Without further assessment, the large number of false negative results may seem to be an issue with the antigen test itself but there are multiple explanations which could lead to the invalidity of the results. This study used RT-PCR as the gold standard diagnostic method however, a study by Rhee et al. (2020) found that RT-PCR positivity can persist for weeks to months after infection of SARS-COV-2. However, concordance between contagiousness and RT-PCR or antigen positivity is not clearly known and therefore, the use of RT-PCR as the gold standard may not be appropriate when assessing the accuracy of the Panbio test.

The study also failed to note the time between onset of symptoms and testing or the cycle-threshold values of RT-PCR, and therefore it was not possible to assess whether a high cycle threshold could be attributed to the low sensitivity of the antigen test. The inclusion criteria of symptoms were also not listed. Without this data, it is not possible assess whether the Panbio test would be suitable for inter-country use as the guidance of COVID-19 symptoms may differ between countries. In addition to the above, epidemiological data on the participants of this study were not given. As noted in some studies, NPS viral loads may differ between adult and paediatric populations and the exclusion of data relating to the age and gender of the participants makes it difficult to exclude data collection bias. The authors do note however that as a pre proof, the ongoing research of the study team will include some of the missing information.

Hommes, FMockenhaupt, FmedRxivSARS-CoV-2 infection, risk perception, behaviour, and preventive measures at schools in Berlin, Germany, during the early post-lockdown phase: A cross-sectional study18 Dec 2020GermanyEurope385Epidemiology - Transmissionhttps://doi.org/10.1101/2020.12.18.20248398
Larosa, EBedeschi, EmedRxivSecondary transmission of COVID-19 in preschool and school settings after their reopening in northern Italy: a population-based study18 11 2020ItalyEurope43Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.17.20229583v1

This study is a pre-print and so should be interpreted with caution whilst awaiting peer review.

This is a prospective study looking at transmission of COVID-19 in schools in the Reggio Emilio province of northern Italy (population 530,000). Schools re-opened in Italy from the beginning of September.

Methods: All SARS-Cov-2 positive tests are reported to the local authority and contact tracing is done. This study analyses consecutive cases that investigation showed attended or worked in a school or nursery between 01.09.20 and 15.10.20. For each of these index cases, everyone in the class was immediately tested. If this was less than 6 days from the last contact with the index case, a 2nd swab was collected at 10-14 days. Only close contacts of the case were isolated unless social distancing was not observed, or a secondary case was identified.

Results

• 43 index cases were found (5 teachers and 38 students)

• 994 students and 204 teachers were identified as possible contacts and tested

• 39 secondary cases were found among the students, an attack rate of 3.9% overall but 0% in pre-school children, 0.44% in primary and 6.64% in secondary children

• No secondary cases amongst the teachers

• The authors were satisfied that all the positive cases were most probably secondary to the identified index case

More details of the contact tracing are given but no indication as to its completeness though it was clearly done on the ground with assessment of the risk of secondary infection in each individual class so that whole classes were not necessarily sent to isolate.

Importantly, infection prevention measures are listed including:

- Masks worn unless at desks and not speaking (exception is primary school where they are never mandatory

- Single desks 1m apart

- Avoiding crowding at school entrance/exists by staggered start/stop times

- Suspension of extracurricular activities

- If class sizes too small for social distancing, class sized halved and a rota system adopted

This study was done as case numbers were rising during the second wave in Italy but concluded 4 weeks before the peak. The authors explain why they do not think this affects their results.

Conclusion: A low secondary attack rate was observed in educational settings in Italy during the start of the second surge of cases, increasing dependant on age with no secondary cases in pre school and 6.6% in secondary children. The low SAR is particularly notable in the youngest children given modest infection prevention measures and no mandatory mask use.

Li, FWong, GLancet Infect DisHousehold transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study18 01 2021ChinaAsia327Epidemiology - Transmissionhttps://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30981-6/fulltext

In this large retrospective from Wuhan, China, household transmissibility of SARS-CoV-2 and risk factors for transmission were assessed based on the epidemiological investigation conducted by the Wuhan Center for Disease Control and Prevention.

Methods: All clinically or laboratory confirmed cases diagnosed in Wuhan between December 2nd, 2019 and April 18th, 2020 and their household contacts were included. A household contact was defined as a close family member or relative with unprotected contact with a case within 2 days before symptom onset or positive PCR test. For each household, the date of first symptoms onset or first positive test of a household member was defined as day 1; primary cases were defined as cases with symptom onset or positive test on day 1 or 2 (allowing for co-primary cases within a household). Later cases were classified as secondary. Notable changes in case identification during the study period included a requirement to report asymptomatic infections from February 1st and testing of all household contacts regardless of presence of symptoms from February 23rd.

Observed secondary attack rate was calculated as the proportion of secondary infections amongst household contacts. Further analysis was conducted using two models. Firstly, a generalised estimating equation (GEE) regression model was used to assess individual and household level risk factors for infection of household contacts. This analysis included only household with a single primary case. Secondly, a binomial transmission model was used to evaluate infectivity and susceptibility to infection accounting for exposure history by comparing the daily probability of transmission from cases to their household contacts between groups. This model also accounted for relative susceptibility of household contacts in assessing infectivity of a primary case.

Results: A total of 27,101 households with 29,578 primary cases with 57,581 household contacts were included. Median household size was 3 (IQR 2-4); median age amongst cases was 56 years (IQR 43-66). Secondary attack rate in houses with a single primary case was 16.0% (95% CI 15.7-16.3%).

Household contacts <20y.o. were 66-86% less susceptible to infection compared to adults >60y.o. in the transmission model (and 68-85% less susceptible in the GEE model). Infants <1y.o. were relatively more susceptible to infection compared with older children aged 2-5y.o. (OR 2.20 (95% CI 1.40-3.44)) and 6-12y.o. (OR 1.53 (95% CI 1.01-2.34)), but less susceptible compared with adults >60y.o. (OR 0.32 (95% CI 0.21-0.50)). Of secondary cases <20y.o. a similar proportion remained asymptomatic (15.3%) compared to the asymptomatic proportion overall (16.0%). Severe or critical COVID was significantly less common in secondary cases <20y.o. (2.4%) compared with those >60y.o. (18.8%)

For primary cases <20y.o. household transmission was 34% less likely to occur compared to primary cases aged 60-79y.o. (OR 0.66 (95% CI 0.48-0.90)) according to the GEE model. In contrast, the transmission model identified primary cases <20y.o. to be more infectious than compared to those aged >60y.o. (OR 1.58 (95% CI 1.28-1.95). Notably only 1.4% of primary cases were <20y.o.(413 / 29,578) and analysis of more refined age groups amongst primary cases was not attempted "due to the limited number of cases among young children".

Both models found that primary cases who remained asymptomatic were less likely to infect household contacts; OR 0.21 (95% CI 0.14-0.31) in the transmission model (for cases after February 1st).

Discussion: The findings of this large contact tracing study are largely in keeping with data from similar studies previously published, including the lower susceptibility of children to SARS-CoV-2 infection and the milder course of COVID-19 in children compared with adults. Similarly, the reduced infectivity of asymptomatic primary cases is in keeping with emerging data from epidemiological studies elsewhere.

The conflicting findings regarding infectivity of primary cases <20y.o. is likely related to the differences between the two models with the GEE model indicating lower infectivity and the transmission model higher infectivity in this age group. The transmission model attempted to adjust for duration of exposure by calculating daily transmission probability (which was inversely proportional to exposure person-days (denominator)). In post-hoc exploratory analysis, the authors attribute the higher infectivity in primary cases <20y.o. indicated by the transmission model to a shorter exposure period from onset of illness to isolation compared with adults (5 days vs 10-11 days). The validity of the adjustment in this model for exposure time may not be entirely sound considering the period of highest infectivity of SARS-CoV-2 occurs just prior to or soon after symptom onset. In addition, children were grossly underrepresented as index cases, with a surprisingly small fraction of asymptomatic cases documented. Oversampling of symptomatic children is likely to overestimate the infectiousness of children more generally, due to the noted disparity between the infectiousness of symptomatic vs asymptomatic cases. Considering the limitations of the model used together with the lack of more detailed age banded analysis due to the limited number of primary cases among young children, the results regarding infectiousness should be interpreted with caution.

Lewis, NKirking, HClin Inf DisHousehold Transmission of SARS-CoV-2 in the United States.16 Aug 2020USANorth America69Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1166/5893024

This study, published on 16th August 2020, recruited COVID-19 patients and their household contacts in two US states, Utah and Wisconsin, from 22nd March to 25th April 2020, to examine SARS-CoV-2 transmission, estimate the household secondary infection rate (SIR) and evaluate potential risk factors for secondary infection within US households.

Background: The Centre for Disease Control and Prevention (CDC) collaborated with state and local health departments in the Milwaukee, Wisconsin, and Salt Lake City, Utah, metropolitan areas to identify laboratory-confirmed SARS-CoV-2 infections in “index patients”. These two areas were chosen based on the presence of interested public health partners and the relatively low COVID-19 prevalence in both regions (thereby reducing the risk of additional community exposure to household contacts). March to May 2020 was a period of shelter-in-place orders and social distancing recommendations across the United States; stay at home orders/recommendations came into effect in both states in late March.

Study population: Local health department staff completed their own investigations of reported cases captured by public health surveillance during the period 22nd March to 25th April 2020 and then informed potential eligible index cases about CDC’s study: index cases were considered eligible if not hospitalised at the time, living with 1 additional person and tested positive for SARS-CoV-2 rRT-PCR from a nasopharyngeal swab collected  10 days prior to enrolment. Households where >1 household contact declined to participate were excluded; households with separate entrances were prioritised (to facilitate patient confidentiality and CDC team infection control). At the time SARS-CoV-2 outpatient testing was limited to individuals meeting CDC criteria for influenza testing in Wisconsin (excluding asymptomatic or mildly symptomatic cases who were not health care workers) and required clinical features (fever, cough or shortness of breath) and an epidemiologic risk factor in Utah. Once enrolled by the CDC investigation team, all household members were classified as either “primary patients” (positive PCR test with symptom onset >1 day prior to symptom onset of others in the household with laboratory-confirmed SARS-CoV-2 infection; this person could differ from the index case if during the investigation infection was confirmed in a person with an earlier symptom onset date than the index case) or “household contacts” (everyone living in the same household as the primary patient). For asymptomatic cases, onset was defined as collection date of first positive PCR test. Secondary infections were defined as household contacts with either respiratory swabs positive for SARS-CoV-2 rRT-PCR or sera positive for SARS-CoV-2 antibodies tested by enzyme-linked immunosorbent assay (ELISA).

Collection of data: Phone questionnaires covering demographics, medical histories and recent symptoms for index patients and all household contacts were administered prior to the first household visit. A household-level questionnaire detailed physical characteristics of the residence. There were 2 in-person visits by the investigation team to each household on day 0 and day 14, collecting a nasopharyngeal swab, a self-collected anterior nasal swab and a blood sample for all household members, including the index patient. Each person completed a daily symptom diary from day 0 to day 14. If a household member became newly symptomatic there was an interim visit at which repeat swabs were obtained for all household contacts.

Characteristics of households: 62 households were enrolled (36 in Utah and 26 in Wisconsin); 4 were excluded where the primary patient could not be identified. The remaining 58 households (34 in Utah and 24 in Wisconsin) comprised 58 primary patients and 188/197 (95%) household contacts (9 household contacts declined participation after initial household enrolment). Median number of persons per household: 4 (range 2-16). Median house size: 2,200 square feet (range 600-8,000). 55/58 (95%) households reported precautionary practices (such as ill persons sleeping in a separate bedroom and using face coverings) at some point following symptom onset of the first confirmed case in the household.

Characteristics of 58 primary patients: Median age: 40 years (range 16-90). <18 yrs 1/58 (2%, aged 16 yrs), 18-49 yrs 39/58 (67%), 50-64 yrs 16/58 (28%), 65 yrs 2/58 (3%). Female 26/58 (45%). Co-morbidities: 21/58 (36%) (lung disease 16%, cardiovascular disease 12%, diabetes mellitus 5%, renal disease 3%, immunopromising condition or medication 3%). Symptoms: respiratory 56/58 (97%), neurological 51/58 (88%), constitutional (chills, fever, myalgia) 50/58 (86%), gastrointestinal 41/58 (71%). 1 primary patient asymptomatic (tested based on a known non-household exposure). Median interval from symptom onset to day 0 household visit: 11 days (IQR 8-16). Median interval from collection of first positive specimen to day 0 household visit: 6 days (IQR 4-8). 3/58 (5%) hospitalised; 1/58 (2%) died.

Characteristics of 188 household contacts: Median age: 22 years (range <1-76). <1 yr 1/188 (0.5%), 1-9 yrs 28/188 (15%), 10-17 yrs 39/188 (21%), 18-49 yrs 88/188 (47%), 50-64 yrs 26/188 (14%), 65 yrs 6/188 (3%). Female 96/188 (51%). Co-morbidities: 60/188 (32%) (lung disease 18%, cardiovascular disease 9%, diabetes mellitus 3%, renal disease 1%, immunocompromising condition or medication 1%, liver disease 1%). 3 pregnant (out of 37 females aged 15-44 yrs, 8%).

Secondary infections among household contacts: Secondary transmission in 31/58 (53%, 95% CI: 41-66%) households. Secondary infections in 52/188 (SIR 28%, 95% CI 22-34%) household contacts: 44/52 (85%) with positive PCR and 46/50 (92%) with SARS-CoV-2 antibodies. Median interval between symptom onset of primary patient and infected household contact 5 days (IQR 4-9). At day 0 initial visit 43/52 (83%) had already acquired secondary infection; 9/52 (17%) acquired secondary infection during the 14 day investigation period. 8/52 (15%) had SARS-CoV-2 antibodies but no positive PCR during the investigation (all 8 symptomatic with symptom onset 2 days after primary patient: 4 seropositive on day 0, 3 seroconverted between days 0 and 14, 1 didn’t have serology test on day 0 but seropositive and PCR negative on day 14).

Repeat analysis excluding contacts with evidence of secondary infection by serology only (to address potential misclassification of secondary infections) and using positive PCR results only: 44/188 (SIR 23%, 95% CI 18-3-%).

Secondary infections by age and family relationships: SIRs were highest among children (<18 yrs old) of the primary patient (18/43, 42%), adult children (18 yrs old) of the primary patient (6/17, 35%) and spouses/partners of the primary patient (11/33, 33%).

However, the SIR in children hides important differences. Of the children <10 years the SIR was significantly lower for both children of the index case (3/17, 18%) and not of the index case (0/12, 0%) compared to children aged 10 – 18 years (child of primary = 15/26, 58%, non-child of primary = 1/13, 8%).

There was only one primary patient aged <18 yrs: their 3 household contacts remained uninfected.

Risk factors for secondary infection in household contacts: Household contacts with diabetes mellitus had higher odds of secondary infection compared with those without (SIR 80% vs 26%, OR 7.8, 95% CI 1.3-47.3). The authors note that collinearity between diabetes mellitus and obesity may have confounded the association. Household contacts of a male primary patient were more likely to acquire secondary infection than those of a female primary patient (SIR 36% vs 18%, OR 2.4, 95% CI 1.1-5.3). Household contacts of a primary patient with an immunocompromising condition had higher odds of secondary infection compared with contacts of a primary patient without an immunocompromising condition (SIR 88% vs 25%, OR 18.1, 95% CI 2.6-125.1). The authors suggested that this could be due to more severe or prolonged illness in these primary patients, resulting in greater viral shedding, or closer caregiving needs required by these patients, resulting in higher risk to contacts. There was only one asymptomatic primary patient: their 2 household contacts remained uninfected. Households with <6 persons had a median of 1 secondary infection (IQR 1-2) and households with 6 persons had a median of 3 secondary infections (IQR 2-4). The risk of transmission within a household was not different based on square footage per person or number of persons per bedroom or bathroom.

Limitations identified by authors: This study assumed that household transmission was responsible for infections in household contacts: while stay-at-home orders should have limited community exposures at the time, this may overestimate household SIR. Potential misclassification of primary patients would affect the analysis. The study population may not be representative of all US households (both states have relatively larger average household sizes and apartment buildings were excluded). Delays in testing and reporting at the time meant that transmission had already occurred by enrolment in many households, which made transmission dynamics more difficult to assess. Additional transmission chains may have occurred after the investigation period.

Conclusions: There was only one primary patient in this study aged <18 years (who didn’t transmit infection to their 3 household contacts), so conclusions cannot be drawn about transmission from SARS-CoV-2-infected children to their household contacts. The study showed a relatively high rate of secondary infection amongst household contacts of SARS-CoV-2-infected adults, with 31/58 (53%) of households having evidence of at least 1 household contact who acquired secondary infection from the primary patient. The SIR was 29% (55/188 household contacts acquiring secondary infection from the primary patient). Children aged <10 years had a lower SIR, where-as children aged 10 – 18years had a higher than average SIR. This highlights the importance of age disaggregated data when analysing infection properties amongst children.

Brotons, PMunoz-Almargo, CClinical infectious diseases SUSCEPTIBILITY TO SARS-COV-2 INFECTION AMONG CHILDREN AND ADULTS: A SEROPREVALENCE STUDY OF FAMILY HOUSEHOLDS IN THE BARCELONA METROPOLITAN REGION, SPAIN12 Nov 2020SpainEurope672Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1721/5979490

A cross sectional survey of 381 quarantined households undertaken between 28 April 2020 and 3 June 2020 in Barcelona, Northern Spain. The households were identified by at least one parent being Real Time PCR positive for SARS-CoV-2. Family members, 672 children (defined as <15 years of age) 357 boys and 412 adults (defined as ≥ 15 years age) 235 male, were tested at home by a rapid SARS-CoV-2 antibody assay using finger-prick capillary blood.

The number of children who were seropositive was 118 of 672 (17.6%, 95% CI 14.8-20.7%) and was not different to the number of adults 77 of 335 (18.7%, 95% CI 15.0-22.8%) who were positive. Very few children had symptoms except one child who developed multi-system inflammatory syndrome (Kawasaki like).

The authors concluded “Children appear to have similar probability as adults to become infected by SARS-CoV-2 in quarantined family households but remain largely asymptomatic once infected”

Limitations to the study include that although similar prevalence of seropositivity was observed between the 2 groups, it cannot be confirmed whether the exposure was in the household given the study period was after the most intense period of community transmission in Spain. In addition, evidence is emerging which suggests children can seroconvert following exposure to the virus without developing clinical or virological infection.

Tosif, SCrawford, NNat CommunImmune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-1911 NOV 2020AustraliaAustralasia3Epidemiology - Transmissionhttps://doi.org/10.1038/s41467-020-19545-8

This is a retrospective case study of three children, of parents with symptomatic COVID-19 disease, who developed immunologic evidence of infection whilst exhibiting only mild or no symptoms. The study was conducted in Melbourne, Australia during March 2020.

Analysis: The two parents, age 38 and 47 years, developed symptomatic COVID-19 infection, comprising cough, coryza, fever and headache. They were SARS-CoV-2 PCR positive on nasopharyngeal (NP) swabs. Seven days later one child (male, age 9 years) developed cough, coryza, sore throat, abdominal pain and loose stools and a second child (female, age 7 years) developed cough and coryza. A third child (female, age 5 years) was asymptomatic. Repeated NP swabs from the children were negative for SARS-CoV-2 by PCR, as were saliva and stool samples.

All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA. Plasma from both parents and one child had IgG antibody against the S1 protein and virus-neutralizing activity detected. All family members, including the children, exhibited SARS-CoV-2-specific antibody features that differed from pre-pandemic controls. Cellular immune profiles and cytokine responses of all three children were similar to the parents at all timepoints.

Conclusions: The authors conclude that despite having no virological evidence of infection, all three children developed antibody responses against various SARS-CoV-2 epitopes. They suggest that the children were infected with SARS-CoV-2 but, unlike the adults, mounted an immune response that was highly effective in restricting virus replication. They speculate whether this will confer protection against re-infection.

Finally, the authors note that the discordance between the virological PCR results and clinical serological testing, despite an evident immune response. This highlights an important difference in studies which aim to either assess for evidence of clinical infection (rt-PCR) or combined evidence of infection or exposure (serology). Testing for rt-PCR only may miss children who have had exposure to the virus. However, testing via serology may detect children who have seroconverted without ever developing clinical or virological infection.

Depending on the purpose of testing or screening programmes, this raises the possibility of false negatives for rt-PCR and false positives for serology. This studies would suggest rt-PCR is superior for understanding the risk of transmission to or from children, as those who seroconvert in the absence of any virological evidence of disease are extremely unlikely to pose a risk of passing infection on to others

Oster, AMBoehmer TKMMWRTransmission dynamics by age group in COVID-19 hotspot counties - United States, April–September 202009 OCT 2020USANorth AmericaEpidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6941e1.htm

This retrospective observational review reports the temporal progress of SARS-CoV-2 infections in ‘hotspots’ across the entire USA, between April and September 2020, with regard to the peaks for distinct age cohorts. Case numbers are not given but children (0-17yrs) are included. Of interest is the trend for young adults (18-24yrs) to lead the outbreak, followed by children, before spreading, in age order, to older cohorts. This was seen in all the regional breakdowns analysed, as well as the overall picture for the US.

The reason for this is not addressed (perhaps due to increased rates of mixing in high risk situations), but the authors highlight the need for policy measures focussed on reducing transmission among young adults, as well as preparation for the likely rise in cases, hospitalisations and fatalities in older age groups which follows from these surges.

Gandini, SScorrano, LmedRxivNo evidence of association between schools and SARS-CoV-2 second wave in Italy08 Jan 2021ItalyEurope112000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.12.16.20248134v2

This is a prospective cross sectional cohort study of school children (6-18yrs), teachers and school staff in Italy. Data was derived from those schools who were reporting their cases to the national database from the ministry of education. A variety of different epidemiological parameters were determined at different times between 20/09/2020 – 05/12/2020. The children were split into 4 groups (Kindergarten 3-5yr olds, elementary 6-10yr olds, middle school 11-13yr olds and high school 14-18yr olds) based on their educational setting. The incidence of positive cases (determined in the time period 20/09/20 – 8/11/2020) was lower in school children (66/10 000 in elementary and middle school and 98/10 000 in high school) than in the population (108/10 000). However, the incidence in teachers and staff members was two-fold higher (220/10 000) than the population. Incidence of new positive cases in elementary and middle school was on average 38.9% lower and in high school (except in 3 regions where it was higher) 9% lower than in the population. The new positive cases were higher in teachers (1.52% of teachers) and staff members (1.96% of staff members) than students (0.32% of students).

Setting New positive cases (% of students) New positive cases (% of teachers) P value

Kindergarten 0.21 2.35 <0.001

Elementary 0.35 1.83 <0.001

Middle school 0.45 1.6 <0.001

High school

Contract tracing information (collected between 23/11/20-5/12/20) gave a least square estimation of secondary cases of 1% per school per week for teachers and students in kindergarten, elementary and middle school. This rate was not statistically different in situations where the index case was teacher or student. Clusters (>2 positive cases in the one week following contact tracing of index case) occurred in 5-7% of schools.

Temporal investigations to determine whether schools were a driver in the second wave, looked at the timings school opening and the increase in the reproduction number (Rt) in different regional pairs. The increase in Rt occurred after school re-opening but time delayed increasing in Rt was shorter in regions that opened later with 5.7 days delay where schools re-opened 22-24 of September compared to 12.4 days where reopening was 14-16 September. A heatmap of Covid 19 cases in the region of Veneto was created for the period of August-early September which showed that the earliest increases in the incidence of new cases occurred in the 20-49yr olds for this 8 week period. Comparison of incidence of cases amongst teachers and the general population aged 25-65 in Veneto between19/09-18/10 shows that the incidence in teachers increases after the increase in the general population with no statistical difference in incidence at the end of this period (12/10 000 teachers and 11.1/10 000 gen population p=0.36). Secondary case analysis for the region of Veneto between 25/11/20-21/12/20 showed 380 student, 30 staff and 114 teachers’ index cases in 339 schools for which contact tracing was performed. 76 secondary cases were found with 71% of these being students. A secondary case among teacher is more frequent when the index case is a teacher than a student (38% vs. 11%, P=0.007). In the regions of Lombardy and Campania the Rt decline started occurring before the school closures were mandated on the 26/10 and 16/10 respectively(other restrictions were placed in the lead up to school closures). In Campania the incidence dropped in amongst students after school closure but continued to increase in the general population accounting for the Rt being >1 until 5-11 of November.

Not all schools nationally were contributing to the database and therefore the incidence may be higher than the figures stated in this paper. The data is also subject to delay in reporting as well as difference in criteria for reporting in different regions. Across all settings students seem to be less effected in terms of being infected and being the index case. Teachers however are more affected than the general population and the study suggests that the school setting confers a greater risk of acquiring the infection. The data from one region in Italy shows that the rate of incidence in teachers is the same as that of The temporal investigations suggests that the school re-opening coincided with a number of other drivers (unknown) occurring before or around the same time which was already poised to start increasing the Rt. You cannot rule out that the school re-opening did not contribute to the increase as all increases occurred after school re-opening. The data presented for the region of Veneto regarding index and secondar cases suggests that index and secondar cases are commonly students with teachers more likely to be secondary case if the index case was a teacher. These results are in a small sample and should be investigated further. The study states that the school closure did not affect the rate of Rt decline but this based on the figures from two regions only provide analysis on the rate of change in Rt in the days after school closure and not more long term and the rates themselves are not stated very clearly. The lag time in Campania between school closure and the Rt dropping below 1 was about a month and it would be interesting to know whether there was a similar time lag in other regions. The study states that the school closures in Campania did not curtail the rising incidence of cases in the population but fail to take into account the drop in incidence they mention amongst students or that the Rt only remained >1 until the 5-11th of November.

Brandal, LWinje, BEuro SurveillMinimal transmission of SARS-CoV-2 from paediatric COVID-19 cases in primary schools, Norway, August-November 202007 01 2021NorwayEurope13Epidemiology - Transmissionhttps://doi.org/10.2807/1560-7917.ES.2020.26.1.2002011

This is a prospective study designed to give a better understanding of the transmission of SARS-CoV-2 in school settings by systematic testing. This was done in the Oslo/Viken areas of Norway.

Since re-opening after the 1st wave, all schools implemented strengthened hygiene measure, physical distancing and had a strong message that children should stay at home with even mild symptoms.

Methods: 13 school contact tracing groups were identified. These had 14 index cases – children aged 5-13 with PCR-confirmed SARS-CoV-2 infection from nasopharyngeal swab, who had attended school within 48h before symptom onset or date of sampling. (8 of these 5-10y, 5 11-13y). 2 index cases were in the same class so treated as 1 contact tracing group.

292 school contacts of these children consented and were included (234 children, 58 adults)

2 Saliva samples were taken from index children and all contacts, the 1st as soon as possible after identification (for index cases this was 2-6 days after the NP sample, and for the contacts the morning after identification), the 2nd at the end of their 10-day quarantine. These were analysed by PCR.

Results: 3 of the contacts (2 children and 1 adult) tested positive on their 1st saliva test and are referred to as primary cases.

2 of these were children (2/234 0.9%) and 1 adult (1/58 1.7%).

No other contacts tested positive on their 2nd saliva test (these would have been secondary cases).

Other: The authors found self-collection of saliva samples to be acceptable, efficient and sensitive: the 1st saliva samples of 11/13 (85%) index cases were positive.

All except 1 index case had initial NP PCR done because of a positive household contact. Only 4 of the index cases were symptomatic at any point.

The authors note that the results are only valid for primary schools.

Caveats

• The incidence of SARS-CoV-2 infection was relatively low though rising during the study period (14-day incidence < 150 cases/100,000 inhabitants by November)

• Unclear how the 13/14 index cases were chosen from much larger group

• Article is not consistent re number of index cases (13 or 14)/contact tracing groups (13)

• 393 contacts were identified with 292 (c75%) consenting to participate in the study

Woolworth, KRTong, VTMMWR Morb Mortal Wkly Rep 2020Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 202006 Nov 2020USANorth America4527Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6944e2

This is a large cohort study of pregnant women with SARS-CoV-2 in the USA gathered through the SET-NET notifiable disease network covering multiple jurisdictions across the country. 5,252 pregnant women testing positive for SARS-CoV-2 were reported on.

Among the 3,912 infants with known gestational age born to women with SARS-CoV-2 infection, 12.9% were preterm (<37 weeks), higher than a US national estimate of 10.2%. The authors state that the data is preliminary and describe primarily women with second and third trimester infection, and their findings are subject to change pending completion of pregnancy for all women in the cohort and enhanced efforts to improve reporting of gestational age. This finding is consistent with other CDC reports describing higher proportions of preterm births among women hospitalized at the time of SARS-CoV-2 infection and includes outcomes for women hospitalized as well as those not hospitalized at the time of infection (representing a population including persons with less severe illness). Studies comparing pregnant women with and without COVID-19 are needed to assess the actual risk of preterm birth.

Non-Hispanic Black and Hispanic women were disproportionally represented in this surveillance cohort. Racial and ethnic disparities exist for maternal morbidity, mortality, and adverse birth outcomes and the higher incidence and increased severity of COVID-19 among women. This means national rates of preterm birth might not be directly comparable.

Further surveillance efforts, including reporting by additional jurisdictions to improve representativeness, and careful analysis of outcomes by race and ethnicity, will permit more direct and targeted public health action.

Information regarding the frequency and severity of perinatal (potentially including in utero, peripartum, and postnatal) infection is lacking. The American Academy of Paediatrics and CDC recommend testing all infants born to mothers with suspected or confirmed COVID-19 however, testing results were infrequently reported in this cohort.

Perinatal infection was uncommon, affecting only 16/610 (2.6%) infants known to have been tested for SARS-CoV-2 and occurred primarily among infants born to women with infection within 1 week of delivery.

Among the infants with positive test results, one half were born preterm, which might reflect higher rates of screening in the ICU. These findings also support the growing evidence that although severe COVID-19 does occur in neonates the majority of term neonates experience asymptomatic infection or mild disease, however, information on long term outcomes among exposed infants is unknown

Sisk, BOlson, LPediatricsNational Trends of Cases of COVID-19 in Children Based on US State Health Department Data06 Dec 2020United States of AmericaNorth America549432Epidemiology - Transmissionhttps://doi.org/10.1542/peds.2020-027425

Background: There has been a discrepancy in the data from the US on the proportion of cases of COVID-19 affecting children when comparing reports from the beginning of the pandemic with more recent reports. This report was from the American Association of Paediatrics and the Children’s Hospital Association in the US.

Methods: Data were collected extracted from state health departments publicly available reports on COVID-19 in children: COVID-19 incidence, trends by region, proportion of cases of COVID-19 occurring in children, hospitalization and mortality rate of COVID-19 in children.

The data came from 49 states, 2 urban centres (New York City (NYC) and Washington DC and 2 territory (Puerto Rico and Guam). Geographic regions were based on census categories: Northeast, Midwest, South and West.

Data was gathered from 16th April 2020 to 10th September 2020, pooled to derive national and regional information.

There were inter states differences in the use and reporting of viral tests.

Results: There was variation in the type of data provided among the states. Age distribution was provided by all states with the exception of 1 state which provided it based on 8% of its cases. Hospitalization rates were provided by 24 states and NYC and mortality rates were provided by 42 states and NYC. There were differences in child age range definitions: 0 to 17 years in 14 states and NYC, 0 to 19 years in 29 states and Washington DC, 0 to 14 years in 2 states and 0 to 20 years in 2 states with 1 state changing the definition on the 13th August from 0 to 24 to 0 to 17. Data from this state were not included on the trend analysis.

From 16th April 2020 to 10th September 2020 there were 549432 child COVID_19 cases, 729 per 100000 children.

Trends in overall number of cases reported per week in each of the 4 regions. There was marked variation in case growth per region:

Midwest: cases grew progressively during this period, peaking in September.

Northeast: although in April this region reported more cases than others, numbers decreased, and number of cases remained the lowest of the 4 regions.

South: Cases increases exponentially, reaching the highest number of cases per week of all 4 regions, peaking at the end of July but remaining high during the subsequent months.

West: Similar pattern of increase as in the South but with a smaller peek in late July, gradually dropping thereafter.

Trend in percentage of overall cases occurring in children:

The percentage of new cases per week occurring in children: this increased from 2.6% in April to 15.9% by the end of data collection in September. By mid-June, it had increased to 12.7%. There was a slight decrease during early July to around 10%, steadying at around 12% till mid-August when the percentage started increasing more rapidly again reaching 15.9% by September 10th.

The cumulative percentage of cases of COVID-19 occurring in children: this increased steadily from 2.2% in the latter part of April to 10% by September 10th. This is below the children’s share of the US population which is 22.6%.

Hospitalization: children made up a cumulative total of 1.7% of the total number of hospitalizations because of COVID-19. Approximately 2% of child cases resulted in hospital admission.

Mortality: Children made up 0.07% if total death because of COVID-19. 0.01% if child cases resulted in death.

The rate of hospitalizations and of mortality have remained stable across the study period.

Authors’ conclusions:

The data confirms that although children can contract COVID-19, severe disease is uncommon. The geographical profile of growth in cases, moving from the North East in April to the South and West in June and to the Midwest in July follow the pattern of the general population.

Comments: The strength of this report lies in its large data base derived from almost the whole of the US. However, there are a number of observations that are necessary:

Trends of cases in the 4 regions: the cases per week are not related to a population denominator and therefore it is not possible to comment on the overall burden of disease in each region. Nor are any adult data given for comparison. However, the most striking feature when comparing the epidemic curves in each of the 4 regions is that there were markedly fewer cases in the Northeast throughout the period of observation, with new cases remaining under 3000/week, whereas in the other 3 regions the cases increased exponentially to approximately 13,000/week in the Midwest, 15,000/week in the West and 22,0000/week in the South. The cases peaked in July in the South and West but were still increasing in September in the Midwest. There is no further information nor discussion as to possible explanations behind the very different pattern seen in the Northeast: is it due to lack of testing or to the implementation of social distancing and other non-pharmacological measures in this region to slow transmission? It is difficult to know how much of the epidemic curves are explained by increasing testing rates.

Percentage of children affected: the increase in the percentage of children affected might be due to either a true increase in transmissibility among children but is more likely to be due to either increasing testing in children relative to testing in adults as the months went on or that the infection rate in older adults was brought under control but community transmission among younger people and children continued.

There were variations between states as to age definitions and unfortunately there was no breakdown of the data into age groups, for example pre-school and school age children which might have yielded important information on transmission.

Grijalva, CTalbot, HMorb Mortal Wkly Rep.Transmission of SARS-COV-2 Infections in Households — Tennessee and Wisconsin, April–September 2020. 06 11 2020USANorth America14Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6944e1

In this prospective study of SARS-CoV-2 transmission, patients with laboratory SARS-CoV-2 infection and their household members were enrolled and followed for 14-days with a symptom diary and daily RT-PCR testing of self-collected nasal and saliva swabs. Households were recruited from Nashville, Tennessee and Marshfield, Wisconsin from April-September 2020. The index case was defined as the first household member to develop COVID-19 compatible symptoms with a positive RT-PCR result. Specimens collected in the first 7 days from enrolment were analysed for this report.

Results: A total of 101 households were enrolled and completed at least 7 days follow up: 101 index cases and 191 household members. The majority of index cases were young adults (65% aged 18-49yo) with a small number of child (5% aged <12yo) and adolescent (9% aged 12-17yo) index cases. Enrolment occurred a median of 4 days (IQR 2-4 days) after illness onset in the index case.

Among household members 102/191 had SARS-CoV-2 detected from a nasal or saliva specimen giving a secondary attack rate of 53% (95% CI = 46%-60%). For the small number of index cases <18yo, secondary attack rate was 53% (95% CI = 31%-74%) for children <12yo and 38% (95% CI 23%-56%) for those aged 12-17yo. One third (33%) of secondary cases remained asymptomatic through 7 days of follow up. Excluding 54 household members who were SARS-CoV-2 positive at enrolment (and therefore may have been infected at the same time as the index case from a shared exposure) the secondary attack rate was 35% (95% CI 23-56%).

Interpretation: The secondary attack rate reported here is higher than in a number of previous reports, possibly owing to the regular testing of household contacts detecting a higher proportion of asymptomatic secondary infections. In addition, many previous reports are from studies conducted in Asia, were prompt quarantine of all household members of an index cases are implemented, often in dedicated facilities or hospitals. Prolonged exposure would be expected to increase the SAR, as would the potential for 3rd generation infections (becoming infected from a different household member who became infected from the index case).

Similar to previous contact tracing studies, the small number of paediatric index cases limits the ability to draw conclusions about the overall contribution of children to SARS-CoV-2 transmission from this data. Furthermore, in the large proportion of household members who had detectable infection at the time of enrolment, determining direction of transmission is not possible as the potential for shared exposure of the index and secondary cases remains.

Notwithstanding limitations, the high secondary attack rate, and the proportion of asymptomatic cases reported here highlight the importance of mitigation measures within households as well as the isolation of all patients with SARS-CoV-2 and prompt quarantine and testing of close contacts to limit onward transmission.

Ng, KKassiotis, GSciencePreexisting and de novo humoral immunity to SARS-CoV-2 in humans06 11 2020UKEurope48Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/11/05/science.abe1107

It has been hypothesised that pre-existing immunity from previous seasonal "common cold" human coronavirus (HCoV) infection may provide individuals with some protection from SARS-CoV-2. In theory, cross-reactive antibodies may account for some of the variation in clinical severity within populations, including the relatively mild course of disease amongst children. In this paper from the UK, serum samples from uninfected adults and children were examined for cross-reactive antibodies to SARS-CoV-2 using a flow-cytometry-based assay. The presence, level, and target(s) of cross-reactive antibodies were assessed along with the ability of the antibodies to neutralise the virus in the laboratory.

Of initial samples from 302 uninfected adults, 5.3% (n=16) had detectable IgG to SARS-CoV-2. These antibodies cross-reacted with the S2 subunit SARS-CoV-2 spike protein (S2 is relatively conserved among coronaviruses compared with the S1 subunit) but not the receptor-binding domain (RBD) which is key in allowing binding to cells to facilitate infection. The level of SARS-CoV-2 cross-reactive antibodies correlated with the level of HCoV IgG and IgA in uninfected individuals, supporting a link between previous HCoV infection and cross-protection. Notably, cross-reactive antibodies were found in individuals both with and without evidence of recent HCoV infection, suggesting that other factors such as frequency of HCoV infection may be important for SARS-CoV-2 cross-protection.

Remarkably, 43.8% (21/48) of SARS-CoV-2 uninfected children (1-16yo) had SARS-CoV-2 cross reactive antibodies (IgG), compared with 2.3% (1/43) of young adults (17-25yo). Amongst children 6-16yo, almost two thirds (62%) had detectable cross-reactive antibodies. This observation is in keeping with the known age distribution of HCoV infection frequency which peaks in children and adolescents. Importantly, sera containing cross-reactive antibodies from uninfected patients demonstrated the ability to neutralise the virus in vitro, preventing viral entry into cells.

This interesting data support the hypothesis that pre-existing cross-reactive antibodies from previous HCoV infection are present in some individuals and may protect against COVID-19. The degree and duration of individual protection conferred by pre-existing cross-reactive antibodies along with any impact on onward transmission of SARS-CoV-2 remain uncertain. The higher prevalence of these pre-existing antibodies in children and adolescents may be an important factor in explaining the milder course of SARS-CoV-2 infection in this age group.

Ludvigsson, JNordenhall, CN Engl J MedOpen Schools, Covid-19, and Child and Teacher Morbidity in Sweden06 01 2021SwedenEurope15Epidemiology - Transmissionhttps://www.nejm.org/doi/full/10.1056/NEJMc2026670

This research letter presents Swedish data on severe COVID-19 in children and schoolteachers from March 1st and June 30th, 2020. Preschools (for children aged 1 to 6 years old) and schools (children 7 to 16 years old) in Sweden remained open throughout the study period; social distancing was encouraged, but wearing facemasks was not. Patients with severe COVID-19, defined as laboratory or clinically confirmed SARS-CoV-2 infection requiring ICU admission, were identified from a national intensive care registry and the Public Health Agency of Sweden.

A total of 15 children were admitted to ICU with COVID-19 during the study period (0.77 per 100,000 children); no child with COVID-19 died. For teachers, the relative risk of requiring ICU care with COVID-19 was not higher compared with the general population (excluding health care workers): sex- and age-adjusted relative risk 1.10 (95% C.I. 0.49-2.49) for pre-school teachers (total 10 admitted to ICU) and 0.43 (95% C.I. 0.28-0.68) for schoolteachers (total 20 admitted to ICU).

This report is consistent with data from other countries indicating children are at very low risk of severe COVID-19. The observation of low incidence of severe paediatric COVID-19, despite schools remaining open aligns with a growing body of evidence that transmission between children in schools is not a major driver of SARS-CoV-2 spread. The lack of an increased risk of severe COVID-19 in schoolteachers is reassuring, again consistent with data elsewhere that risk of in-school transmission of SARS-CoV-2 from children to teachers is low when age (the predominant risk factor) and sex are adjusted for. A notable caveat is that during most of the study period, testing criteria were restricted to the most severe cases only. Therefore it is highly likely that a significant number of non-severe infections went undocumented.

Jiehao CaiMei ZengVirologica Sinica Comparison of Clinical and Epidemiological Characteristics of Asymptomatic and Symptomatic SARS-CoV-2 Infection in Children04 Nov 2020ChinaAsia49Epidemiology - Transmissionhttps://doi.org/10.1007/s12250-020-00312-4

Chinese researchers are ahead of the rest of the world in Covid-19 research, not just because the pandemic struck them first, but also because they immediately set about detailed and systematic investigation of their cases. This important paper gives extensive data on all 49 children with SARS-CoV-2 infection confirmed by RT-PCR in Shanghai between 19th January and 30th April 2020. Of these 21 (43%) were asymptomatic. 38 (78%) were imported from outside China (mostly from Europe and the US), and their policy of screening all new arrivals might explain this high proportion. There will have been many more domestic asymptomatic cases that were never detected, so this is not an estimate of population prevalence. None of the asymptomatic cases subsequently became symptomatic. 43% had had contact with confirmed or suspected Covid-19 cases, mostly household.

All these children (mean age 11.5 +/-5.1 years) were admitted to hospital, even if asymptomatic, until two nasopharyngeal PCR swabs were negative 24 hours apart. They were then followed up for 2 weeks. None became seriously ill. The most common symptoms, as expected, were cough (43%) and fever (33%), which was mostly < 39˚C and lasted a mean 2.5 days; but significant numbers had sore throat (16%) and rhinorrhoea (14%). 40/49 underwent chest CT scanning and/or chest X-ray, including, controversially, some of the asymptomatic children. Lung lesions – ground-glass opacities and patchy infiltrates - were found in 20 of these, including 5 who had no symptoms. Only 1 progressed to clinical pneumonia, treated with Azithromycin. Blood tests were largely unremarkable: most had normal cell counts and CRP levels.

They also did sequential IgG and IgM SARS-CoV-2 specific antibody tests: 28% of the symptomatic children had positive antibodies at diagnosis, rising to 36% after 14 days. By contrast, 67% of the asymptomatic group were antibody positive at diagnosis, perhaps because they had unknowingly had the infection for longer.

An important epidemiological observation was viral shedding: nasopharyngeal swabs remained PCR positive for around 14 days, with little difference between the symptomatic and asymptomatic groups. They also tested stool sequentially for viral RNA: surprisingly, this remained PCR positive for much longer: mean 31 (+/- 19) days in those with symptoms, and 28 (+/-13) days in those without. None had diarrhoea at any stage.

The public health implications of this are significant: asymptomatic children remain PCR- positive just as long as those with symptoms. Also, we do not yet know to what extent faecal-oral transmission might occur. In the meantime we should be encouraging good toilet hygiene for all.

Bi, QAzman, AmedrxivHousehold Transmission of SARS-COV-2: Insights from a Population-based Serological Survey04 11 2020SwitzerlandEurope626Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.04.20225573v1

This study is a pre-print and so should be interpreted with caution whilst awaiting peer review.

In this household-based population study from Geneva, Switzerland, serosurvey, symptom and contact data were applied to transmission models to determine risk of transmission of SARS-CoV-2 within and from outside of households as well as risk factors for transmission. Participants were recruited as part of the SEROCoV-POP study between April 3rd and June 30th 2020.

Serological testing for anti-SARS-CoV-2 IgG antibodies was performed in each participant. Self-reported data on demographics, household composition, symptoms consistent with SARS-CoV-2 and frequency of extra-household contacts was collected. Chain binomial transmission models were used to determine the probability of extra-household infection and the probability of being infected from a single infected household member.

Of 10,587 invited participants, 4543 members of 2627 households were able to provide complete data for all household members including a blood sample. Median house size was 2 (IQR 1-2), median age was 53 (IQR 34-65). Overall seroprevalence was 6.6%; seroprevalence was lower in young children 5-9y.o. (4.8%), and children 10-19y.o. (6.8%) compared with young adults 20-49y.o. (9.1%).

The probability of being infected by a single infected household member was 17.2% overall. Risk was lowest among young children 5-9y.o. at 7.5% (95% CI 1.3%-20.3%) and highest amongst those >65y.o. at 30.2% (95% CI 14.3-48.2%). Risk of being infected by a household member was similar in those aged 10-19y.o. (16%) compared with those aged 20-49y.o. and 50-64y.o. respectively (17%) Risk of infection from extra-household exposures was 5.1% overall, highest in adults 20-49y.o. (7.4%). Notably, schools were closed locally throughout the study period.

Symptoms consistent with COVID-19 (fever, cough, shortness of breath, or loss of smell or taste) were reported in 70.6% of seropositive participants overall; only 37.5% of seropositive young children (3/8) reported symptoms. Asymptomatic seropositive individuals had significantly lower odds of infecting another household member compared with symptomatic individuals (OR 0.25, 95% CI 0.10-0.56).

The household attack rate reported here falls within the range reported in previous household contact tracing studies. The lower susceptibility of young children is also consistent with previous data from epidemiological studies. Of note those in the broad age bracket 10-19y.o. had similar susceptibility to adults. Importantly, these data suggest asymptomatic individuals are significantly less likely to transmit SARS-CoV-2 within households. Whilst age of the index case did not appear to impact infectivity in this model, the relative lack of symptoms in children could possibly translate to a lower risk of onward transmission from paediatric cases. Limitations include direction of transmission being inferred from modelling rather than detailed case ascertainment and contact tracing.

Forbes, HTomlinson, LmedRxivAssociation between living with children and outcomes from COVID-19: an OpenSAFELY cohort study of 12 million adults in England02 Nov 2020EnglandEurope5738498Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.11.01.20222315v1

Study Question: Does living with children alter the risk in adults of SARS-CoV-2 infection and its outcome compared to not living with children?

Background: this study addresses the issue of the role of children in the transmission of SARS-CoV-2.

Methods: This was a large, population-based cohort study involving 40% of the population in England. The exposure was children in the household, classified into 3 subgroups: no children under 18 years in household, any child aged 0 to 11 years in the household and no children in the 0 – 11 age group in the household but at least one or more children aged 12 to 18 years in the household.

There were 5 Outcomes:

1. Evidence of SARS-CoV-2 infection recorded in primary care defined as a code indicating either a clinical diagnosis a positive swab test or sequelae from COVID-19

2. Hospital admission with ICD-10 code indicating COVID-19 in primary diagnosis field

3. ICU admission with COVID-19

4. COVID-19 related death

5. Post hoc non-COVID-19 death from death certificate

This study was done through OpenSAFELY, a data analytics platform created on behalf of NHS England to address urgent COVID-19 research questions. It links the Primary Care records of 24 million people (40% of England’s population) currently registered with GP surgeries which use The Phoenix Partnership (TPP) SystmOne software. The records are linked to Secondary Uses Service (SUS) hospital admissions, to Intensive Care National Audit & Research Centre (ICNARC) COVID-19-related Intensive Care Unit (ICU) admissions and to the Office for National Statistics (ONS) mortality records. The study population included all adults aged ≥18 years, registered and active for three months, in an English TPP general practice on 1st February 2020.

Multivariate Cox regression Hazard Ratios (HRs) were obtained from data from 1st Feb to 3rd Aug 2020 for each of the 5 outcomes, comparing adults living with and without children in the household, allowing for clustering, stratifying by geographic area to allow for regional variation in infection rates. HRs were adjusted for: age, sex, ethnicity, number adults in household, IMD, BMI, smoking, hypertension or high blood pressure, chronic respiratory disease, asthma, cancer, chronic liver disease, stroke or dementia, other neurological disease, reduced kidney function, end-stage renal disease, solid organ transplant, asplenia, rheumatoid, lupus or psoriasis, other immunosuppressive condition.

Results: there were 9,157,814 adults aged ≤65 years and 2,567,671 aged >65y (after exclusions of households with less than 3 months at the GP practice, households without ID, households with more than 10 people and care homes, households missing basic demographics (age, sex, ethnicity)).

Number of children under 18 years: 5738498

28% of ≤65s lived with children under 11y and 9% lived with children aged 12-18 years.

2.3% of >65s lived with children under 11y and 1.1% lived with children aged 12-18 years

Risk in adults aged ≤65 years:

a) who live with children aged 0 to 11 years:

There was no association with increased risk of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission. There was a reduction in the risk of dying from COVID-19 (HR 0.75, 95%CI 0.62 – 0.92).

b) who live with children aged 12 to 18 years:

There was a small increase in recorded infection (HR 1.08, 95%CI 1.03-1.13), but no association with hospital, ICU admission or death from COVID-19.Risk in adults aged >65 years:

a) who live with children aged 0 to 11 years:

There was no evidence of association with any outcome.

b) who live with children aged 12 to 18 years:

There was no evidence of association with any outcome.

Living with children of any age was associated with a lower risk of dying from non-COVID-19 causes in the ≤65 years but no association was seen in the >65 group.

Extensive sensitivity analyses which included for example, assumptions on the distribution of high- risk occupations, didn’t materially altered the results from the comorbidity adjusted models, although there were higher recorded infections in the period three weeks after school closures. However, there was no increased risk for any of the other outcomes. There was no evidence of a “dose-response” related to the number of children in the household.

Interpretation: the data shows that at a population level, transmission from school age children does not result in an increased risk of serious outcomes from COVID-19 among the adults they live with. Crucially, this study found no evidence of severe outcomes of COVID-19 comparing periods before and after school closures.

Comments: this is a carefully conducted, large scale population-based study. It is powered enough to look at several outcomes and has taken into account many potential confounders as well as looking for important interactions.

Hurst, JKelly, MJPIDSSARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study03 Nov 2020USANorth America382Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1693/5952826

In this prospective clinical and epidemiological study from Duke University Health System (DUHS), USA, risk factors, clinical manifestations and nasopharyngeal viral loads of a cohort of non-hospitalised children (<21 years old) with confirmed SARS-CoV-2 infection were documented. Cases were identified between April 7th and July 16th either through clinical presentation to DUHS or contact tracing of children with close contact with a confirmed case.

A total of 382 children were included; median age 9.7 years (IQR 4.8-15.9; 81% were of hispanic ethnicity. The majority (286/382 - 75%) received clinical testing for SARS-CoV-2 infection, whilst the remainder were tested specifically as part of the study. Overall 57% had a parent with SARS-CoV-2, 25% a sibling and 27% an "other" contact. 

In total 293 (77%) had confirmed SARS-CoV-2 infection. Infected children were more likely to be of Hispanic ethnicity (88% vs 57%) and have a co-infected sibling (49% vs 29%) than non-infected children. Asthma was less common amongst SARS-CoV-2 infected children (6% vs 17%). Of children with an infected sibling 46/145 (32%) did not have an identified adult close contact with SARS-CoV-2; median age amongst these 46 children was 12 (IQR 8.2-16.2).

The most common symptoms were fever (42%), cough (34%) and headache (26%). Asymptomatic cases accounted for 30% of confirmed infections; with a higher proportion asymptomatic amongst those 6-13 y.o. (39%), compared to 0-5 y.o. (25%) and 14-20 y.o. (24%). Children 0-5 y.o. and those 6-13 y.o. had significantly shorter duration of illness compared to adolescents (median 4 vs 7 days). Only one infant required hospitalisation. SARS-CoV-2 virals loads did not vary between age groups and there was no association between viral load and presence of symptoms. Viral loads were highest in the 3 days prior to symptom onset and declined thereafter.

This study represents one of the largest clinical and epidemiological studies of non-hospitalised children with SARS-CoV-2 infection. The findings of mild illness children with SARS-CoV-2 infection here is similar to previous reports. In addition this data suggest a shorter duration of illness in children 0-13 y.o. compared with older children. Secondary attack rates could not be calculated as case identification was not exclusively by prospective contact tracing. Furthermore, it was not possible to determine direction of transmission within households, although some cases of sibling to sibling transmission amongst the 46 cases without a close adult contact is plausible; notably these children were older compared to the overall study population. Similar to adult data, viral load was found to peak in the pre-symptomatic phase

Dugas MSchmidt HIJIDAssociation of contact to small children with a mild course of COVID-1901 Nov 2020GermanyEurope00000Epidemiology - Transmissionhttps://doi.org/10.1016/j.ijid.2020.09.003

We don’t yet know why children appear to suffer Covid-19 less severely than adults. One interesting theory is that they have transient cross-reactive immunity from prior frequent exposure to non-Covid coronaviruses, which cause only minor respiratory infections. If so, one would expect adults who have close contact with young children and hence exposure to similar viruses to likewise have enhanced immunity to Covid-19.

This small study from Germany investigated this by questioning about 4000 adults who had recovered from confirmed Covid-19. Some were recruits from a plasma-donation trial, others were ICU survivors. Of the 1186 who responded, about 7% had jobs that involved daily close child contact (e.g. nursery and primary teachers and paediatricians), and 23% had their own children under 10 years. Most of the cohort had had only mild Covid symptoms, and the authors considered that those with child contact in this group were over-represented compared to the German population, suggesting that child contact was protective against severe symptoms. By contrast those who had no child contact were more likely to have received intensive care than those who had (40% of in-patients vs 16%, p=0.056).

This study should not be over-interpreted: it could be biased because of low response rate, lack of objective confirmation and small numbers. However it might prompt future prospective studies, with full immunology data and adequate numbers, possibly using vaccine trial volunteers.

Okarska-Napierała, MKuchar, EEmerg Infect Dis SARS-CoV-2 Cluster in Nursery, Poland01 Oct 2020PolandEurope8Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/27/1/20-3849_article

This research letter from Poland describes an outbreak of Covid-19 in a nursery in June 2020. The presumed index case was a 52 year old symptomatic worker who contracted Covid-19 from a symptomatic family member. Subsequently 4 other workers at the nursery tested positive one of whom was symptomatic. 8 children at the nursery tested positive though none had symptoms and a total of 11 relatives of nursery children tested positive all of whom were asymptomatic. During the time of the outbreak a mean of 25 children attended daily. At the time, the national prevalence rate of Covid-19 was 1% compared to 27% in the nursery cluster. The authors felt the national rate was too low to account for the nursery outbreak and that children were effective mediators of transmission to adults. This episode confirms the potential for transmission to adults via young children, and is consistent with other outbreaks in childcare/educational facilities which have predominantly been sparked by an adult index case.

Gilliam, WOmer, SPediatricsCOVID-19 Transmission in US Child Care Programs01 Oct 2020United statesNorth America0Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/pediatrics/early/2020/10/16/peds.2020-031971.full.pdf

This is a study from the US to compare Covid 19 outcomes in child care providers who continued to provide childcare during the first three months of the pandemic versus those who did not, to assess levels of transmission of Covid 19 in childcare facilities.

Methods : A multi-state canvas of US child care workers was conducted from May 22 to June 8 2020 via a Qualtrix online survey. Participants were canvassed mainly through two large national child care organisations as well as child care workforce registries. Three rounds of reminders were sent and offer of entry into a raffle on completion of survey was given to incentivise responses.

Inclusion criteria, was those who self-identified as a childcare worker, who was working in direct contact with children pre pandemic, and could provide data on Covid 19 outcome and childcare exposure. Covid 19 outcome was determined by i. a positive Covid 19 test, or ii. hospitalisation with covid 19. Information on confounders, such as geographical location, and Covid mitigation measures used were also recorded.

Results : The link was accessed by 94,390 individual’s self-identifying as a child care worker across 28 states in the US. 82,741 individuals consented to take part in the study and 57,335 (69.3%) chose to participate by providing enough detail on childcare exposure and COvid 19 outcome.

51.4% of respondents reported that their facility had closed and was still closed at time of survey.

Respondents reported that child care facilities that remained open had smaller group sizes, considerable infection mitigation efforts were in place, and the 81.1% of children served were <6 years old.

Results indicated no association between COVID-19 outcome and exposure to child care (odds ratio [OR], 1.06; 95% CI, 0.82 to 1.38; P = 0.66). in further analysis Covid 19 was associated with high level of community infection, with race and ethnicity, and with being a home based child care provider rather than at a facility.

Conclusions : Overall, this study did not provide evidence that child care was a significant contributor to COVID-19 transmission to adults. Rates were higher among those who identified as American Indian/Alaskan Native, African American/Black, or Latinx, as well as those working in counties with high COVID-19 death rate.

Authors caution that these results should be interpreted within the context of community transmission rates, mitigation practices within child care programs, and that this was primarily in children under 6 years of age.

Wada, KShobugawa, YBMJ Paed OpenInfection and transmission of COVID-19 among students and teachers in schools in Japan after the reopening in June 2020.29 Sep 2020JapanAsia168Epidemiology - Transmissionhttps://bmjpaedsopen.bmj.com/content/4/1/e000854

This article (published on 29th September 2020) reports confirmed COVID-19 cases among students and teachers in elementary schools (ages 6-12 years) and junior high schools (ages 13-15 years) in Japan from 1st June to 31st July 2020.

Background: Elementary and junior high schools in Japan began closing on 2nd March 2020 as a result of the COVID-19 pandemic and remained closed until the end of May 2020. They reopened on 1st June 2020 with infection control guidelines in place, including physical distancing, face masks and hand washing. There were restrictions on attending school if a household member had symptoms of COVID-19 and for positive cases until non-infectious. Where judged necessary depending on numbers of positive cases in particular schools, affected classes, year groups or schools were closed for a few days to disinfect classrooms and monitor symptoms in students and teachers. Additionally, teachers were asked to avoid high-risk settings outside school. These guidelines were developed by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), which also requested all schools and governing boards of education to report cases of COVID-19 in students and teachers to local public health centres, which conducted active surveillance to identify and trace close contacts and to assess routes of transmission. This study reports on confirmed COVID-19 cases in all elementary and junior high schools for a two month period from 1st June 2020, when schools reopened, to 31st July 2020, when the summer holidays began. During the study period the Japanese government reported 19,115 confirmed cases of COVID-19 in Japan.

Numbers of schools, students and teachers involved in this study: 2019 data for the schools covered in this study: 19,738 elementary schools in Japan (ages 6-12 years) with 6,368,550 students and 421,935 teachers; 10,222 junior high schools in Japan (ages 13-15 years) with 3,218,137 students and 246,825 teachers.

Cases of COVID-19 reported in schools from 1st June to 31st July 2020: Elementary schools: 105 student cases, 29 teacher cases. Junior high schools: 63 student cases, 10 teacher cases. Combined: 168 student cases, 39 teacher cases. Total 207 confirmed cases in both students and teachers in both types of school covering ages 6-15 years during this 2 month period. There were no reported deaths in students or teachers. [NB Data supplied from table in article, rather than text.]

Routes of possible transmission for student cases as assessed by local public health centres: Positive cases in elementary schools resulting from transmission in households 75/105 (71%), transmission in schools 1/105 (1%), transmission outside households or schools 9/105 (9%), returning from other countries 3/105 (3%), unknown 17/105 (16%). Positive cases in junior high schools resulting from transmission in households 38/63 (60%), transmission in schools 6/63 (10%), transmission outside households or schools 3/63 (5%), returning from other countries 2/63 (3%), unknown 14/63 (22%).

Routes of possible transmission for teacher cases as assessed by local public health centres: Positive cases in elementary schools resulting from transmission in households 5/29 (17%), transmission in schools 0/29, transmission outside households or schools 3/29 (10%), returning from other countries 0/29, unknown 21/29 (72%). Positive cases in junior high schools resulting from transmission in households 1/10 (10%), transmission in schools 0/10, transmission outside households or schools 0/10, returning from other countries 0/10, unknown 9/10 (90%).

Conclusions: During this two month period after schools reopened at the beginning of June 2020 in Japan, the number of reported confirmed cases of COVID-19 in elementary and junior high schools was relatively low in both students and teachers (168 cases in students and 39 cases in teachers). Household transmission was identified by local public health centres as the source of infection for most cases in students (71% of elementary school student cases and 60% of junior high school student cases), with only 1 student case (1%) in elementary schools and 6 student cases (10%) in junior high schools identified as transmitted in schools. The route of transmission was unknown for 16% of elementary school student cases and 22% of junior high school student cases. However, for teacher cases in both types of school the route of transmission was unknown in the majority of cases (72% of elementary school teacher cases and 90% of junior high school teacher cases). The authors speculate that this may be a consequence of teachers being asked to avoid high-risk behaviours such as attendance at social gatherings, which may result in unsuccessful contact tracing if there are negative consequences to disclosure of activities. No teacher cases were identified as having been transmitted in school settings. The authors conclude that efforts to reopen schools safely will continue in order to protect children’s rights to learn and socialise.

Wang, MPang, JFront. Med.Effectiveness of surgical masks in reducing acute respiratory infections in non-lealth care settings: a systematic review and meta-analysis25 Sep 2020SingaporeInternational7448Epidemiology - Transmissionhttps://doi.org/10.3389/fmed.2020.564280
Viner, REggo, RJAMA PediatrSusceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis.25 Sep 2020WorldwideInternational41640Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2771181

This systematic review and meta-analysis (published on 25th September 2020) of 32 studies from 21 countries examines the evidence in published and unpublished literature on susceptibility to and transmission of SARS-CoV-2 among children and adolescents compared to adults. How easily do children and adolescents become infected by SARS-CoV-2 and how infectious are they once infected? Factors influencing the transmission of SARS-CoV-2 in different age groups include the risk of exposure to the virus, probability of being infected on exposure (susceptibility), extent to which symptoms develop once infected, viral load becoming high enough to transmit and then the likelihood of making infectious contact with others (dependent on social contact patterns and behaviour).

Study selection: The authors of this review, who are based in the UK, the Netherlands and Australia, undertook a rapid systematic review of published and preprint literature as well as data from a national public health website reporting government statistics and studies. Included studies were limited to: 1. contact-tracing studies (with systematic follow-up of all contacts to establish secondary attack rates in different age groups) to assess differential susceptibility and 2. population screening studies (identifying infection or prior infection through detection of viral RNA or antibodies) to assess prevalence. These two types of study are likely to be the most informative and least subject to bias when investigating the role of children and adolescents compared to adults in the chain of infection of SARS-CoV-2. Symptom-based studies underestimate SARS-CoV-2 infection in children, because children experience milder illness and have more asymptomatic infection than adults, so studies were required to include data on proven SARS-CoV-2 infection (by PCR or serology) and report in children/adolescents compared with adults either the rate of secondary infections or infection prevalence/seroprevalence. Exclusions included studies of single household/institution outbreaks and hospitalised patients, clinical studies, symptom-based cohorts, modelling studies, clinical contact prevalence studies, residual sera seroprevalence studies, studies of overlapping populations where time periods also overlapped and seroprevalence studies only in children with no adult comparison group.

Data sources: A search of two electronic databases on 16th May 2020, with an update on 28th July 2020, yielded 3,465 studies on PubMed (of which 113 were examined in full and 9 included) and 10,461 studies on the medical preprint server medRxiv (90 examined in full and 7 included). Reference checking and professional contacts identified a further 6 and 10 studies respectively, totalling 32 studies comprising 41,640 children and adolescents and 268,945 adults included in the review.

Total 32 included studies: contact-tracing studies 18/32 (3/32 based in schools), population screening studies 14/32.

Assessment of included studies: Data were extracted (using PRISMA guidelines) on country, study type, study context (social distancing measures/school closures in place), case definition, testing and sampling methods and infection rates in children and adults. The methodological quality of each included study was assessed as high, medium, low or uncertain, using a critical appraisal checklist for prevalence studies plus 2 additional criteria assessing risk of bias (whether symptomatic contacts/individuals were more likely to participate than asymptomatic ones and whether the obtained sample was more than 75% of the intended sample).

Quality of included studies: high 2/32, medium 22/32, low 7/32, uncertain 1/32.

Results from contact-tracing studies (evidence of differential susceptibility): 18 studies from: mainland China (6/18), USA (2/18), Taiwan, Japan, South Korea, Israel, Netherlands, Brunei, India (each 1/18) plus 3/18 based in schools from Australia, Ireland and Singapore.

Secondary attack rates reported in children/adolescents vs adults:

Lower in 11 studies (China, Taiwan, Japan, USA, Israel, Netherlands)

No significant difference in 3 studies (China, Brunei, India)

Higher in those < 19 yrs in 1 study (South Korea)

Lower in younger children but as high/higher in teenagers than adults in 3 studies (South Korea, India, Brunei)

Random-effects meta-analysis of secondary attack rates in children/adolescents vs adults: Data included from 14 studies from China, South Korea, Taiwan, Japan, Israel, India, USA, Brunei, Netherlands; data were combined on children and adolescents < 20 yrs and compared with an adult group  20 yrs.

Pooled odds ratio estimate of secondary infection for children vs adults 0.56 (95% CI, 0.37-0.85) with high heterogeneity (I2 = 94.6%)

Meta-analysis of a subgroup of 7 studies from China, USA, Israel, South Korea using only household contacts (assumed to have a similar exposure to infection from index cases so more likely to reflect relative susceptibility):

Pooled odd ratio estimate of secondary infection for children vs adults 0.41 (household contacts only) (95% CI, 0.22-0.76) (I2 = 91.4%)

Meta-analysis of a subgroup of 8 studies from China, South Korea, Israel, India, USA, Brunei, Netherlands grouped by age of child; ages differed across studies, so children defined < 10-14 yrs, adolescents > 10-12 yrs & < 20 yrs, adults  20 yrs:

Pooled odds ratio estimate of secondary infection (being an infected contact) for:

Children < 10-14 yrs vs adults 0.52 (95% CI, 0.33-0.82), significant difference

Adolescents vs adults 1.23 (95% CI, 0.64-2.36), non-significant difference

3 school-based contact-tracing studies found minimal transmission from child or teacher index cases.

Results from population screening studies (evidence of prevalence): 14 studies from Iceland, Italy, Sweden, England, Spain, Netherlands, Brazil, Iran, Georgia, Switzerland, Japan, Germany. Data from these studies were heterogenous and not suitable for meta-analysis.

4/14 virus prevalence studies (oro/nasopharyngeal PCR testing): 3 national prevalence studies (Iceland and Sweden, undertaken while primary schools open, and Italy undertaken just before lockdown while schools open) showed lower prevalence among children/adolescents than adults. 1 nationally representative survey (England, covering lockdown and subsequent month) showed no significant differences by age.

10/14 seroprevalence studies (antibodies): 3/10 nationally representative, 4/10 regional/municipal, 3/10 post-outbreak. A lower seroprevalence was found in children and in some adolescents compared with adults in studies from Spain, Netherlands, Iran, USA, Switzerland and Japan, but no difference by age in a study from Brazil. 2 post-outbreak studies from Italy and Germany found lower seroprevalence among children/adolescents than adults, the third post-outbreak study (from Germany) found no difference by age.

Separating children < 10 yrs from adolescents 10-19 yrs suggested that seroprevalence of children < 10 yrs was lower than adults, but that seroprevalance of adolescents 10-19 yrs was similar to adults (not formally tested in this review).

Limitations identified by authors: Prevalence of SARS-CoV-2 in a particular age group within a population depends on exposure, susceptibility, proportion of that age group within the population, mixing rates and mitigating interventions, therefore isn’t a direct indicator of susceptibility or transmission. Many study types are underpowered to identify age differences. Studies and study types open to very significant bias were excluded from this review, but only 2 out of 32 studies were identified as high quality and nearly all studies were open to bias. Most studies were from high and middle income countries in Europe and East Asia. The age bands of the studies were not aligned, making direct comparisons challenging. The sensitivity of tests (both PCR and serology) may differ by age and confound findings. Strict control and social distancing measures (eg school/workplace closures, travel restrictions) will affect results of both types of study included in this review; lockdowns decrease contacts outside households, but increase contacts within households, so extrapolating results from these studies to unmitigated environments is problematic. Numbers of nominated and traced children appeared low in some contact-tracing studies. The number of children tested in most of the included population screening studies was low (usually less than the 15-25% of the population under 18 yrs in most countries) and probably reflects lower recruitment of children.

Conclusions: Contact-tracing studies in this review indicated that children have lower susceptibility to SARS-CoV-2 infection than adults, with only one study finding higher odds of infection in those younger than 20 years versus adults, but this was only in 10-19 year olds. Children and adolescents had 44% lower odds of secondary infection compared with adults 20 years and older. Lower susceptibility appeared to be confined to those younger than 10-14 years. Population screening studies mostly indicated lower prevalence and seroprevalence in those younger than 20 years versus adults, with no studies reporting higher prevalence in children and adolescents. Seroprevalence in adolescents appeared similar to adults in all studies. Overall, the preliminary findings indicate that children younger than 10-14 years are less susceptible to SARS-CoV-2 infection than those older than 20 years, while adolescents seem to have similar susceptibility and prevalence rates to adults. The transmission of SARS-CoV-2 is not directly addressed in this review, although there is some weak evidence that children and adolescents play a limited role. Further studies of this type are urgently needed, sufficiently powered across different age groups and including repeated testing over time, in different locations and settings (particularly low income settings) and under different mitigating circumstances.

Otte im Kampe, EHaas, WEuro SurveillSurveillance of COVID-19 school outbreaks, Germany, March to August 202024 Sep 2020GermanyEurope114Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.38.2001645

In this study from Germany, national surveillance data on COVID-19 school outbreaks from 28th January to 31st August 2020 are reported. All primary and secondary schools were closed in Germany from 16th March with gradual re-opening from 20th April for secondary schools and 4th May for primary schools. A range of non-pharmaceutical interventions to limit transmission in schools were employed with decisions on specific interventions made by individual states. Laboratory confirmed cases were identified from the national surveillance system and all school outbreaks with two or more cases were analysed.

Of 8,841 total COVID-19 outbreaks during the period, comprising 61,540 cases, only 48 (0.5%) outbreaks occurred in schools with a total of 216 cases. Almost half of these cases (47.2%) occurred in adults >21 years; 10 of 48 school outbreaks involved only adult cases. There were 114 paediatric cases; 39 in 15-20 year olds, 45 in 11-14 year olds and 30 in 6-10 year olds. Following re-opening of schools an average of 2.2 outbreaks with 4 cases per outbreak were reported nationally. The largest outbreak (20 cases in students aged 13-14) occurred prior to non-pharmaceutical mitigation measures. Notably, at the time of schools re-opening in Germany the incidence of COVID-19 in the general population was low.

These data are reassuring regarding risk of transmission within schools. The number of COVID-19 outbreaks occurring in schools represented a small proportion of the total number of outbreaks and the number of cases per outbreak in schools was small; consistent with limited onward transmission within school classes. Importantly, adults within schools represent a significant proportion of cases linked to outbreaks. Whilst transmission in schools is possible, with non-pharmaceutical measures to mitigate risk of transmission within schools and, importantly, adequate public health capacity to rapidly identify, test and isolate suspected cases and contacts, the impact of school outbreaks of COVID-19 in Germany has been minimal.

This study adds further evidence that schools can be re-opened safely in the setting of low community COVID transmission with appropriate mitigation measures within schools and adequate public health capacity to test, trace and isolate in a timely manner.

Fong, MWWu, PEuro survCOVID-19 cases among school-aged children and school-based measures in Hong Kong, July 2020. 16 Sep 2020Hong KongAsia000000000Epidemiology - Transmission https://doi.org/10.2807/1560-7917.ES.2020.25.37.2001671

This brief report from Hong Kong adds to the evidence of low transmission rates of SARS-CoV-2 in schools. All schools in Hong Kong closed in January 2020 and did not re-open until the end of May. No cases occurred in school-age children until early July, and the schools then closed early for summer on 13 July. By that time twenty COVID-19 cases had been identified, and they studied these in detail. Fifteen were linked to household or community clusters, not school. For the 5 school-acquired cases (all secondary school), and 7 of the 15 non-school-acquired cases, all children in their schools were tested. No other cases were detected. None are known to have acquired the virus since.

They speculate that the reasons for low transmission in their schools compared to elsewhere (e.g. Israel;

www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.29.2001352) may have been their rigorous infection control measures; e.g. daily temperature checks, face-masks at all times, spacing of desks, half-day schooling and staggered arrival and departure times.

Milani, GConstantino, GJAMA Pediatr.Frequency of Children vs Adults Carrying Severe Acute Respiratory Syndrome Coronavirus 2 Asymptomatically14 Sep 2020ItalyEurope83Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2770117

In this retrospective study, frequency of asymptomatic infection with SARS-CoV-2 was compared between adults and children admitted to a hospital in Milan between March 1st to April 30th, 2020. A nasopharyngeal swab was taken from all patients on admission during this period, with repeat sampling at 12-48 hours if initial test was negative. Individuals with any symptoms compatible with SARS-CoV-2 infection or history of recent exposure to SARS-CoV-2 were excluded.

Amongst 83 children and 131 adults included , the most common reasons for admissions were surgical intervention, neurological disease and trauma. 

Asymptomatic children were significantly less likely to test positive for SARS-CoV-2 compared with asymptomatic adults (1.2% vs 9.2%; OR 0.12 (95% CI, 0.02-0.95))

No patients who tested positive progressed to develop symptoms in the subsequent 48 hours.

Although limited by the single-centre retrospective design, the inherent differences between hospitalised adults and children as well as the timing of the study (during school closures), these data go against the hypothesis that children are at higher risk of asymptomatic carriage of SARS-CoV-2 compared with adults, but are limited by the bias of non-random sampling and an unknown wider community prevalence of infection among both children and adults; most serological surveys have demonstrated lower rates of infection in children generally during the first wave of the pandemic.

Lopez, ASTran, CHMMWR Morb Mortal Wkly Rep 69(37): 1319-1323Transmission Dynamics of COVID-19 Outbreaks Associated with Child Care Facilities - Salt Lake City, Utah, April - July 202011 Sep 2020USANorth America110Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6937e3.htm

Outbreaks/transmission occurred in 17 childcare facilities in Salt Lake City, USA, between 01/04-10/07/20, and detailed information is given for 3. 110 children were involved (43 male, 58 male, 9 gender not specified), aged 0.2-16yrs (median 7yrs). 12 paediatric and 10 adult cases occurred in the facilities or in household contacts of confirmed/suspected cases. The index cases in all 3 facilities was an adult staff member. There was evidence of adult-to-adult, adult-to-child, child-to-adult, and child-to-child transmission. The greatest number of cases acquired directly from the adult index case occurred in a facility where adult staff were not required to wear masks.

Ehrhardt, JBrockmann, SEuro SurveillTransmission of SARS-CoV-2 in children aged 0 to 19 years in childcare facilities and schools after their reopening in May 2020, Baden-Württemberg, Germany10 Sep 2020GermanyEurope557Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.36.2001587

Schools and childcare facilities were closed in Germany on 17th March. There was initially very limited reopening for children of emergency workers until between 4th May and 15th June when all school children went back and final full opening of childcare facilities on 29th June. During March there were over 1000 cases/day locally, and this had reduced to <100 when the reopening began.

To try to prevent transmission in schools, all sites reduced capacity by 50%, excluded sick children, cleaned surfaces, ventilated rooms and encouraged hand hygiene and cough etiquette. Some schools asked for mask use outside classrooms and secondary schools asked children to physically distance from each other.

Method: All lab-confirmed cases of SARS-CoV-2 in children 0-19 years between 25th May and 5th August 2020 (I week after school re-opening to 1 week after closure for school summer holidays) in the state of  Baden-Württemberg (population 10.8m). As each case was found, local health officials initiated "thorough contact investigations".

For this study, data on school or childcare attendance whilst presumed infectious (from 2 days before onset of symptoms or, if asymptomatic, from 48hrs before positive test) was collected.

Main Findings: 557 cases of SARS-CoV-2 infection in children aged 0-19 (17.9% of the 3,104 cases of all ages in the state during this time period). Information on school attendance was found for 453 (81.3%) of these. 137 of these children attended school/childcare setting for at least 1 day whilst presumed infectious. Nasopharangeal swabs were taken, 3-5 days after index case identified, from 2,300 close contacts of the index cases and from close contacts of secondary cases. 6 index cases were found to have infected 11 additional pupils (3 in childcare settings, 1 in a primary school, 7 in secondary age education)

Conclusions: This study shows a low rate of transmission: 1 new case per approximately 25 infectious school days (137 infected children in school for, say, 2 days when infectious) which may be even less as the 104 index cases for whom no school attendance data was obtained may have been in school while infectious and contributed to the 11 infections [I'm not sure this latter conclusion is justified] An Irish study had similar findings although a study from Israel reports a large outbreak from an over-crowded school where mask usage had been abandoned due to a heat wave.

The authors note that group sizes will increase as all return to full-time school and advocate strict ventilation of classrooms and wearing of masks in and out of classrooms

Link-Gelles, RBandy, UMMWRSecondary Transmission of SARS-CoV-2 in Child Care Programs — Rhode Island, June 1–July 31, 202028 Aug 2020USANorth America18945Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6934e2.htm

Following the reopening of state childcare programs with enhanced hygiene regulations in Rhode Island, USA, cases were examined for evidence of any transmission in the childcare setting, between 01/06/20-31/07/20. Of the 52 cases who were positive on testing or judged to be ‘probable’ in the absence of a test, 30 were children (median age 5 years) and 22 were adults (20 staff and 2 parents). Cases were found in 29/666 of the reopened programs. 20 had a single case with no evidence of any onward transmission. 5 programs had between 2-5 cases but without evidence of onward transmission. In the remaining 4 programs, onward transmission could not be ruled out. 10 cases occurred in one program which was found not to have been adhering to the enhanced state hygiene regulations.

This review highlights that in an area with relatively low levels of community transmission, basic infection prevention measures were effective and no significant transmission events were observed in childcare settings.

Hao LeiYuelong ShuJ InfectionHousehold transmission of COVID-19-a systematic review and meta-analysis25 Aug 2020chinaEverywhere2500Epidemiology - Transmissionhttps://doi.org/10.1016/j.jinf.2020.08.033

Normally systematic reviews and meta-analyses are done only after research studies have accumulated over a long period of time. However with COVID-19, as in so many ways, the whole process has been accelerated. This brief review attempts to summarise the published evidence around rates of household transmission of the SARS-CoV2 virus from studies conducted in January-March 2020. Their search came up with 24 papers reporting 18 studies from China, 2 from South Korea, 2 from USA and 1 each from Taiwan and Germany. Only one study was prospective: the others were case ascertainment (13), or retrospective cohort studies (10).

The key outcome meta-analysed was the household secondary attack rate (SAR), i.e. the number of identified cases divided by the number of household contacts. They found huge variations in SAR, ranging from 4.6% to 90%. This did not seem to depend on location. This degree of heterogeneity would suggest that the studies were very different in their methods and outcome measures. The pooled SAR was estimated at 27% (95% CI 21-32).

Some studies compared at-home and outside-home contacts, and found consistently, but not surprisingly, that home contacts were much more likely to transmit the virus: about 10 times the risk (OR 10.7; 95% CI 5.7-20.2).

More relevant to paediatricians, from the 8 studies where ages were reported, they found that adults were about 4 times more likely to become infected from household contacts than children (OR 3.7; 95% CI 2.8-4.9).

There is so much data missing from this meta-analysis that any conclusions must be guarded. Case definitions, testing accuracy, confidence that infection was acquired within the home rather than externally, and population demographics, will all have varied. There is also no distinction made between family households, and adult house-sharers: this may be particularly relevant as students return to universities.

Ismail, SLadhani, SmedRxivSARS-CoV-2 infection and transmission in educational settings: cross-sectional analysis of clusters and outbreaks in England24 Aug 2020EnglandEurope70Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.08.21.20178574v1

This article is a preprint so should be interpreted with caution pending peer review This study, posted on medRxiv on 24th August 2020, uses Public Health England national surveillance data about COVID-19-related situations in educational settings across England gathered during the month of June, following the partial re-opening of schools in England from 1st June 2020, with follow-up until 31st July 2020.

Background: Schools across England were closed from 20th March 2020 because of rising COVID-19 cases. Vulnerable children and those with keyworker parents were able to continue attending school throughout the remainder of the spring term and the summer term. As part of gradual easing of lockdown measures, there was a partial re-opening of early years settings and primary schools from 1st June 2020, with children attending early years settings (nurseries and preschools for < 5 yr olds) and selected years in primary schools (reception (age 4-5 yrs), year 1 (age 5-6 yrs) and year 6 (age 10-11yrs)) allowed to return to school with strict infection control measures (including smaller classes separated into social bubbles (groups of staff and pupils who perform all activities together and don’t mix with other bubbles), social distancing and hand hygiene). This was followed on 15th June by the partial return to school of year 10 (age 14-15 yrs) and year 12 (age 16-17 yrs) in secondary schools, sixth forms and further education colleges. Attendance was not mandatory, not all schools re-opened and many eligible children did not return to school during the remainder of the summer term (June to mid-July 2020). In particular, attendance of older children in years 10 and 12 was much lower than in early years settings and primary schools.

Data collection: Public Health England (PHE) is responsible for the surveillance and public health management of COVID-19 in the community in England, including within educational settings. Suspected or confirmed cases of COVID-19 must be reported by institutions to their local PHE Health Protection Team (HPT), which performs a risk assessment for each event and decides on necessary investigations and measures. All events are recorded on HPZone, a national online database used to record health protection-related events requiring public health management, and reviewed daily at a national level. Missing information is obtained from outbreak reports or directly from the local HPT or educational setting. All COVID-19 situations reported to HPTs during the month of June 2020 were followed up for at least 14 days after the educational settings closed for the summer term. Educational settings include nurseries, preschools, infant schools, junior schools, primary schools, secondary schools, further education colleges, and settings catering to children of mixed age groups, or those of any age with special educational needs and/or disabilities (SEND).

Definitions: A case of COVID-19 was confirmed by a verifiable positive SARS-CoV-2 PCR from an upper respiratory tract sample. Cases were classified into 3 types:single confirmed cases, co-primary cases (2 or more confirmed cases with a common epidemiological link who were diagnosed at the same time – often asymptomatic siblings diagnosed during contract tracing after a positive result in a parent), outbreaks (2 or more epidemiologically linked cases where sequential cases were diagnosed within a 14 day period)

Educational settings were categorised into 3 groups: early years, primary schools (reception, year 1 and year 6 only) and secondary schools (years 10 and 12 only).

SARS-CoV-2 infections in educational settings in England: PHE received 170 reports of COVID-19-related events in educational settings in England from 1st to 30th June 2020. Public health investigations identified SARS-CoV-2 infections in only 101/170 (59%) of these events.

Breakdown of these 101 confirmed events:

Single confirmed cases: 67 events/101 (66%) involving 30/67 (45%) children and 37/67 (55%) staff members

Co-primary cases: 4 events/101 (4%) involving 10 children (0 staff)

Confirmed outbreaks: 30 events/101 (30%) involving 121 cases with 30/121 (25%) in children and 91/121 (75%) in staff

Total 198 confirmed cases: 70/198 (35%) in children, 128 (65%) in staff

Single confirmed cases: Occurred mainly in primary schools with 45/67 events (67%) (21 cases in children, 24 cases in staff) and early years settings with 10/67 (15%) (5 cases in children, 5 cases in staff). Secondary schools had 4/67 events (6%) (2 cases in children, 2 cases in staff). Other settings (mixed age groups, SEND, colleges) had 8/67 events (12%) (2 cases in children, 6 cases in staff).

Co-primary cases: In the 4 co-primary events involving 10 children, the co-primary cases lived in the same household. All 10 children were asymptomatic and had been tested because they were household contacts of an index case (a parent in 4/5 households).

Confirmed outbreaks: Primary schools 18/30 events (60%), early years 7/30 (23%), secondary schools 2/30 (7%), SEND schools 3/30 (10%). Affected contact bubbles were excluded in all 30 outbreaks and 13 settings also decided to close on an interim basis or for the rest of term.

Primary school outbreaks: 9/18 (50%) outbreaks involved staff only (affecting 32 people), of which 5/9 events had only 2 confirmed cases. The other 4/9 events had 4, 5, 6 and 7 confirmed cases. In 3 of these latter events the source was not identified, but the outbreak was propagated through contact between administrative and teaching staff in the school. Contact tracing in the final latter event was unusual in that 3/4 positive staff had probably acquired their infections separately from household members with confirmed COVID-19. 7/18 (39%) outbreaks involved staff and students, with a student the most likely index case in 6/7. In 5/7 of these the child index case was identified through testing of the whole household when parents (healthcare workers in 3 cases) had tested positive for SARS-CoV-2. The 7th outbreak involving staff and students was likely staff to pupil. The final 2/18 primary school outbreaks involved possible transmission between 2 children only, although acquisition in the household or community could not be ruled out.

Early years settings outbreaks: A staff member was the index case in all 7/7 (100%) outbreaks. 2/7 outbreaks involved only staff (2 and 12 confirmed cases, the latter following community exposure linked to a religious festival), 5/7 outbreaks involved staff transmission to small groups of children (maximum 4).

Secondary school outbreaks: Only 2 events involving only staff, with 2 confirmed staff cases each.

SEND settings outbreaks: 3 events with 2/3 involving staff only (6 and 2 confirmed staff cases), 1/3 with staff to child transmission (7 staff members positive with 1 child infected, at which point wider testing was carried out).

Source of infection: Single confirmed cases: not systematically collected.

Co-primary events: 10 children acquired infection from a household member.

Confirmed outbreaks: staff-to-staff 15/30 (50%), staff-to-student 7/30 (23%), student-to-staff 6/30 (20%), student-to-student 2/30 (7%). The likely source of infection identified in 27/30 children involved in an outbreak was a household contact in 8/27 (30%), school staff member in 17/27 (63%) and another student in 2/27 (7%). The likely source of infection identified in 61/91 staff members involved in an outbreak was a household contact in 9/61 (15%, these staff members were all likely index cases in the educational setting), 46/61 (75%) from another staff member and 6/61 (10%) from a student.

Number of secondary cases per index case in 30 confirmed outbreaks: For staff members as index case: only 1 secondary case in 11 outbreaks, between 2 and 9 secondary cases in 11 other outbreaks. For child as index case: only 1 secondary case in 5 outbreaks, 2 secondary cases in 3 outbreaks.

Correlation with regional COVID-19 incidence: There was a strong correlation between number of outbreaks in educational settings in June 2020 and regional COVID-19 incidence (0.51 outbreaks for each SARS-CoV-2 infection per 100,000 in the community, p=0.001). There was no correlation between single cases and regional incidence, nor between single cases or outbreaks and regional population size. National daily reports of positive SARS-CoV-2 PCR results collated by PHE for COVID-19 surveillance were used to calculate average weekly regional prevalence of infection.

Limitations identified by authors: Generalisation of these findings need to take into account the fact that educational settings started opening in England when SARS-CoV-2 incidence was low and only in regions with low community transmission. Stringent infection control measures were in place and only 1.6 million of 8.9 million students nationally attended any educational setting during this period. In particular, attendance by secondary school students was very low and these findings are unlikely to be generalisable to the full opening of secondary schools. Only a few settings were selected for wider testing.

Conclusion: SARS-CoV-2 infections and outbreaks were uncommon across all educational settings in England during June 2020. Outbreaks were usually small in size and 53% involved only one secondary case linked to the index case. Where the index case was a child, the maximum number of secondary cases was 2 (compared with 9 for staff members). Staff members had an increased risk of infection compared to students in any educational setting and the majority of cases linked to outbreaks were in staff.

Buonsenso, DSali, MmedRxiv preprintSeroprevalence of anti-SARS-CoV-2 IgG antibodies in children with household exposition to adults with COVID-19: preliminary findings12 Aug 2020ItalyEurope53Epidemiology - Transmissionhttps://doi.org/10.1101/2020.08.10.20169912

This article is a preprint so should be interpreted with caution pending peer review

This is a study of the prevalence of anti-SARS-CoV-2 IgG in children with household exposure to SARS-CoV-2, compared to adults exposed to the same index cases. It is a pre-print of a short report, containing only a summary of the data from an on-going study. The authors state that all data are available upon request.

Analysis; From a cohort of 405 adults diagnosed with COVID-19 as outpatients, 33 were identified as living with children younger than 18 years of age; 30 of these agreed to participate in the study. They had a total of 80 same-household contacts of whom 53 were children and 27 adults.

A total of 44 of the 80 same-household contacts (55%) had anti SARS-CoV-2 IgG. 16/27 (59%) adults and 28/53 (53%) children were seropositive (P > 0.05). Similar relative frequencies of seropositivity where present in children more than 5 years of age (21/39, 54%) and those less than 5 years (7/14, 50%) (P > 0.05).

10/28 children (35.7%) and 5/16 adults (33.3%) adults with anti SARS-CoV-2 IgG had previously been diagnosed with COVID-19.

Conclusions; The authors conclude that household transmission of SARS-CoV-2 is high in both adults and children, with similar rates of SARS-CoV-2 IgG in all age groups, including younger children. They claim that the real burden of the SARS-CoV-2 pandemic in children is underestimated.

Teherani, MJaggi, PJ PEDIAT INF DIS SOCBurden of illness in households with SARS-CoV-2 infected children11 Aug 2020USANorth America32Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa097/5891283?rss=1

In this study from Atlanta, USA, household transmission was assessed in symptomatic children with laboratory-confirmed SARS-CoV-2 infection diagnosed from March 16th to June 14th 2020. 

Household contacts were identified by interviewing the patient's parents including:- the presence, absence and timing of symptoms consistent with COVID-19 in all household members, 

- any other household members with laboratory-confirmed SARS-CoV-2 infection and the likely household index case (the first household member to develop symptoms or test positive)

Of 138 children diagnosed, 32 (23%) families who were contactable and consented to interview were included.

Of the 32 cases:

- median age was 12.7 (IQR 8.3-15.7) - 15 were hospitalised for a median of 3 days (IQR 2-13); 17 were discharged from ED

Of the 144 identified household contacts:- 58 were children, 86 were adults- only 29 (20%) were reported to have had SARS-CoV-2 testing- 67 (46.5%) developed symptoms consistent with COVID-19 including:31 (21.5%) after the identified paediatric case36 (25%) before the identified paediatric case

In 7/32 (22%) the identified paediatric case was determined to be the household index case (the first to develop symptoms) with suspected transmission to one or more adult household contacts. 

This study has several notable limitations including:- the small cohort size and the low response rate to interview. - the reliance on parental recall of symptoms to determine transmission direction- the lack of systemic measurement or reporting of proportion of contacts with laboratory-confirmed SARS-CoV-2 infection - the possibility of exposures outside of the household - over half of adult household contacts identified were essential workers, including 14 households with potential occupational exposure to SARS-CoV-2 identified.

As a result of these limitations it is difficult to draw broad conclusions from this study. It is clear that transmission from children infected with SARS-CoV-2 to others can occur, the frequency of this transmission and the relative contribution to disease transmission overall remains poorly defined. 

Maltezou, HPape, AJ. Med. VirolTransmission dynamics of SARS‐CoV‐2 within families with children in Greece: a study of 23 clusters07 Aug 2020GreeceEurope43Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/10.1002/jmv.26394

A study of Covid-19 transmission dynamics among 23 household clusters in Greece, identified through a national registry. Diagnosis of Covid-19 was made by PCR testing of respiratory samples with viral load classified as low, medium or high.

Study period: 26/02/2020 to 03/05/2020

Participants: 109 household members (66 adults and 43 children).

Results: The median attack rate per cluster was 60% (range: 33.4%‐100%). An adult member with COVID‐19 was the first case in 21 (91.3%) clusters. Transmission of infection occurred from an adult to a child in 19 clusters and/or from an adult to another adult in 12 clusters.

There was no evidence of child‐to‐adult or child‐to‐child transmission.Children were more likely to have an asymptomatic infection compared to adults (40% versus 10.5%, p‐value=0.021). In addition, infected children were significantly more likely than adults to have a low viral load (40.7% versus 18.5%, p‐value=0.016). It is noted in the discussion that five clusters came to attention because an infant was hospitalised, but no children required intensive care.

Limitations: it was unclear how clusters were selected and what the exclusion or inclusion criteria were.

This study adds evidence that children are much lower risk than adults for transmission of Covid-19, consistent with them having a low viral load.

Szablewski, CStewart, RMMWRSARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp — Georgia, June 202007 Aug 2020USANorth America409Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm6931e1

Question: The question addressed by this report is the transmissibility of SARS-CoV-2 among children and young people in a group setting. The background is to what extent opening schools after the summer holidays might contribute to community transmission of COVID-19.

Setting: investigation of an outbreak of COVID-19 at a camp for children and young people in Georgia, USA between 17/06/202 to 27/06/2020

Methodology: Department of Public Health outbreak investigation

Results: From 17th – 20th June staff and trainees held orientation course at camp. On 21st June trainees left, staff stayed, and 3 senior staff and 363 campers arrived at camp. Median age campers = 12 years (range 6 – 19), median age of staff = 17 years (range 14 – 59).

Variety of indoor and outdoor activities including daily vigorous singing and cheering

Risk mitigation measures at the camp: -evidence of negative viral SARS-CoV-2 within 12 days of arriving in staff, trainees and campers.-Cloth masks for staff (but not campers), cabin cohorts of <26 people, staggering cohorts for use of outdoors, physical distancing, cleaning and disinfection.-Not implemented: opening windows and doors for increased ventilation.

Index case: a teenage member of staff who developed COVID symptoms on the evening of 22nd June who left the camp on 23rd June.

Case definition: positive viral SARS-CoV-2 test in any camp attendee (staff, trainee or camper) up to 14 days after leaving the camp.

Measure of transmission: attack rates (numbers with positive test/total number of attendees)

Attack rates: -per age group were: 6 – 10 year = 51/100 = 51%, 11 – 17 = 180/409 = 44%, 18 – 21 = 27/81 = 33%, 22 – 59 = 2/7 = 29%.

-per type of attendee: trainee (17th – 21st June) = 26/134 = 19%, staff (17th – 27th June) = 66/117, camper (21st – 27th June) = 168/346 = 49%

Analysis: Transmission from staff is possible and probable, more so than from children:Having a negative COVID test with 12 days of arriving still allows infection and transmission subsequently, after negative test and date of arrival to the camp.This could have happened to member(s) of staff or campers.

Information was not provided on age composition of cabins but likely mixed.

It is estimated that the earliest transmission can occur is after 48 hours after infection. Index case developed symptoms on the evening of the 22nd, less than 48 hours after campers arrived.

On the 21st June, trainees were leaving as campers were arriving. The attack rate among trainees was 19%. It is unlikely that there was an opportunity for transmission from campers to trainees on that day. There infections are more likely to have arisen from contact with an infected fellow trainee or member of staff sometime between 17th and 20th June before the campers arrived.

The likelihood of transmission depends on the amount of contact and susceptibility. The campers were at the camp between 3 and 6 days. Had a camper brought in COVID with them, he/she would have had to have an extremely high rate of contact with many staff, trainees and campers to explain the high attack rates seen in all groups. In addition, the 6 days window (from the 21st June when the campers arrived to the 27th, is a short time and doesn’t allow for a long chain of transmission to explain the high attack rates seen in all groups. A more likely explanation is that the attack rates are the result of multiple chains of transmission arising from an infected staff or trainee early on.

It is possible that cases may have arisen before camp attendance or acquired after campt attendance, up to 14 days after leaving the camp.

Sources of measurement error: In the calculation of attack rates, the denominator was made up of attendees whose viral test result was not available to DPH on the assumption that not all negative results were consistently reported by the laboratory. It is not known how many people were not tested. The specificity of PCR SARS-CoV-2 averages about 70% allowing for false negatives.

Impression: this is a very interesting report, but the data do not support any definitive statement about the ability of children to transmit SARS-CoV-2. The report shows that children can be infected in large outbreaks given the high attack rates, but it doesn’t answer the question on transmissibility by children.

Kim, JChoi, EArchives of disease in childhoodRole of children in household transmission of COVID-1907 Aug 2020South KoreaAsia107Epidemiology - Transmissionhttps://adc.bmj.com/content/early/2020/08/06/archdischild-2020-319910
MacCartney, KWood, NLancet Child Adolesc Health Transmission of SARS-CoV-2 in Australian educational settings: a prospective cohort study03 Aug 2020AustraliaAsia22Epidemiology - Transmissionhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30251-0/fulltext

In this epidemiological study from New South Wales (NSW), Australia (state population 8.1 million), the transmission of SARS-CoV-2 in schools and early childhood education centres (ECECs) was examined during the first wave of infections between January 25th to April 9th 2020.  Schools and ECECs remained open throughout the study period with distance learning at schools implemented on March 23rd, and physical attendance limited to children children without other care options - leading to a decrease in attendance from 90% to 10% for the last 2 weeks of the study period.

All adult and paediatric laboratory-confirmed cases of SARS-CoV-2 infection in NSW who attended a school or ECEC whilst infectious were identified. Schools were closed temporarily on initial case notification to allow for contact tracing and generally re-opened after 24-48 hours. Close contacts underwent home quarantine for 14 days after last exposure and were instructed to undergo PCR testing if they developed symptoms of infection. Selected educational settings were offered enhanced investigation of contacts which included upper respiratory tract swab for PCR at day 5-10 and serology testing at day 21 regardless of symptoms. 

In total, 27 index cases were identified including 15 adults and 12 children (median age 15 years (IQR 14-16)) - 8 of whom were in high school. A total of 1448 close contacts were identified, including 633 (44%) who underwent PCR or serology testing. Of 18 secondary cases identified, 10 were children and only 2 were due to child to child transmission. Only 1 case of child to adult transmission was identified; 8 cases of adult to child and 7 cases of adult to adult staff transmission occurred. The overall attack rate was 1.2% - 0.3% for child to child contacts, 1.5% for adult staff to child contacts and 4.4% for adult to adult staff contacts. One large cluster occurred in an ECEC facility with a single adult index case in which 6/12 (50%) adult staff and 7/25 (28%) children were infected. 

This data is in keeping with other school contact tracing studies from Ireland and France demonstrating low attack secondary attack rates in children exposed in educational settings. The higher rate of staff to student and staff to staff transmission relative to transmission from a child index case to others is in keeping with other data suggesting "children are unlikely to initiate or propagate outbreaks". Importantly, the authors point out the intensive tracking and contact tracing in this study was only possible in the context of low numbers of case introductions to schools, underpinned by effective control and suppression of community transmission at a statewide level.

This study highlights that schools are able to be kept open safely with effective case identification and contact tracing in the context of an effective epidemic response in the general population. 

Hecht, JRoberts, DMod PatholSARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers 02 Aug 2020USANorth America0Epidemiology - Transmissionhttps://doi.org/10.1038/s41379-020-0639-4

Although SARS-CoV-2 infection in pregnant women has been widely documented in a variety of settings, only a handful of cases of probable vertical transmission from mother to fetus have been reported and in only two of these cases was evidence of infection of the placenta provided. The authors of the study reviewed here have sought to determine whether the apparent low frequency of vertical transmission of SARS-CoV-2 is due to a low rate of placental infection and/or a low rate of viral transmission across the placenta.

In this retrospective study the placentas of nineteen women with evidence of Covid-19 infection were examined. All of the women had tested positive to SARS-CoV-2 using commercial assay RNA testing performed of nasopharyngeal swabs. The swabs were taken at an average of three days prior to delivery and the median gestational ages of the pregnancies was 36 weeks and 4 days (range 22- 41 weeks). An additional “negative test” was also included as a “negative control”; this case seems to have been included in the results of the test-positives. The placentas were subjected to the following investigations: gross and histologic examination; evidence of direct placental SARSCoV-2 expression shown by the presence of viral nucleocapsid, using in situ hybridisation (ISH), or of viral RNA, using immunohistochemistry (IHC); evidence of the expression of the receptor protein, ACE2, and the priming protein, TMPRSS2, using IHC; expression of these proteins is required for SARS-CoV-2 to infect the placenta.

For comparison, there were three control groups of placentas: 10 placentas of mothers who had histories and histopathological evidence of RNA viral infections other than SARS-CoV-2; 130 placentas from pregnancies in which the baby suffered hypoxic ischaemic encephalopathy; 120 “normal” controls.

The main findings were that, although there was evidence of ACE2 expression in the syncitiotrophoblast (ST) and extra-villous trophoblast (EVT) of all test-positive placentas, and in the cytotrophoblast of 14, there was SARS-CoV-2 nucleocapsid in only two placentas and SARS-CoV-2 RNA in two. TMPRSS2 expression was only present weakly in the villous endothelium of ten placentas and rarely in the ST. Of note, there was a polarised pattern of ACE2 expression, highest on the stromal side of the ST; this is relatively distant from the maternal circulation. There were no characteristic findings on gross and histologic examination.

The authors conclude that, although the placenta is capable of being infected by SARS-CoV-2, this is a rare event. They speculate that the explanation for placental infection being infrequent may be a combination of the polarised pattern of ACE2 expression “away from the maternal blood” and the “pronounced paucity” of TMPRSS2 expression in the trophoblast.

Madewell, ZDean, NmedRxi (preprint)Household transmission of SARS-CoV-2: a systematic review and meta-analysis of secondary attack rate01 Aug 2020USA InternationalInternationalEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.07.29.20164590v1

This systematic review examined 40 published studies of household secondary transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The investigators were from the United States. Nineteen of the 40 identified published studies were from China, 5 from South Korea, 4 from the USA, 2 from Spain and one each from Australia, Brazil, Brunei, Germany, India, Israel, Italy, Singapore, Taiwan and the UK. The meta-analysis included all identified publications prior to 29 July 2020.

The secondary attack rate (SAR) for each household or family was calculated as follows: The denominator was the number of exposed contacts, and the numerator was the number who became infected with SARS-CoV-2 or developed COVID- 19. Following meta-analyses, the secondary attack rate (SAR) estimate from all 40 publications was 0.188.

The subgroup secondary attack rate (SAR) estimate from symptomatic index cases to household and family contacts (16 studies) was 0.199 (range 0.039 to 0.446); whereas the subgroup SAR estimate from asymptomatic index cases to household and family contacts (3 studies) was 0.07 (range 0 to 0.054). The analysis also found that household secondary attack rates (SARs) were higher to spouses than other family contacts, and in households with one contact than households with three or more contacts.

The secondary attack rate (SAR) estimate for adult (≥18 years) household and family contacts was 0.310 (range 0.089 to 0.696). The secondary attack rate (SAR) estimate for children (<18 years) household and family contacts was 0.157 (range 0.040 to 0.269) (9 studies).

Stein-Zamir, CMiskin, IEurosurveillanceA large COVID-19 outbreak in a high school 10 days after schools' reopening, Israel, May 202023 Jul 2020IsraelMiddle East1161Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.29.2001352#html_fulltext

This rapid communication (published 23rd July 2020) describes an outbreak of COVID-19 in May 2020 in a public high school in Jerusalem, Israel, shortly after the re-opening of schools after 2 months of mandatory closure.

Background: Israel’s schools were closed by the government on 13th March because of the COVID-19 pandemic and were fully re-opened on 17th May (with a partial re-opening prior to that on 3rd May for kindergartens, grades 1-3 and grades 11-12). Requirements for school re-opening included daily health reports, hygiene, facemasks, social distancing and minimal interaction between classes. The population of Israel is 9.1 million (median age 30 years); the Jerusalem health office serves 1.25 million residents (median age 23.5 years) characterised by moderate to low socioeconomic status and large households.

Outbreak: The school subject to the outbreak was a regional public school with 1,190 students aged 12-18 years (grades 7-12), who travel from suburbs and neighbourhoods by public or school bus, and 162 staff members. The school schedule is 6 days per week for 38-40 hours weekly. The school re-opened after 2 months closure on 18th May: a student case of COVID-19 was notified on 26th May (the source of infection was unknown; at this point close contacts (4 household, 50 students and 14 teachers) were instructed to self-isolate) and then a second student case (in a different grade and epidemiologically unlinked to the first case) was notified on 27th May, at which point the whole school was closed and most of the remaining school community was tested between 28th and 30th May by nasopharyngeal swab PCR for SARS-CoV-2 (26 students and 10 teachers had not attended school since re-opening and were therefore excluded; 1,161/1,164 students and 151/152 teachers were tested) The two initial positive cases attended school 19th to 21st May and reported mild symptoms.

Results of testing: 153/1,161 (13.2%) students (median age 15 yrs for positive cases) and 25/151 (16.6%) staff (median age 40 yrs for positive cases) tested SARS-CoV-2 positive, with males slightly overrepresented in grades 7 to 10 and amongst staff. Gender: 597/1,161 (51%) male of all students tested and 86/597 (14%) of male students positive; 564/1,161 (49%) female and 67/564 (12%) of female students positive; 51/151 (34%) male of all staff tested and 9/25 (36%) of male staff positive; 100/151 (66%) female of all staff tested and 16/100 (16%) of female staff positive. Grades 7-9 (median ages 13-15 yrs) had higher positive rates than grades 10-12 (median ages 16-18 yrs). The age/grade and gender of the two initial cases are not given.

Symptoms reported: The two initial student cases reported mild symptoms (anosmia, ageusia, fever and headache). Questioning of those in the school community with subsequent positive SARS-CoV-2 tests revealed symptoms in 66/153 (43%) of students and 19/25 (76%) of staff. Commonest symptoms reported were cough, headache, fever, sore throat and myalgia. There was one emergency room visit recorded (age of patient not given) and no hospitalisations.

Factors suggested which may have facilitated outbreak: An environmental school inspection reported crowded classes: 35-38 students per class in class areas of 39-49 m2, allowing 1.1-1.3 m2 per student, where distancing between students and between students and teachers was not possible. There was an extreme heatwave from 19th to 21st May during which schoolchildren were exempted from wearing facemasks for 3 days and the school air-conditioning functioned continuously (separate systems for each class). Daily travel time to school approximates to 20-45 minutes on public or school buses. Most students also participate in extracurricular activities such as sports or dance for an average of 2-4 hrs per week. The authors cite the “three C’s” to be avoided to minimise risks of outbreaks: closed spaces with poor ventilation, crowded places and close-contact settings. They reference the European Centre for Disease Prevention and Control’s June 2020 report on air-conditioning and ventilation systems and COVID-19, which recommends increasing air exchange rate and outdoor air use and decreasing air recirculation to reduce spread in indoor spaces.

This study demonstrates the potential for widespread infection with education settings. The chain of transmissions cannot be eludicated from this study. Given the concurrent relaxation of multiple lockdown measures, it is unclear how much transmission occurred within the school and how many cases were imported in following community transmission.

Park, YJeong, KEmerg Infect DisContact tracing during coronavirus disease outbreak, South Korea, 202016 Jul 2020South KoreaAsia153Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-1315_article

And Kim, Choe et al 2020. These papers will be reviewed as a pair, as they analyse the same data but use differing methods, which have altered the conclusions in each.

Both studies utilise data from South Koreas national public health database of COVID-19 cases and contact tracing. They aim to assess the infectiousness of different cohorts, but assessing how many secondary infections result from each “index case” – defined as those who are first determined within a household (or according to symptom chronology). Park et al looks at several different age categories, and compares SAR according to age. Kim at al only looks at children <18yrs

There is one important difference between the two papers. Park et al just analyses the raw numbers to produce a SAR. Park et al take into account that many of the index cases actually shared the same initial exposure as some of their secondary cases, meaning that they most likely both became infected at the same time by the same 3rd party, but as one of them developed symptoms before the other, they were misclassified as an index case. They removed these cases from the analysis.

Park et al found the following household SAR per age brackets; 0-9y 5.3%, 10–19y 18.6%, 20y + between 7% (20-29y) and 18% (70-79y). There was a marked difference in the number of index cases in each age group, with only 29 aged 0-9, and 124 aged 10 – 19 (compared to 1695 aged 20 -29). These results suggest that young children appear to be significantly less infectious than adults, but that children aged 10 – 19 were just as infectious as adults.

Kim et al corrected for shared exposure. Of the 41 secondary infections from the 248 contacts, only 1 did not share the same exposure, giving an SAR of 0.5% for children <18years in this cohort. Using the same methodology, a different paper found an SAR in adults of 7%.

These papers make 2 important points: firstly, they present some evidence that children may be less infectious than adults. The absolute SAR being so extraordinarily low (0.5%) cannot be extrapolated out of this setting, as South Korea uses intensive infection prevention measures in households, including isolating every individual member from each other, and children are cared for by parents wearing full airborne precaution PPE. In addition, correcting for shared exposure will bias the SAR downwards as some of these cases are likely to be true secondary cases. It is however interesting that this appears lower than the SAR for adults using similar methods of analysis.

The next important point is how much care must be taken interpreting these data. When Park et al was published, it made media headlines about older children being just as infectious as adults, and many schools changed their policies on that data. When Kim et al was published a few weeks later, it became clear that this conclusion was not tenable based on the original data, due to the confounding of shared exposures. When so many potential confounders exist, it is very important to take each study with a pinch of salt and interpret it in the context of the evidence which has preceded it.

In conclusions, these studies together provide some evidence towards the theory that children with COVID-19 may be less infectious than adults. More direct data is needed to gain clarification on the infectiousness of children.

Torres, JPO'Ryan, MClin Infect DisSARS-CoV-2 antibody prevalence in blood in a large school community subject to a Covid-19 outbreak: a cross-sectional study10 Jul 2020ChileS America1000Epidemiology - Transmissionhttps://academic.oup.com/cid/article/doi/10.1093/cid/ciaa955/5869860

This cross-sectional study describes in detail the effects of an outbreak of Covid-19 at a school in Santiago, Chile, probably arising from a single adult index case. As well as PCR nasopharyngeal antigen swabs, they followed up with home-administered blood antibody tests in a stratified sample, and asked staff, students and parents about symptoms and contacts. This presented an opportunity to examine the relationship between symptoms, antigen and antibody positivity across the age range, and the role of asymptomatic transmission, in a previously unexposed population.

The private school has 2600 students across all school years, and 318 staff. The outbreak started on March 13th 2020, only 9 days after Chile’s first case, and spread rapidly, possibly because of a series of parents’ evenings. The school was immediately closed, before the general lockdown in Chile.

Symptomatic, antigen-positive Covid-19 occurred in 7 students, 18 staff and 27 parents. There was one death.

A stratified sample of 1009 students and 235 had home IgG/IgM antibody-testing from 4th-19th May. Of the students, 9.9% were positive; of the staff, 17% were positive. Antibody positivity was associated with younger age (possibly because the index adult dealt with early years children), previous antigen positivity on PCR, and contact with a confirmed case, as expected.

More interestingly, they asked about symptoms through questionnaires: the antibody-positive children reported a range, with the most common being abdominal pain (21%) and fever (17%), but 40% reported no symptoms at all. Of the antibody-positive staff, weakness, myalgia and hyposmia were more prevalent, and 18% had no symptoms. Many of those with symptoms and positive antibodies had had negative antigen tests. Covid-type symptoms occurred in some who were both antigen and antibody negative.

An interesting side-issue is that they found home-testing kits for blood antigens to be effective and acceptable to their population: these could be widely used in seroprevalence studies.

This study cannot answer perhaps the most important question: to what extent can asymptomatic children spread the virus? However, they could conclude that adults (parents and staff) were disproportionately affected in terms of both symptoms and antibody-positivity compared to children, and that control of spread in schools should concentrate on preventing adult-to-adult transmission.

Yung CFThoon KCJ PediatrHousehold Transmission of SARS-CoV-2 from Adults to Children02 Jul 2020SingaporeAsia213Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334921/

This paper from Singapore considers the transmission of SARS-CoV-2 from known infected adults to paediatric household contacts. Data collection was between 5 March 2020 to 30 April 2020 (8 week period). All paediatric household contacts (whether symptomatic or not) of people with confirmed COVID-19 were screened using nasopharyngeal swabs/RT-PCR. 223 adults (from 137 households) had laboratory-confirmed COVID-19. Their paediatric household contacts equated to 213 children (less than 17 years old) who were all tested, and of these, 13 cases were detected (from 7 households). This demonstrates a 6.1% rate of infection among children who were part of households with an individual with laboratory confirmed COVID-19.

Of the 13 cases in children, two children displayed symptoms: one child had a sore throat and one child had an isolated episode of pyrexia.

Looking at age distribution of paediatric household contacts, they found that:- of all those <5 years, 1.3% were infected- of all those 5-9 years, 8.1% were infected- of all those 10-16 years, 9.8% were infected

If the mother was the household index case, the rate of infection in children was highest (11.1%).

It is unclear why the 223 adults who had laboratory-confirmed COVID-19 were initially tested. However, the paper states that patients identified to have COVID-19 were isolated in hospital, so it is also unclear how much exposure the children would have had to the confirmed ‘household’ case of COVID-19.

L'Huillier, AEckerle, IEmerg Infect Dis. Culture-Competent SARS-CoV-2 in Nasopharynx of Symptomatic Neonates, Children, and Adolescents30 Jun 2020SwitzerlandEurope23Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-2403_article#suggestedcitation

In this study from Switzerland, nasopharyngeal samples of 23 children with PCR confirmed SARS-CoV-2 infection were inoculated into a cell culture to determine the presence or absence of of viable virus. All children aged <16 years, daignsosed at the Geneva University Hospital laboratory between January 25th

 

Of the 23 children with SARS-CoV-2 +ve PCR, median age was 12 years (range 7 days to 15.9 years), the majority (13/23 - 57%) had symptoms of upper respiratory tract infection and 7/23 (30.4%) were admitted to hospital. All samples were taken within 5 days of symptom onset (20/20 where reported), median 2 days (IQR 1-3 days). Median viral load was 3.0 x 10^6 copies / mL (IQR 6.9 x 10^3 - 4.4 x 10^8).

Viable SARS-CoV-2 virus was isolated in half (12/23 - 52%) of children including an infant diagnosed at 7 days of age. Virus isolation was associated with higher viral load (median 1.7 x 10^8 vs 6.9 x 10^3 in culture negative patients).

The results here demonstrate that children with symptomatic SARS-CoV-2 infection have similar viral loads to those seen in adults. Similar to adults, children, particularly those with high viral loads, can also shed viable virus particles early in the course of illness. These findings confirm that transmission of SARS-CoV-2 by children is plausible. It remains however that children appear less susceptible to infection compared with adults in the first instance and when infected tend to experience milder symptoms and therefore as a whole are unlikely to be major drivers of transmission. Indeed, this study identified only 23 paediatric cases of SARS-CoV-2 infection in a region severely affected by the pandemic.

Whilst children with symptomatic SARS-CoV-2 infection can shed viable virus, the small proportion of paediatric cases observed globally indicate a limited role of symptomatic children in disease transmission. 

Fontanet, AHoen, BmedRxivSARS-CoV-2 infection in primary schools in northern France: A retrospective cohort study in an area of high transmission29 Jun 2020FranceEurope510Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.06.25.20140178v2
Yung, CNg, KClincal infectious diseasesNovel coronavirus 2019 transmission risk in educational settings25 Jun 2020SingaporeAsia119Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciaa794

A study of contact tracing of 3 clusters of confirmed COVID-19 within schools in Singapore. Only close contacts of the affected students were placed into quarantine for 14 days, not complete year groups/schools/or classes. Target health measures implemented included terminal cleaning and interventions to reduce mixing (examples were cancelling of extra-curricular activities and staggered break times). For 3rd incident in day care, the school was closed due to increasing cases amongst staff, and all students were tested regardless of exposure/symptoms.

Case 1: 12yr male in secondary school infected at home (sibling of case 2). Attended on day 1 of symptom and subsequently quarantined. 8 classmates developed compatible symptoms, all tested negative.

Case 2: 5yr male in primary school. Attended on day 1 of symptoms and quarantined. 34 classmates developed compatible symptoms, all tested negative.

Case 3: Multiple adult staff members in pre-school involved in cluster. 70% of all students tested, all negative.

These findings are consistent with the small number of other studies of transmission within a school setting so far, which have demonstrated infrequent transmission from children.

Wongsawat, JDisthakumpa, AJ Paediatr Child HealthRisk of novel coronavirus 2019 transmission from children to caregivers: A case series22 Jun 2020ThailandAsia3Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1111/jpc.14965
Ferraiolo AArioni CMedicinaReport of Positive Placental Swabs for SARS-CoV-2 in an Asymptomatic Pregnant Woman with COVID-1922 Jun 2020ItalyEurope1Epidemiology - Transmissionhttps://doi.org/10.3390/medicina56060306
Tomb, RGunson, RJ InfectRetrospective screening for SARS-CoV-2 in Greater Glasgow and Clyde ICUs between December 2019 and February 202015 Jun 2020ScotlandEurope23Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295493/
Rovida, F.Cereda, D.Clin Microbiol InfectLow risk for SARS-CoV2 symptomatic infection and early complications in paediatric patients during the ongoing CoVID19 epidemics in Lombardy12 Jun 2020ItalyEurope27Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289743/
Kayem, G.Winer, N.J Gynecol Obstet Hum ReprodA snapshot of the Covid-19 pandemic among pregnant women in France04 Jun 2020FranceEurope181Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270811
Han, MChoi, EEmerg Infect Dis Viral RNA Load in Mildly Symptomatic and Asymptomatic Children with COVID-19, Seoul04 Jun 2020South Korea Asia12Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/10/20-2449_article
Gao, Y.Xu, R.Indian J Pediatr. Clinical Features and Treatment Protocol in Eleven Chinese Children with Mild COVID-1904 Jun 2020ChinaAsia11Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269701/
Nassih, HSab, IIndian J PediarAbsence of Evidence of Transmission of Coronavirus Disease 2019 from a Young Child to Mother Despite Prolonged Contact01 Jun 2020MoroccoNorth Africa1Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292798/pdf/12098_2020_Article_3382.pdf
Somekh, EStein, MPaediatric infectious disease journalThe Role of Children in the Dynamics of Intra Family Coronavirus 2019 Spread in Densely Populated Area01 Jun 2020IsraelMiddle East58Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/The_Role_of_Children_in_the_Dynamics_of_Intra.96128.aspx

This is a brief study of the transmission dynamics within households in Bnei Brak, an area of Isreal with high population density and high proportion of young people (almost 50% of its population are <18yrs). They assessed 13 family clusters and tested every member of their households by PCR, regardless of the presence or absence of symptoms. The index case was identified by date of onset of symptoms (this is standard practice but does leave open the possibility of mis-classifying the index case if they were truly asymptomatic).

The results were as follows; Excluding index cases, 58.3% of adults tested positive, 32.5% of children aged 5 – 17 tested positive, and 11.8% of children aged <5yrs tested positive. In 12/13 families the index case was an adult. The other case was a 14yr old male.

This evidence is consistent with almost all other household contact tracing studies which have demonstrated a significantly lower secondary attack rate in children compared to adults. A strength is the clear documentation that all household members were tested regardless of symptoms, and for clarity the index case was not included in the rates of infection making secondary AR better defined.

Behera, P.Parameswaran, G.F1000Research 9 (no pagination)(315)SARS-CoV-2 epidemic in India: epidemiological features and in silico analysis of the effect of interventions30 May 2020IndiaAsia109Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262570/
Wong, JChaw, L Influenza Other Respir VirusesAsymptomatic transmission of SARS‐CoV‐2 and implications for mass gatherings30 May 2020MalaysiaAsia2Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1111/irv.12767
Yang, MSu, WPublic HealthA three-generation family cluster with COVID-19 infection: should quarantine be prolonged?30 May 2020TaiwanAsia1Epidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S0033350620302055
Heavy, LMcDarby, GEuro Surveill No evidence of secondary transmission of COVID-19 from children attending school in Ireland, 202028 May 2020Ireland Europe3Epidemiology - Transmissionhttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.21.2000903

This is an epidemiological study describing cases of Covid-19 in Irish school setting in March 2020. Cases were identified by screening all cases of SARS-CoV-2 notified to public health departments in the Republic of Ireland, to identify children under the age of 18 years, and adults who had attended the school setting.

Six cases were identified, 3 school going children, and 3 adults (1 a teacher, and 2 who conducted educational session in a school). 5 out of 6 cases presented symptomatically with fever or cough, the final case was asymptomatic and screened due to a household cluster. Contact-tracing records were reviewed to identify cases of secondary transmission.

A total of 1155 contact of these six cases were identified. In the school setting, among 924 child contacts and 101 adult contacts identified, there were no confirmed cases of COVID-19. The only documented transmission that occurred from this cohort was from an adult case to other adults working environment outside school.

In conclusion no case of onward transmission to other children or adults within the school occurred. In the case of children, no onward transmission was detected at all. Furthermore, no onward transmission from the three identified adult cases to children was identified.

Limitations of the study, was only symptomatic contacts were tested, and so asymptomatic secondary cases were not captured. Also, in Ireland, when a case was identified, all children and staff within the school were excluded thus limiting the potential for further transmission within the school setting once a case was identified. All Irish schools closed on March 12th 2020 and remain closed.

Chen, MZhao, DJournal of Infection and Public HealthA SARS-CoV-2 familial cluster infection reveals asymptomatic transmission to children27 May 2020ChinaAsia2Epidemiology - Transmissionhttps://doi.org/10.1016/j.jiph.2020.05.018
Posfay-Barbe, KL'Huillier, APediatrCOVID-19 in Children and the Dynamics of Infection in Families26 May 2020SwitzerlandEurope40Epidemiology - Transmissionhttps://doi.org/10.1542/peds.2020-1576

This is a report of the first 40 paediatric patients presenting to Geneva University Hospital’s surveillance network (Switzerland). The aim of the study was to describe the clinical presentation of the patients and the dynamics of their familial clusters. Out of a total of 4310 SARS-CoV-2 cases, 40 (0.9%) were in children <16 years.

Clinical Presentation: Patients presented to medical care, and were confirmed via RT-PCR. Median age, years (IQR) 11.1 (5.7-14.5), 22/40 (56%) were female. The most common presentation was cough 32 (82%), Fever 26 (67%), nasal discharge 25 (64%). Most were previously healthy; with comorbidities reported in only 26% of patients; asthma (10%), diabetes (8%), obesity (5%), premature birth (5%) and hypertension (3%). Seven patients were admitted, none needed ICU care or Sars Cov2 specific therapy

Family Clusters: Family cluster evaluation was conducted by phone. 111 household contacts (HHC) were identified; 39 mothers, 32 fathers, 23 pediatric siblings, 8 adult siblings and 7 grandparents.

Family member was suspect if they had fever of acute respiratory symptoms. 61/111 had RT-PCR conducted. 77% (85/111) of household contacts (HHC) were symptomatic. Adult HHC were suspected or confirmed to have covid symptoms before the child 79% (31/39) of cases. In only 8% (3/39) of households did the study child develop symptoms first. 85% (75/88) of adult HHC developed symptoms at some point, compared to 43% (10/23) of pediatric HHC, which was statistically significant (p<0.001). Mothers were statistically more likely to develop symptoms than fathers (36/39 v 24/32, p=0.04). Due to the need for symptoms to qualify for testing, there is the possibility of undercounting paediatric infections due to their being more likely to have asymptomatic or oligosymptomatic infection.

The authors conclude that children are uncommonly the index case in family clusters of Sars CoV2. Household contacts who are children are less likely to be symptomatic than adult contacts. Children are most likely to be infected inside of family clusters, albeit at a time in Switzerland when creches and schools were closed.

De Ioris, MRaponi, MJ Pediatric Infect Dis SocDynamic viral SARS-CoV-2 RNA shedding in children: preliminary data and clinical consideration of Italian regional center23 May 2020ItalyEurope22Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa065/5842265?searchresult=1

This study at a paediatric hospital in Rome tracked SARS-CoV-2 shedding (nasopharyngeal, faecal, urinary and conjunctival) by following a cohort of 22 children during their hospital stay, collecting clinical and microbiological data.

Study design: The study ran from 16th March to 12th April in the COVID centre at Bambino Gesu Pediatric Hospital and collected data on 22 inpatients with an initial positive nasopharyngeal swab (either prior to admission or on admission). RT-PCR for SARS-CoV-2 RNA on nasopharyngeal and conjunctival swabs and stool and urine samples were repeated every 2-3 days for each child while they were inpatients until they had two consecutive negative results in the absence of new symptoms. Kaplan-Meier analysis was used to estimate the duration of symptoms and viral shedding for symptomatic patients: patients whose last swab/sample was still positive were censored at the date of the last swab.

Study population: 15/22 (68%) male, 7/22 (32%) female. Median age 7 years (range 8 days to 17.5 years). 4/22 neonates (1/4 tested because mother positive and 3/4 tested because midwife positive). 2/22 comorbidity (Angelman syndrome, suspected genetic syndrome and autism). 13/22 patients were discharged before the end of the study period (median inpatient stay 7 days, range 3-15 days).Symptoms: 4/22 (18%) asymptomatic (including 2/4 neonates, the other 2/4 had low grade fever and poor feeding). 18 symptomatic patients: 15/18 (83%) fever, 10/18 (55%) respiratory symptoms, 7/18 (39%) diarrhoea and vomiting, 3/18 (17%) seizure. Symptoms had resolved in all 18 before discharge from hospital. Median duration of symptoms was 8 days (range 2-21 days). 15/22 had a positive stool sample at admission: of these 7/15 (47%) had respiratory symptoms and 3/15 (20%) had diarrhoea and vomiting.

Viral shedding: At diagnosis: 22/22 (100%) had positive nasopharyngeal swab (by definition), 15/22 (68%) had positive stool sample, 1/22 (5%) had positive urine sample (re-test 2 and 5 days later was negative; another patient had initial negative urine test but repeat 3 days later was positive) and 2/22 (9%) had positive conjunctival swab (both were negative 2-3 days later). A detailed table charting the dates of inpatient stay, onset and end of symptoms and positive/negative swabs/samples for each patient is supplied: the full screen of faecal, urinary and conjunctival sampling was performed at variable intervals after the initial positive nasopharyngeal swab (up to 5 days later in several cases). For symptomatic patients: (1) from date of symptom onset to negative nasopharyngeal swab: median 8 days (range 2-17 days) and (2) from date of symptom onset to negative stool sample: median 14 days (range 10-15 days). Estimate of persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab 52% and for stool sample 31%.

The authors note the need to confirm the clinical relevance of faecal SARS-CoV-2 shedding in terms of the risk of transmission via the faeco-oral route.

Wolf, GProtzer, UJ Paed Inf Dis SocClinical and Epidemiological Features of a Family Cluster of Symptomatic and Asymptomatic SARS-CoV-2 Infection22 May 2020GermanyEurope3Epidemiology - Transmissionhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa060/5842074
Yuan, CXiao, HEmerging microbes & infectionsViral loads in throat and anal swabs in children infected with SARS-CoV-218 May 2020ChinaAsia2138Epidemiology - Transmissionhttps://www.tandfonline.com/doi/pdf/10.1080/22221751.2020.1771219?needAccess=true

This is a retrospective review of RT-PCR testing results of 2138 paediatric patients with suspected SARS-CoV-2 infection at Wuhan Children’s Hospital in Hubei, China, from 1 January to 18 March 2020. All children were tested using throat swabs (TS); a subset of 212 were also tested using anal swabs (AS). Changes in viral load in both throat and anal swabs were monitored in 13 patients.

Findings: 217/2138 (10%) confirmed cases on EITHER throat or anal swab.78/217 confirmed cases had both types of swab: 24/78 (31%) positive for both TS & AS, 37/78 (47%) TS pos/AS neg, 17/78 (22%) TS neg/AS pos. For those cases where the TS and AS results didn’t match (i.e. TS pos/AS neg or TS neg/AS pos):

Asymptomatic: 12/37 (32%) TS pos & 10/17 (59%) AS posGI symptoms: 7/37 (19%) TS pos & 6/17 (35%) AS posCough: 16/37 (43%) TS pos & 4/17 (24%) AS posFever: 20/37 (54%) TS pos & 5/17 (29%) AS posCT evidence of pneumonia: 25/37 (68%) TS pos & 10/17 (59%) AS posTime from positive to negative for PCR assay: 7 days for TS pos & 6 days for AS posThe viral loads detected on throat swabs and anal swabs showed no difference.

Zhao FLiu YJ GastroThe Time Sequences of Oral and Fecal Viral Shedding of Coronavirus Disease 2019 (COVID-19) Patients16 May 2020ChinaAsia30Epidemiology - Transmission https://www.gastrojournal.org/article/S0016-5085(20)30663-6/pdf
Schwartz, NStewart, RMMWRAdolescent with COVID-19 as the Source of an Outbreak at 3-week Family Gathering - 4 States, June-July 2020010 May 2020USANorth America8Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/69/wr/mm6940e2.htm

This is a case report of a cluster associated with a paucisymptomatic child index case in the USA.

A 13y old girl, had a known exposure to COVID-19 but 4 days after exposure she had a negative rapid antigen test. 2 days later she had nasal congestion but travelled with her immediate family to a large gathering of the wider family. 14 people stayed in the same house for between 8 and 21 days and practiced no social distancing.

12 of these 14 people experienced symptoms and were classed as confirmed/probable/suspected COVID-19 cases.

Another 6 family members visited on 2 occasions (10 hours and 3 hours) but remained outdoors and socially distanced. None experienced any symptoms and 4 had negative RT-PCR tests 4 days after the last exposure.

Details of the days at which various members showed symptoms and the testing that was done are shown in the paper.

The index case had a 9y old brother and 10 y old cousin but all the others at the gathering were teenagers or older, the oldest being the grandparents who were 72.

This paper illustrates

• The high transmission rate of SARS-Cov-2 within households

• The necessity for 14 days self-isolation after exposure

• That outdoors, with social distancing, transmission is much less

Rosenberg, ENew York State Coronavirus 2019 Response TeamClinical Infectious DiseasesCOVID-19 Testing, Epidemic Features, Hospital Outcomes and Household Prevalence, New York State - March 202008 May 2020USANorth America50Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa549/5831986

This epidemiological study examined the first 229 positive cases diagnosed in New York State outside of the city of New York from 2nd March to 12th March 2020 and described their outcomes. In addition, from the 5th March to the 17th March, they screened any household contacts of the positive patient. There was one ‘source’ patient under 5 years of age and 7 ‘source’ patients from 5 to <18 years of age. Household screening identified a further 42 children with COVID-19. No children <18 years of age required hospitalisation but it appears they only had complete data on 18/50 positive children.

Household contact with positive patients of any age found that likelihood of the contact being positive for SARS-CoV-2 increased with the contact’s age. Of the 25 children screened <5 years of age, 5 (20%) were positive and of the 131 screened age 5 to <18 years 37 (28.2%) were positive, compared to 16/29 (55%) of contacts aged 65+ years (p 0.002). This supports previous studies which shows a lower prevalence of SARS-CoV-2 infection in children <18 years. Unfortunately it does not described whether the household contacts of the 50 source children were positive for the infection too which could contribute to the discussion about whether children spread SARS-CoV-2 as effectively as adults and would require completion of the missing data and more in-depth analysis of the findings.

Mao, LYuan, ZBMJ Infect DisA child with household transmitted COVID-1907 May 2020ChinaAsia1Epidemiology - Transmissionhttps://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05056-w
Zhang, JYu, HScienceChanges in contact patterns shape the dynamics of the COVID-19 outbreak in China29 Apr 2020ChinaAsia756Epidemiology - Transmissionhttps://science.sciencemag.org/content/early/2020/04/28/science.abb8001

This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghia) using 3 arms:

Surveys conducted within cities studying contacts between individuals, finding that during lockdown all contact except for those within households ceased – backing up evidence that about 90% of infections during this period occurred by household transmission

Most importantly for us – an age stratified model of susceptibility to acquiring infection was produced by assessing the data from the Hunan CDC, whereby every positive case found in Hunan had recent contacts placed under quarantine for 14 days and was tested for COVID-19. They estimated odds ratios for age groups to become infected, and performed statistical adjustment for clustering and correlation structures of contacts exposed t the same index case (generalized linear mixed model regression). Their finding was that susceptibility to infection increased with age, lowest in children 0-14 years (OR 0.34, 95% CI 0.24 – 0.49 – reference participants aged 15 – 64yrs).

Finally using the above data they estimated the effects of non-pharmceutical interventions on reducing spread of COVID-19. They found that closing schools was likely to significantly impact the R0 but not enoght to be a useful measure on its own. They describe social distancing as implemented in China, to be a sufficient measure to control COVID-19

This is the latest, and one of the most comprehensive of a number of studies to demonstrate significantly lower attack rate in children to adults, suggesting decreased susceptibility to infection.

Jiang XQiu JJ Med VirolAsymptomatic SARS‐CoV‐2 infected case with viral detection positive in stool but negative in nasopharyngeal samples lasts for 42 days24 Apr 2020ChinaAsia1Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25941
Luo, YXiao, WEmerg Infect DisAsymptomatic SARS-CoV-2 infection in household contacts of a healthcare provider, Wuhan, China.24 Apr 2020ChinaAsia2Epidemiology - Transmissionhttps://wwwnc.cdc.gov/eid/article/26/8/20-1016_article
Song, RLi, XJ. Infect.Clinical and epidemiological features of COVID-19 family clusters in Beijing, China23 Apr 2020ChinaAsia7Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(20)30229-2/pdf

This early epidemiological study from Beijing describes four family clusters identified from January 16th through to January 29th 2020. All 4 index cases were adults. SARS-CoV-2 infection was confirmed in 18 of 20 contacts, including 7 of 8 children. The clinical course in these children ranged from asymptomatic infection to mild disease. PCR positivity was shorter in paediatric cases (range 5-17 days) compared with adults (7-37 days).

The transmission from adults index cases to children in this study is consistent with other studies of transmission dynamics in family clusters. Similarly the mild clinical course in children is in keeping with larger studies. The high household attack rate in this report may be due to the delay in diagnosis of the index cases, possibly owing to the timing of the study early in the pandemic.

Liu, SKuo, HJ Med VirolThree Taiwan's domestic family cluster infectionsof coronavirus disease 201923 Apr 2020TaiwanAsia1Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25949
Jiang, XMa, MJ. Infect.Transmission Potential of Asymptomatic and Paucisymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections: A 3-Family Cluster Study in China 22 Apr 2020ChinaAsia1Epidemiology - Transmissionhttps://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa206/5823691
Li, WChen, JClinical Infectious DiseasesThe characteristics of household transmission of COVID-1917 Apr 2020ChinaAsia100Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa450/5821281

This retrospective study calculated secondary attack rates of COVID-19 amongst 392 household contacts of 105 SARS-CoV-2 RT-PCR positive index cases hospitalised at Zaoyang First People’s Hospital (250 km from Wuhan) and Chibi People’s Hospital (150 km from Wuhan) between 1st January and 20th February 2020.

Study design: Households were eligible for the study if the index case was the only member of the household with a clear history of exposure to Wuhan, its residents or high-risk sites in the 14 days before onset of illness (the assumption then being that the only exposure of household contacts to SARS-CoV-2 was via the index case). Once index cases were confirmed, household contacts were quarantined for 14 days in local government sites and monitored daily, with at least 2 nasopharyngeal swabs (taken at the beginning and mid-point of quarantine). Variables analysed retrospectively in this study (using medical notes and telephone interviews) included household size, age/gender/symptoms of index cases and household contacts, time between onset of illness of the index case and hospitalisation (range 0-11 days) and spouse/non-spouse relationships.

Key paediatric findings: 100 of the 392 household contacts were under 18 years of age (median 6.5 yrs, IQR 4-11 yrs); of these, only 4 children became infected (all male, 1 aged 0-5 yrs, 3 aged 6-17 yrs). This secondary attack rate of 4% for children compares with 21% for the adult household contacts (60 out of 292 infected) and 16% overall (64 out of 392).

Of interest: 14 of the 105 index cases self-quarantined within the home immediately after onset of symptoms before hospitalisation (wearing masks, eating and residing separately from the rest of the household); in these households there was a 0% secondary attack rate, versus 18% in those households where the index case didn’t self-quarantine before hospitalisation. In households where the index case was afebrile, 13% of household contacts became infected, versus 19% where the index case had fever. In households where the index case had no cough, approximately the same proportion of household contacts became infected as in households where the index case had a cough (17% vs 16%). 9 of the infected household contacts were asymptomatic (14%), but this figure isn’t broken down by age in the article. [Note: there are some discrepancies between calculations in the text and data tables; data from tables used here.

This article provides further reassurance to the growing body of evidence of lower attack rates of COVID-19 in children as compared to adults, as well as a signal that symptomatic patients are higher risk of transmitting the virus than those who do not develop symptoms.

Pathak, EHambleton, IJPHMPCOVID-19 in Children in the United States: Intensive Care Admissions, Estimated Total Infected, and Projected Numbers of Severe Pediatric Cases in 202016 Apr 2020USANorth AmericaEpidemiology - Transmissionhttps://pubmed.ncbi.nlm.nih.gov/32282440/

This study uses data from modelling studies of the COVID-19 outbreak China in January and February 2020 (in particular, adjusted pediatric severity proportions and adjusted pediatric criticality proportions) plus data from US PICU cases (and therefore estimates of total SARS-CoV2 cases in children derived from this) to model and project potential PICU bed occupancy from COVID-19 under a variety of “cumulative pediatric infection proportion” scenarios (how many children in total get infected).

Essentially – a modelling study to try and predict how many children in the US might need PICU from COVID-19.

The headline is if 5% of children in the US get infected with SARS-Cov2, 1086 children would be predicted to need PICU. If 50% of children get infected with SARS-CoV2, 10865 children would be predicted to need PICU, which is a lot.

There are 2 major issues with this study. One which is addressed (albeit, perhaps not sufficiently) is the denominator issue. To determine what proportion of cases need PICU, you need to know how many children in total were infected in the population the data in the model was derived from. To put it bluntly, we have absolutely no idea what-so-ever how many children this is. We will not know the answer to this until we have comprehensive sero-surveillence data from children (testing antibodies), which is unlikely to be available for some time. This makes this type of projection an interesting thought experiment, but nothing more.

The second, glaring issue, is the evidence from around the world that nothing close to anything they have projected has come to fruition in any other developed country which is several weeks ahead of the US in regards to COVID-19. Italy, Spain, France, UK, have all had handfuls of children needing intensive care from COVID-19. The US has the benefit of looking into its future, and fortunately it doesn’t look anything like the projections in this study.

Jing, QYang, YmedRxiv (preprint)Household secondary attack rate of COVID-19, and associated determinants15 Apr 2020ChinaAsia254Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2020.04.11.20056010v1

A pre-print, this article should be interpreted with caution until it has undergone peer review.

This is study from Guangzhou, China documenting the attack rate amongst 2075 close contacts of 212 confirmed COVID-19 cases from January 7th to February 17th 2020.

There were 97 non-primary cases amongst 770 household contacts giving an attack rate of 12.6% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.3%.

In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.27 for close contacts and OR 0.23 for household contacts)

Only 10/217 (5%) of primary cases were children.

Although the criteria for testing contacts in this study are not entirely clear, the results suggests that children are less susceptible to SARS-CoV-2 infection compared with adults with similar exposure. This is in contrast to earlier data from Shenzhen, China suggesting similar attack rates in children, but is in keeping with more recent epidemiological data from Iceland and Italy.

Danis, KSaura, CClinical Infectious DiseasesCluster of coronavirus disease 2019 (Covid-19) in the French Alps, 202011 Apr 2020FranceEurope1Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciaa424

This is a study of a cluster of COVID-19 cases in the French alps liked to a single index case. A child became infected and was symptomatic, but despite attending 3 schools during this time with exposure to 112 different school contacts the child did not transmit the infection to any other contacts.

Whilst a single case study, this evidence suggests different transmission dynamics from children, supporting other data which consistently demonstrates reduced infection and infectivity of children in the transmission chain.

Pan, AWang, CJAMAAssociation of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China10 Apr 2020ChinaAsia536Epidemiology - Transmissionhttps://jamanetwork.com/journals/jama/fullarticle/2764658
Xiao, ZZheng, TJ Infect Dev CountrExamining the incubation period distributions of COVID-19 on Chinese patients with different travel histories08 Apr 2020ChinaAsiaEpidemiology - Transmissionhttps://jidc.org/index.php/journal/article/view/32379707/2227

Although all ages are affected by COVID-19, this paper makes it clear that the number of infected children is tiny compared to those in adults. The authors analyse incubation periods by age, finding that this increases in length in adults from aged 20 to 70+. The findings regarding children are more difficult to interpret due to small case numbers and therefore large confidence intervals, but it appears that 6 to 20 year olds may have a longer incubation period than young adults aged 20 to 60. The results for 0-5 year olds are fairly inconclusive. The authors then examine incubation in relation to travel history, finding that those who were affected by local community spread had longer incubation periods than those who had contracted the virus directly in Wuhan. They conclude that the virulence of the virus may decrease with intergenerational transmission, but that more work is needed.

Chen, DLei, CJMVFour cases from a family cluster were diagnosed as COVID-19 after 14-day of quarantine period08 Apr 2020ChinaAsia4Epidemiology - Transmissionhttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25849

This paper was a case study of a family who was seen at First Affiliated Hospital of Guangzhao Medical  University. The family had four of six family members positive for SARS-CoV-2, all more than 14 days after the time of suspected exposure in Wuhan. The family had left Wuhan on 22nd January, and completed quarantine for two weeks, however subsequently developed symptoms. At the time of their diagnosis there were no known cases in their local area. They were managed  at the First Affiliated Hospital of Guangzhao Medical  University. The average length of time from leaving Wuhan until symptoms was 25 days. Diagnosis was made for patients by nasopharyngeal swabs via qRT_PCR (twice positive).

Within the family there was one paediatric patient who was diagnosed with SARS-CoV-2 (Patient 3), a 7 year old boy who became unwell on February 21st. His grandparents were the first in the family to be determined positive. His father was also positive but asymptomatic. HIs sister and mother were negative, although it was noted the sister did have radiological findings on chest imaging, but that these were not stereotypical for cover and she also tested negative for SARS-CoV-2.

Patient 3's symptoms were a low grade temperature of 37.3.  There are no details provided regarding his blood tests. He had CT chest showing right lobular and sub segmental ground-glass opacities. There were no further details given regarding the child's other symptoms or management.

Of the adult patients - all patients had normal WCC, but the grandparents both had reduced lymphocyte count.

Zhu, YShort, KMedRxivChildren are unlikely to have been the primary source of household SARS-CoV-2 infections30 Mar 2020InternationalInternational19Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.26.20044826

A pre-print, the information should be treated with caution until it has undergone peer review.

This study includes a review of symptom frequency in children, but most interestingly examines available case series in the literature of family clusters of COVID-19 to determine what contribution is made of children to the chain of transmission. Clusters were taken from China, Singapore, the USA, South Korea and Vietnam, totalling 31 household transmission clusters. Of these cases, only 3 (9.7%) had a child as the index case. Considering a worst case scenario (whereby ALL infected children were the index case in their family and had been mislabelled as a secondary in some studies), still children would only account for 6/28 (21%) infection clusters. They compare this to the H5N1 epidemic where children were the index case in 54% of household clusters. This provides further evidence that children appear to have a fairly limited role in the transmission of COVID-19, which has implications for non-pharmaceutical interventions such as school closures.

Davies, NJit, MMedRxivAge-dependent effects in the transmission and control of COVID-19 epidemics24 Mar 2020UKEuropeEpidemiology - Transmissionhttps://doi.org/10.1101/2020.03.24.20043018

A pre-print, the information should be treated with caution until it has undergone peer review. This is a mathematical modelling study from the London School of Hygiene and Tropical medicine, examining the explanation for the relatively low numbers of childhood cases of COVID-19. They assess three plausible explanations, including:

-Assortative mixing patterns or school closures decreasing mixing and spread between children.

-Children exhibiting lower susceptibility to infection.

-Children having a lower propensity to show clinical symptoms.

They tested these hypotheses by fitting an age structured model to epidemic data from six countries (China, Japan, Singapore, South Korea, Italy and Canada). The details of the modelling and simulations are highly specialist, but essentially they found that there was a strong age dependence in the probability of developing clinical symptoms. There are many implications to this, including limited efficacy of school closures in halting the spread of the pandemic, and that regions with older populations may see disproportionate more cases, in particular during the latter stages of the pandemic. They note that understanding the role of subclinical infection remains vital to informing policy to stem the spread of disease. We should remember this is based on mathematical modelling, and further clinical and epidemiological information will be necessary to confirm or refute their hypothesis.

Wang, ZZhang, RJournal of infectionHousehold transmission of SARS-CoV-221 Mar 2020chinaAsia18Epidemiology - Transmission https://www.journalofinfection.com/article/S0163-4453(20)30169-9/pdf

This is a retrospective case series of 85 patients admitted to Union Hospital in Wuhan City, Hubei Province, China and their households, one household per index case. The aim was to attempt to determine the transmission rate of SARS-CoV-2 among household members.

All patients were confirmed infected with SARS-CoV-2 with real-time reverse transcription polymerase chain reaction (RT-PCR) assays on throat swabs. The admission dates were February 13 and February 14, 2020. The city had been under lockdown measures since the 23rd of January.

The composition of these 85 households was 107 (45%) male adults, 115 (48%) female adults and 18 (7%) children.

64 (60%) of 107 male adults and 66 (58%) of 115 female adults were confirmed infected with SARS-CoV-2, only 2 (11%) of 18 children became positive. As a whole, there were totally 240 cases in these 85 households, with 132 (55%) of them were confirmed with SARS-CoV-2 infection and 57 (24%) cases were negative in RT-PCR assays.

The researchers found there was a secondary transmission rate of 30% and this increased to 50% for households with 2 contacts, they compared this to previous studies on other two coronavirus pneumonia epidemics which reported secondary transmission rates among household contacts of 5% for Middle East respiratory syndrome coronavirus (MERS-CoV) and 10.2% for severe acute respiratory syndrome coronavirus (SARS-CoV). The researchers concluded this demonstrated the need for stringent quarantining of household contacts.

This research did have some limitations. The researchers did not clarify what criteria they were using to guide testing nor did they quantify exactly how long they followed up household contacts for. It reproduces similar studies which have found significantly lower attack rates in children.

Jeong, EOsong Public Health Res PerspectCoronavirus Disease-19: Summary of 2,370 Contact Investigations of the First 30 Cases in the Republic of Korea20 Mar 2020South KoreaAsia155Epidemiology - Transmissionhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104686/pdf/ophrp-11-81.pdf

This paper from the Republic of Korea reports findings from the contact tracing of the first 30 positive COVID-19 cases in that country. 2,370 individuals were traced based on being in "close contact" with a case (being within 2 metres of a case) or "daily contact" (proximity without close contact). Of these, 155 were aged 0-19 years. Of these, one 10-19 year old tested positive giving a secondary attack rate of 1.49 (0.08 - 9.13). The mode of contact giving the greatest overall attack rate was being 'household contact' but these details are not presented specifically in relation to children.

Mizumoto, KNishiura, HMedRxIVAge specificity of cases and attack rate of novel coronavirus disease (COVID-19)13 Mar 2020JapanAsia176Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.09.20033142

A pre-print, the information should be treated with caution until it has undergone peer review.

This is a series of the 313 domestically acquired cases of COVID-19, in Japan, up until March 7th 2020. It looks at the ages of patients who acquired the disease and compares this to those exposed (n=2496) to estimate attack rates.Of note, there was a significantly lower attack rate in children (7.2% in males and 3.8% in females) than in the older populations (up to 22% in 50–59 year olds). This attack rate in children is similar to that observed in Shenzen, but much lower than observed in older adults in Japan. This suggests children are much less likely to acquire the disease than adults if exposed. This is at odds with the findings from Shenzen, and the reason for this disparity is unclear.

Bi, QFeng, TMedRxIVEpidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts24 Feb 2020ChinaAsia20Epidemiology - Transmissionhttps://doi.org/10.1101/2020.03.03.20028423
Pan, XLiu, JLancet: Infectious DiseasesAsymptomatic cases in a family cluster with SARS-CoV-2 infection19 Feb 2020ChinaAsia1Epidemiology - Transmissionhttps://doi.org/10.1016/S1473-3099(20)30114-6

This case study looks at another family cluster of COVID-19 involving asymptomatic patients. It involved a 3yr old boy who was positive for SARS-CoV-2 despite having no symptoms, normal bloods and a normal CT.

Fuk-Woo Chan, JYuen, KYLancetA familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster24 Jan 2020ChinaAsia1Epidemiology - Transmissionhttps://doi.org/10.1016/S0140-6736(20)30154-9

This case study looks at a family cluster, including a patient who had not traveled to Wuhan. There was one child, aged 10 in the cluster. They were asymptomatic but had bilateral ground-glass opacities on x-ray with essentially normal bloods.

Breslin, NGoffman,DNCBICoronavirus Disease 2019 among asymptomatic and symptomatic pregnant women9th April 2020USANorth America43Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144599/

This is a retrospective case-controlled study of 43 women who had presented to 2 affiliated hospitals in New York City between 13/03/20 and 27/03/20 and had positive nasopharyngeal swabs for SARS CoV 2 PCR. The average BMI of these women was 30.9 (60.5% had a BMI ≥30) and 18 women had co-morbidities (mild asthma being the most common). 29 women had COVID-19 related symptoms and underwent testing at presentation. 3 of these women were admitted for management of COVID-19 symptoms and 4 were admitted (unclear when in the two-week study period) for obstetric indications. 14 women were asymptomatic and had presented for obstetric reasons. 2 of these women were tested due to COVID-19 symptom onset during admission and went onto require ITU level care. The other 12 asymptomatic women were tested as part of the universal testing on admission to the delivery unit. Of the 18 women admitted for obstetric indications, 10 were planned admissions (9 inductions and 1 elective section). 4 COVID-19 symptomatic women (incl.1 preterm labour) and all asymptomatic women gave birth to a total of 18 babies (10 vaginal deliveries and 8 c-sections for obstetric reasons) with good APGAR scores. All babies had nasopharyngeal swabs on day 0; 15 babies were negative, 2 babies had initial unclear and then negative on repeat swab on day 1-2 and 1 baby had an indeterminate result and was clinically managed as ‘presumptive negative’. There were 3 admissions to NICU (n=1 preterm 34+6 n=1 antenatal diagnosis of multicystic dysplasic kidney and n=1 Resp distress with suspected sepsis – COVID-19 swab -ve). Babies not requiring NICU were kept with mothers and breast feeding encouraged with advice on strict hand hygiene and mask wearing. All babies have been discharged home.

There are two clear inconsistencies noted in this paper. Firstly, there is a different mean age of pregnant women stated in the table to that which is stated in the body of the text. Secondly, there is a mention of ‘3 of the 28 babies’ being admitted to NICU whereas elsewhere in the paper it consistently quotes 18 babies; this maybe a mis-print. There is also ambiguity in the way that results are presented for the symptomatic women for whom treatment was not required for their COVID-19 symptoms on initial presentation; the flowchart figure shows 26 patients with mild disease with 4 admissions for obstetric reasons, but the text reports 25 patients were stable for discharge. The most striking finding in this paper is the number of women who present with obstetric reasons and with no COVID-19 symptoms, who tested positive for COVID-19. This is even more poignant given that the 2 women requiring ITU level care were asymptomatic at presentation and were the only ones to require this level of support in this report. It is also important to note that 5 of the inductions of labour were in asymptomatic women for worsening pathologies such as cholestasis, reduced fetal movement and chronic and gestational hypertension and that one of symptomatic women went into preterm labour. It is reassuring that all neonates born, regardless of COVID-19 symptom status at presentation, did well clinically with most babies being kept with mothers post partum. The neonates were not assessed for IgG and IgM status.

Egerup, PNielsen, HObstet Gynecol.Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns27 Oct 2020DenmarkEurope1206Neonatal https://journals.lww.com/greenjournal/Fulltext/9900/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.29.aspx

This is a prospective cohort study conducted at a single centre in Denmark between 4th of April 2020 and 27th of April 2020. They recruited 1313 women (72% of all admissions), their partners (n=1188) and newborns (n=1206). The women and partners were tested for antibodies in the blood and a nasopharyngeal swab taken for PCR. Umbilical cord blood was taken to look for antibodies in the neonate. The iFlash 1800 kit was used for detecting antibodies and a positive IgM and IgG was defined as a level ≥8 arbitrary units/ml and ≥10 arbitrary units/ml.

With antibodies Without antibodies

Mothers 28 1285

Mothers with +ve swab at admission 0 1 (and 2 inconclusive)

Mothers with prev. +ve swab 3 2

Mothers reporting prior symptoms 14 (50%) 383 (31%)

Partners 32 1156

Partners with +ve swab at admission 1 (and 1 inconclusive) 0 (and 1 inconclusive

Partners with prev. +ve swab 2 1

Partners reporting prior symptoms 20 (65%) 329 (30%)

Newborn 17 (3/17 born to mothers negative for Ab) 1189

The only statistically significant baseline characteristic difference was that 61% of women in the antibody positive group were Blood group A compared to 41% in the Ab -ve group (p=0.034). There was no difference in the rate obstetric or neonatal complications between the two groups. 82% of neonates with antibodies were born to mothers who were also positive for antibodies (67% of antibody positive women had neonates with antibodies). The 3 neonates who born to mothers who were negative to antibody had levels which were close to the cutoff and therefore this result was determined to be concordant. All neonates were IgM negative. The study reports an adjusted prevalence of 2.6% in the women and 3.5% in the partners based on the serological results. They also report 37% increase in absolute risk of mother being Ab+ve if living with a partner who is Ab+ve and a 39% absolute risk of infection if the partners tested +ve.

This study has a small number of antibody positive participants and case control study would have been a better design to see if there was an association with antibody positivity and obstetric and neonatal outcomes. With regards to the frequency of the antibody it would have been better to choose a population who had already been determined to have had COVID infection or be asymptomatic carriers. Furthermore, the small numbers mean that risk have wide confidence intervals and they assume that mothers were living with their partners and that the partners contracted the infection first. The study is conducted in a young (mean age 31) population with normal BMI and a largely asymptomatic or mild COVID infection profile. The study does not provide details of ethnic background. The study does not provide a break down of IgM positivity in the mothers and partners. The high percentage of neonates with antibodies born to mothers with antibodies is reassuring but further study of this cohort of positive women is needed to determine what characteristics may hinder the transfer of these antibodies. It is also reassuring that all neonates were IgM negative, but we must keep in mind that the mothers were largely asymptomatic or had mild disease.

In conclusion, the results from this study are unreliable. They had two aims, to determine the frequency of antibody (wrong cohort) and to see if they had an association with obstetric and neonatal outcomes (wrong design).

Colomer, BMatías del Pozo, VFront PediatrNeonatal Infection Due to SARS-CoV-2: An Epidemiological Study in Spain23 Oct 2020SpainEurope40Neonatalhttps://www.frontiersin.org/articles/10.3389/fped.2020.580584/full

This is a national prospective observational study looking at postnatally acquired COVID 19 infection in neonates between the study period of 3/04/20 to 18/05/20. Of the 79 hospitals who were entering information into the national registry, 21 hospitals recorded 40 cases of postnatally acquired infection. These cases were split into community acquired and nosocomial and the clinical course, treatment, investigations and follow-up were analysed. Of the baseline characteristics analysed between the two group, statistically significant difference was noticed with the Noscomial group having smaller anthropometric measurements, greater number of preterms and lower rates of breast feeding. In both groups there was a greater prevalence of male infants.

This study provides the largest cohort assessment of babies and their clinical course following postnatally acquired COVID infection. The study describes a predominantly mild course of illness with respiratory infection being the most common clinical manifestation. Prematurity seems to be a possible risk factor for severe disease manifestation, along with other underlying background conditions and co-infections. In a minority of cases, it also reports white cell count abnormalities. The CXR abnormalities, when present, are similar to finding from other age group populations. In the majority of cases in both groups there was a source of infection identified(most commonly mother), indicating that the baby is unlikely to be the index case and that strict infection-control measures should be implemented to minimise horizontal transmission. They also report the use of hydroxychloroquine, the efficacy and appropriateness of which cannot be determined based on the information provided in this study. This study has had problems with missing data and they also do not look at the perinatal history of these babies. Overall, the descriptions provided by this study are helpful bear in mind in our own clinical practice.

Gale, CKurinczuk, JThe Lancet Child & Adolescent HealthCharacteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance 09 Nov 2020UKEurope66Neonatalhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30342-4/fulltext

The aim of this prospective study, reported by an eminent group of perinatal epidemiologists and academic clinicians, was to measure the population-level incidence, characteristics, transmission and outcomes of SARS-CoV-2 infection in neonates in the UK who received inpatient treatment for the infection in hospital. The data collection period was two months (1st March 2020 – 30th April 2020).

The data sources for identification of infected babies were the British Paediatric Surveillance Unit linked to national testing, the obstetrics surveillance database and paediatric intensive care (PIC) audit data. The defined outcomes included the UK incidence of (hospital-based) neonatal SARS-CoV-2, the incidence of severe neonatal SARS-CoV-2 disease, the proportion of these babies who acquired the infection by “vertical” transmission, the proportion who acquired the infection nosocomially and the clinical outcomes for infected babies.

A total of 66 infected babies met the inclusion criteria, giving an incidence of 5·6 [95% CI 4·3–7·1] per 10,000 livebirths during those two months. Of these, 28 (42%) had severe neonatal SARS-CoV-2 infection (incidence 2·4 [1·6–3·4] per10000 livebirths) and 16 (24%) were preterm. The criteria for “severe” follow the initial Dong et al paper, with any 2 of: Temperature >37.5, apnoea, cough, tachypnoea, respiratory distress, oxygen requirement, poor feeding, vomiting or diarrhoea, plus one of: low WCC, low lymphocytes, or CRP >5mg/L and: abnormal chest x-ray.

The most common signs at presentation were hyperthermia and poor feeding or vomiting but respiratory signs were also reported to be common. Of those tested, 55% had a raised serum lactate (>2mmol/L), 29% had a CRP >5mg/L and 9% had a low lymphocyte count.

With regard to ethnicity:

- 36 (55%) babies were from white ethnic groups (incidence 4·6 [3·2–6·4] per 10,000 livebirths)

- 14 (21%) were from Asian ethnic groups (incidence 15·2 [8·3–25·5] per 10000 livebirths)

- 8 (12%) were from Black ethnic groups (incidence 18·0 [7·8–35·5] per 10000 livebirths)

- 7 (11%) were from mixed/other ethnic groups (incidence 5·6 [2·2–11·5] per 10000 livebirths).

With regard to route of transmission

- 17 (26%) babies were born to mothers with known perinatal SARS-CoV-2 infection

- 2 (3%) were considered to have possible vertically acquired infection (SARS-CoV-2-positive sample within 12 hours of birth where the mother was also positive)

- 8 (12%) babies had suspected nosocomially acquired infection.

With regard to outcome:

- median length of stay was 7 days (IQR* 2-55) for babies admitted to a neonatal unit and 2 days (IQR* 0-4) for those admitted to a PIC unit

- 58 (88%) babies had been discharged home by July 28, 2020

- 7 (11%) were still admitted on July 28th

- 1 (2%) had died of a cause unrelated to SARS-CoV-2 infection

- 42% of neonates met the criteria for severe disease compared with 6% of older children, indicating that disease severity is greater in infected neonates.

A number of limitations of this study are acknowledged by the authors, including: the limited range of data available from the surveillance sources; the cross-sectional nature of the data; the low frequency of testing of neonates at 12 hours which compromises the estimation of vertical transmission; the absence of longitudinal data relating to the relationship between breastfeeding and SARS-CoV-2; the inability to estimate overall infection rates in the population as the study was confined to hospital patients.

Key messages from this study are: the high proportion of babies from Black, Asian, or minority ethnic groups requires further investigation; separation of newborn babies from their SARS-CoV-2 positive mothers is not justified; disease severity appears to be greater in neonates than older children.

Dong, LYin, MmedRxivEvaluation of vertical transmission of SARS-CoV-2 in utero: nine pregnant women and their newborns08 Jan 2021ChinaAsia9Neonatal https://www.medrxiv.org/content/10.1101/2020.12.28.20248874v1

The primary aim of this study was to characterise, first, the distribution of SARS-CoV-2 viral proteins (spike proteins and nucleoproteins) within the placentas of pregnant women diagnosed as having contracted Covid-19 infection and, second, to determine whether specific receptor proteins (ACE2, CD147 and GRP78), which are required for the virus to enter human cells, are present in the placenta.

The maternal subjects for the study were seven women who had tested positive using a “throat swab virus nucleic acid test” within 15 days of delivery at term. The controls were two uninfected women who delivered at term. The median gestational age of the nine pregnancies was 40 weeks (range 38-42 weeks). Amniotic fluid, colostrum and throat swabs taken from the neonates at 0, 24 and 48 hours after delivery, were tested for SARS-CoV-2 using RT-PCR testing.

The study found that the viral proteins were present in the syncytiotrophoblast (maternal side) of the placenta and that the ACE2, CD147 and GRP78 receptors were also present on the cell membranes. However, the viral proteins were not found in those parts of the placenta which were in direct contact with the fetus – the villous stroma and the interstitial blood vessels. There were fewer receptors in the membranes of the syncytiotrophoblasts of uninfected women. There was no evidence of the virus in amniotic fluid, colostrum or neonatal throat swabs.

The inference is that the SARS-CoV-2 virus can gain access to the maternal side of the placenta and then increase the expression of the receptors required to enable its entry into placental cells. However, breaching the “placental barrier” appears to be more of a challenge for the virus, possibly because of a lack of, or inaccessibility to, the requisite cell membrane receptors on the fetal side of the barrier. These findings are in accord with reports from previous placental studies and may help explain the finding of a growing number of clinical studies that in-utero transmission of SARS-CoV-2 from mother to fetus rarely occurs.

Patberg EKhullar PAJOGCOVID-19 Infection and Placental Histopathology in Women Delivering at Term20 Oct 2020USANorth AmericaNeonatal https://www.sciencedirect.com/science/article/pii/S0002937820311947

The evidence to date indicates that transmission of SARS-CoV-2 from mother to foetus during pregnancy (“vertical transmission”) is rare. It has been suggested that one reason for this is that co-expression of two receptors (ACE-2 and TMPRSS2), both of which are required for entry of the virus into host cells, rarely occurs in third trimester placentas. Does this mean, then, that we need have no concerns about babies born to mothers who acquired SARS-CoV-2 during pregnancy if the babies are born at term and appear well at birth? The authors of this study of placentas speculate that such an assumption is not yet justified and that their findings raise the question of whether these babies should receive long-term follow-up.

In a retrospective study of placentas they found that, in comparison with a control group of 56 term singleton placentas from SARS-CoV-2 negative pregnancies, signs of fetal vascular malperfusion - the presence of avascular villi and/or mural fibrin deposition – were more common in 77 singleton term placentas from mothers who were SARS-CoV-2 positive during pregnancy. The changes were seen in 32.5% of these placentas. After adjustment for maternal age, race/ethnicity, mode of delivery, preeclampsia, fetal growth restriction and oligohydramnios the frequency of fetal placental vascular malperfusion abnormalities was significantly higher in the SARS-CoV-2 positive group (OR= 12.63, 95% CI [2.40, 66.40]). The changes were present in placentas from both symptomatic and asymptomatic Covid-19 mothers. The distribution of the abnormalities was global in pattern, involved endothelial damage and was suggestive of altered flow rather than the thrombotic phenomena which have been associated with Covid-19. There was no association of findings of maternal placental vascular malperfusion with SARS-CoV-2 positivity. Neonatal outcomes including birthweight, Apgar scores and NICU admissions were similar between the groups and all babies of the Covid-19 mothers tested negative for SARS-CoV-2 using PCR.

Similar findings have been reported in some, but not all, previous studies. The authors acknowledge the limitations of this retrospective study, including the selective nature of the controls (most were from caesarean section deliveries pregnancies while the SARS-CoV-2 positive group were mainly vaginal deliveries) and the lack of information concerning the stage of pregnancy at which the virus was acquired. They emphasise that their study was confined to full term pregnancies.

The study also looked at “villitis of unknown etiology” and a similar trend was found but this did not reach statistical significance using a multivariate model.

This report raises some important questions for paediatricians. Do these vascular abnormalities on the fetal side of the placenta, if confirmed in prospective studies, have implications for the future health and development of the baby, child and adult? What do we know about long term outcomes for babies born to mothers who contracted SARS-CoV-2 during pregnancy? Have we been too complacent? It is important that long term prospective observational studies are carried out to answer these questions.

Kalamdani, PMondkar, JIndian PediatricsClinical Profile of SARS-CoV-2 Infected Neonates12 Oct 2020IndiaAsia12Neonatalhttps://www.indianpediatrics.net/epub102020/RP-00250.pdf

This is a retrospective case record review of infants with SARS-CoV-2 infection, born in hospital to infected mothers in Mumbai, India between 1 April 2020 to 31 May 2020

Of 1229 women admitted to the hospital in labour during the study period, 185 (15.05%) tested positive for SARS-CoV-2 infection, as ascertained by real time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs. Three (1.7%) mothers had fever and two of these three also had mild breathlessness.

The infants of these infected mothers were then tested and 12 (6.48%) were found to be positive for SARS-CoV-2 infection - 50% were tested at 48 hours, 25% at 72 hours

The median gestational age of the infected group was 38 weeks and the ratio of males to females was 2:1. No infected neonate had respiratory symptoms, lethargy or neurological symptoms. Three had fever and two had feeding difficulty. None required NICU admission and all remained with their mothers in the postnatal wards. All were breastfed. All infants in this group remained healthy at 2 months of age as ascertained by telephone follow-up.

Liver function tests were carried out in 9 infected infants and the authors state that “marked elevation of LDH levels and mild transaminitis were observed”. The actual results in the accompanying Table are: mean AST 75 IU/L, mean ALT 29 IU/L and mean LDH 1462 IU/L.

The authors conclude that SARS-COV-2 infection in neonates is mainly mild or asymptomatic and that infected neonates can be successfully roomed-in with their mothers and be breastfed.

Fenizia, CSavasi, VNat CommunAnalysis of SARS-CoV-2 vertical transmission during pregnancy12 Oct 2020ItalyEurope31Neonatalhttps://www.nature.com/articles/s41467-020-18933-4

This is a prospective multicentre cohort study conducted in Italy. Pregnant women who tested positive for SARS CoV 2 were recruited between March and April 2020. 31 women were included in the study and these women and their newborns were investigated for evidence of congenital infection. They analysed maternal plasma (viral RNA, IgG and IgM), vaginal swab, placenta, umbilical cord plasma (viral RNA, IgG and IgM), amniotic fluid, newborn nasopharyngeal (NP) swab and breast milk (viral RNA, IgG and IgM). According to the Shah et al classification, one newborn was confirmed to have congenital infection (case no 17) and another (case no 25) was a possible congenital infection.

Patient No 17 Patient No 25

Gestation at delivery Preterm (34/40) Term

Mode of delivery Vaginal Vaginal

Maternal illness severity Severe Mild

Maternal plasma viral genome Positive Negative

Maternal plasma antibody IgG and IgM positive IgG and IgM positive

Placental Viral RNA Positive Positive

Vaginal Viral RNA Positive Negative

Umbilical cord plasma viral genome Positive Negative

Umbilical cord plasma antibody IgG positive IgM negative IgG and IgM positive

Newborn NP swab Positive Positive then Negative at 48hrs

Neonatal clinical condition Asymptomatic at birth Asymptomatic at birth

Along with patient 17, patient no 4 (Severe maternal infection) was the only other maternal serum that was positive for the viral genome. IgM was positive in 32.1% of maternal serum and 3.3% (1 out of 30) umbilical cord and IgG was positive in 63.3% of maternal serum and 40.0% of umbilical cord sample. Of the 10 breastmilk sample tested, viral RNA and IgM was positive in only case no 1 (10%). They also conducted proinflammatory 84 gene pannel analysis on placental specimens from case no 17, 25 and 31 and compared it to an uninfected control placenta. There was a generalised immune activation profile in the cases (even in case 31 who had recovered 4 weeks before delivery) compared to the control. The hyeractivation profile was most evident in case no 17 and 25 compared to case 31. A 27 cytokine assay was carried out on maternal plasma from the 4 cases and these reflected the profiles seen at the level of the mRNA in the placenta.

This study shows that congenital infection with SARS CoV 2 may be possible. Maternal illness severity may be an influential factor in the vertical transmission as there is greater proinflammatory activation both at the placental and systemic levels in the severe manifestation of the infection. Also the only two cases in which viral genome was isolated in maternal serum had severe COVID infection As patient 17 was the only one to deliver prematurely it is also important to ask whether severe infection with SARS CoV2 triggers premature labour. However, patient 25 had a mild infection but their umbilical cord bood was IgM positive and therefore confer the possibility of vertical transmission. The study is too small and therefore further research is needed to draw conclusions.

Dumitriu, DGyamfi-Bannerman, CJAMA PediatricsOutcomes of Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection at a Large Medical Center in New York City12 Oct 2020USANorth America101Neonatalhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2771636

This is a retrospective cohort study conducted on women who either tested positive to SARS CoV 2 on swab (n=99) or were symptomatic with radiological findings consistent with SARS Cov2 (n=1). The women were admitted to two centres in New York City between 13th March 2020 to 24th April 2020. They were tested either because they were symptomatic (n=22) or as part of the universal screening which introduced later in the study period. The women were categorised into asymptomatic/mild disease (n=90) or severe/critical (n=10) based on the Wu and McGoogan classification. The women in the severe/critical group were older (34 vs 28 p=0.04), had more pregestational diabetes (2 vs1 p=0.03) and a lower gestation at delivery (37.9 vs 39.1 p=0.02). 50% of the severe critical had c-sections compared to 40.7% of asymptomatic/mild (not a statistically significant). All obstetric and neonatal care was carried out as per usual with vaginal deliveries, delayed cord clamping, skin to skin, rooming in for well-baby nursery (WBN) infants and encouragement of breast feeding (with appropriate infection control measures of hand and breast hygiene and mask wearing). There were 101 infants born to these mothers, with 19 infants being admitted to NICU (8 preterms, 8 congenital malformations, 2 respiratory distress syndrome and 1 suspected sepsis) and 82 to WBN. Of the babies in WBN, those born to mothers with severe/critical illness were at higher risk for requiring phototherapy (30% vs 7% p=0.04).The study defines vertical transmission as a positive swab on the initial swab and a postnatal transmission as a positive on subsequent swabs. Initial swabs were done on D0 of life (n=15), D1 of life (n=79) and D3 of life (n=7). Of the 141 neonatal swab tests performed (101 initial and 40 subsequent), 135 were negative, 4 were invalid and negative on repeat and 2 were indeterminate. Indeterminate indicated detection of low viral load and was taken to be a positive result in this study. These results were from swabs taken as the initial swab and therefore the study reports a transmission rate of 2%. The particulars of these two cases are outlined below.

Neonate 1 Neonate 2

Maternal illness Asymptomatic/Mild Asymptomatic/Mild

Mode of delivery Vaginal Nonemergent c-section for pathological fetal heart rate

Initial test Day 3 of life after maternal symptom development D0 of life as mother had intrapartum symptoms

Breast feeding Breast fed once Breast fed during hospital stay

Clinical course Uncomplicated Uncomplicated

Repeat test Not done On D2 was negative

Follow-up Well at assessment in clinic on D6 of life Well at assessment in clinic on D6 of life

55 infants were seen in follow-up clinics at time points ranging from D3 to D10 of life who were all well at assessment. 20 of these infants plus 3 other infants had 32 nonroutine encounters (up to D25 of life) but did not have SARS CoV 2 infection at each of these events.

The important aspect of the results from this study is that usual obstetric (vaginal delivery, delayed cord clamping) and immediate postnatal care (skin to skin, breastfeeding, rooming-in, delayed bathing) does not seem to affect the rate of postnatal/peripartum transmission. It is interesting that there is a significant difference is in the gestation at delivery between the asymptomatic/mild and severe/critical groups of women. However, there was no preterm rupture of membranes or preterm labour in the severe/critical group and only 1 preterm birth. Therefore, could the earlier birth have been down to c-sections for maternal reasons. Maternal age and pregestational diabetes seem to be risk factors in development of severe illness in the mother. The study claims a 2% transmission rate, but this is based on indeterminate swab results. Neonate 1 was tested on D3 (mother was not following infection control measures prior to developing symptoms and testing positive) and therefore could have been horizontally acquired. There is no antibody test performed/reported. Though the study does not offer an explanation for the increased phototherapy need in the WBN severe/critical maternal illness babies, it is likely that feeding (especially breast feeding) would have been affected due to the maternal illness. The follow-up assessments findings are reassuring, but longer-term follow-up is required.

Flannery, DPuopolo, KmedRxivTransplacental Transfer of SARS-CoV-2 Antibodies 11 Oct 2020USANorth America72Neonatalhttps://www.medrxiv.org/content/10.1101/2020.10.07.20207480v1

This single-centre cohort study was conducted in Pennsylvania, USA between 09/04/20-08/08/20 and it looks for SARS CoV 2 antibodies in the maternal/newborn dyads. They used cord blood samples and maternal serum (all discarded specimens) to determine the presence and levels of antibodies. They also looked at the results of maternal and neonatal napsopharyngeal PCR tests for SARS CoV 2. They used ELISA to detect IgG and IgM to SARS CoV 2 spike protein receptor binding domain with a cut off at 0.48 arbitary units to define seropositivity.

During the study period, there were 83 seropositive (IgG and/or IgM) mothers and 72/83 newborns who were IgG positive (all were IgM negative). Of the 11 seronegative babies were born to seropositive women, 5 were born to mothers who were only IgM positive and 6 other seronegative newborns had mothers who’s IgG was significantly lower (1.27 vs 5.22 arbitrary units, P=0.005) than the levels of the 72 mothers who’s newborns were positive for IgG. All babies born to the 1388 seronegative women, also tested negative for the antibodies. 50/83 of the seropositive women were asymptomatic. All but one of the 83 women underwent a nasopharyngeal swab and 44/82 of these were positive. 20 out of the 83 babies underwent nasophargngeal swab testing and they were all negative. There was a positive correlation with the level of SARS-CoV-2 IgG in maternal serum and cord (Pearson’s r2=0.7852, P<0.001). Moderate and critical illness (n=8) severity was associated with higher maternal serum IgG and IgM and their infants had higher cord IgG level (not statistically significant). Transplacental transfer ratio (infant IgG level divided by maternal IgG level) was used as a marker of transfer efficiency. Transfer ratio did not differ across illness severity. In symptomatic women (n=26), there was a positive correlation (Pearson’s r2=0.3845, P<0.001) with the time between the symptom-prompted viral PCR testing (used as a surrogate marker for viral exposure) and delivery, and the transfer ratio. There was no association between maternal demographics and pregnancy health characteristics and cord blood seropositivity. There was no difference in the transfer ratio between term and preterm infants.

Despite the small sample size of this study, it is the largest published cohort to show the presence of IgG antibodies in the cord blood, thus showing transplacental transfer of SARS CoV 2 antibodies. The absence of IgM in the cord blood adds weight to the notion that in-utero fetal infection with SARS CoV2 is rare. The study also shows that the higher the antibody level in the mother the higher the cord blood antibody (what might this mean for immunodeficient mothers?) level and the greater the length of time between onset of symptom and delivery the greater the transfer efficiency. Both associations have not been shown before. However, it is important to point out that the longest time period between testing and delivery was in those with moderate to critical illness and this could have caused the higher levels and acted as a confounding variable. Though this study shows no relationship between illness severity and transfer ratio, this may have been because of the small sample size in the moderate to critical illness category. The other positive correlations which were not statistically significant may have been because of the small sample size in this study. The clinical use of this study is limited as it does not show whether infants with the IgG against SARS CoV 2 have a better outcome when exposed to the virus. Further studies are required.

Flaherman, VGaw, LClin. Infect. DisInfant Outcomes Following Maternal Infection with SARS-CoV-2: First Report from the PRIORITY Study18 Sep 2020USANorth America263Neonatalhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1411/5908705

The Pregnancy CoronavIrus Outcome ReIsTrY (PRIORITY) study is based in the USA and collects data on US women aged ≥13 years of age, who were suspected or confirmed to have SARS-CoV-2 during their pregnancy. The data presented in this first report was collected between 22/03-22/06. The demographics were collected at the time of enrolment and the outcome data was collected at time of infant birth and 6-8 weeks postnatally. All data was as presented by mothers and infant electronic medical records were used to confirm specifically reported disease or occurrence of events. The infant outcome measures were: birth defects, NICU admission, abnormal newborn examination, positive test for SARS-CoV-2, respiratory complications, gestational age at birth, preterm birth, birthweight, gender, fast or difficulty breathing, upper respiratory infection, apnoea, rooming-in with mother and breastfeeding at 6-8 weeks. The outcome rates were compared between those infants born to mothers who tested positive with those born to mothers who tested negative for SARS-CoV-2.

The study reports on outcomes for 179 women who tested positive and 84 who tested negative for SARS-CoV-2 (a total of 263 infants). Due to the staggered nature of outcome measures being introduced in this study, not all measures were collected in all infants. There was no significant difference in the occurrence of outcome measures between the two groups. The study then reports on comparison on the rate of outcome occurrence in those babies born to mothers who tested positive at differing times prior to delivery.

Those babies who were born to mother who tested positive 0-14d prior to delivery were also less likely to room-in.

This is a weak study with many limitations. Firstly, the comparison group of who acted as the control included asymptomatic and symptomatic women who tested negative. This creates bias created by false negative results from swab tests in whom the clinical symptoms may typify a coronavirus infection. Though this study is nationwide, most women participating were white (58% of positive and 59% of negative), thus making generalisability difficult. The data on outcome measure is not available for all 263 infants in this study, in part due to the late introduction of certain outcome measures once the study period had commenced (in May 2020). Therefore, the small sample size is made even smaller, thus creating type 2 error. Though the study shows significant higher in NICU admission and lower gestation at birth for women who tested positive within 14 days of delivery, the reason and timing for testing is not standardised across provider centres. Therefore, it is difficult to say that the difference observed in these groups were related to timing of virus exposure in-utero.

Diriba, KGetu, EEur J Med ResThe effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal–fetal transmission: a systematic review and meta-analysis04 Sep 2020EthiopiaAfrica1316Neonatalhttps://eurjmedres.biomedcentral.com/articles/10.1186/s40001-020-00439-w

Although the broader aims of this ambitious study are outlined in the title, a primary objective appears to have been to provide point estimates of a range of outcome prevalences, in both mothers and babies, associated with infection in pregnancy caused by SARS-CoV-2, MERS-CoV, and SARS-CoV.

The stated process for literature selection and appraisal was that of a systematic review, using primarily the standard critical appraisal instruments of the Joanna Briggs Institute. However, the authors report that the methodological framework for the study was one which was described for scoping studies, and it may be that the outcomes of this study might be seen to be in line with those of a scoping study rather than providing the precision of useful point estimates, given the heterogeneity of the meta-analysis data.

The robustness of the processes of the systematic review is difficult to evaluate, given the limited description in the text, no doubt in part attributable to word count restrictions. I did not identify a defined PICO, or equivalent, although the inference would be that the “population” and “intervention” were combined as pregnant women who had contracted infection caused by one of the three viruses; no “comparator” was referred to. The stated primary outcome was “the pregnancy outcomes observed” which were listed as: preterm birth (PTB; either before 37 or 34  weeks of gestation); preeclampsia; preterm prelabor rupture of membranes (pPROM); fetal growth restriction (FGR); miscarriage; maternal death; mode of delivery; other clinical features; laboratory findings; coexisting disease. The keywords used for the literature search were: coronavirus; novel coronavirus-2019 infection; pregnancy; Middle East respiratory syndrome; severe acute respiratory syndrome; severe acute respiratory syndrome coronavirus-2, and vertical transmission. It is difficult to be confident that these terms would identify all reports of the outcomes of stated interest, such as maternal symptoms, laboratory findings and neonatal mortality. Although it is stated that Boolean operators were employed, there is no description of how they were used. Only studies reported in English during the period 2003 – 2020 were included and all study designs, including case reports and at least one placental study, were eligible. A more detailed critique of the methodology of the systematic review is outside the scope of this review.

Of the papers selected for the review, 25 related to SARS-CoV-2, 7 to MERS-CoV, and 7 to SARS-CoV. However, in terms of patient numbers the SARS-Co-V-2 group predominated, with 1271 identified pregnancies, compared with 12 and 33 respectively in the other two groups; the outcomes were reported separately for each of the three viruses. The following outcomes from this study focus on babies born to mothers who were infected with SARS-CoV-2 - the reported findings relating to the mothers is beyond the scope of this report.

Some of the reported outcome numbers and statistics would benefit from clarification but the findings relating to selected outcomes for the babies are shown in the table, compared with those of a UK-based prospective cohort study of pregnant women hospitalised with confirmed SARS-CoV-2, which was also included in this systematic review; the UK study included a historical non-infected comparator group, for which outcome data are also shown in the table.

None of the studies in this systematic review were found to have provided evidence of proven in-utero (“vertical”) transmission of Sars-CoV-2 from the mother to the fetus in utero.

The heterogeneity of the selected studies, and of the resulting outcome data, included in this systematic review is high, with an I2 value of 98% in a meta-analysis of one of the maternal outcomes. The risk of selection bias is, therefore, also high and the reported pooled prevalence outcomes must be viewed with caution. However, the broader findings of the review concur with previous studies that the risks of preterm delivery, caesarean section and NICU admission are increased for babies born to mothers infected with Sars-CoV-2; the data concerning perinatal mortality perhaps require further scrutiny. This systemic review has also identified a large number of studies relating to Sars-CoV-2 infection in pregnancy and possibly provides direction to more focused studies of relevant outcomes. The findings also support the evidence from previous studies that in-utero transmission of Sars-CoV-2, if it occurs, is uncommon.

Demers-Mathieu, VMedo, EJ. PerinatolDifference in levels of SARS-CoV-2 S1 and S2 subunits- and nucleocapsid protein-reactive SIgM/IgM, IgG and SIgA/IgA antibodies in human milk01 Sep 2020USANorth AmericaNeonatalhttps://www.nature.com/articles/s41372-020-00805-w

This is a case-control study making multiple comparison between different groups of human milk samples to determine the difference in the levels of SARS-CoV-2 antibodies. The study collected two groups of human breast milk samples; 2020 HM (n=41) was collected between 30/02/20 - 03/04/20 and 2018 HM (n=16) was collected between 06/09/18 – 29/11/18. Both groups were further subdivided into those who were vaccinated (2020 HM n=26) to influenza and/or tetanus, diptheria and polio during pregnancy and those who were unvaccinated (2020 HM n=15). The mothers from the 2020 HM were not asked about their COVID 19 infection/exposure but were asked about viral respiratory symptoms in the preceding year. Mothers did not have an infection of any kind at the time of milk collection. All donor mothers resided in the USA, had negative HIV, HTLV, Hep B, Hep C and syphilis status, completed a health questionnaire and were not using specific medications. The presence and levels of secretory IgM (SIgM)/IgM, IgG and SIgA/IgA antibodies to SARS-CoV-2 S1 and S2 subunits and nucleocapsid were determined using ELISA. The S1 and S2 subunits are integral to the virus binding to host cell and the subsequent release of the viral RNA into the cell, respectively. Nuclocapsid protein binds to viral RNA to form the capsid, as well as interacting with the viral membrane proteins during assembly. The paper clearly describes the experiment protocol used to quantify the levels of antibodies in different samples.

This study demonstrates the presence of antibodies to SARS CoV2 S1+S2 subunits and nucleocapsid in human breast milk, with SARS CoV2 S1+S2 reactive IgA and SARS CoV2 nucleocapsid reactive IgM being the highest levels of the antibody isotype to the antigens. The detection of these antibodies in the 2018 HM suggests that there may be cross reactivity from exposure to other coronavirus or other virus families. The authors also note that the human milk antibodies are polyreactive and have the ability recognise a variety of antigens. This may suggest that breastfeeding babies may allow transferring of SARS CoV2 related immunity to the infant whether mother was specifically exposed to COVID 19 or not. It is interesting that there is a higher level of SARS CoV2 S1+S2 IgG in the vaccinated and the influenza vaccinated group. This adds weight to the importance of driving home the public health aspect of getting vaccinated during pregnancy. There is no information available on whether the mothers were diagnosed with or had exposure to COVID 19. However, the self-reported viral symptoms group having higher levels of SARS CoV2 S1+S2 IgG suggests that clinical manifestation of viral infection increases the production of antibodies. The detection of these antibodies in human milk does not translate into avoidance of clinical manifestation of infection in infant. Further studies are required to assess the outcome of babies who are fed with breastmilk containing the antibodies against SARS CoV2 antigens, when exposed to COVID-19.

Kotlyar, ATal, RAm J Obstet Gynecol.Vertical Transmission of COVID-19: A Systematic Review and Meta-analysis29 Jul 2020Multiple countriesInternational979Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820308231

This is a systematic review and meta-analysis of case reports (n=30) and cohort/case series (n=39) published up until 28th of May 2020. Authors identified the articles in Pubmed, Embase, MedRXiv and BioRXiv databases using the free text terms for SARS-CoV-2, COVID-19,coronavirus, coronaviridae, pregnancy, fetus, infant, mother-to-child, mother-to-infant, maternal fetal, virus transmission, disease transmission, and vertical transmission. The articles met the inclusion criteria of containing a population of SARS COV 2 positive pregnant women with data available on the results of COVID testing on the neonates born to these women. The testing on the neonates need to have been carried out within 48 hours of birth for the study to be eligible for inclusion.

The 30 case reports contained 44 women who were SARS CoV2 +ve and 43 neonatal results were gleaned from these studies. Majority of these women were in their 3rd trimester (29/30 of the case reports) and of the 44 women, 32 delivered via c-sections. Within these case reports, 4 out of 20 placentas were positive for SARS CoV2. Special mention is made of the case report by Vivanti et al who showed SARS CoV2 RNA positivity at multiple sites ,including neonatal blood sample.

Quantitative analysis of transmission rates was analysed only on the cohort/case series findings to minimise selection bias. The rate of transmission as determined by positive nasopharygeal swabs on the neonate was the primary outcome. However other samples were also pooled for analysis of transmission rates. The heterogeneity of the cohort/case series for rates of transmission as assessed by the nasopharyngeal swabs (n=38), was assessed using the Random effects model which was to provide a more conservative estimate. The heterogeneity was shown not to be statistically significant with an I2 of 0% (95% CI 0.0-35.6%). Quality of the 39 cohort/case series articles were assessed using the Newcastle-Ottawa scale, with 13 being assessed as good, 16 moderate and 10 low quality. The authors make a distinction between the studies reported from China and those reported by the rest of the world as they site two different forms of the virus, D614 and G614 respectively.

This systematic review shows that there is evidence for vertical transmission of COVID 19 in a minority of pregnant women in their 3rd trimester. The rates described in this paper are not applicable to women in the first trimester and this is an area that needs further research. There is variation in the quality of the cohort/case series included in this meta-analysis with only 13 of the 39 being assessed to be of good quality. The samples were collected within 48 hours of birth thus minimising, but not eliminating the chances of horizontal acquisition of the virus. The best indicator of in-utero infection is the detection of IgM in neonatal serology which showed a similar transmission rate as that demonstrated by the nasopharyngeal swab results. The rates of transmission calculated for all but the nasopharyngeal swabs are based on a small sample size and thus open to a wide margin of error. The authors comment that the variation in the transmission rates produced by testing different samples warrants the need for multiple sites to be tested to minimise false negative rates. Placental histology has shown evidence of abnormalities especially of the vasculature, thus raising the possibility that the damaged placenta may hinder intrauterine growth and development (e.g. through pre-eclampsia or placental abruption). Therefore, long-term follow is required before conclusions can be drawn about the effects of maternal infection on the neonate. These studies do not consider asymptomatic women, although as the inclusion criteria is based on lab confirmation rather than clinical symptom diagnosis, and therefore some may still have been included. Further questions regarding the role of maternal disease severity in affecting the transmission rate needs research. The studies included are those written in English or have been translated into English, therefore missing out on others who may greatly influence the outcomes reported in this paper.

Overall, this paper is noteworthy when it comes to counselling women regarding the risks of vertical transmission of COVID infection (quoting the pooled rate or ‘rest of world’ rate form nasopharyngeal swabs) in the later stages of pregnancy, all the while bearing in mind that the severity of maternal infection is likely to play a role in influencing the rates mentioned in this paper.

Gao, JChen, LEmerg Infect DisDisappearance of SARS-CoV-2 Antibodies in Infants Born to Women with COVID-19, Wuhan, China03 Jul 2020ChinaAsia24Neonatal https://wwwnc.cdc.gov/eid/article/26/10/20-2328_article

This letter reports on SARS-Co-V-2 antibody concentrations in 24 infants born to mothers with PCR-confirmed COVID-19 who had developed symptoms of Covid-19 infection prior to delivery, the symptom-onset to delivery interval ranging from 0-60 days. They were compared with 40 infants born to mothers without Covid-19.

All babies were admitted to the neonatal section of Tongji Hospital (Wuhan, China) between January 19–April 12, 2020. The 40 infants born to the Covid-19 negative mothers are reported to have had throat and anal swabs which all tested negative for SARS-CoV-2 nucleic acid, using a qualitative SARS-CoV-2 RT-PCR test. The 24 infants born to Covid-19 positive mothers are also reported to have had negative nucleic acid PCR tests but there are no details concerning the swabs which were taken. It is reported that none of these infants had complications related to pneumonia but there are no other clinical details concerning the babies.

Antibody testing was implemented in early March. Quantitative measurement of IgG and IgM was performed using the IFlash3000 Chemiluminescence Immunoassay Analyzer (YHLO Biotech). IgM or IgG titres >10 AU/mL were considered to be positive. For the 40 babies born to Covid-19 negative mothers it is reported that antibody assays were negative but there is no information concerning the timing or number of tests performed.

Each of the 24 infants born to Covid-19 positive mothers had at least one test for both IgG and IgM from 0-75 days following delivery (median number of tests 3, range 1-6 – my calculations from data in the table). Of these, 15 (62.5%) had detectable IgG on at least one occasion between 0 and 75 days following delivery and 6 (25.0%) had detectable IgM. The paper provides graphs of IgG and IgM titres plotted against time over the 75–day period following birth which the authors interpret as showing a slower rate of decline of IgG in the babies in whom both IgG and IgM were detectable compared with those in whom only IgG was detected.

The placenta of the infant with the highest IgG and IgM titres at birth showed slight inflammation with slight fibrin deposition and lymphocyte infiltrates; a photograph of the histology is included in the paper. The significance of these findings is not clear.

The authors comment that, although the presence of IgM antibodies, which do not cross the placenta, suggests vertical transmission of SARS-Co-V-2 from mother to fetus, the negative PCR tests do not support this conclusion.

The authors acknowledge that interpretation of the data in this study is limited by the small sample size for each data point with regard to antibody concentrations, but it seems reasonable to conclude that:there was a rapid decline in both IgG and IgM serum concentrations over the first two months of life in babies born to mothers who developed Covid-19 in the last two months of pregnancythere was a trend for the decline in IgG concentrations to be slower in babies in whom both IgG and IgM was present at birth compared with those with IgG only, but the numbers were too small for statistical interpretation both passive and active antibody protection against SARS-CoV-2 infection in newborn infants born to Covid-19 positive mothers may last only a few weeks

Hantoushzadeh, S.Aagaard, K.American Journal of Obstetrics and GynecologyMaternal death due to COVID-1901 Jul 2020IranMiddle East9Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305160
Chhabra, A. Subramaniam, RIndian Journal of Anaesthesia Anaesthetic management of a COVID-19 parturient for caesarean section - Case report and lessons learnt.23 Jun 2020IndiaAsia1Neonatalhttp://www.ijaweb.org/article.asp?issn=0019-5049;year=2020;volume=64;issue=14;spage=141;epage=143;aulast=Chhabra
NawsherwanWang, SIndian J PediatrImpact of COVID-19 Pneumonia on Neonatal Birth Outcomes22 Jun 2020ChinaAsia7Neonatalhttps://link.springer.com/content/pdf/10.1007/s12098-020-03372-2.pdf
Nyholm, SDiderholm, BActa PaediatricaInvasive mechanical ventilation in a former preterm infant with COVID‐1922 Jun 2020SwedenEurope2Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15437
Deng, G.Yin, M. J HepatolCharacteristics of pregnant COVID-19 patients with liver injury.20 Jun 2020China Asia6Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305728/
McDevitt, K Pathak, S. J InfectOutcome of universal screening of neonates for COVID-19 from asymptomatic mothers 19 Jun 2020UKEurope9Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303651/

This study is reported as a letter to the Editor.

The North West Anglia NHS Foundation Trust based in Peterborough, UK, introduced universal screening for SARS-CoV-2 of all in-patients, including asymptomatic newborn infants, on 27th April 2020. The testing method was naso-pharyngeal RT-PCR of nasopharyngeal swabs.

Between 27th April and 21st May 2020 481 infants were delivered, of whom 418 were screened. Nine infants (2.2%) tested positive within the first 24 hours of life, three within three hours. The gestational ages ranged from 364 to 422 weeks and birthweights from 2815 to 4420 g. Only one infant developed signs of illness – an oxygen requirement for 2 hours and high flow humidified nasal cannulae for 22 hours, a chest X-ray showing streaky hila and hazy consolidation in both lower lobes. Seven babies were re-tested at one to seven days of age and all were negative.

With regard to mode of delivery, three babies were born by ELCS elective caesarean section, three by EMCS and three by SVD. No details concerning membrane rupture-delivery interval are provided. All mothers were asymptomatic and only one tested positive to SARS-CoV-2. Five mothers who tested negative were re-tested at un-specified times and all were again negative.

The authors considered the following explanations for the positive tests:

Contamination of the specimens – this was considered to be unlikely as the specimens were taken on different days by different members of staff, all of whom were wearing PPE.

False positive results – this was also considered unlikely as the CT values of the RT-PCR were 29-31 and the specificity was 100% at a CT of 35, with a positive predictive value of 100%.

Maternal false negative results – these could not be rules out but were unlikely as all mothers were asymptomatic and three of the positive swabs were taken within three hours.

The mothers might have been positive previously and, although they were no longer shedding viral RNA in the nasopharynx, they had shed RNA or RNA fragments into the amniotic fluid and these were still within the newborns’ nasopharynx on the first day of life but cleared by the second test. Possible confirmation of this by maternal/infant serology was not available at the time.

This paper is published as the first report of the outcome of universal screening of newborn infants for SARS-CoV-2. The explanation for the finding of 2.2% positive naso-pharyngeal swab RT-PCR tests in the babies of asymptomatic mothers is currently not certain.

Dong, YChen, WEmerging Microbes & Infections Antibodies in the breast milk of a maternal woman with COVID-19 18 Jun 2020ChinaAsia1Neonatalhttps://www.tandfonline.com/doi/full/10.1080/22221751.2020.1780952

This paper relates to a single mother-baby dyad and reports on SARS-2-CoV antibodies in the breast milk and blood of the mother, who was suffering from Covid-19 at the time of delivery, and in the blood of her baby.

The mother was 33 years old at presentation and had developed clinical symptoms consistent with SARS-CoV-2 infection two weeks before the spontaneous onset of labour at 382 weeks gestation. She was admitted to a hospital maternity unit where RT-PCR testing of a throat swab was positive for SARS-CoV-2 and a chest X-ray showed patchy ground-glass opacities in the periphery of left lung. Laboratory blood testing showed a mild elevation of hepatic enzymes, a reduction on the proportion of lymphocytes (15.6%) and an increase in the proportion of neutrophils (80%).

The woman gave birth in a negative-pressure operating room and PPE was worn by all attendants. A female infant, weighing 2950 g, was delivered; the route of delivery is not stated but it appears to have been vaginal. Apgar scores were 9 at 1 minute and 10 at 5 minutes. Mother and baby were nursed in separate ICU isolation facilities following the birth. The mother initially received antibacterial treatment with azithromycin and ornidazole in an ICU ward and, 10 days following the birth, was transferred to a designated hospital for Covid-19 treatment in a different city; she was discharged home, well, 25 days after delivery. It appears that mother and baby had no contact with each other during this time and it is not stated whether the baby received maternal expressed breast milk at any time.

For the mother, RT-PCR testing of throat swabs showed positive results, with low CT values for SARS-Co-V-2, tested positive 11, 15 and 18 days following delivery, becoming negative at 21 days. All body fluids, including breast milk, and faeces tested negative for SARS-Co-V-2 throughout.

For the baby, naso-pharyngeal swabs were taken at birth and at 25 days of age, both testing negative to RT-PCR for SARS-Co-V-2. No other clinical details are provided concerning the baby.

ELISA assay immunoglobulin testing of maternal and infant serum, and of breast milk, was performed using SARS-CoV-2 spike protein as antigen. The results are shown in the table.

* Breast milk from SARS-CoV-2 negative mothers had a mean titre of 0.98 * Breast milk from SARS-CoV-2 negative mothers had a mean titre of 0.90This is possibly the first published report of: - the detection of SARS-Co-V-2 IgG and IgA antibodies in breast milk - the apparent disappearance of SARS-Co-V-2 IgG antibodies, presumed to have been acquired by a neonate via placental transmission, after six weeks. The implications of these observations for the health of babies born to mothers with a recent history of Covid-19 infection remains to be determined.

Khoury, RDolan, SObstet GynecolCharacteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers16 Jun 2020USANorth America245Neonatal https://journals.lww.com/greenjournal/Abstract/9000/Characteristics_and_Outcomes_of_241_Births_to.97310.aspx
Chambers, CAldrovandi, GmedRxivEvaluation of SARS COV-2 in breastmilk from 18 infected women16 Jun 2020USANorth America64Neonatal https://doi.org/10.1101/2020.06.12.20127944

This is a letter to the editor of the journal in which the authors report their finding on detection of SARS COV-2 in the breast milk of 18 infected mothers in the USA. A total of 64 breastmilk samples were collected between 27/03 and 06/05, pre and post the mothers testing positive for COVID. All samples were tested with quantitative RT-PCR for SARS Cov-2. 26 of these samples (from 9 mothers) also underwent tissue culture for the replication component of SARS Cov-2. The researchers also tested the Holder Pasteurization technique in eliminating the virus. They spiked 2 donor breast milk samples with the virus and then testing the samples with RT-PCR and the tissue culture method after the spiked samples had been subjected to the pasteurisation.

Of the 64 samples of breastmilk which were tested for viral RNA, only one sample tested positive and this was noted to have been on the day of symptom onset in that mother. All 26 samples which underwent tissue culture for the replication component of the virus, including the sample which tested positive for the viral RNA, were negative. Both donor milk samples were negative on RT-PCR and tissue culture following pasteurisation.

It is a very small sample and there is no standardisation of when the milk was collected from each woman and how frequently it was collected (varying between only one sample contributed to 12 samples from the same mother). It would have also been useful to know the COVID swab and/or antibody status of the infants. The merits of this study lie in the use of the tissue culture for replication components of the SARS CoV 2 which has not been used by the previous case studies which only looked for viral RNA in breast milk. The tissue culture is likely to be a more clinically meaningful way of analysing the breastmilk to determine infection risk to infant. It is reassuring that Holder pasteurisation method (also commonly used by milk banks in the UK) in donor breast milk can neutralise the virus. Further large-scale study is required to draw firm conclusions.

Blitz, MNimaroff, MAm J Obstet GynecolMaternal mortality among women with coronavirus disease 2019 admitted to the intensive care unit15 Jun 2020USANorth America7Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294262/pdf/main.pdf
Sentiles, LDeruelle, PAm J Obstet GynecolCOVID-19 in pregnancy was associated with maternal morbidity and preterm birth15 Jun 2020FranceEurope21Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294260/pdf/main.pdf
Griffin, ISchenkman, AAm J PerinatolThe Impact of COVID-19 Infection on Labor and Delivery, Newborn Nursery, and Neonatal Intensive Care Unit: Prospective Observational Data from a Single Hospital System13 Jun 2020USANorth America62Neonatal https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1713416
Bani Hani, D. A.Aleshawi, A. J. Am J Case Reports Successful Anesthetic Management in Cesarean Section for Pregnant Woman with COVID-19.12 Jun 2020JordonMiddle East1Neonatalhttps://www.amjcaserep.com/download/index/idArt/925512
Li, YLu, XIJIDComparison of Hospitalized Patients with pneumonia caused by COVID-19 and influenza A in children under 5 years11 Jun 2020ChinaAsia57Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30462-8/fulltext

This Case Series of three infants with SARS-CoV-2 infection paper is published as a Brief Report.

The paper is a report of three full-term babies (39-41 weeks) who were admitted from home to the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital Colorado (CHCO) after presentation to the hospital’s Emergency Department (ED) between March 28, 2020, and April 1, 2020. Ages at onset of “symptoms” were 16, 25 and 31 days and ages at admission were 17, 27 and 33 days respectively. Two were exclusively receiving breast milk at the time of admission; there are no details regarding feeding for the third infant. The mothers of two infants had a recent history of upper respiratory symptoms but there was no history of ill contacts for the third.

All of the babies had fever, rhinorrhea, and mild hypoxia with oxygen saturations in room air of 80–90%; the youngest infant also had tachycardia, systemic vasodilation, and bilateral conjunctivitis and received 20 mL/kg normal saline fluid resuscitation in the ED. There is no description of other abnormal respiratory signs such as cough or work of breathing. Blood gases for all three infants were reported to be normal. All were treated with supplemental oxygen of 0.25 -1.0 l/min via nasal cannulae and with systemic antibiotics. Chest X-rays of all three showed low lung volumes with hazy opacities but no focal consolidation. Diagnosis

The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs for SARSCoV-2 which were taken in the ED; there was no repeat testing and no mention of antibody testing.

The youngest infant had initial lymphopenia, which resolved before discharge, subsequent neutropenia which ws ongoing at the time of discharge and a mildly elevated CRP (1.5mg/dL). CRPs in the other two infants were 1.1 and 1.2mg/dL and blood procalcitonin levels were within the normal range; liver function tests and other haematological tests were normal in all three and microbiology tests, including virology, were negative. The babies were discharged home when they had been afebrile for at least 24 hours, after stays of 77-81 hours. Details of follow-up are not given but two infants showed decreased absolute neutrophils at some point after discharge.

The paper provides details of three of the youngest patients reported to have developed community-acquired SARS-CoV-2. The authors state that the three infants (one was just outside the neonatal age range) met the diagnostic requirements proposed by Chinese researchers: (1) clinical symptoms including fever and the need for respiratory support, (2) abnormal chest radiographs, and (3) being at high risk for SARS-CoV-2 infection due to close contact with a person with symptoms consistent with SARS-CoV-2 or living in an area with widespread CA-SARS-CoV-2. All three had mild to moderate courses with short hospital stays, which is consistent with previous reports in the paediatric literature. The authors advise that caregivers of neonates should wear face masks and wash their hands before handling neonates in the community and that isolation from positive family members would be prudent.

Preßler, JWellmann, SPediatric Allergy & ImmunologyPostnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study09 Jun 2020GermanyEurope61Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pai.13302

This letter to the editor in Pediatric Allergy and Immunology presents data on 61 deliveries where there had been varying degrees of unprotected parental contact with SARS-CoV-2-infected midwives, nurses and doctors during the first week (precontainment) of a COVID-19 outbreak affecting 36 staff members in a large maternity and perinatal centre in Bavaria, Germany. Two previous papers in the same journal, published 22 April 2020 and 15 May 2020, have reported on containment strategies, symptoms, SARS-CoV-2 RT-PCR tests and antibody responses (IgG and IgA) in hospital staff during the outbreak. The index case was a midwife returning from holiday in Ischgl, Austria on 8 March 2020, who became unwell during a nightshift on 9 March at Regensburg University Hospital obstetric clinic; the first positive SARS-CoV-2 RT-PCR test result was received on 15 March and at that point contact tracing, testing and containment measures were introduced.

Study design: 66 families were identified with an infant born at the clinic during the week of 9 to 15 March where parents had had unprotected contact with SARS-CoV-2-infected medical staff; of these, 61 families consented to a prospective cohort study involving serial symptom interview, serial SARS-CoV-2 RT-PCR screening in throat rinsing fluid (parents) and faeces (infants) and serum IgA and IgG antibody studies (parents and infants) 4-5 weeks post-partum. Serum and breast milk were also tested using a different antibody assay to verify antibody responses. The authors note in their paper of 15 May 2020 that IgM antibody testing would have been useful, but that validated and certified IgM tests were not available to them at that time.

Key neonatal findings: The median gestational age at delivery was 39.3 weeks. Infants in the study received skin-to-skin care, rooming-in and breastfeeding in line with the hospital’s usual practice. The authors state that antepartum infections can be excluded and that any neonatal infections probably occurred via postnatal horizontal transmission in the family setting. 16/61 families reported parental symptoms consistent with COVID-19 within 2 weeks postpartum (one or both parents), although only 5/16 symptomatic families had COVID-19 confirmed based on RT-PCR and antibody evidence. 3 infants of these 5 symptomatic PCR-positive families developed non-specific signs of infection, including fever, dyspnoea and compromised circulation, at 5, 10 and 26 days old, and were admitted to NICU. Details of treatment are not supplied, but symptoms resolved for all 3 within a few days. Blood cultures and tests for non-SARS-CoV-2 viruses were negative. 2/3 symptomatic neonates had PCR positive faeces (one of these still had PCR positive faeces at 4-5 weeks) and 1 asymptomatic neonate also had PCR positive faeces at 4-5 weeks. None of the 3 SARS-CoV-2 PCR positive neonates nor the uninfected neonates had elevated or even borderline antibodies [note that there is some minor disparity between results summarised in the text and the detailed figure showing results in individual families]. Only one mother had IgG-positive breast milk (serum IgG also positive at 4-5 weeks, serum IgA negative, PCR positive at 1 week but not at 4-5 weeks, infant symptomatic at day 5 with negative faecal PCR at 1 week/4-5 weeks and negative serum IgG/IgA at 4-5 weeks).

This paper describes the clinical presentation and course of the 27 children and young people with COVID who required paediatric intensive care in and around Paris at the height of the corona virus peak in France. The total population of all ages of the Ile de France , the region for which this centre is responsible for tertiary paediatric referrals, is around 12 million. During the time covered by the study, there were around 5000 COVID deaths in France, with the Ile de France region being the hardest hit.

Knight, MKurinczuk, JBMJCharacteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study08 Jun 2020UKEurope12Neonatalhttps://doi.org/10.1136/bmj.m2107
Martínez-Perez, OBaud, DJAMAAssociation Between Mode of Delivery Among Pregnant Women With COVID-19 and Maternal and Neonatal Outcomes in Spain08 Jun 2020SpainEurope78Neonatal https://jamanetwork.com/journals/jama/fullarticle/2767206

This paper reports an observational study from 96 level 2 or 3 maternity hospitals in Spain. The study, which appears to have been prospective, looked at outcomes related to mode of delivery for mothers and their neonates, where the mother was RT-PCR test positive for SARS-CoV-2 infection within 14 days of delivery. Only singleton pregnancies and mothers with no or “mild”* COVID-19 symptoms, and their neonates, were included in the comparison. Multivariable logistic regression was performed assessing the association between mode of delivery and maternal and neonatal outcomes. The regression model included adjustments for maternal age, body mass index, comorbidities, need for oxygen supplementation at admission, abnormal chest x-ray findings at admission, nulliparity, smoking, and prematurity.

Seventy-eight mothers and babies were included, 11 of the mothers receiving oxygen supplementation, at a point not stated. Forty-one (53%) delivered vaginally, 8 at < 37 weeks gestation, and 37 (47%) by caesarean section (CS), 29 for obstetrical indications and 8 for COVID-19 symptoms without other obstetrical indications; 18 of the CS deliveries were at <37 weeks gestation.

For the mothers, the outcomes reported were: no “severe adverse outcomes**” for those who delivered vaginally compared with 5 (13.5%) Intensive Care Unit (ICU) admissions among those who delivered by CS; 2 (4.9%) mothers who delivered vaginally had “clinical deterioration***” after birth compared with 8 (21.6%) among the CS group. After adjustment for potential confounding factors, birth by CS was significantly associated with clinical deterioration (adjusted odds ratio, 13.4; 95% CI, 1.5-121.9; P = .02).

For the babies, 8 (19.5%) who delivered vaginally and 11 (29.7%) born by CS were admitted to the Neonatal Intensive Care Unit (NICU). After adjustment for confounding factors, birth by CS was significantly associated with an increased risk of NICU admission (adjusted odds ratio, 6.9; 95% CI, 1.3-37.1; P = .02). Three (4.2%) of the 72 babies who were tested within 6 hours after birth had a positive SARS-CoV-2 RT-PCR result. Repeat testing at 48 hours was negative. None of these developed COVID-19 symptoms within 10 days. In addition, 2 babies born by CS at term, who were test negative at birth and who had contact with their parents following delivery, developed COVID-19 “symptoms” within 10 days, becoming test positive. Their “symptoms” resolved within 48 hours.

In their discussion, with regard to adverse outcomes, the authors observe that all patients (presumed meaning mothers) with vaginal delivery had excellent outcomes while 13.5% of mothers undergoing CS had severe outcomes. There is no indication that there was a statistical difference for adverse outcomes. For clinical deterioration, after adjusting for confounding factors, the authors concluded that CS remained independently associated with an increased risk of clinical deterioration for the mother and an increased risk of NICU admission for the baby.

This paper is the first to report that CS is associated with a possible increased risk of clinical deterioration for mothers, and NICU admission for babies, in pregnancies where the mother is RT-PCR test positive for SARS-CoV-2 infection at or near the time of delivery. The authors acknowledge that the confidence intervals were wide and estimates “fragile”. The raw data show that there was excess of some risk factors in the pregnancies delivered by CS, including prematurity and maternal BMI >30, oxygen requirement at admission and abnormal chest X-ray. Interpretation of the outcome data is, therefore, heavily dependent on the robustness of the multiple regression analysis.

Gregorio-Hernandez, RMartinez-Gimeno, AEur J PediatrPoint-of-care lung ultrasound in three neonates with Covid-1905 Jun 2020SpainEurope3Neonatalhttps://link.springer.com/article/10.1007/s00431-020-03706-4
Silverstein, J. S.Penfield, C. A AJPAcute Respiratory Decompensation Requiring Intubation in Pregnant Women with SARS-CoV-2 (COVID-19)04 Jun 2020USANorth America2Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272216/
White, ADietz, RNeonatologyNeonates Hospitalized with Community-Acquired SARS-CoV-2 in a Colorado Neonatal Intensive Care Unit 04 Jun 2020USANorth America3Neonatalhttps://doi.org/10.1159/000508962

This Case Series of three infants with SARS-CoV-2 infection paper is published as a Brief Report.

The paper is a report of three full-term babies (39-41 weeks) who were admitted from home to the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital Colorado (CHCO) after presentation to the hospital’s Emergency Department (ED) between March 28, 2020, and April 1, 2020. Ages at onset of “symptoms” were 16, 25 and 31 days and ages at admission were 17, 27 and 33 days respectively. Two were exclusively receiving breast milk at the time of admission; there are no details regarding feeding for the third infant. The mothers of two infants had a recent history of upper respiratory symptoms but there was no history of ill contacts for the third.

All of the babies had fever, rhinorrhea, and mild hypoxia with oxygen saturations in room air of 80–90%; the youngest infant also had tachycardia, systemic vasodilation, and bilateral conjunctivitis and received 20 mL/kg normal saline fluid resuscitation in the ED. There is no description of other abnormal respiratory signs such as cough or work of breathing. Blood gases for all three infants were reported to be normal. All were treated with supplemental oxygen of 0.25 -1.0 l/min via nasal cannulae and with systemic antibiotics. Chest X-rays of all three showed low lung volumes with hazy opacities but no focal consolidation. Diagnosis

The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR) assay of nasopharyngeal swabs for SARSCoV-2 which were taken in the ED; there was no repeat testing and no mention of antibody testing.

The youngest infant had initial lymphopenia, which resolved before discharge, subsequent neutropenia which ws ongoing at the time of discharge and a mildly elevated CRP (1.5mg/dL). CRPs in the other two infants were 1.1 and 1.2mg/dL and blood procalcitonin levels were within the normal range; liver function tests and other haematological tests were normal in all three and microbiology tests, including virology, were negative. The babies were discharged home when they had been afebrile for at least 24 hours, after stays of 77-81 hours. Details of follow-up are not given but two infants showed decreased absolute neutrophils at some point after discharge.

The paper provides details of three of the youngest patients reported to have developed community-acquired SARS-CoV-2. The authors state that the three infants (one was just outside the neonatal age range) met the diagnostic requirements proposed by Chinese researchers: (1) clinical symptoms including fever and the need for respiratory support, (2) abnormal chest radiographs, and (3) being at high risk for SARS-CoV-2 infection due to close contact with a person with symptoms consistent with SARS-CoV-2 or living in an area with widespread CA-SARS-CoV-2. All three had mild to moderate courses with short hospital stays, which is consistent with previous reports in the paediatric literature. The authors advise that caregivers of neonates should wear face masks and wash their hands before handling neonates in the community and that isolation from positive family members would be prudent.

Costa, SCattani, PCMIExcretion of SARS-CoV-2 in human breast milk02 Jun 2020ItalyEurope2Neonatalhttps://doi.org/10.1016/j.cmi.2020.05.027

This is a letter to the editor in which the authors describe the protocol used for testing for SARS COV 2 in human breast milk from 2 mothers who delivered in March 2020 at their hospital in Rome, Italy. They used the Seegene Allplex 2019-nCOV assay with special precautions taken with breast milk sample collections including dedicated electric pumps and aseptic technique for sample collection. A positive sample was identified if the cycle threshold vale was <40. Both patients were symptomatic (patient 1 requiring oxygen) at the time of delivery with positive nasopharyngeal swabs for SARS COV 2. Patient 1 delivered via emergency c-section due to fetal distress at 35+5 weeks. Patient 2 delivered via elective section due to previous section at term. Both infants had negative nasopharyngeal swabs, were clinically well and did not receive breast milk. Neonate of patient 1 had positive PCR on placental tissue, cord blood and 3 (D4, D5, D7) out of 6 (D4-D8 and D10) of the breast milk samples collected. All samples were negative for neonate of patient 2.

This letter raises the possibility of mother to infant viral transmission (albeit intermittent) directly through breast milk, rather than the previously thought of likely route which was through maternal respiratory droplets whilst breast feeding. The standardised method of breastmilk collection under aseptic technique minimises the risk of cross contamination. The letter calls for prohibiting breastfeeding until mother’s isolation period has ended and viral clearance is assessed. As neonates were not given the breastmilk, we cannot be sure whether the passing of viral RNA through breastmilk might have resulted in clinical infection in the neonate. Further large population-based studies are required to change current policies regarding breastfeeding in active cases of maternal COVID infection.

San-Juan, RAguado, JLancetIncidence and clinical profiles of COVID-19 pneumonia in pregnant women: A single-centre cohort study from Spain01 Jun 2020SpainEurope6Neonatalhttps://www.thelancet.com/action/showPdf?pii=S2589-5370%2820%2930151-6
Luo, QChen, HPre printSafety of Breastfeeding in Mothers with SARS-CoV-2 Infection01 Jun 2020ChinaAsia23Neonatalhttps://www.medrxiv.org/content/10.1101/2020.05.30.20033407v1
Piersigilli, FDanhaive, OThe Lancet, Child & Adolescent HealthCOVID-19 in a 26-week preterm neonate01 Jun 2020BelgiumEurope1Neonatalhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30140-1/fulltext
Zhu, CXia, YJ InfectRisk from Detectable Severe Acute Respiratory Syndrome Coronavirus 2 in Breastmilk01 Jun 2020ChinaAsia5Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270809/
Breslin, ND'Alton, MGynecology MFMCoronavirus disease 2019 in pregnancy: early lessons27 May 2020USANorth America2Neonatalhttps://reader.elsevier.com/reader/sd/pii/S2589933320300410?token=4C959DDF7EB12D7B76B1E63FA1F96A0989263A0BB2CECE20E5FCBFB628A46B1701A439F7D08AD5DEFCC46CCEBD5E24F0
Yilmaz, RUzun, STJ Clin AnesthAnesthetic management for cesarean birth in pregnancy with the novel coronavirus (COVID-19)27 May 2020TurkeyEurope1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250746/pdf/main.pdf
Fontanella, F.t Baalman, J. H. Eur J Obstet Gynecol Reprod Biol. COVID-19 infection during the third trimester of pregnancy: Current clinical dilemmas.26 May 2020Netherlands and Ireland, UKEurope2Neonatalhttps://www.ejog.org/article/S0301-2115(20)30337-7/fulltext
Campbell, KPettker, CMJAMAPrevalence of SARS-CoV-2 Among Patients Admitted for Childbirth in Southern Connecticut26 May 2020USANorth America30Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2766650
Salik, IMehta, BJournal of Clinical AnesthesiaTetralogy of Fallot palliation in a COVID-19 positive neonate25 May 2020USANorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0952818020308540?via%3Dihub
Carvalho, WJohnston, CClinicsNeonatal SARS-CoV-2 infection25 May 2020BrazilSouth America1Neonatalhttps://www.clinicsjournal.com/wp-content/uploads/articles_xml/1807-5932-clin-75-e1996/1807-5932-clin-75-e1996.pdf
Tang, MWBiermond, BJAm J HematolImmune Thrombocytopenia during Pregnancy due to COVID-19 23 May 2020Netherlands Europe1Neonatalhttps://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.25877

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2.

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

.Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

McLaren, RAMinkoff, HLAJOGDelivery for respiratory compromise among pregnant women with coronavirus disease 201923 May 2020USANorth America9Neonatalhttps://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930567-6
Precit, MBard, JJ Paediatric Infect Dis SocA Case Report of Neonatal Acute Respiratory Failure Due to SARS-CoV-222 May 2020USANorth America1Neonatalhttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa064/5842097
Pereira, APerez-Medina, TActa Obstetricia et Gynecologica Scandinava Clinical course of coronavirus disease‐2019 in pregnancy22 May 2020Spain Europe23Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/aogs.13921
Alsharaydeh, IObeidat, NInt J Gynaecol ObstetChallenges and solutions for maternity and gynecology services during the COVID-19 crisis in Jordan22 May 2020JordanMiddle East2Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13240
Groß, RMünch, JLancetDetection of SARS-CoV-2 in human breastmilk21 May 2020GermanyEurope2Neonatal https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31181-8.pdf

The study primarily relates to the SARS­CoV­2 content of the breast milk of two “nursing mothers” who shared a room postnatally, with their babies, and who developed swab-positive mild Covid-19 infection after birth - three days and six days respectively. The gestation and birthweights of the babies are not reported but they seem to have been full term, well at birth and initially well for the first few days following delivery.

The babies developed abnormal respiratory signs, one with jaundice, at 8 days and 11 days respectively, both becoming swab positive for SARS­CoV­2 at about the same ages and both being admitted to a Neonatal Unit. One infant, who also tested positive for RSV, subsequently required mechanical ventilation. It is stated that one infant recovered but the outcome for the ventilated infant is not given.

The patient identification and recruitment processes are not described.

Breast milk was collected, after feeds and after nipple disinfection, from each mother starting at eight days and four days respectively after development of Covid-19 symptoms. Samples were collected on postnatal days 12-15 for the first mother and 10, 12, 13, 14 and 25 for the second. Testing for SARS­CoV­2 RNA was performed using RT­qPCR. Information on the method of nipple disinfection is not provided.

A separate laboratory-based study investigated the effect of breast milk on viral recovery rates by “spiking” breast milk with serial dilutions of a SARS­CoV­2 stock.

The main findings of potential importance are:1. The breast milk of one of the mothers tested positive for SARS­CoV­2 RNA at 10-13 days after birth. Testing of breast milk from the other mother was negative.2. Quantification using Ct values corresponded to 1∙32 × 10⁵ copies per mL in whole milk and 9∙48 × 10⁴ copies per mL in skimmed milk.3. An 89∙2% reduction in recovery rate in whole milk and 51∙5% in skimmed milk, suggesting that the actual viral loads in whole milk of the mother could be even higher than detected.

This study provides the first report of the detection of viral RNA in human breast milk collected from a mother who had clinical signs of Covid-19 confirmed by PCR testing of swabs. This does not provide evidence that the RNA was indicative of infectious virus or that transmission of the virus to the baby occurred via breastmilk.

Perrone, SEsposito, SJ Med VirolLack of viral transmission to preterm newborn from a COVID‐19 positive breastfeeding mother at 11 days postpartum21 May 2020ItalyEurope1Neonatalhttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26037
Zeng, YChen, DObstetrics & GynaecologyUpdate on clinical outcomes of women with COVID‐19 during pregnancy21 May 2020ChinaAsia16Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13236
Qadri, FMariona, FJ Matern Fetal Neonatal MedPregnancy affected by SARS-CoV-2 infection: a flash report from Michigan20 May 2020USANorth America16Neonatalhttps://www.tandfonline.com/doi/full/10.1080/14767058.2020.1765334
Joudi, NLyell, DAmerican Journal of Obstetrics & Gynecology MFMPreeclampsia treatment in severe acute respiratory syndrome coronavirus 220 May 2020AmericaNorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300902
Du, YLv, J J Anesth. Anesthesia and protection in an emergency cesarean section for pregnant woman infected with a novel coronavirus: case report and literature review.19 May 2020ChinaAsia1Neonatalhttps://link.springer.com/article/10.1007/s00540-020-02796-6
Savasi, VCetin, IObstetrics & GynecologyClinical Findings and Disease Severity in Hospitalized Pregnant Women with Coronavirus Disease 2019 (COVID-19)19 May 2020ItalyEurope57Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/Clinical_Findings_and_Disease_Severity_in.97347.aspx?sessionEnd=true
Yu, YShen, Y Int J Gynecol ObstetSevere COVID‐19 in a pregnant patient admitted to hospital in Wuhan19 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13232
Lokken E. M. Rah, SAmerican Journal of Obstetrics and GynecologyClinical Characteristics of 46 Pregnant Women with a SARS-CoV-2 Infection in Washington State19 May 2020USA North America8Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305585
Yang, HXiong, GArchivesEffects of SARS-CoV-2 infection on pregnant women and their infants: A retrospective study in Wuhan, China19 May 2020ChinaAsia24Neonatalhttps://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2020-0232-SA
London, VMinkoff, HAM J PerinatolThe Relationship between Status at Presentation and Outcomes among Pregnant Women with COVID-1919 May 2020USANorth America55Neonatalhttps://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0040-1712164.pdf
Cook, JGupta, ALCAHHorizontal transmission of severe acute respiratory syndrome coronavirus 2 to a premature infant: multiple organ injury and association with markers of inflammation19 May 2020UKEurope1Neonatalhttps://doi.org/10.1016/S2352-4642(20)30166-8

This is a single case report of an ex-27 week preterm male infant, who presented on the 30/03 to King’s College Hospital, London at 8 weeks of age (35 weeks CGA). He had a relatively stable NICU course requiring 3 days of ventilation and had been discharged 10 days prior to presentation. Household members were asymptomatic and there were no cases of COVID 19 prior or post his discharge from NICU. Symptoms (not specified) had commenced 2 days prior to admission. At presentation he was in presumed septic shock with unrecordable BP, lactic acidosis and respiratory distress and was intubated and commenced on 4 antibiotics and acyclovir. Investigations on admission included a CXR (bilateral airspace opacification), nasopharyngeal swab (positive for SARS COV2) and blood culture (grew Staph. epi). Urine, CSF and respiratory secretions were negative and subsequent 2 blood cultures were negative. 2 further nasopharyngeal swabs on day D7 and D15 of admission continued to be positive. On D8 there was respiratory deterioration (repeat CXR showing worsening bilateral opacification) and he was commenced on HFOV with iNO. Remdesivir was also commenced at this time and continued for a 10 day course. Ferritin and LDH peaked just before D8 and IL6 and IL10 were the highest on D8 (no levels available prior to D8). CRP was highest on admission and had quickly declined, with no rise associated with the respiratory deterioration. He was switched back to conventional ventilation on D16, extubated to Highflow on D22 and off all respiratory support on D24. He was discharged from PICU to the general paediatric ward on D25 to continue weaning off sedation (no neurological sequalae reported). There was evidence of liver (raised AST and GGT) and renal (raised creatinine with peak around D7) impairment along with bone marrow dysfunction (drop in platelet and WCC) initially which improved during the admission. There was no change in the viral load between admission and D16-17 of admission.

This case report is the first to chart the clinical course of a SARS COV 2 related hyperinflammatory state in a baby with a background of being born very preterm. The timing from NICU discharge to symptom onset makes it likely that the SARS COV 2 infection was acquired post discharge. The report does not explain why the ETT is barely visible/not present on the second CXR. It is not possible to say whether the IL6 and IL10 peaks were on the day of deterioration or whether this may have preceded it (as was the case in LDH and ferritin levels), since there were no interleukin levels prior to D8. Unlike ferritin and LDH, interleukin levels are not routinely tested outside tertiary centres. Therefore, the former two markers are a more feasible option for purposes of basing day to day clinical decision-making but may not be specific to SARS COV2 related hyperinflammation. CRP levels did not correspond to the respiratory deterioration. It is unclear whether the drop in all WCC lines and platelets suggestive of the marrow suppression and the acute renal and liver dysfunction were secondary to the shock at presentation or part of the hyperinflammatory state. It would have been helpful to know about the coagulation and fibrinogen status in this case. It is also noteworthy that Remdesivir did not change the viral load during the acute period of the admission. Therefore, it stands to reason that administration of this antiviral did not contribute to the clinical improvement, as suggested by the authors.

Future studies need to look at whether the specific inflammatory markers delineated in this case report could be used to predict which infant is susceptible to hyperinflammatory state and help steer the early course of management (e.g. early switch to HFOV).

Ahmed, I.Tan, B.K.British Journal of HaematologyFirst Covid‐19 maternal mortality in the UK associated with thrombotic complications18 May 2020United KingdomEurope1Neonatalhttps://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16849?af=R
Patane, LCornolti, GAJOG MFMVertical transmission of Covid-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with Covid-19 positive mothers and neonates at birth18 May 2020ItalyEurope2Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300896
Panichaya, PUthaisan, JEur J Obstet Gynecol Reprod BiolProlonged viral persistence in COVID-19 second trimester pregnant patient18 May 2020ThailandAsia1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233222/pdf/main.pdf
Fang, HDunjin, CObstetrics & GynaecologyBe aware of misdiagnosis—Influenza A H1N1 in a pregnant patient with suspected COVID‐1918 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13183
2. Dumpa, VNoor, A Cureus Neonatal Coronavirus 2019 (COVID-19) Infection: A Case Report and Review of Literature17 May 2020USANorth America1Neonatalhttps://www.cureus.com/articles/32203-neonatal-coronavirus-2019-covid-19-infection-a-case-report-and-review-of-literature
Mehta, HRezai, FElsevierNovel coronavirus-related acute respiratory distress syndrome in a patient with twin pregnancy: A case report16 May 2020USANorth America2Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229956/pdf/main.pdf
Cooke, WSoulsby, KEur J Obstet Gynecol Reprod Biol. SARS-CoV-2 infection in very preterm pregnancy: Experiences from two cases15 May 2020United KingdomEurope2Neonatalhttps://www.ejog.org/article/S0301-2115(20)30276-1/pdf
Doria, MSilva, PTEur J of O&G & Reproductive BiolCovid-19 during pregnancy: a case series from an universally tested population from the north of Portugal15 May 2020PortugalEurope11Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227580/pdf/main.pdf
Calderaro AChezzi CInt J Infect DisSARS-CoV-2 infection diagnosed only by cell culture isolation before the local outbreak in an Italian seven-week-old suckling baby14 May 2020ItalyEurope1Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30342-8/fulltext
Kirtsman, MSha, PcmajProbable congenital SARS-Cov-2 infection in a neonate born to a woman with active SARS-Cov-2 infection 14 May 2020CanadaNorth America1Neonatalhttps://www.cmaj.ca/content/cmaj/early/2020/05/14/cmaj.200821.full.pdf
Perlman, JPace, JOJAAPDelivery room preparedness and Early Neonatal Outcomes During COVID19 pandemic in New York City14 May 2020USANorth America247Neonatalhttps://doi.org/10.1542/peds.2020-1567

is a prospective cohort study of women delivering at New York Presbyterian Hospital between 22/03/2020 and 15/04/2020. Specific infection control protocols (figure 1) were implemented for minimising risk of horizontal transmission from mother to their babies and to the staff involved in deliveries, transfer and/or admission to NICU. There were 326 deliveries, all of whom were tested with initial result turnaround time of 24hrs reducing to 2hrs by the end of the study. 31 mothers tested positive for SARS COV2 (15 asymptomatic and 16 symptomatic) and 9 were classified as patient under investigation (PUI), with results being awaited at the time of delivery. 2 babies from positive mothers (both preterm 33+2 and 32+3) and 4 babies from PUI mothers required CPAP and were admitted to NICU and placed in isolation. The 4 babies of the PUI mothers who were admitted to NICU were moved out of isolation following a negative test result in their respective mothers. The 2 preterm babies were tested at 24hrs, 48hr, 7 days and 14 days of life with all tests being negative. They were moved out of isolation after 2 negative tests and separated from their mothers for 14d from the onset of maternal symptoms. However, no symptoms listed for one of the mothers, therefore separation length unclear. All other swab +ve mothers (n=29) were kept with their babies in the well-baby nursery (WBN) with breast feeding allowed. All 29 WBN babies tested (x1) negative within 24hrs of birth and were discharged within 48 hours.

The effectiveness of the infection control measures used is only reliably demonstrated in the 2 preterm admissions to NICU, where there was repeated testing and in whom there was postnatal separation from their SARS COV2 positive mother. As almost half of the positive women were asymptomatic (one of whom had the preterm delivery), the results highlight the importance of universal testing with rapid turnaround times, to allow efficient PPE use to minimise horizontal transmission and prevent unnecessary separation of mother and baby. Given the negative swab status of babies born to positive mothers, vertical transmission is unlikely but cannot be ruled out without testing for the immunoglobulin status.

Taghizadieh, A Valizadeha, HRespiratory Medicine Case ReportsAcute kidney injury in pregnant women following SARS-CoV-2 infection: A case report from Iran.13 May 2020Iran Middle East1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219375/
Baergen, RHeller, DPediatr Devel PatholPlacental Pathology in Covid-19 Positive Mothers: Preliminary Findings.12 May 2020United states North America20Neonatalhttps://journals.sagepub.com/doi/pdf/10.1177/1093526620925569

This is a rapid communication letter in a pathology journal describing 20 placentas of Sars-Cov-2 positive mothers at Weill Cornell Medical Center, New York. Clinical details of both mothers and infants are also described. This hospital screened all expectant mothers for Sars-COV-2 by RT PCR. These are results of the examination of the first 20 placentas received by the pathology department

Clinical features; 4 woman were symptomatic peripartum; 2 had fever on presentation, 1 had been admitted with hypoxia and pneumonia but discharged pre delivery, 1 was re-admitted day 3 postpartum for hypoxia and shortness of breath, the rest were asymptomatic. Mothers were aged median 31 years (13.5 years) 4 women had pre-existing conditions ( 1 sickle trait, 1 chronic diabetes, 1 hypertension, 1 hypothyroid). No woman required ICU admission.

There was 19 singletons, and 1 set of twins. No infant tested positive for Sars CoV-2. Five infants were born at 32 - <37, and the rest from 37 weeks gestation. All infants had 5-minute Apgars of 8 or 9, were admitted to the well-baby nursery, and discharged home.

Pathology Features; Placental tissue was not tested for Sars Cov 2. Nine placenta (45%) had evidence of fetal vascular malperfusion. In three cases this was intramural fibrin deposition it one or two areas; in two cases there was foci of stromal-vascular karyorrhexis, and in the other four there was widespread foci of stromal-vascular karyorrhexis. In all cases vascular malperfusion was graded as mild. In one woman who had pneumonia and acute hypoxia, placenta showed evidence of ascending infection with acute chorioamnionitis and acute funisitis. Four other cases showed chronic villitis though its relationship to SArs COV 2 is unclear.

Conclusion; Authors conclude that Sars Cov2 in mothers, may be associated with a propensity for thrombosis in fetal circulation. However, they caution this might also be unrelated and further work is needed.

Lorenz, NGrober, KThe Pediatric Infectious Disease JournalNeonatal Early-Onset Infection With SARS-CoV-2 in a Newborn Presenting With Encephalitic Symptoms12 May 2020GermanyEurope1Neonatalhttps://journals-lww-com.libproxy.ucl.ac.uk/pidj/Citation/9000/Neonatal_Early_Onset_Infection_With_SARS_CoV_2_in.96175.aspx

This is a letter describing a case of encephalitic and respiratory symptoms in a neonate with positive SARS-CoV-2 nasopharangeal and rectal swabs.

The mother was symptomatic (mild respiratory infection, loss of smell and taste, fever 38.1C) during delivery and confirmed SARS-CoV-2 positive after delivery.

The baby, born at 40+3 weeks gestation by vacuum extraction, developed lethargy and therapy refractory fever at 24 hours of life, progressing by 54 hours of life to symptoms described as encephalitic (lethargy with hyperexcitability, high pitched cry). Nasopharyngeal and rectal swabs were positive for SARS-CoV-2 (CSF was negative). No other viral or bacterial pathogens were isolated from blood/CSF/nasopharyngeal or faecal samples.

Respiratory symptoms developed from day 4 requiring oxygen and continuous positive airway pressure therapy, and a viral pneumonia was diagnosed on day 10. The baby recovered and was discharged on day 14 (SARS-CoV-2 swabs still positive at discharge).

Liu, PZhang, YJ Allergy Clin ImmunolThe immunologic status of newborns born to SARS-CoV2-infected mothers in Wuhan, China11 May 2020ChinaAsia51Neonatalhttps://www.sciencedirect.com/science/article/pii/S0091674920306400
Polonia-Valente, RRodriguez, TEur J Obstet Gynecol Reprod Biol.Vaginal delivery in a woman infected with SARS-CoV-2 – The first case reported in Portugal11 May 2020Portugal Europe1Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211642/
Perrone, SEsposito, SActa BiomedReport of a series of healthy term newborns from convalescent mothers with COVID-19.11 May 2020ItalyEurope4Neonatalhttps://europepmc.org/article/med/32420961
Knight, MKurinczuk, JNDPHCharacteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV 2 infection in the UK: A national cohort study using UK obstetric surveillance system11 May 2020UKEurope247Neonatalhttps://doi.org/10.1101/2020.05.08.20089268

As a pre print this study should be interpreted with caution until it has undergone peer review.

This is a prospective observational national cohort study carried out across all 194 consultant-led maternity units in the UK. It captured data from women admitted to hospital with confirmed SARS CoV 2 between 01/03/20 and 14/04/20, with tests having been carried out only if the woman was symptomatic. 427 women were studied and compared to a historical control sample of 694 women admitted between 01/11/17 – 31/10/18 (a historical sample was chosen to avoid confounding by including asymptomatic or minimally symptomatic carriers of COVID). The total number of maternities in the study period was 86293 and therefore the incidence of admission the SARS CoV 2 confirmed women was 4.9 per 1000 maternities. The median gestation at admission was 34 weeks (IQR 29-38 weeks), with 81% of admissions in the 3rd trimester. The results showed that there was a statistically significant risk of admission with SARS CoV 2 patients who had the following factors:

From a Black and Minority Ethnicity group: adjusted OR 4.49 (3.37-6.00). Even after sensitivity analysis which excluded women from London, West Midlands and North West England which had high rates of general infection OR 3.67 (2.55-5.28)

Overweight: adjusted OR 1.91 (1.37-2.68)

Obese: adjusted OR 2.20 (1.56-3.10)

Pre-existing medical condition (asthma, hypertension, cardiac disease or diabetes):adjusted OR 1.52 (1.12-2.06) Maternal age ≥ 35: adjusted OR 1.35 (1.01-1.81)Being a current smoker reduced the risk of admission, with adjusted OR 0.3 (0.17-0.51).The odds ratio for each significant factor outlined above was adjusted for the other significant factors which became confounding variables. There were 40 admission to level 3 critical care with 4 requiring ECMO. There were 5 maternal deaths recorded, 3 of whom had been admitted to critical care. SARS CoV 2 associated maternal mortality was 5.6 (1.3-13.1) per 100,000. Only 9 women were treated with antivirals (oseltamivir, lopinavir/ritonavir and/or remdesivir). 61 women were given corticosteroids for the maturation of fetal lung.

247 women in this cohort gave birth (singleton/multip proportion not stated) to a live infant (n=243) or had a pregnancy loss (n=4). 59% of women gave birth via c-section with 20% under general anaesthetic compared to 29% of the control group with 7% of women delivering under GA. There were 63 (26%) preterm births (<37 weeks) and 29 of these were documented as being secondary to COVID 19 infection; the other reasons stated were iatrogenic, fetal compromise and other obstetric conditions. This is compared to 8.9% of births in the control group being born preterm. There were 5 neonatal deaths, including 3 stillbirth; in two of the cases of stillbirths, it is unclear whether COVID 19 infection contributed to death. The rate of pregnancy loss, still birth, livebirth and neonatal death was not statistically different between the groups. The NICU admission rate was 26% (majority for prematurity) and 5% in the cohort and comparison groups, respectively. 12 infants tested positive for SARS CoV 2, with 6 being within the first 12 hours of life (early). 1 in the early positive and 5 in the later positive groups were admitted to NICU.

This is a national study reporting on the largest cohort of SARS CoV 2 positive pregnant women admitted to hospitals with symptoms. There is likely to be an underestimation of the true effect size presented in this report as analysis was carried out in only those patient in whom data was returned and not on the entire cohort of admissions in the specified time period. The results convincingly show important risk factors (maternal age, black and minority ethnicity, BMI, and pre-existing medical condition) for admission and thus confers the severe of infection in these risk groups. The black and minority ethnicity risk factor, which existed even after the sensitivity analysis, requires urgent further analysis and study as it was the biggest risk factor and one which has not been demonstrated to be the case in other coronavirus strains. The supposed protective factor of current smoker status is not explained in this report but could reflect lower current prevalence of smoking in pregnancy in general compared to the prevalence at the time of the historical sample. The report also highlights that most of the admission with SARS CoV 2 was in the second and third trimester thus providing weight for the precautions currently being taken in this group of women. However, they also correctly identify that there may be a sampling bias as those in the first trimester may be being admitted to hospital via routes other than the maternity services. There was a higher rate of preterm deliveries (statistical significance unknown) which is difficult to interpret but raises questions as to what extent the maternal infection may cause fetal compromise triggering preterm birth.

2% of babies tested positive for SARS CoV 2 suggesting a risk of vertical transmission, especially since 3 of the positive cases were pre-labour, c-section delivered babies. However, the IgG or IgM status of the infants is unknown and there were no placental, umbilical cord, etc samples taken/reported. The discussion states that mothers and infants were kept together with infection control measures (surgical face masks) and the low rates of neonatal infection supports continuation of this practice. However, 6 of the 12 infants testing positive for SARS CoV2 required neonatal unit admission, majority of whom were classed as late infections as they tested positive after 12 hours of life. There is no information provided on the reason for these admissions and what support and/or treatment was required during this time. It is important to point out that the report does not specially say that all other infants born to this cohort of mothers were tested for SARS CoV 2 and found to be negative. Further questions are raised in the two cases of stillbirth which may have been caused by COVID 19. There is also no clarification on the characteristics of the cases of neonatal death (e.g. were they preterm, was mother critically ill in ITU, etc) which would have added greatly to the analysis of this report.

Although this study does not provide enough detail to draw firm conclusions, it provides an important basis for further avenues where research is needed

Kuhrt, KShennan, AAm J Obstet Gynecol MFMPlacental abruption in a twin pregnancy at 32 weeks’ gestation complicated by coronavirus disease 2019 without vertical transmission to the babies08 May 2020UKEurope2Neonatalhttps://www.sciencedirect.com/science/article/pii/S2589933320300781
Algarroba, GVintzileos, AAJOGVizulaisation of SARS-CoV-2 virus invading the human placenta using electron microscopy08 May 2020USANorth America1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0002937820305494
Blauvelt, CGaw, SObstet Gynecol.Acute Respiratory Distress Syndrome in a Preterm Pregnant Patient With Coronavirus Disease 2019 (COVID-19)08 May 2020USANorth America1Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/Acute_Respiratory_Distress_Syndrome_in_a_Preterm.97348.aspx
Vallejo, V.Ilagan, J.G.Obstetrics & GynecologyA Postpartum Death Due to Coronavirus Disease 2019 (COVID-19) in the United States.08 May 2020USANorth America1Neonatalhttps://journals.lww.com/greenjournal/Abstract/9000/A_Postpartum_Death_Due_to_Coronavirus_Disease_2019.97350.aspx
Lang, G.JZhao, H Zhejiang Univ-Sci B (Biomed & Biotechnol) Can SARS-CoV-2-infected women breastfeed after viral clearance?*08 May 2020ChinaAsia1Neonatalhttps://link.springer.com/content/pdf/10.1631/jzus.B2000095.pdf
Fox, APowell, RmedRxivEvidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-1908 May 2020USANorth America15Neonatalhttps://www.medrxiv.org/content/10.1101/2020.05.04.20089995v1.full.pdf
Munoz, A CBoukas, KNEJMLate-onset neonatal sepsis in a patient with covid-1907 May 2020USANorth America1Neonatalhttps://www.nejm.org/doi/full/10.1056/NEJMc2010614
Govind, AYoong, WEur J Obstet Gynecol Reprod Biol .Re: Novel Coronavirus COVID-19 in Late Pregnancy: Outcomes of First Nine Cases in an Inner City London Hospital07 May 2020United KingdomEurope9Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204671/pdf/main.pdf
Ochiai, D.Tanaka, MInt J Gynaecol Obstet. Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan06 May 2020JapanAsia52Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13252
An, P.Ye, Y.CMAJPostpartum exacerbation of antenatal COVID-19 pneumonia in 3 women06 May 2020ChinaAsia3Neonatalhttps://www.cmaj.ca/content/cmaj/early/2020/05/06/cmaj.200553.full.pdf
Ng, KTang, JPediatr Infect DisCOVID-19 in Neonates and Infants: Progression and Recovery06 May 2020UKEurope8Neonatalhttps://journals.lww.com/pidj/Abstract/9000/COVID_19_in_Neonates_and_Infants__Progression_and.96180.aspx
Li, JChen, DInt J Gynaecol ObstetCritically ill pregnant patient with COVID-19 and neonatal death within two hours of birth05 May 2020ChinaAsia1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13189
Wu, YHuang, HBJOGCoronavirus disease 2019 among pregnant Chinese women: Case series data on the safety of vaginal birth and breastfeeding05 May 2020ChinaAsia5Neonatalhttps://pubmed.ncbi.nlm.nih.gov/32369656/

This is a retrospective case-controlled study of 43 women who had presented to 2 affiliated hospitals in New York City between 13/03/20 and 27/03/20 and had positive nasopharyngeal swabs for SARS CoV 2 PCR. The average BMI of these women was 30.9 (60.5% had a BMI ≥30) and 18 women had co-morbidities (mild asthma being the most common). 29 women had COVID-19 related symptoms and underwent testing at presentation. 3 of these women were admitted for management of COVID-19 symptoms and 4 were admitted (unclear when in the two-week study period) for obstetric indications. 14 women were asymptomatic and had presented for obstetric reasons. 2 of these women were tested due to COVID-19 symptom onset during admission and went onto require ITU level care. The other 12 asymptomatic women were tested as part of the universal testing on admission to the delivery unit. Of the 18 women admitted for obstetric indications, 10 were planned admissions (9 inductions and 1 elective section). 4 COVID-19 symptomatic women (incl.1 preterm labour) and all asymptomatic women gave birth to a total of 18 babies (10 vaginal deliveries and 8 c-sections for obstetric reasons) with good APGAR scores. All babies had nasopharyngeal swabs on day 0; 15 babies were negative, 2 babies had initial unclear and then negative on repeat swab on day 1-2 and 1 baby had an indeterminate result and was clinically managed as ‘presumptive negative’. There were 3 admissions to NICU (n=1 preterm 34+6 n=1 antenatal diagnosis of multicystic dysplasic kidney and n=1 Resp distress with suspected sepsis – COVID-19 swab -ve). Babies not requiring NICU were kept with mothers and breast feeding encouraged with advice on strict hand hygiene and mask wearing. All babies have been discharged home.

There are two clear inconsistencies noted in this paper. Firstly, there is a different mean age of pregnant women stated in the table to that which is stated in the body of the text. Secondly, there is a mention of ‘3 of the 28 babies’ being admitted to NICU whereas elsewhere in the paper it consistently quotes 18 babies; this maybe a mis-print. There is also ambiguity in the way that results are presented for the symptomatic women for whom treatment was not required for their COVID-19 symptoms on initial presentation; the flowchart figure shows 26 patients with mild disease with 4 admissions for obstetric reasons, but the text reports 25 patients were stable for discharge. The most striking finding in this paper is the number of women who present with obstetric reasons and with no COVID-19 symptoms, who tested positive for COVID-19. This is even more poignant given that the 2 women requiring ITU level care were asymptomatic at presentation and were the only ones to require this level of support in this report. It is also important to note that 5 of the inductions of labour were in asymptomatic women for worsening pathologies such as cholestasis, reduced fetal movement and chronic and gestational hypertension and that one of symptomatic women went into preterm labour. It is reassuring that all neonates born, regardless of COVID-19 symptom status at presentation, did well clinically with most babies being kept with mothers post partum. The neonates were not assessed for IgG and IgM status.

Hirshberg, A.Srinivas, S. K. Am J Obst & GynCare of critically ill pregnant patients with coronavirus disease 2019: a case series.03 May 2020USANorth America3Neonatalhttps://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930515-9
D. BuonsenoValentini, PAJPNeonatal late onset infection with Severe Acute Respiratory Syndrome Coronavirus 202 May 2020ItalyEurope2Neonatalhttps://pubmed.ncbi.nlm.nih.gov/32359227/

This is a case series of 2 neonates born to mothers admitted to a hospital in Rome, Italy. Mother of Neonate 1 was admitted 19/03 with respiratory symptoms with positive nasopharyngeal swab for SARS CoV-2 and was commenced on anti-virals and hydrossichloroquine. On 26/03, her baby was born at 38+3 weeks via c-section (reason not stated) in good condition. Amniotic fluid, placental swabs, and baby’s nasopharyngeal swabs on day 1 and 5 were negative. Neonatal blood IgM was negative, but IgG was slightly positive. Baby remained clinically well during their 5-day inpatient stay and breast milk tested each day remained negative. Mother who has discharged on the same day as baby, was still positive for SARS CoV-2 at discharge. At home she breastfed baby whilst wearing a mask. At follow-up on day 15 baby tested positive on nasopharyngeal swab but remained clinically well (breastmilk remained negative). On day 25 the baby continued to remain clinically well. Mother of Neonate 2 was admitted 23/03 with respiratory symptoms requiring oxygen with positive swab and was commenced on the same treatment. On 28/03 her baby was born at 35+5 weeks via emergency c-section due to fetal bradycardia, in good condition. The placental swab and cord blood were positive but amniotic fluid and nasopharyngeal swabs on day 1 and 3 were negative. Breast milk was positive on day 1, 2 and 4. Baby was discharged on day 13 along with mother who was negative at discharge. Baby was given expressed breastmilk at home by father. On day 18, the baby was clinically well with negative swabs and the breast milk was also negative. On day 24 the baby remained clinically well. In both cases mother and baby were separated at birth and both babies were formula fed during their inpatient stay.

The result of a positive swab at follow-up in Neonate 1 (having previously been negative), on the background of being clinically well and breast fed by a mother a who was positive at discharge suggest colonisation rather than late onset infection. It would have been useful to have tested immunoglobulin levels at this point and again at later follow-up to look for the presence of IgM. It also might suggest the need for extra distancing measures as that taken by the family of Neonate 2 during feeding. However, as neonate 1 remained clinically well, there is not enough evidence to suggest that disrupting direct breastfeeding confers any benefit. There is ambiguity in the maternal admission for neonate 2 with the figure suggesting admission at 34+4 weeks gestation with commencement of treatment, but the body of text stating admission at 35+0 weeks. This may represent a readmission and if so, brings into question the need for much more careful monitoring of COVID positive pregnant women to reduce the risk severe infection and thus fetal compromise which led to the preterm delivery. It is noteworthy that in Neonate 2’s case, the placental swabs, umbilical cord blood and breast milk were positive, which in previous studies have not been the case. However, immunoglobulins were not tested on Neonate 2. Given the negative swabs at birth and no mention of respiratory support requirement or clinical instability following birth, it is unlikely that the positive results indicate a risk of vertical transmission.

De Socio, G. V. Francisci, DMed J Hematol & Infect disDelivery in Asymptomatic Italian Woman with SARS-CoV-2 Infection.01 May 2020Italy EuropeNeonatalhttps://www.mjhid.org/index.php/mjhid/article/view/2020.033/3768
Baud, DPomar, LJAMASecond-Trimester Miscarriage in a Pregnant Woman With SARS-CoV-2 Infection30 Apr 2020SwitzerlandEurope1Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2765616
Xu, L.Wang, L.Sci Bull (Beijing)Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates28 Apr 2020ChinaAsia5Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186128/
Sun, MZhang, JBJAEvidence of mother-to-newborn infection with Covid-1927 Apr 2020ChinaAsia3Neonatalhttps://bjanaesthesia.org/article/S0007-0912(20)30281-6/fulltext
Ferrazzi, ECetin, IBJOGVaginal delivery in SARS‐CoV‐2 infected pregnant women in Northern Italy: a retrospective analysis27 Apr 2020ItalyEurope42Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.16278

This is a retrospective clinical notes analysis of women with SARS-CoV-2 (confirmed on nasopharyngeal swab prior to, or within 36 hours of, delivery) who were admitted to, and delivered in, hospitals within Lombardy and Units of Padua and Modena between 1 March 2020 and 20 March 2020. Women and newborns were followed up until discharge from hospital or 25 March, whichever came first.

42 women were included in the study. Five were diagnosed with COVID-19 in the 36 hour post-partum period. The majority suffered mild or moderate symptoms of COVID-19. Nineteen (45%) were diagnosed with pneumonia, 4 of whom admitted to critical care unit.

Over half (24, 57%) delivered vaginally. Of the remaining 18 women who had elective caesarean sections, 8 were for obstetric reasons unrelated to COVID-19 and 10 were due to worsening respiratory compromise. There were no emergency c-sections.

There were 3 preterm deliveries before 34 weeks (details of more specific gestation are not given). Two of these were delivered by caesarean section because of maternal respiratory compromise secondary to COVID-19. One mother spontaneously delivered vaginally before 34 weeks.

The paper doesn’t state whether there were any multiple births, so it is presumed 42 babies were delivered. Three babies were admitted to NICU, 2 because they were preterm and 1 because of respiratory distress. This baby was born vaginally in good condition but separated immediately from his mother because of post-partum haemorrhage. He developed gastrointestinal symptoms on day 1 and respiratory failure on day 3 requiring mechanical ventilation on NICU. His SARS-CoV-2 swab result was equivocal on day 1 but positive 3 days later.

Women known to have COVID-19 but asymptomatic or with only mild symptoms were allowed to breastfeed wearing a surgical mask.

Three babies tested positive for SARS-CoV-2: the neonate with respiratory failure described above and 2 other babies whose mothers were diagnosed COVID-19 within 36 hours after delivery and who had breastfed their babies without wearing a mask. These 2 babies tested positive on days 1 and 3, respectively. No other babies tested positive for SARS-CoV-2 during the study period.

The authors are clear that their data is only relevant to pregnancies in the third trimester. However, their data supports the theory that maternal SARS-CoV-2 infection does not increase the risk of preterm birth. Their results also suggests that vaginal delivery may be appropriate in mild cases of COVID-19-19, reserving caesarean section for women with severe respiratory compromise where delivery will improve maternal respiratory function, and does not confer a high risk of intrapartum SARS-CoV-2 transmission to the neonate.

Buonsenso, D.Moro, F.Ultrasound in Obstetrics & GynecologyClinical role of lung ultrasound for the diagnosis and monitoring of COVID ‐19 pneumonia in pregnant wome26 Apr 2020ItalyEurope2Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/uog.22055
JustinMulveyAnn. Diagn. Pathol.Analysis of Complement Deposition and Viral RNA in Placentas of COVID-19 Patients25 Apr 2020USANorth America5Neonatalhttps://www.sciencedirect.com/science/article/pii/S1092913420300708?via%3Dihub
Lu, DYang, XJ Med VirolAsymptomatic COVID-19 infection in late pregnancy indicated no vertical transmission24 Apr 2020ChinaAsia1Neonatalhttps://onlinelibrary.wiley.com/doi/10.1002/jmv.25927
Zhou, C. G.Caughey, A. B. J Matern Fetal Neonatal MedAntenatal corticosteroids for pregnant women with COVID-19 infection and preterm prelabor rupture of membranes: a decision analysis.24 Apr 2020USANorth America0Neonatalhttps://www.tandfonline.com/doi/full/10.1080/14767058.2020.1763951
Hu, XChen, LObstet GynecolSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vertical Transmission in Neonates Born to Mothers With Coronavirus Disease 2019 (COVID-19) Pneumonia24 Apr 2020ChinaAsia7Neonatalhttps://journals.lww.com/greenjournal/Citation/9000/Severe_Acute_Respiratory_Syndrome_Coronavirus_2.97384.aspx
Sharma TBhatla NInt J Gynaecol ObstetManagement of the first patient with confirmed COVID‐19 in pregnancy in India: From guidelines to frontlines23 Apr 2020IndiaAsia1Neonatalhttps://doi.org/10.1002/ijgo.13179
Yan, JYang, HAJOGCoronavirus Disease 2019 in pregnant women: a report based on 116 cases23 Apr 2020ChinaAsia116Neonatalhttps://doi.org/10.1016/j.ajog.2020.04.014

This is a retrospective cohort observational study of pregnant women with admissions to 25 different hospitals in China with a diagnosis of COVID pneumonia. A total of 116 women were captured during the study period of 30/01/20 - 24/03/20. 65 women had lab confirmed SARS COV2 on rt-PCR from pharyngeal swabs. 51 cases were clinically diagnosed based on the New coronavirus pneumonia prevention and control programme, published by the national health commission of China (all had abnormal CT chest findings on admission). The commonly reported symptoms were fever and cough, but in 23.3% of cases there were no symptoms. Mean maternal age at admission was 30.8 (SD +/- 3.8) There were 9 women with gestational diabetes and 5 women with hypertension, 4 of whom had pre-eclampsia. 8 women required ITU admission with 1 case requiring ECMO, 76 women had been discharged and there were no maternal deaths at the study end point. Below is the breakdown the women who presented before 37 weeks of gestation.

A total of 99 women delivered 100 babies (x1 set of twins) with 85 women delivering via c-section. 86 neonates underwent pharyngeal swabs, 10 of whom had paired amniotic fluid and cord blood testing, with all samples being collected in the operating or delivery room. There was also 6 vaginal swab tests and 12 women had their breast milk tested. All tests were negative for SARS COV2. The rate of all- cause preterm birth was 21.2% (21/99). The rate of spontaneous preterm birth, where there was spontaneous preterm rupture of membranes, was 6.1% (6/99). There were 47 babies admitted to NICU for further management, with one neonatal death secondary to neonatal asphyxia following delivery at 35+2 due to severe maternal pneumonia (required ECMO).

This report provides a useful comparison to the national cohort report published by UKOSS. There are similar rates of maternal ITU admission, ECMO requirements and neonatal death rate being reported in the two studies. There is a 26% preterm delivery rate with UKOSS compared to the 21% reported in this study. There is a higher rate of c-section deliveries in this report compared to UKOSS (59%). Unlike the 2% of babies testing positive for SARS COV2 in UKOSS, there were no positive cases in this cohort. There are overlaps in the results from 4 other smaller case series already published, with 33 of the cases having already been reported on. The neonatal outcome data is incomplete with not all babies having been tested with nasopharyngeal swabs, no breakdown of reason for NICU admission and level of support required and important data on the specifics of the infection status of the neonatal death not reported. The authors accept that maternal infection with COVID does increase the rate of preterm births <37 weeks but report that there is no increase in the rate of spontaneous preterm births. There is no control group or national statistic given for this comparison statement. The report does not expand on what clinical criteria were met for 23.3% of women who had no symptoms to warrant a diagnosis of COVID pneumonia, i.e. did they undergo CT chest without the presence of any symptoms.

Salvatori GCampana ABreastfeeding medicineManaging COVID-19-Positive Maternal–Infant Dyads: An Italian Experience22 Apr 2020ItalyEurope2Neonatalhttps://www.liebertpub.com/doi/full/10.1089/bfm.2020.0095?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

This is a case report from Italy of two neonates who’s mothers contracted coronavirus postnatally. Their mothers tested positive on NPA after developing symptoms. At the time of presentation the neonates were 10 and 18 days of age. Both babies tested positive on NPA however only one displayed any symptoms (cough, diarrhoea, poor feeding.) Neither baby required admission.

Expressed breast milk samples of both mothers were analysed and SARS-CoV-2 was not detected by RT-PCR.

The authors conclude that based on this mothers who test positive should be encouraged to continue breast feeding.

Al-Kuraishy, HAli, ZAsian Pacific Journal of Reproduction 9(3): 156-158. COVID-19 pneumonia in an Iraqi pregnant woman with preterm delivery21 Apr 2020IraqMiddle East1Neonatalhttp://www.apjr.net/preprintarticle.asp?id=282984
Lyra, JGuimaraes, MActa Med PortCesarean Section in a Pregnant Woman with COVID-19: First Case in Portugal20 Apr 2020PortugalEurope1Neonatalhttps://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/13883
Liao, J.Li, J.Gynaecology and Obstetrics Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID‐19 pandemic19 Apr 2020ChinaAsia10Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/ijgo.13188
Zamaniyan, MAzizi, SPrenat. Diagn.Preterm delivery in pregnant women with critical COVID-19 pneumonia and vertical transmission17 Apr 2020IranMiddle East1Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/pd.5713?af=R
Parat, MRatner, AJClin Infect Dis. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress17 Apr 2020United States North America2Neonatalhttps://doi.org/10.1093/cid/ciaa452

This is a case series of two infants presenting with fever to a hospital in New York during on week in March 2020. Neither presented with respiratory symptoms, and both had Sars Cov2 infection confirmed without other aetiology despite febrile infant work ups.

First; a 25-day old full-term male infant, presented with fever, irritability and facial rash. Parents had sore throat and subjective fever but had not sought medical attention for themselves. Full routine work up with CSF, blood, urine samples and routine respiratory PCR panel was taken. SARS CoV2 PCR positive on nasal swab. Treated empirically until cultures negative at 48 hours, recovered well.

Second; a 56-day old ex 35-week male infant, presents with fever only. He had no other symptoms, and no sick contacts. Bloods, urine and routine respiratory PCR panel was taken. Infant did not have lumbar puncture. SARS CoV2 PCR was positive on nasal swab. Treated empirically until cultures negative at 36 hours.

Authors discuss the need to maintain high index of suspicion for SARS-CoV-2 infection in febrile infants during a community outbreak, and the importance of strict infection control measures in paediatric emergency department.

Koumoutsea, EVMalinowski, AKJournal of tjrombosis and haemostasisCOVID‐19 and acute coagulopathy in pregnancy17 Apr 2020CanadaNorth America2Neonatalhttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14856
Li, MLi, XPLoS OneThe SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study16 Apr 2020ChinaAsia0Neonatalhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230295

The study explores the presence of Angiotensin-converting enzyme 2 (ACE2) within the placenta and the developing baby by analysing online available data on RNA sequencing from areas of the maternal-foetal interface and from various foetal organs. They found ACE2 was highly expressed in a variety of cells in the decidua and placenta, as well as a variety of foetal organs including heart, liver and lung, but not kidney. They suggest these findings demonstrate potential routes for vertical transmission, placental dysfunction and pregnancy complications, and call for further clinical analysis to ascertain the relevance of these results.

Han, MSChoi, EHClin Infect DisSequential analysis of viral load in a neonate and her mother infected with SARS-CoV-216 Apr 2020KoreaAsia1Neonatalhttps://academic.oup.com/cid/article/doi/10.1093/cid/ciaa447/5820869

This is a case report of a 27 day-old female neonate with confirmed SARS-CoV-2 infection. Over the course of a short and reasonably mild illness, samples were tested from the nasopharynx, oropharynx, plasma, urine, stool and saliva. SARS-CoV-2 RNA was detected in all samples. Early in the infection, viral load was highest in the nasopharynx and oropharynx, decreasing to undetectable at day 17. Viral load in stool, however, remained high throughout, despite cessation of gastrointestinal symptoms. This was in contrast to the mother's stool sample in which viral load was undetectable earlier.

Patek, PKhandhar, PClinical PediatricsSARS-CoV-2 Infection in a 2-Week-Old Male With Neutropenia15 Apr 2020USANorth America1Neonatalhttps://journals.sagepub.com/doi/full/10.1177/0009922820920014?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&
Lowe, BBopp, BAustralian & NZ Journal of Obstetrics & GynaecologyCOVID‐19 vaginal delivery – a case report15 Apr 2020AustraliaOceania1Neonatalhttps://doi.org/10.1111/ajo.13173
Zhoujie, PShi, YJ Infect Public HealthUnlikely SARS-CoV-2 vertical transmission from mother to child: A case report11 Apr 2020China Asia1Neonatalhttps://doi.org/10.1016/j.jiph.2020.04.004
Xiong, XPang, QJournal of Medical VirologyVaginal delivery report of a healthy neonate born to a convalescent mother with COVID­‐1910 Apr 2020ChinaAsia1Neonatalhttps://doi.org/10.1002/jmv.25857

This is a case report of a 25-year-old primiparous woman. She was 33+1 gestation at presentation to hospital in Bejing on the 29th of January, with symptoms of suspicious of COVID-19 infection and having recently travelled from Wuhan. Following a positive result on rt-PCR for SARS COV2 from a throat swab and abnormal findings on chest x-ray, she was treated with antiviral and corticosteroids (does not specify). She was discharge home on the 4th of February. Follow-up rt-PCRs were negative and CT chest was normal. She underwent a normal vaginal delivery on the 7th of March, giving birth to a 38+4 weeks gestation male infant with a BW of 3.07Kg and no requirement for resuscitation. All samples collected at the time of birth were negative for SARS COV 2 (maternal cervical secretions, maternal rectal swab, neonatal throat swab, neonatal rectal swab, amniotic fluid and breast milk). Detection for placental presence of N-protein of SARS COV2, (a structural component of the viral particle) using immunohistochemical analysis, was negative. Serological antibody testing carried out at birth (using INNOVITA detection kit) showed that the mother was positive for IgG and IgM antibodies to SARS COV-2 whereas baby was negative to both. Mum and baby were discharged on the 10th March. The report does not mention whether there was infant separation from mother postnatally nor the reason for the inpatient stay following birth.

The negative rt-PCR result from key samples from mother and infant collected at birth, adds to the existing evidence against vertical transmission of COVID-19 infection. It is also encouraging to note that the pregnancy continued post infection and resulted in an outwardly healthy term infant. The absence of viral N-protein from placental tissue does not discount the placenta as a site of viral replication as there was no clinical evidence of an active infection at the time of delivery. The absence of IgM in the infant’s serology on a background of positive IgM in the mother seems to suggest that the infant did not suffer the infection in-utero. However, IgG antibodies which regularly cross the placenta, being negative in the infant whilst being positive in the mother raises questions of validity of the test in the infant.

Cao, DSun, GInt. J. Infect. Dis.Clinical analysis of ten pregnant women with COVID-19 in Wuhan, China: A retrospective study10 Apr 2020ChinaAsia11Neonatalhttps://www.ijidonline.com/article/S1201-9712(20)30263-0/fulltext
Alzamora, MCLa Rosa, MA, J PerinatolSevere COVID-19 during Pregnancy and Possible Vertical Transmission08 Apr 2020USA or Peru (not clear)Unclear1Neonatalhttps://www.thieme-connect.com/products/ejournals/html/10.1055/s-0040-1710050

This is a case report of one pregnant patient presenting to a hospital in March 2020. It is unclear from the article whether this was in Lima, Peru or Texas, USA (both institutions are listed).

The mother had presented to another hospital three days earlier with four days of fatigue, fever, malaise, and later shortness of breath. She was known to have diabetes mellitus. She was admitted for three days and then deteriorated, requiring transfer and intubation. Maternal serology on postpartum day 1 was negative for IgG and IgM, but was positive for both when testing was repeated on postpartum day 4.

A caesarean section was performed at 33/40 due to maternal respiratory compromise. The baby had Apgars of 6 and 8, and weighed 2970g. The neonate was intubated (thought to be due to maternal sedation side effects) in another room and was isolated immediately. There was no breastfeeding. Neonatal serology at birth was negative for IgG and IgM. Neonatal nasopharyngeal swab at 16 hours was PCR positive. The baby was ventilated for 12 hours and then extubated onto CPAP. Although initially improving, on Day 6, the neonate had mild respiratory difficulty and cough requiring oxygen via nasal cannula.

This case report suggests the possibility of vertical transmission.

Zhang, ZBi, YEuropean Respiratory JournalNovel Coronavirus Infection in Newborn Babies Under 28 Days in China08 Apr 2020ChinaAsia4Neonatalhttps://doi.org/10.1183/13993003.00697-2020

This study aimed to identify neonates (<28 days) who were COVID positive. Data was  retrieved from central government and local health departments across China. The data was screened for newborn babies <28 days of age with positive COVID nucleic acid detection between 8th December 2019 and 13th March 2020. Patients identified were then interviewed and further info was collected from local hospitals.

Out of 81026 COVID cases, four neonatal cases were identified. Three of these were male, and the ages were: 30 hours; 17 days; 5 days; 5 days

One patient had shortness of breath; one had fever, cough, and vomiting; one had fever only; and one was asymptomatic.

Radiology: Three had CT - increased lung markings in all.

Bloods: no information reported

Maternal info: All four mothers were positive for COVID (3 before delivery, 1 after delivery). All born by c section. Three were separated from mothers after birth and were not breastfed. One stayed with the mother and was breastfed for 16 days until symptoms started.

Outcomes: all four were hospitalised. None required intensive care or intubation/ventilation. None had severe complications.

The authors suggest these findings indicate intrauterine transmission is possible.

Yang, PZhao, DJournal of Clinical VirologyClinical characteristics and risk assessment of newborns born to mothers with COVID-1908 Apr 2020ChinaAsia7Neonatalhttps://www.sciencedirect.com/science/article/pii/S1386653220300986
Wu, XWang, XIJGORadiological findings and clinical characteristics of pregnant women with COVID‐19 pneumonia08 Apr 2020ChinaAsia21Neonatalhttps://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13165
Yang, HJin, ZjinfClinical features and outcomes of pregnant women suspected of coronavirus disease 201907 Apr 2020ChinaAsia57Neonatalhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152867/pdf/main.pdf
Kalafat, EKoc, EUltrasound in Obstetrics and GynaecologyLung ultrasound and computed tomographic findings in pregnant woman with COVID‐1906 Apr 2020TurkeyAsia1Neonatalhttps://doi.org/10.1002/uog.22034

This is a single case report of a 32-year-old primiparous woman in Ankara, Turkey. She has thalassemia trait but was not anaemic and was 35+3 weeks at the time of developing symptoms on the 20th of March. She presented to the outpatient obstetric clinic on the 23rd of March with worsening symptoms. The lung ultrasound was abnormal but she self-discharged. No swabs were taken at this time. She re-presented on the 25th of March with worsening symptoms, abnormal vital signs and reduced fetal movement. She underwent a repeat lung ultrasound (abnormal), repeat swabs (positive for SARS COV-2) and a CT scan (changes typical of COVID-19 infection). An elective c-section was performed in view of her worsening lung function.

Baby was born in good condition without the cover of steroids as the team were uncertain about the effect this may have on the COVID 19 infection. Cord blood, swabs from the maternal and fetal side of the placenta, baby’s NPA and throat swabs and breast milk were all negative on rt-PCR for SARS COV2. Baby remained well without respiratory support requirement and feeding with expressed breast milk. It is unclear whether mother and baby were separated from birth, as mother was initially stable after delivery but went on to be intubated on the 27th of March.

The focus of this case report was on the early recognition of COVID 19 in pregnant women through lung ultrasound. From a neonatal standpoint, it continues to support previously published evidence of a good outcome for neonates born to COVID 19 positive mothers and the absence of SARS COV2 on rt-PCR from key samples taken at the time of delivery that might otherwise have suggested vertical transmission. However, it is important to note that no antibody testing was performed on baby.

Gidolf, SJosefsson, HActa Obstetricia et Gynecologica ScandinavicaCOVID‐19 in pregnancy with comorbidities: More liberal testing strategy is needed06 Apr 2020SwedenEurope2Neonatalhttps://doi.org/10.1111/aogs.13862

Case report of a primigravida mother who presented with symptoms of malaise, hoarseness and mild headache after being referred to hospital due to hypertension and proteinuria at 36 weeks gestation. Mother had NPA sent for 'Covid-19 RNA' which was positive. A cesarean section was performed due to developing signs of eclampsia. The mother maximally required 1-3L oxygen via nasal cannulae, CRP peaked at 88 and CT chest showed signs typical of Covid-19 pneumonia. 

Both babies stayed with mother after delivery and were tested for Covid-19 via NPA at 34 hours and 4.5 days of age. Tests were negative. Twin 1 required CPAP for 40 minutes, nil else. Twin 2 was well. Covid-19 tests on breastmilk and vaginal secretions on day 5 also negative

Kamali Aghdam, MEftekhari, KInfectious DiseasesNovel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report01 Apr 2020IranMiddle East1Neonatalhttps://www.tandfonline.com/doi/full/10.1080/23744235.2020.1747634

This brief case report from Iran is of a 15 day old male from Mousavi Hospital in Zanjan, Iran. Date of admission was not available. Symptoms were fever and lethargy with his parents having fever and cough. He initially appeared tachycardic and febrile with sats of 93% on RA. He was given Vancomycin, Amikacin and Oseltamivir. SARS-CoV-2 was detected on RT-PCR. His parents were not tested as they did not meet the testing criteria at the time (hospitalisation).

Radiology: Chest X-ray had nil findings

Bloods: WCC 6.7, Lymphocytes 36%, Neutrophils 42% and CRP 1 (normal).

Comorbidities: There was an incidental finding of patent foramen ovale on Echo.

Outcome: He had improvement by day 2 of admission and was cleared for discharge on day 6.

Iqbal, SRuiz, MNEJMAn Uncomplicated Delivery in a Patient with Covid-19 in the United States01 Apr 2020USANorth America1Neonatalhttps://www.nejm.org/doi/full/10.1056/NEJMc2007605
Lee, DAn, JKorean Journal of AnesthesiologyEmergency cesarean section on severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) confirmed patient.31 Mar 2020South KoreaAsia1Neonatalhttps://doi.org/10.4097/kja.20116
Chen, SShao, YJournal of Medical VirologyClinical analysis of pregnant women with 2019 novel coronavirus pneumonia28 Mar 2020ChinaAsia5Neonatalhttps://doi.org/10.1002/jmv.25789
Breslin, ND'Alton, MAmerican Journal of Obstetrics and GynecologyCOVID-19 in pregnancy: early lessons27 Mar 2020USANorth America7Neonatalhttps://doi.org/10.1016/j.ajogmf.2020.100111
Dong, LYang, JJAMAPossible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn26 Mar 2020ChinaAsia1Neonatalhttps://jamanetwork.com/journals/jama/fullarticle/2763853

This is a case report that would suggest that vertical transmission of COVID-19 can occur. A 34+2 primiparous woman was diagnosed with COVID-19 (she was symptomatic with fever and respiratory difficulty and had classic CT chest findings and a positive nasopharyngeal swab for SARS-CoV-2). She was treated with antiviral medications, antibiotics and corticosteroids.

Her female infant was delivered by caesarean section 4 weeks after the onset of her mother’s symptoms in good condition with Apgars of 9 and 10. Although the infant’s nasopharyngeal swabs were negative, her IgM antibodies against SARS-CoV-2 were raised at 2 hours post-delivery and cytokine levels were elevated. The risk of environmental infection was minimised: the caesarean was performed in a negative pressure room, the mother wore an N95 mask and did not hold her infant and the infant was immediately isolated in NICU. Maternal vaginal secretions were negative for SARS-CoV-2, which would also suggest the infection did not happen at birth. As IgM antibodies do not cross the placenta, the infant’s elevated IgM antibody levels suggest that she was infected in utero. Moreover, IgM antibodies usually do not appear until 3 to 7 days after infection. The infant also had raised IgG antibodies, but IgG is transferred placentally so this may reflect maternal or infant infection. The mother’s breast milk was negative for SARS-CoV-2 1 week following delivery.

Zeng, LZhou, WJAMA PedNeonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China26 Mar 2020ChinaAsia3Neonatalhttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2763787

This is a cohort study following 33 neonates born to COVID-19 positive mothers, recruited Wuhan Children’s Hospital, Hubei Province, China, between January 2020 and February 2020. The authors describe three cases of early-onset neonatal COVID-19, which they suggest implies vertical transmission. However, amniotic fluid, cord blood and maternal breast milk of the mothers of all 3 positive neonates were negative for SARS-CoV-2, therefore it is unclear whether the infection was transmitted vertically or environmentally.

Three of the 33 neonates tested positive for COVID-19 on day 2 of life (positive nasopharyngeal or anal swabs). All 3 were born by caesarean section, two at term and the third at 31+2 for premature rupture of membranes and foetal distress.

Clinical features: The two term COVID-19 positive neonates had fever, although the authors don’t define what temperature they consider fever. These two neonates were also lethargic, but neither had respiratory distress. Neonate 3 was the most unwell, although this may be due to prematurity, poor condition at birth and sepsis rather than COVID-19. He was born at 31+2, required resuscitation at birth and had poor Apgars of 3, 4 and 5 at 1, 5 and 10 minutes, requiring non-invasive ventilation for respiratory distress. His blood cultures were positive for Enterobacter agglomerates.

Bloods: Neonate 1 (fever and lethargy) had normal bloods except raised procalcitonin (0.09 microgram/L). Neonate 2 (fever, lethargy and vomiting) had a leucocytosis, lymphocytopenia and elevated CK. Neonate 3 (premature with sepsis) had leucocytosis, thrombocytopenia and coagulopathy with prolonged PT (21 sec) and APTT (81.9 sec).

Radiology: All 3 had radiological evidence of pneumonia on CXR.

The authors state that because strict infection control and infection prevention procedures were implemented during delivery, SARS-CoV-2 isolated from their upper respiratory tracts or anuses was therefore maternal in origin. However, although it is stated in the illustration that one neonate was immediately quarantined after birth, it’s not clear whether this was the case for the other two babies. Plus, the negative amniotic fluid and cord blood does raise the question as to whether these neonates were truly infected in utero or not.

Zeng, HFan, JJAMAAntibodies in Infants Born to Mothers With COVID-19 Pneumonia26 Mar 2020ChinaAsia6Neonatalhttp://jamanetwork.com/article.aspx?doi=10.1001/jama.2020.4861

This report outlines the course of 6 mothers who were symptomatic for COVID-19 in their last trimester, and gave birth to 6 liveborn infants. This study is notable for antibody testing of both mothers and infants. The accuracy of the antibody tests are suspiciously high given current struggles to produce adequate tests around the world, and should be treated with a high degree of caution.

All 6 infants were born in good condition, and all tested negative for SARSCoV-2 viral throat swabs and blood PCR. Unsurprisingly all infants had elevated IgG or SARS-CoV-2 (as this crosses the placenta), but notably 2 infants had raised IgM (39.9AU/ml and 16.25AU/ml). This raises the possibility of intrauterine infection, similar to another case of an infant with raised IgM (Dong et al JAMA). Issues with cross reactivity of IgM are well described, and so whilst full validation of these tests is awaited internationally, this should be treated with caution.

Zheng, QJin,LReprod Dev MedSingle cell RNA expression profiling of ACE2 and AXL in the human maternal-fetal interface25 Mar 2020N/AN/A0Neonatalhttp://www.repdevmed.org/article.asp?issn=2096-2924;year=2020;volume=4;issue=1;spage=7;epage=10;aulast=Zheng;type=0

This paper reports analysis of a public single cell RNA sequencing database for the mRNA expression profile from cells from the decidua and placenta, which represent the mother-foetus interface. The authors specifically examined angiotensin converting enzyme 2 (ACE-2) receptor expression. They compared this to AXL receptor tyrosine kinase expression, which plays a key role in Zika Virus transmission because of the known vertical transmission in that disease.

They found that expression of ACE-2 was low in these mother-foetal interface cells, and that expression of AXL was higher in several of these. They conclude with the speculation that "the ratio of SARS CoV 2 infected mother to fetus transmission will be significantly lower than that of Zika Virus, because the expression of ACE2 is very low in early maternal–fetal interface cells". More research is needed.

Zambrano, LRodrigues-Morales, ATravel Medicine and Infectious DiseaseA pregnant woman with COVID-19 in Central America25 Mar 2020HondurasNorth America1Neonatalhttps://doi.org/10.1016/j.tmaid.2020.101639
Yu, NWu, JLancet: Infectious DiseasesClinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study24 Mar 2020ChinaAsia7Neonatalhttps://doi.org/10.1016/S1473-3099(20)30176-6

This is a retrospective study of 7 pregnant mothers infected with COVID-19 between Jan 1st and Feb 8th at Tongji Hospital in Wuhan, China. They were all at term (range 37/40 – 41+2/40). The mothers were all symptomatic, mainly with fever, cough, shortness of breath and diarrhoea. They all delivered via emergency caesarian section. All mothers did well.

The babies were all born with normal apgars. 4 babies were discharged home and not tested for SARS-CoV-2 and never developed symptoms (including at 28d follow up phone call. 3 children were tested, of which one was positive at age 36hrs (reported in separate study, Wang et.al Clinical infectious Diseases, but did well with no fever or cough and mild shortness of breath). The other 2 tested negative and were later discharged without complication.

Fan, CWang, SClinical Infectious DIseasesPerinatal Transmission of COVID-19 Associated SARS-CoV-2: Should We Worry?17 Mar 2020ChinaAsia2Neonatalhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa226/5809260

This is a case series of two women (both physicians) infected with SARSCoV-2 during the third trimester in late January, Wuhan China. They gained consent to collect swabs from the mother, specimens of maternal serum, cord blood, placental tissue, amniotic fluid, vaginal swab and breast milk. All the above tested negative for SARS-CoV-2 by PCR

The first neonate was isolated immediately following delivery via caesarean section, and no swabs were positive for SARS-CoV-2. The baby was treated for lung infection on day 3 due to low grade fever and “diffuse haziness” on both lung fields with lymphopaenia.

The second neonate was also delivered via caesarean section and reportedly developed mild neonatal pneumonia and lymphopaenia, treated again with antibiotics (no indication of time course). Similarly there was no evidence of vertical transmission with all products of conception testing negative, as did the infant. There were no maternal complications in either case.

This paper provides further reassurance that there is no evidence of vertical transmission, and of a relatively mild disease course for mothers. In the event of both children being treated for pneumonia but testing negative, it is hard to know if this was understandable overcautiousness or true infection. In either case, the infants did well.

Lui, WWong, ZFront. Med.Clinical characteristics of 19 neonates born to mothers with COVID-1917 Mar 2020ChinaAsia19Neonatalhttps://link.springer.com/content/pdf/10.1007/s11684-020-0772-y.pdf

This is a case controlled study of 19 women who were admitted to 2 different hospitals in Wuhan, China between 31/01/2020 and 29/02/2020. All women were in the third trimester of pregnancy with the lowest gestion at symptom onset being 35+2. Women were aged between 26-38 years with no underlying co-morbidities. 10 women were confirmed with positive results from SARS COV-2 RT PCR and 9 were diagnosed clinically. All women had CT chest changes consistent with viral pneumonia. 6 women received antiviral (umifenovir) for a 5 day course which was completed prior to delivery. All women delivered in isolated room; 18 c-sections and 1 vaginal delivery. All 19 infants were born in good condition (mean gestational age 38.6 and birthweight 3.293Kg) and separated from mother immediately after birth for a 14-day period. Neonatal throat swab, gastric fluid straight after birth, urine and stool were all negative for RT PCR on the neonate. Amniotic fluid and cord blood of 19 babies and 10 breast milk specimens were all negative. However, all neonates were formula fed. In the neonate, there was no clinical, radiological (no time point mentioned as to when the x-ray was taken) haematological or biochemical evidence of COVID 19 infection (blood tests carried out at 24 hours of life).

Results are consistent with previously published studies showing that key samples collected from mother and baby at time of delivery show no evidence of vertical transmission. The difference in this study was that blood test and chest x-ray were all normal. Zhu et al had previously published abnormal blood results (thrombocytopenia and raised LFTs) and pneumothorax and shortness of breath in neonates born to COVID 19 positive mothers. This study does not carry out antibody testing on the neonate which would be a crucial element in disproving the occurrence of vertical transmission. It also important to note that the results are only applicable to babies born in their last trimester with otherwise uncomplicated pregnancies to mothers who are otherwise healthy with no underlying co-morbidities.

Chen, YLiu, YFrontiers in Paediatrics: NeonatologyInfants Born to Mothers With a New Coronavirus (COVID-19)16 Mar 2020ChinaAsia4Neonatalhttps://doi.org/10.3389/fped.2020.00104

This is a case series of 4 mothers symptomatic with COVID-19 in Wuhan. All babies were born after 37/40 with reasonable APGARS. All babies were then isolated from their mothers and formula-fed. All tested negative for SARSCoV-2. Two babies had a rash (which sound very much like normal newborn rashes) and one had transient tachypnoea of the newborn, briefly requiring CPAP and made a full recovery. There was no evidence of vertical transmission.

Li, NYang, LMedRxIVMaternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study13 Mar 2020ChinaAsia17Neonatalhttps://doi.org/10.1101/2020.03.10.20033605

This was a case-control study (Jan 24 – Feb 29) in Wuhan, China16 women with confirmed COVID-19 pneumonia and 18 suspected cases (typical CT chest findings but PCR negative) were used as cases, and 121 women randomly selected from the same period were selected as controls, and a further were 121 selected from 2019 as controls to avoid the impact of mental stress from lockdown.Complications in mother were found in 70% in COVID19 cases – much higher than in controls. We will mainly focus on infants. 17 babies were delivered to the 16 mothers (15 singletons, one set of twins) with confirmed COVID-19. Preterm delivery was higher in the cases, with 23.5% of confirmed COVID19 mothers birthing prematurely compared to 5% of controls. However, mean gestation was still 38+2 in the cases.There was no difference in APGAR scores, no cases of vertical transmission and no neonatal complications.

Wang, SFeng, LClinical Infectious DiseasesA Case Report of Neonatal 2019 Coronavirus Disease in China12 Mar 2020ChinaAsia1Neonatalhttps://doi.org/10.1093/cid/ciaa225

This study from the US assessed the transmission of SARS-CoV-2 infection within 17 selected schools in Wood County, Wisconsin between August 31st to November 29th 2020. During the study period, the majority of students attended in-person learning (estimated 12.4% attending virtually) and infection mitigation measures were employed at all schools including mask wearing for all students and teachers, limitations on mixing between classes and between staff. Community transmission of SARS-CoV-2 in Wood County during the study period was high with test positivity ranging from 7% up to 40% from community samples.

All cases occurring in students or staff during the study period were reported. For each case, infection source was determined though case investigation conducted by the public health department or school administration. Contact tracing was carried out with close contacts required to quarantine at home with further investigation undertaken for contacts who experienced symptoms during quarantine. Surveillance testing and routine testing of contacts was not undertaken.

A total of 4,876 students attending in-person (1,529 primary and 3,347 secondary) and 654 staff were included. A total of 191 of cases were reported within schools; 133 student and 58 adults. Incidence in schools was 37% lower than in the surrounding community (3,454 vs 5,466 cases per 100,000 persons). Of 191 cases, only 7 (3.7%) were associated with in-school transmission, all occurring between students; no staff infections were linked to in-school transmission. No transmission between students and staff or between students in separate classrooms was documented. Compliance with mask wearing in classrooms ranged from 92.1% to 97.4% according to teacher survey responses.

This study adds to a growing body of data demonstrating limited transmission of SARS-CoV-2 in schools with a variety of infection mitigation measures. In contrast to a number of these recent papers, the low number of cases of in-school transmission here was observed despite high levels of transmission in the surrounding community. The authors acknowledge that the study did not include surveillance testing of children, and therefore asymptomatic transmission was not assessed, but highlight recent epidemiological data suggesting asymptomatic cases are much less likely to transmit SARS-CoV-2. Notwithstanding this limitation, the results here suggest that keeping schools open, even in the setting of moderate to high community transmission may be possible with minimal in-school SARS-CoV-2 transmission, provided appropriate mitigation strategies are employed.

Mogharab, VJavdani, FJournal of the Formosan Medical AssociationThe first case of COVID-19 infection in a 75-day-old infant in Jahrom City, south of Iran08 Mar 2020IranMiddle East1Neonatalhttps://www.sciencedirect.com/science/article/pii/S0929664620301078?via%3Dihub
Theuring, SMockenhaupt, FMedRxivSARS-CoV-2 infection and transmission in school settings during the second wave in Berlin, Germany: a cross-sectional study21 Jan 2021GermanyEurope352Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.27.21250517v1

This article is a pre-print and has not been peer-reviewed.

Methods: This was a cross-sectional analysis of a longitudinal study conducted in Berlin, Germany during the second wave. The initial sampling took place in June 2020 during the period of low incidence and the second sampling took place during the first 2 weeks of November 2020, when the incidence was comparatively high. Schools were divided into 3 socio-economic strata and in each stratum, two districts were randomly selected. Within the 2 districts, 2 primary schools and 2 secondary schools were randomly selected: a total of 24 schools. 65% of students participated (range: 13%-96%). A brief medical history, forehead temperature, oro-nasopharyngeal swabs and finger-prick blood samples were taken from students and staff. Household members attended a mobile clinic for symptom assessment and finger-pricking. Self-collected swabs were collected with instructions given prior. Participants undergoing quarantine or isolation were visited at home. SARS-COV-2 infection was determined by RT-PCR and antibodies were detected by ELISA. For classes with detected SARS-COV-2 infection, all associated students, staff and household members were re-tested after one week via self-sampling. No re-testing was done if the positive participant was quarantined.

Results: 1119 participants in 24 schools consisting of 177 primary and 175 secondary students, 142 staff and 625 household members were enrolled. 19 participants withdrew consent (17 students and 2 staff). Median age of primary and secondary students was 11 and 15 respectively. Half of students were female, and staff were predominately mid-aged and female. (91.2% 114/125). Most household members were adults (73.8% 461/625).

Fever was present in 1.7%, 8.0% and 2.9% of primary school students, secondary school student and staff respectively. Current symptoms were reported in 15.8%, 20.1% and 21.3% respectively. The most common complaints being rhinorrhoea, headache, sore throat and cough. Symptoms in the 2 weeks preceding were reported by 60% of participants with headache (37.3% 121/324), sore throat (15.7% 51/324) and rhinorrhoea (14.8% 48/324) being the most common.

All schools implanted basic hygiene measures such as hand washing and air ventilation at least 3 times daily. 10/22 schools had a hygiene commissioner and most students and staff reportedly adhered to hand hygiene and sneezing etiquette. 18/24 classes had fixed teaching groups but mixing of classes outside of school was possible in almost all schools (22/24). 15 classes did not have facemask obligation in the classroom (15/24) but outside the classroom, it was obligatory for almost all schools (22/24).

SARS-COV-2 infection occurred in 8/24 classes affecting 1-2 individuals per class (6 primary school students; 2 in one class and 3 secondary school students; 2 in one class). All positive participants were isolated within an average of 3 days (1-5 days). Schools being the origin of infection was possible in 3/8 households.

6/9 infected students were asymptomatic, and prevalence increased with inconsistent face mask use in school or during contact outside of school. No new school-related infections of students or staff were observed at re-testing which was conducted 1 week after a positive test. However, there were 7 new infections detected among individuals associated with the affected classes and not included in the study. The attack rate in households connected to positive classes was 1.1%

Discussion:

Only 3/8 household infections originated in schools which suggests that attending lessons may not be the primary reason for infection. An increase in prevalence was observed in those who had inconsistent facemask use, case contacts outside of school, those who attended social gatherings and walked to school in groups. Therefore, the closure of schools may decrease the transmission of the virus amongst students and staff; however, this is related to the events preceding and proceeding lessons. One member of staff was infected (1/140) which is in line with other studies and argues against the increased risk of infection for staff in schools. The study did find that the majority of students who tested positive were from the low socio-economic stratum. Insufficient social distancing related to household crowding and the inability to effectively isolate may be a contributing factor to increase the transmission of the virus.

The limitations to the study include the use of self-swabs in household members. Although instructions were provided to individuals, the possibility of incorrect method of sampling cannot be completely excluded. In addition to this, selection bias could have been an issue as participation was voluntary and patient responses to questionnaires were not evidenced or confirmed. Those who knowingly participated in social gatherings and did not adhere to IPC guidance may have incorrectly completed some questions to avoid embarrassment; this would have resulted in incorrect data and results. However, it is understandable that this factor would have been difficult to control. The study has however reduced the possibility of bias through the random selection of schools across Berlin, the use of laboratory methods such as RT-PCR and ELISA.

Atherstone, CNeatherlin, JMMWR Morb Mortal Wkly RepSARS-CoV-2 Transmission Associated with High School Wrestling Tournaments — Florida, December 2020–January 202129 Jan 2021USANorth America130Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm7004e4

Amongst the mass of ‘big data’ reports on transmission of Covid-19, anecdotal case studies can still be illuminating. This brief report from the Centers for Disease Control (CDC) in the US, shows how a single case can play out when infection control restrictions are inadequate.

In December 2020, high school wrestling tournaments were still permitted in the state of Florida. Two such tournaments were held on 4th and 5th December, and just one of the participants tested positive for SARS-CoV2 on PCR, on 7th December. Ten high schools from two counties had participated, involving 130 people (118 students and 12 supervising adults). Public Health officials tested 54 (41%) of these, and 38 (70%) were positive. Of these, 446 close contacts at home and school were identified. 95 (21%) of these were tested, and 41 (43%) were positive. Eight were asymptomatic. Attack rates were highest amongst fellow wrestlers (20%), and household contacts (30%). One adult contact died. As a result of the ensuing isolation and quarantine of all these contacts, an estimated 1700 in-person school days were lost. In the county with the most participating schools, this one outbreak had the effect of lifting it into the highest category for SARS-CoV-2 transmission.

Before this episode, contact sports in Florida were permitted with mitigating precautions – face-coverings, distancing etc. except when actually wrestling, which this study has demonstrated was ineffective at preventing transmission.

Reukers, Dvan den Hof, SmedRxivHigh infection attack rates of SARS-CoV-2 in Dutch households revealed by dense sampling26 Jan 2021NetherlandsEurope117Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.26.21250512v1.full

This article is a pre-print and has not been peer-reviewed.

Methods: This is a prospective cohort study of household secondary attack rates of SARS-CoV-2, carried out in the region of Utrecht (the Netherlands) between 24th March and 6th April 2020.

Population: Complete households were enrolled and followed-up for 4 to 6 weeks. Index cases (any adult testing positive for SARS-Cov-2 on an upper respiratory tract swab, with at least one child in their household) were sourced from reports from the local Public Health Service and contacted by research staff to request enrolment in the study. Persons living in the same household as the index case -except for infants under 12 months of age- were defined as household contacts using the following strata: adults: ≥ 18 years of age, adolescents: 12 to 17 years of age and children: 1 to 11 years of age.

Study procedures: Three home visits were scheduled during the follow-up period. Demographics and baseline characteristics of the household contacts were recorded through study questionnaires at visit 1; symptom diaries were filled-out by the household contacts for two-weeks after the first study visit, and further follow-up was completed 2 to 3 weeks (visit 2) and 4 to 6 weeks (visit 3) after enrolment to ascertain any history of symptoms suggestive of COVID-19 since the last contact. The day of symptom onset, as reported by the study participants, was set as the first day of illness. Transmission within the household was excluded if household contacts reported day of symptom onset 2 weeks prior the first day of illness (or first positive test result) of the index case. Naso (NP) and oropharyngeal (OP) swabs were collected at enrolment and at visit 2. Serum, oral fluid, and faeces were collected at each home visit. Detection of SARS-CoV-2 in NP, OP, oral fluid and faeces was carried out by RT-qPCR; SARS-Cov-2 antibodies in serum were detected using a commercial ELISA.

A primary case was defined as the most likely first case on the household, based on laboratory confirmation, symptom onset and travel history. A household contact was defined as primary case if SARS-CoV-2 infection was laboratory confirmed and the symptom onset occurred between 2 and 14 days before the index case.

Statistical analysis: Secondary attack rates were estimated excluding the index case but including the primary case through logistic regression, using generalised estimating equations with household as the unit of clustering. A stochastic SEIR transmission model was fitted to estimate transmission routes in the house.

Results: Fifty-five households with 242 participants (all household members) and 55 index cases were included. Among 187 household contacts, 70 were children aged between 1 and 11 years and 46 were adolescents, between 12 and 17 years of age. No transmission was detected in 17 households and in 11, every member got infected with SARS-CoV-2. Not every index case was the primary case (n = 10/55).

Laboratory confirmed SARS-Cov-2 infection was detected in 21/70 children (30.0%), 21/46 adolescents (45.7%) and 36/71 adults (50.7%). The overall household secondary attack rate was 43% (95% CI 33%-53%), being lower in children (35%, 95% CI: 24%-46%) compared to adolescents (41%, 95%CI: 27%-56%) and adults (51%, 95%CI: 39%-63%). These findings were confirmed by transmission models.

In the univariate analysis, no significant association was found between sex, household size, severity of the infection of the index case and being a healthcare worker. In a multivariate analysis adjusted by age group and sex, being a child was associated with decreased probability of infection (95%CI not provided; p = 0.006). Severe cases (i.e. a history of dyspnoea, visit to the emergency department or admission to hospital) were described in adults (7/36; 20.0%) and adolescents (2/21; 10.0%) but not in children.

Considerations: transmissibility of SARS-Cov-2 within households was investigated using a prospective cohort study and frequent testing. A dense sampling protocol and a follow-up period of at least 4 weeks may explain high household secondary attack rates across all the age groups. Children remained less susceptible compared to adolescents and adults.

Kubiak, JMYang, YJAJOGSARS-CoV-2 serology levels in pregnant women and their neonatesPre-proof. Accepted 21 JAN 2021USANorth America39Neonatalhttps://doi.org/10.1016/j.ajog.2021.01.016

The impact that Sars-CoV-2 infection has on pregnant women and their fetuses has been the focus of many reports over the past year or so. Inferences drawn from existing data are somewhat at variance: a recent RCM/RCOG report states that “there is no good quality evidence comparing the risk of severe COVID-19 infection in pregnant women and non-pregnant women of the same age”1 while a recent information video on the RCOG web-site advises that “if a pregnant woman does have coronavirus she does not appear to be more likely to be more severely unwell compared to others”.2 In contrast, in the US, a CDC review of the evidence states that “intensive care unit admission, invasive ventilation, extracorporeal membrane oxygenation, and death were more likely in pregnant women than in nonpregnant women”.3 There is also debate about the extent to which materno-fetal “vertical” transmission occurs.4

The paper by Kubiak et al et al is a report of a study which measured “semi-quantitatively” serum IgG and IgM concentrations in pregnant women and their newborn babies. The study was conducted at the Weill Cornell Hospital in New York from March to May 2020, after universal SARS-CoV-2 antibody testing had been introduced for all women giving birth at the hospital. At that time 10-15% of all parturient women in the city were positive to SARS-CoV-2 RT-PCR testing. A total of 88 women were included – 67 who tested positive as a result of universal screening and 21 who were tested “due to suspicion of SARS-CoV-2 infection or exposure”. Umbilical cord blood was also taken from the babies of these mothers for SARS-CoV-2 antibody testing. The gestational ages of the pregnancies is not given for either group. Of the 88 women 10 were found to have IgM antibodies only, 24 had both IgM and IgG antibodies and 54 had IgG antibodies only.

For the first part of the study a retrospective “chart review” was performed to document any symptoms reported by these mothers at the time of, or prior to, delivery; the mothers were then categorised as either “symptomatic” (37/88 = 42%) or “asymptomatic” (51/88 = 58%). It was found that both symptomatic and asymptomatic pregnant women mounted a detectable IgM and IgG response but IgG levels were significantly higher in the symptomatic mothers compared with asymptomatic mothers.

The second part of the study sought to determine the time course of antibody appearance and disappearance in symptomatic women. Information concerning the timing of the onset of symptoms was available for only 34 of the women. Analysis of the 34 available data points showed that IgM levels peaked at about 15 days after the onset of symptoms and IgG levels started to peak at about 30 days, some of which “could last over 90 days”.

For the neonates, umbilical cord blood was available for 50 of the original 88 mothers. Of these, 39 (78%) had detectable antibodies, all of which were IgG: 24 were born to mothers who were IgG positive, 14 to mothers who were both IgM and IgG positive and one to a mother who was IgM positive at a low concentration. All 39 babies were negative on RTR-PCR testing for SARS-CoV-2. It was further found that:

- the mothers of neonates with SARS-CoV-2 specific IgG had significantly higher IgG levels than the mothers of neonates without IgG

- there was a positive correlation between the IgG levels in the cord blood and the maternal serum IgG levels

- maternal IgG levels (but not IgM levels) and oxygen supplementation were predictive of cord blood IgG levels.

The authors comment that, first, the pattern and timing of the appearance of IgG and IgM in the serum of pregnant women mirrors that of the general population and, second, that an immune response is mounted in asymptomatic pregnant women, albeit weaker than in those who are symptomatic, again, similar to the general population. They suggest that a “certain level” of IgG in the mother may be necessary for sufficient antibody to be transferred to the fetus.

The significance of these findings, particularly with regard to protection of the fetus, is uncertain. The study cohort was small and no information concerning outcomes for the neonates or clinical details concerning the mothers or the pregnancies was provided. The authors acknowledge that a prospective longitudinal study is required to investigate the course of antibody levels in mothers contracting SARS-CoV-2 infection at different stages of pregnancy and to determine whether they are relevant to neonatal outcomes. They speculate that the “classic” patterns of IgG and IgM responses seen, which are similar to those reported in previous vaccination studies of pregnant womenn relating to other infections, may provide reassurance for those involved in future studies of SARS-CoV-2 vaccination in pregnant women.

Buonsenso, DValentini PmedRxivPreliminary Evidence on Long COVID in children26 Jan 2021ItalyEurope129Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1

This article is a pre-print and has not been peer-reviewed.

This report of an ongoing cross-sectional study investigating the persistence of symptoms after COVID-19 in children in Italy was posted on medRxiv on 26th January 2021.

Study population: 129 children aged 18 years and under diagnosed with microbiologically-confirmed COVID-19 at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (the largest hospital in Rome) between March and November 2020 were included in the study. 62 (48%) female; mean age 11 years. Reported ethnicity: white 89%, black 3%, Latino/Hispanic 7%, Arab 1%. Comorbidities: 13/129 (10%) neurology, 6/129 (5%) dermatology, 5/129 (4%) asthma, 4/129 (3%) allergic rhinitis, 3/129 (2%) obesity, 1/129 (1%) each of cardiology, gastroenterology, oncology, immunology, genetic disorder, rheumatology.

Severity of acute phase of COVID-19 in cohort: 33/129 (25.6%) were asymptomatic and 96/129 (74.4%) were symptomatic at the time of initial illness. 6/129 (4.7%) were hospitalised. 3/129 (2.3%) were admitted to PICU. The high hospitalisation and ICU admission rate indicate the symptomatic children represent the more severe end of the clinical spectrum of disease.

Complications after acute phase of illness in cohort: 3/129 (2.3%) were diagnosed with MIS-C and 2/129 (1.6%) developed myocarditis. 3/129 (2.3%) were diagnosed with asthma.

Collection of data: Caregivers were interviewed about their child’s health after COVID-19 using a questionnaire developed by the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) Global Paediatric Long COVID Working Group for the evaluation of persisting symptoms. Interviews were carried out by two paediatricians from 1 September 2020 to 1 January 2021, either online or in the outpatient department. Time from COVID-19 diagnosis to interview: < 60 days 31/129 (24%), 60-119 days 30/129 (23%), 120 days or more 68/129 (53%). The average time from diagnosis to interview was 162.5113.7 days. The study is designed to continue periodic assessments until 24 months after COVID diagnosis and to include household members of different age groups, with or without COVID-19, as a control group.

Persistent symptoms at follow-up: 54/129 (41.9%) had no symptoms at interview, 46/129 (35.7%) had 1 or 2 symptoms and 29/129 (22.5%) had 3 or more symptoms. The most frequently reported symptoms were insomnia (24/129, 18.6%), respiratory symptoms (19/129, 14.7%), nasal congestion/rhinorrhoea (16/129, 12.4%), fatigue (14/129, 10.8%), muscle pain (13/129, 10.1%), joint pain (9/129, 6.9%) and concentration difficulties (13/129, 10.1%). Symptoms were more common in symptomatic or hospitalised children, but they were also described in those individuals who were asymptomatic during the acute phase. 29/68 (43%) of children assessed at 120 days or more after diagnosis were still distressed by these symptoms. A detailed table in the report lists occurrence of different persisting symptoms at follow-up interview categorised into asymptomatic/symptomatic patients at time of acute illness, hospitalised or not and number of days from initial diagnosis.

The major limitation of this study is a lack of control group, especially of healthy children. Respiratory symptoms and nasal congestion are extremely common in children of all ages, and many of the other reported symptoms are vague and might be more common to children during emotionally stressful times such as the pandemic and lockdowns. Reports of prolonged symptoms in children who initially had no symptoms at all are especially difficult to interpret.

Schoeps AZanger PmedRxivCOVID-19 transmission in educational institutions August to December 2020, Rhineland-Palatinate, Germany: a study of index cases and close contact cohorts08 feb 2020germanyEurope14594Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.04.21250670v1

This is a preprint that has not undergone peer review.

Introduction: This is a case control study of transmission of Covid 19 in educational and daycare settings from August to December 2020 in the Rhineland-Palatinate region of Germany. This area is one of 16 Federal states of Germany with a population of 4.1million people. Schools were open after summer break from August 2020 with infection control measures and were closed on December 16th due to a hard lockdown in the region.

Methods: Covid 19 cases included in this study, if it was in a child or teacher who attended a school or day care centre, for at least one day of the infectious period. Cases were notified to the district public health authority (DPHA) and contact tracing commenced. All “Category 1” contacts were offered testing. In general terms in Germany, Category 1 contacts are regarded as someone who stayed <1.5 meters for 15 minutes or longer with a positive case, or was in the same room (i.e. irrespective of distance) for 30 minutes or longer. For schools and educational settings Category 1 contact is “all persons in crowded or unclear situations, or when resources at the DPHA do not allow for an individual risk assessment”.

A “secondary case” was defined as having contact with the index case and testing positive within the quarantine period of the index case. Of note contact persons and secondary cases not attending the educational setting were not included in this study. Secondary attack rates (SAR) defined as the proportion of secondary cases among contact persons of a given index case.

Results; 16% of the 74,733 COVID-19 cases notified in Rhineland-Palatinate in 2020 were younger than 20 years, which approximated the population proportion of 18·3% in this age group. 1,954 notifications fitted the criteria for the study, with 84% of which were notified during the study period. 784 independent notified index cases attending an educational institution prior to diagnosis of a SARS-CoV-2 infection (591 students/children, 157 teachers, 36 unknown role). Full information on PCR-testing was available for 441 of these index cases with 14,591 contact persons (median 25 contacts per index case, IQR 17-40).

Secondary attack rate was higher for teacher > student/child, IRR=3·17, p<0·001), and in day centres > secondary schools IRR=3·23, p<0·001), SAR was lower in pre-/asymptomatic < symptomatic ( IRR=0·47,p=0·02).

Including the further 343 index cases with complete information on secondary cases, but missing information on number of contact persons tested, cluster level risk was also associated more with teachers, and day care centres. 83% of index cases led to no in school secondary cases. Average cluster size was 2.5 cases.

Discussion: The authors conclude low transmission of Covid 19 cases in educational settings under preventative measures with high community incidence rates. They found approximately 1·3% of school contacts of an index case will become positive. The risk of causing a cluster and the mean number of secondary cases was higher when teachers were identified as index cases compared to students. They recommend increase attention to work place safety in an educational and day care setting with a focus on contact between teachers.

Ouldali, NAngoulvant, FJAMAAssociation of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children01 02 2021FranceEurope111Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2776054

To date there have been no comparative data to inform optimal therapy for MIS-C / PIMS-TS with treatment largely based on Kawasaki disease guidelines using IVIG with or without steroids. In this retrospective cohort study of children with MIS-C from France, treatment outcome with IVIG & methylprednisolone was compared to that of IVIG alone.

All cases of MIS-C fulfilling the WHO criteria reported to the French national surveillance system between 1st April and 22nd October 2020 were included; reporting of suspected MIS-C cases was mandatory in France from April 2020. The primary endpoint was treatment failure defined as persistent fever at 48 hours from treatment initiation or recrudescence of fever within 7 days. Children treated with IVIG and methylprednisolone as initial therapy were compared with those receiving IVIG alone using. To account for differences between the groups, propensity score matching based on baseline clinical data (age, sex, co-morbidities, hospital, symptoms, cardiac dysfunction, CRP, PICU admission before treatment and positive SARS-CoV-2 serology) was used to compare the two treaments (1:2 ratio).

A total of 111 patients with confirmed MIS-C were identified, 106 who received treatment with IVIG with or without methylprednisolone. Median age was 8.6 years (IQR 4.7-12.1), 94% had gastrointestinal symptoms, 47% had left ventricular dysfunction, 67% were initially admitted to PICU, 41% were received haemodynamic support and 26% ventilatory support. A total of 34 children received initial treatment with IVIG & methylprednisolone and 72 with IVIG alone. The methylprednisolone dose used was 0.8-1mg/kg twice daily for 5 days (30 of 34 children) or 15-30mg/kg daily for 3 days (4 of 34 children). The children receiving combination therapy had a more severe initial presentation and were more likely to have ventricular dysfunction (65% vs 39%) be admitted in PICU (91% vs 58%) and be receiving haemodynamic support (62% vs 32%).

Treatment failure occurred in 9% (3/34) of children treated with IVIG & methylprednisolone compared with 51% (37/70) treated with IVIG alone. In the propensity score matched analysis (32 children in the IVIG & methylprednisolone matched with 64 children with IVIG alone), combination treatment was associated with a 28% absolute reduction in treatment failure (9% vs 38% OR 0.25 (95% CI 0.09-0.70)). Similarly, combination therapy was associated with a lower odds of requiring second line treatment (OR 0.19 (95% CI 0.06-0.61)), subsequent haemodynamic support (OR 0.21 (95% CI 0.06-0.76)) and development of new left ventricular dysfunction (OR 0.20 (95% CI 0.06-0.66)). On follow up to 6th January 2021 no long-term cardiovascular complications of persistent inflammatory syndrome had been reported.

The findings of this study suggest that initial treatment with methylprednisolone in combination with IVIG leads to improved outcomes in children with MIS-C compared with IVIG alone.

Smith, BWang, DmSphereSeroprevalence of SARS-CoV-2 antibodies in children and adults in St Louis, Missouri, USA03 FEB 2021United StatesNorth America555Epidemiology - Transmissionhttps://doi.org/10.1128/mSphere.01207-20

Aim: Serological studies provide information on the risk for transmission and the immunological state of the population. The aim was to determine in a sero-prevalence study, the extent of SARS-CoV-2 infection in adult and paediatric cohorts from the St. Louis metropolitan area early in the pandemic.

Methods: The adult serum/plasma samples were residual samples sent to Barnes-Jewish Hospital for vitamin D testing between 27 April 2020 and 12 May 2020. Residual paediatric specimens came from either the emergency department or outpatient clinics at St. Louis Children’s Hospital between 14 April 2020 and 8 May 2020.

An in-house enzyme-linked immunosorbent assay (ELISAs) was used using the spike protein of SARS-CoV-2 to estimate IgG seropositivity to SARS-CoV-2.

Results: The paediatric cohort had 555 children (286 females, 269 males) with a median age of 9 years (range, 2 days to 17 years). Adult samples included 503 individuals (296 females, 207 males) with a median age of 61 years (range, 18 years to 93 years)

A Bayesian regression model was used that accounted for test performance. The estimated seroprevalence rates in adults was 3.11% (95% CI, 0.92% to 5.32%) and in children was 1.71% (95% CI, 0.04% to 3.38%). Further estimates were given per age band. There was lower estimated seropositivity in children under 5 years than in adults in any age band, and none of the samples from children under 4 years of age were identified as seropositive.

Authors’ conclusions: Children and adults are susceptible to SARS-CoV-2 infection and develop antibody responses. The results are consistent with other evidence that young children may be infected by SARS-CoV-2 at a lower rate than adults. The results are not generalizable to the general St. Louis population as the samples were taken from medical patients early in the pandemic and given that the dates overlapped with a stay-at-home order this may have led to the samples originating from sicker patients as routine medical visits were significantly curtailed.

Comments: this seroprevalence study is of limited value as the samples came from a group of patients attending hospital clinics and as such are unlikely to represent the general population of St Louis.

Choe, YJLee, SWEmerg Infect Dis 27(4).Surveillance of COVID-19-Associated Multisystem Inflammatory Syndrome in Children, South Korea.04 Feb 2021South KoreaAsia3Clinical - PIMS-TShttps://wwwnc.cdc.gov/eid/article/27/4/21-0026_article

An early release report of a prospective national surveillance system from S Korea, between May-Nov 2020. During this time, S Korea had 2287 cases of SARS-CoV-2 in children aged 0-19 years. 9 cases of possible MIS-C were reported, and 3 were confirmed by the Case Assessment Committee as having evidence of COVID-19 exposure (3-4 weeks previously).

Age range 11-14 years. Two male and 1 female. None had pre-existing medical conditions. All had GI symptoms/signs, hypotension, “marked” leucocytosis, and “elevated” inflammatory markers (no detail given). 2 had mucocutaneous symptoms/signs. Cardiac involvement: L coronary a. dilatation, mitral regurgitation, LV dysfunction. Pulmonary involvement: oedema, effusion. Abdominal involvement: mesenteric lymphadenitis, hyperechoic liver, hypertrophic gall bladder.

All 3 received IVIg and aspirin, and 1 was subsequently given Anakinra and pulsed methylprednisolone. 2 were admitted to ICU and given inotropes. None required mechanical ventilation. Duration of hospitalization 10-19 days. Duration of ICU stay 6-7 days. No deaths and no major sequelae reported to date.

This survey suggests that the increase in Kawasaki Disease (KD)-like presentations associated with SARS-CoV-2 seen in Europe and the US, where KD has a relatively low incidence, is not seen in S Korea, where KD has a relatively high incidence.

In previous studies, GI involvement in KD has been associated with a higher risk of failure to respond to IVIg therapy, and this was seen in 1 of the 3 cases of MIS-C reported here. The authors suggest this association merits further study.

Gillespie DZenilman JmedRxivThe Experience of Two Independent Schools with In-Person Learning During the COVID-19 Pandemic29 Jan 2021USANorth AmericaEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.01.26.21250065v1

This article is a pre-print and has not been peer-reviewed.

This pre-print, posted on 29 January 2021, reports the experience of 2 large independent K-12 schools in the United States during the first term of the 2020-21 academic year, from August to December 2020, as they implemented a range of SARS-CoV-2 mitigation strategies, including periodic universal testing.

Background: Schools closed across the US from March 2020 because of the COVID-19 pandemic and transitioned to virtual learning. Due to continuing high levels of infection over summer 2020, most school districts delayed in-person education or used a hybrid virtual/in-person approach for the first term of the 2020-21 academic year. However, the two K-12 independent schools (5 to 18 year olds) investigated in this report, located in the South (School A, 2320 students and staff) and Mid-Atlantic (School B, 1200 students and staff), returned to in-person learning for the term, using a collaborative approach following the Centers for Disease Control and Prevention (CDC)’s guidelines designed to prevent the transmission of SARS-CoV-2, while also implementing aggressive laboratory screening similar to that which colleges and universities were using. The two school reopening plans, developed in consultation with medical advisers, had some differences, but were based on 4 major elements: stakeholder engagement, physical infrastructure, policies and operations, and laboratory screening and testing of students and staff for SARS-CoV-2.

Interventions undertaken to sustain in-person education in both schools: Stakeholder engagement included a community contract (implied for School A and electronically signed by parents for School B) covering agreement to avoid large gatherings, quarantine the entire family if one member had a positive test, report COVID-19 symptoms proactively to the school and reduce in-community activities. Physical infrastructure measures included spacing of desks, staggered class starts, block scheduling, limited numbers in restrooms, hand sanitising, disinfection of frequent-touch surfaces (including UV light disinfections of classrooms at school B at the end of the day), MERV air filters, window opening in classrooms and buses, and temperature checking at main school entrances. Changes in policies and operations included social distancing at drop-off, mask wearing (removed only for eating and drinking), cancellation of most extracurricular activities (varsity sports continued at School A, but with regular testing of players and small pod training), no conversation during lunch (except if eating outside, movies shown during lunch to limit talking), no all-school congregating, quarantine policies off campus of 10 days (School A) and 14 days (School B) for positive pupil and 14 days (both schools) for family of positive pupil. Both schools had detailed contingency plans for transitioning to virtual learning if necessary, using metrics such as community positivity rate, in-school positivity rate and presence of in-school transmission.

SARS-CoV-2 testing procedures during the term: A case was defined as a person with a positive laboratory test for SARS-CoV-2. Testing protocols differed slightly between schools and evolved during the term based on testing options, availability and logistics. School A conducted 9 rounds of universal testing (UT) of the entire student body and staff from August to December 2020 (number of tests conducted in each round varied from 1934 to 2687 tests); School B conducted 8 rounds (from 743 to 1666 tests per round). Both schools also tested the entire school population after the Thanksgiving break. Both schools transitioned from nasal swab PCR to saliva-based tests as the term progressed, enabling more frequent testing. Saliva specimens were pooled (up to 24 specimens per pool); if a pool was positive individual samples were tested. Each universal testing event required 2-3 days to implement and obtain all results. Both schools also tested contacts of positive cases and athletes. School B also conducted twice weekly sewage testing, but these results were not useful in real-time, because of delays in obtaining results and the difficulty in interpreting them in a 1200 person school. Contact tracing for positive cases was implemented by school officials in partnership with local health authorities to determine the likely source of exposure. Parents were encouraged to report any test results obtained outside school.

Categorisation of positive cases: Positive cases were grouped into 3 categories: Self-reported (SR) if the person was symptomatic or had a known contact and was tested at school or independently; universal test (UT) if the person was asymptomatic and tested as part of regular screening; or converted during quarantine (CDQ) if the person was identified as a known contact due to UT or contact tracing and was quarantining when they tested positive. A cluster analysis was used for each case to identify common linkages, source of introduction and potential route of transmission. Those who tested positive were grouped into clusters based on the site of exposure (family, community or school). A cluster was defined as any event involving 2 or more linked cases in school. The average reproductive rate was calculated as the number of secondary cases generated by contact with the infectious person. It was assumed that each outbreak represented only one generation of transmission (assumed to be valid since the overall infection rate was low).

Number of positive cases during term: School A had 112 cases (4.9% of students, faculty and staff) between 5 August and 20 December 2020. Categorised as: SR 30/112 (27%), UT 60/112 (54%), cases through contact tracing based on UT-identified cases 22/112 (20%). 11/112 (10%) were identified during the initial testing from 5 to 10 August, i.e. before term started. 59/112 (53%) were identified during the 3 weeks following the Thanksgiving break. The largest outbreak at School A was linked to a non-school sanctioned, sports-related event. School B had 25 cases (2% of students, faculty and staff) between 24 August and 20 December 2020. Categorised as: SR 3/25 (12%), UT 21/25 (84%), cases through contact investigation resulting from a UT case 1/25 (4%). In both schools, cases peaked in the period after school breaks (summer holiday, fall break, Thanksgiving break).

Presence of symptoms in different age cohorts: Combined for both schools: lower school students (grades 1-6): 1/39 symptomatic (3%); middle school students (grades 7-9): 5/20 symptomatic (25%); upper school students (grades 10-12): 5/57 symptomatic (9%); adults: 10/21 symptomatic (48%). No cases required hospitalisation.

Community incidence and positivity rates: Community incidence rates correlated with school infections (Pearson correlation 0.9, p<0.01 for School A; 0.8, p<0.05 for School B). There was no correlation between community positivity rates and in-school introduction (correlation 0.57, p>0.1 for School A; 0.27, p>0.1 for School B). Using multipliers based on contemporaneous seroprevalence studies, in-school rates were consistently below community infection rates.

Virus introductions into each school: 45 cases were determined to have been introduced into School A and 24 into School B; these numbers exclude positive cases from before school started (round 1 of UT), SR cases occurring more than 1 week before UT, all cases linked with an off-campus, non-school sanctioned event over Thanksgiving break at School A, all secondary cases and all SR cases occurring after the last round of UT (this probably underestimates transmission, since only cases with tracking data are analysed).

In-school transmission: In School A the 45 introduced cases (as defined above) resulted in 5 secondary infections; in School B the 24 introduced cases resulted in 1 secondary infection. Combined, there were 6 secondary cases from 69 traceable introduced cases (9%). Chance of an outbreak per infected individual: School A 5/47 (11%, 95% CI 4-22%), R0 0.49, overdispersion parameter k 0.05 (95% CI 0.014-0.15); School B 1/22 (4.5%, 95% CI 0.5-19.3%), R0 0.02, overdispersion parameter k 300 (not overdispersed). Chance of an outbreak per introduction: School A 5/45 (11%, 95% CI 4-23%), R0 0.5, overdispersion parameter k 0.05 (95% CI 0.01-0.14); School B 1/24 (4.2%, 95% CI 0.5-17.9%), R0 0.04, overdispersion parameter k 200 (not overdispersed). 72% of in-school transmission cases in School A were associated with noncompliance with school mask wearing rules. There was no evidence of student-to-teacher or teacher-to-student transmission in either school.

Outbreak clusters: There were 6 outbreaks in School A, with a minimum number of 3 secondary cases. The largest outbreak had 28 cases and was traced to an off-campus party. The relative lack of single case transmissions, but many non-transmission events, suggests an overdispersed chance of transmission in School A. School B was not overdispersed, since the only outbreak had a single transmission event. In 6/7 clusters across both schools, there was clear noncompliance with mitigation protocols (e.g. close proximity in classrooms or cafeteria, off-campus socialising). Major off-campus sources identified were family exposure (including siblings returning from college) and off-campus activities including parties and other gatherings. However, the source of the majority of infections could not be determined.

Conclusions: School leadership acknowledged that introductions related to community exposures outside school would occur at community rates, but wanted to be certain that schools did not play a role in amplifying cases, i.e. that in-school transmission was limited. Both schools were able to successfully maintain in-person schooling for the full term, despite rising community numbers and other neighbouring school closures. The majority of cases identified did not lead to larger chains of transmission. Outbreaks mainly occurred when mitigating protocols were not followed, in and out of school. There was no correlation between in-school infections and community positivity rates, but there was a correlation with community incidence rates. In the schools, positivity rates (positive tests/total number of tests) and case incidence (positive tests/population) were the same, because everybody was tested; whereas only a small proportion of the community is tested. Transmission (secondary infections) was bimodal, with 91% of traceable introduced cases having no secondary transmission and 9% of introduced cases accounting for all identified clusters. The rate of positive cases was highest following school breaks and when there was clear evidence of students attending social or family events in the community, and lowest when in-person schooling continued uninterrupted. In-school infections peaked each time students returned from a prolonged school break. Few cases occurred in staff and these all seemed to have had out-of-school introduction sources. There were no severe cases among students or staff; most cases were asymptomatic and none required hospitalisation. R0 estimates were consistently below 1, indicating that in-school transmissions did not represent sustainable outbreaks. The testing protocols served as a gauge of the effectiveness of mitigation protocols, identified risky activities, enabled school officials to adjust protocols in real time and provided reassurance for families and faculty. Temperature screening was not useful, because most cases were asymptomatic. Sewage surveillance was also not useful. The major limitation of this data is that it reflects the experience of two schools with substantial financial and organisational resources, which are not available to most schools; the school populations are likely to have a lower burden of chronic disease and better access to medical care, so results may not be generalisable. Additionally, the testing protocols changed over time and initially began with lower frequency of testing than ideal, so school transmissions might have been missed during this period. Testing frequency increased when less expensive and easier to implement pooled saliva testing became available. Challenges include asymptomatic infections, out-of-school social activities, violation of face mask rules and return to school after extended breaks.

Deep, ARamnarayan, PCrit Care MedAcute Kidney Injury in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic: Experience from PICUs across United Kingdom01 Dec 2020United KingdomEurope116Clinical - PIMS-TShttps://pubmed.ncbi.nlm.nih.gov/33044282/

Introduction: The authors present a multicenter observational study from 24 PICU’s in the United Kingdom, 15 of which provided data for the study on 116 children. Their aim was to study the prevalence, evolution, and clinical factors associated with acute kidney injury (AKI) in children admitted to PICUs with pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 (PIMS-TS) between March 14, 2020, and May 20, 2020.Initial presenting features of 78 of these patients have been reported previously, although no details regarding AKI in this cohort have been published previously. Cardiac features in 6 and renal features in 23 patients have also been presented in single-center reports.

Results: De-identified data collected as part of routine clinical care were analyzed. All children were diagnosed and staged for AKI based on the level of serum creatinine above the upper limit of reference interval values according to published guidance. Severe AKI was defined as stage 2/3 acute kidney injury. Uni- and multivariate analyses were performed to study the association between demographic data, clinical features, markers of inflammation and cardiac injury, and severe AKI.

Any-stage AKI occurred in 48 of 116 patients (41.4%) and severe AKI in 32 of 116 (27.6%) patients, which was mostly evident at admission (24/32, 75%). In univariate analysis, body mass index, hyperferritinaemia, high C-reactive protein, Pediatric Index of Mortality 3 score, vasoactive medication, and invasive mechanical ventilation were associated with severe AKI. In multivariable logistic regression, hyperferritinaemia was associated with severe AKI (compared with non-severe AKI; adjusted odds ratio 1.04; 95% CI, 1.01–1.08; p = 0.04). Severe AKI was associated with longer PICU stay (median 5 days [interquartile range, 4–7 d] vs 3 days [interquartile range, 1.5–5 d]; p < 0.001) and increased duration of invasive mechanical ventilation (median 4 days [interquartile range, 2–6 d] vs 2 days [interquartile range, 1–3 d]; p = 0.04).

Conclusions: The authors found severe AKI occurred in just over a quarter of this cohort of children admitted to United Kingdom PICUs with PIMS-TS. They concluded that the prevalence of AKI in PIMS-TS is high, and most patients who develop AKI do so either at admission or within 48 hours. Factors associated with severe AKI include high BMI, raised CRP, hyperferritinaemia, and high PIM3 score at admission. Hyperferritinaemia was significantly associated with severe AKI. Severe AKI was associated with increased duration of stay and ventilation. The authors conclude though short-term outcomes for AKI in PIMS-TS for this cohort appear good, long-term outcomes are unknown and less well understood, indicating the need for close follow-up by a multidisciplinary team.

Cohen C AValkenburg S AmedRxivSARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection02 Feb 2021Hong KongAsia24Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.02.02.21250988v1.full-text

SARS-CoV-2 infections in children are widely reported to cause mild illness. The authors at the University of Hong Kong and Hospitals (Kowloon West Cluster (KW/EX-20-039 (144-27)), Kowloon Central / Kowloon East 136 cluster (KC/KE-20-0154/ER2) and HKU/HA Hong Kong West Cluster (UW 20-273, UW20- 137 169), Joint Chinese University of Hong Kong) carried out an ex-vivo quantitation of cellular T and B cell response and monocyte response to coronavirus infection in children and adults seeking to explain possible reasons for the observed factor.

Assessed were 24 children (aged 2-13 yrs) and 45 adults aged ( 20-65 years), symptomatic and asymptomatic but SARS-CoV-2 RT-PCR confirmed, admitted to Hong Kong Hospitals ( 1- 14 days) whom they followed up through discharge (6-60 days) and through convalescence (61-180 days). Asymptomatic blood donor SARS-CoV-2 RT-PCR negative adults were used as controls.

Nine (38%) children and 9(20%) adults were asymptomatic. They had 55 early acute samples and 95 longitudinal samples available for the ex-vivo analysis from 46 subjects.

Using observation of the induced gamma interferon (IFNγ+), they assessed CD4+ and CD8+ T cell response to structural, accessory and non-structural SARS-CoV-2 proteins and compared those responses between SARS-CoV-2 positive and negative adults and with SARS-CoV-2 positive children. They found that the majority (94%) of SARS-CoV-2 infected adults gave a higher IFNγ+ CD4+ T cell induced response to structural proteins than 79.4% SARS-CoV-2 positive children (p=0.0031) and 50% of SARS CoV-2 negative adults (p=<0.01). Infected children had significantly reduced CD8+ recposnes to SARS-CoV-2 structural or non-structural proteins when compared to both SARS-CoV-2 positive adults and SARS-CoV-2 negative adults. Infected children had reduced total monocyte reaction and reduced inflammatory type monocytes. They also showed bone marrow monocyte recruitment comparable to SARS-CoV-2 negative adults comparted to infected aults.

The authors observed stable CD4+ T call responses over time but increasing CDF8+ T cell responeses with age. CD8+ T cell response therefore appears to be less experienced and maturted in children at the time that they may become infected with SARS-CoV-2 than in adults.

Specific IgG response to SARS-CoV-2 was similar between SARS-CoV-2 infected children, infected adults, and negative adults.

Limitations: This is a small sample providing a situation analysis.

Graff, KAbuogi, LPediatr Infect Dis JRisk Factors for Severe COVID-19 in Children01 Feb 2021USANorth America454Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Risk_Factors_for_Severe_COVID_19_in_Children.95881.aspx

This retrospective cohort study aimed to identify risk factors associated with hospital admission and development of severe COVID-19 in children and young people infected with SARS-CoV-2. They report extremes of age (within the paediatric population), comorbidity and raised CRP as predictors of severe disease.

Cohort: The study analysed data from every SARS-CoV-2 positive (on PCR) patient <21 years old within Children’s Hospital Colorado between 15 March and 8 July 2020, amounting to 454 children and young people. Median age was 11 years, 42.1% were female. Almost 55% were Latino or Hispanic, which represented a significantly greater proportion of cases than the general paediatric population at the hospital, or in the wider community.

Results: Of the 454 children testing positive, 85 (18.7%) required hospital admission. 19 of those were asymptomatic and admitted for reasons other than COVID-19, so weren’t included in further analysis. 36 children with symptomatic SARS-CoV-2 infection required respiratory support, which ranged from low flow oxygen therapy via nasal cannulae to ECMO (1 case). 11 children required critical care. There was 1 death (ECMO patient).

Risk factors for admission were young age (0-3 months) and age >20 years, as well as comorbidities. Obesity also increased the odds of admission. Similar risk factors were associated with need for respiratory support, including age 0-3 months or >20 years, gastrointestinal disease and asthma. Those children that required critical care had a significantly higher CRP on admission than those that did not need critical care. There were more males than females testing positive for SARS-CoV-2, but male sex wasn’t predictive of more severe disease. Latino/Hispanic ethnicity was overrepresented in the study population, and associated with higher odds of needing respiratory support on univariable analysis, but not on multivariable analysis.

Discussion: This study had a relatively large cohort and analysed a large amount of data. Its findings are a very useful addition to the body of evidence on management of COVID-19 in children. Young infants and young adults were at greatest risk of hospital admission and severe disease, with underlying comorbidities being another risk factor. Ethnicity appeared to be relevant, although lack of support on multivariable analysis meant the factors underlying this remain unclear. Raised CRP on admission was predictive of severe disease. Obesity also emerged as an apparent risk factor for admission and respiratory support, although had to be excluded from multivariable analysis due to missing data.

Allan-Blitz, JTKlausner, JDPediatr Infect Dis J 40(3): e132-e133Prevalence of Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Youth01 MAR 2021USANorth America54501Epidemiology - Transmissionhttps://journals.lww.com/pidj/Fulltext/2021/03000/Prevalence_of_Asymptomatic_Severe_Acute.31.aspx
Brookman, SGupta, ALancet Child Adolesc HealthEffect of the new SARS-CoV-2 variant B.1.1.7 on children and young people10 Feb 2021UKEurope80Epidemiology - Disease Burdenhttps://doi.org/10.1016/S2352-4642(21)00030-4

It is a comparison of data, relating to SARS-CoV-2 infection in children and young people (CYP), gathered during 1 March to 31 May 2020 and 1 Nov 2020 to 19 Jan 2021 in the United Kingdom.

In the first wave (March to May 2020), 20 CYP (aged 18 years or younger and positive for SARS-CoV-2) were admitted to King’s College Hospital in south London. In the second wave (Nov 2020 to Jan 2021), 60 CYP positive for SARS-CoV-2 were admitted.

The authors state that during the second wave, the B.1.1.7 variant accounted for an estimated 70% of infections in London, whereas during the first wave infection was predominantly with earlier lineages.

No significant differences were found in age, proportion of patients with comorbidities, proportion of patients from Black, Asian, and minority ethnicity background, or deprivation score between CYP admitted to hospital and positive for SARS-CoV-2 in the two waves.

More CYP were admitted during the second wave. The authors conclude that this was due to an increased prevalence of SARS-CoV-2 within their local community, which was also reflected in a larger number of adults being admitted in the second wave.

The authors state that they found no evidence of more severe disease in children and young people during the second wave, indicating that infection with the B.1.1.7 variant does not result in an appreciably different clinical course to the original strain.

Zimmerman, KBenjamin, DPediatricsIncidence and Secondary Transmission of SARS-CoV-2 Infections in Schools 08 01 2021USANorth America773Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/01/06/peds.2020-048090

Amongst the growing number of studies examining transmission of SARS-CoV-2 in schools, many are not from settings with persistent high community SARS-CoV-2 transmission. In this study from North Carolina, USA, data on SARS-CoV-2 incidence in school districts participating in the ABC Science Collaborative (ABCs) following re-opening of schools in August 2020 are analysed. Participating schools used a hybird model of in-person and virutual learning with 50% of children receiving in person instruction on Monday/Tuesday and 50% on Thursday/Friday. Community transmission remained high (>1 PCR confirmed case per 1000 residents / fortnight) in the participating districts for the majority of the study period.

ABCs is a partnership between Duke University, the University of North Carolina and school districts which was formed with the aims of 1) educating school leaders, staff and the community, 2) have school-specific data to drive decision making, and 3) generate new science to improve health-outcomes in children. Mitigation strategies were in place at all participating schools including (i) universal masking of all >/= 5 years of age (ii) 6-foot distancing and (iii) hand washing; daily symptom monitoring and temperature checks were also performed. The primary outcome of this study was number of within-school transmissions of SARS-CoV-2 as determined by contact tracing by the local health department through the 9-weeks following schools re-opening.

Of 115 school districts, 56 participated in ABCs and 17 were open for in-person learning through the entire 9-week term. Data was analysed from the 11 of these 17 schools which reported weekly SARS-CoV-2 incidence and secondary (in-school) transmission. These 11 districts comprised more than 90,000 students and staff who attended in-person schooling during the study period.

There were a total of 773 community-acquired SARS-CoV2 infections documented during the study period. Only 32 cases of in-school transmission were reported through the 9-week school term: 6 in pre-kindergarten, 11 in elementary (primary) schools, 6 in middle schools, 5 in high schools, and 4 in K-12 schools. No cases of child-to-adult transmission were documented. All three clusters (of >/= 5 cases) of in school transmission in participating schools were linked to absence of face coverings either during meals, in very young children or in children with substantial special needs. Instances of child-to-child and adult-to-child transmission were not analysed due to confidentiality concerns.

Key contributors to the success of the program were identified by superintendents of participating districts including high rates of adherence to masking, clear communication and reporting of confirmed cases, efficient contact tracing, sharing of resources and detailed scheduling of the school day to allow adherence to mitigation measures. Challenges included the need to quarantine individuals (total of >3000 children and staff over the 9 weeks), compliance fatigue and ensuring family cooperation with contact tracing.

This study is limited by the lack of universal testing of contacts, which was not enforced as a requirement for return to school. Although this may have led to an underestimation of secondary cases, especially amongst asymptomatic individuals, the relative lack of large clusters or ongoing chains of transmission despite participating schools remaining open are consistent with limited SARS-CoV-2 transmission in this setting. This study adds to the growing body of evidence that in-school transmission of SARS-CoV-2 is limited in the setting of appropriate mitigation measures, even with high levels of transmission in the surrounding community. The success of the ABCs collaboration in North Carolina highlights the strength of a data-informed policy approach, as well as the importance of education, clear communication and cooperation between school districts.

Hobbs, CFlannery BmedRxivEstimated SARS-CoV-2 Seroprevalence in Children and Adolescents in Mississippi, May Through September 202008 FEB 2021USANorth America1603Epidemiology - Disease Burdenhttps://doi.org/10.1101/2021.02.05.21250792

Question: What is the extent of infection with SARS-CoV-2 among children and adolescents in Mississippi during the period from May to September 2020.

Methods: retrospective seroprevalence study using one of two methods (Ortho VITROS and CDC ELISA), depending on sample volume, to measure antibodies to SARS-CoV-2 in blood samples that had been collected for clinical reasons from patients aged less than 18 years of age. CDC ELISA was used in sample volumes of <0.3mls.

Setting: University of Mississippi Medical Center which provides clinical laboratory services for university hospitals and 12 other hospitals in the state of Mississippi.

Results: 175 samples out of 1603 (10.9% (9.4–12.4)) tested positive overall. A higher rate of prevalence of antibodies was seen in: children aged less than 1 year, non-whites and in those tested using the CDC ELISA technique. There were no sex differences. The seroprevalence increased from May to September from 2.6% (0.3–5.2) to 16.9% (9.9–24.2). The ratio of estimated infections based on seroprevalence to the cumulative number of reported COVID-19 cases by the previous month in the state of Mississippi was 69.6 (8.2 – 141.9) in May 2020 decreasing to 13.0 (7.6 – 18.7) in September.

Discussion: The authors concluded that in children and adolescents under 18 years of age the seroprevalence of SARS-CoV-2 infection increased as the months went, that the extent of COVID-19 infections in children and adolescents was underestimated during the months of May through to September 2020. With better contract tracing and identification this improved. There was a higher seroprevalence in non- whites’ minorities as seen in adult seroprevalence studies.

Comments: the main drawback of this study is the likelihood of sample bias, which the authors acknowledge in the Discussion. Higher seroprevalence was found in the youngest age, which is a surprising finding. However, the seroprevalence by age bands are uninterpretable given that the figures have not been adjusted for population in each age band nor for differences in the ethnic/race distribution. The seroprevalence was higher with the CDC ELISA assay, which was used if the sample was small, a situation most likely to arise in the youngest children. There is no information on distribution of the 2 assays per age band. The authors do not address this. It is not clear why the months from May to September were chosen nor was any information given as to where in the epidemic curve was Mississippi at the time of the study.

González-Donapetry, PGarcía-Rodriguez, JPediatr Infect Dis JThink of the Children Evaluation of SARS-CoV-2 Rapid Antigen Test in Pediatric Population23 January 2021SpainEurope440Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/Think_of_the_Children__Evaluation_of_SARS_CoV_2.95859.aspx

A study undertaken in the Paediatric Emergency Department, La Paz, Spain between 25th September and 14th October 2020. Paired nasopharyngeal swabs were taken from a total of 440 children aged 0-17 years, median age 3 (IQR 1-7), 59.1% of whom were male. The paired samples were tested for SARS-CoV-2 using a rapid antigen detection test and reverse transcription quantitative PCR.

Only 18 (4.1%) children age range 0-15, median age 6 (IQR 0-8) tested positive by reverse transcriptase PCR and of these 14 were positive by the rapid antigen test. No child with a positive antigen test had a negative RTqPCR. The sensitivity and specificity of the rapid antigen test were 77.78% (95% CI 51.92 - 92.63) and 100% (95% CI 98.88 - 100) respectively with a Kappa coefficient of 0.87 (p<0.001)

The authors conclude “The sensitivity of COVID-19 Ag Rapid Test Device is lower in children than in adults. Nevertheless, considering the good values of specificity, negative and positive predictive values this test could be used as a frontline test to obtain quick results, although the negative values with COVID-19 high clinical suspicion should be confirmed using RT-qPCR

Pace, RMcGuire, Mmbio Characterization of SARS-CoV-2 RNA, Antibodies, and Neutralizing Capacity in Milk Produced by Women with COVID-1909 Feb 2021USANorth America18Neonatalhttps://mbio.asm.org/content/12/1/e03192-20

The primary aims of this prospective study from the US are expressed in the title of the paper. Eighteen lactating women, with an average age of 34.2 ± 4.7 years, who tested positive to SARS-CoV-2 within eight days of recruitment, were included. Fifteen had symptoms of COVID-19 , at some stage, but none were hospitalised because of COVID-19. The “mean time post partum (s.d.)” was stated to be 6.8 months (+/- 7.8), the mathematics of which I am still trying to get my head round. Breast milk and breast swabs were collected in the participants’ homes using “virtual” instructions or, for two inpatients, in hospital. The milk was analysed for IgA and IgG targeting SARS-CoV-2 and for the ability of the samples to neutralize SARS-CoV-2. Well established laboratory methodologies were used and validated between two laboratories. Thirty seven samples were collected and analysed. Milk samples collected prior to the pandemic were analysed as controls. In addition the milk Na+ and K+ concentrations were measured, a ratio of >0.6 having been shown to indicate subclinical mastitis, which has been found to be associated with high viral content in breast milk. Nipple/areola swabs were collected by 15 women, before and after cleaning of the breast with soap and water, and tested for SARS-CoV-2 RNA.

A key study outcome was that none of the milk samples contained detectable SARS-CoV-2 RNA, using Rt-qPCR. With regard to antibodies, 76% (26/34) of milk samples contained SARS-CoV-2-specific IgA and 80% (22/27) contained SARS-CoV-2-specific IgG; the concentrations of IgA were higher than those of IgG. Both classes of SARS-CoV-2-specific antibody were also found in the pre-pandemic control group samples but the milk produced by women with COVID-19 had higher anti-RBD* IgA and IgG concentrations than milk collected from women before the pandemic (P=0.00013 and P=0.03 respectively). Functionally, 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity in vitro, whereas milk samples from the control group did not do so. The milk Na/K ratios were >0.6 in 12 (36%) samples, suggesting subclinical mastitis in 9 participants; however, as no SARS-CoV-2 RNA was found in the samples, the authors concluded that the mastitis was unlikely to be attributable to SARS-CoV-2 virus. Of the 70 breast swabs, eight had evidence of SARS-CoV-2 RNA, only one reaching the threshold value for conclusive SARS-Co-V positivity.

The absence of detectable virus in the milk samples, together with the presence of neutralising antibodies, led the authors to conclude that their data did not support mother-to-infant transmission of SARS-CoV-2 via milk but did support recommendations to encourage breastfeeding in women with mild-to-moderate COVID-19 illness. They also concluded that there findings were consistent with the recommendations of the World Health Organisation that there is no need for mothers who have confirmed or suspected COVID-19 to wash their breasts before feeding unless they have coughed over their exposed breasts, in which case they should gently wash the breast with soap and warm water before feeding.

These findings are broadly in line with a recently published systematic review of studies of the presence of the SARS-CoV-2 genome and/or antibodies in breast milk, which reported that the genome was present in the breast milk of 5% of women with confirmed COVID-19 and that anti-SARS-CoV-2 antibody was found in the milk of 83%.1

*RBD = receptor-binding domain

Metbulut, AMisirlioglu, EPediatr Allergy ImmunolEvaluation of Cutaneous Symptoms in Children Infected with COVID-1908 Feb 2021TurkeyAsia5143Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pai.13467

This is a prospective study evaluating the incidence and types of cutaneous manifestations associated with COVID-19 infections in children.  The study was conducted in Ankara City Children’s Hospital in Turkey between 11 March and 30 September 2020.

In the study period, there were a total of 5143 children who tested positive for Covid-19.  Of these, only 13 (0.25%) developed cutaneous lesions.  The median age of these children was 6 years and 77% were boys.  The most common skin manifestation associated with Covid-19 in the study was maculopapular exanthema (61.5%, n:8) followed by urticaria (23%, n:3).  Two of the patients with maculopapular exanthema had Multisystem Inflammatory Syndrome in Children (MIS-C) which is known to be associated with a rash.  Two other patients presented with severe cutaneous adverse reactions (SCARs); namely Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS).   The use of any drug therapy suspected to be causing a rash was terminated during the study.   The patient with SJS died and all other patients recovered and were discharged home.

This study confirms that skin manifestations are rarely associated with Covid-19 infection with children.  When present, the cutaneous symptoms vary from mild to severe.  The authors note that 6 of the 13 children had a history of drug usage and it is unclear whether their cutaneous symptoms were secondary to Covid-19 infection itself or the drug given.  They conclude that more studies would help to confirm and understand the skin involvement in COVID-19.

Neeland, MSaffery, RNat. Comm.Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children.17 Feb 2021AustraliaOceania48Clinical - Clinical Featureshttps://www.nature.com/articles/s41467-021-21414-x
Chua, GTKwan, MYWEmerg Microbes and infectSaliva viral load better correlates with clinical and immunological profiles in children with coronavirus disease 201920 Feb 2021ChinaAsia91Clinical - Clinical Featureshttps://doi.org/10.1080/22221751.2021.1878937

Background: Pediatric COVID-19 studies focusing on the association between clinical outcomes and immunological profiles in children with COVID-19 are lacking. Furthermore, the association between respiratory tract viral load and immunological profiles has yet to be explored.

Methods: Demographics, immunological profiles, nasopharyngeal swab (NPS), and saliva samples collected on admission, and hospital length of stay (LOS) were assessed in children below 18 years with COVID-19 admitted to the Princess Margaret Hospital or Queen Elizabeth Hospital in Hong Kong between 12 March and 8 August 2020

Results: 91 patients were included between March and August 2020. NPS and saliva viral loads were correlated (r = 0.315, p = 0.01). Symptomatic patients had significantly higher NPS and saliva viral loads than asymptomatic patients. Serial NPS and saliva viral load measurements showed that the log10 NPS (r = −0.532, p < 0.001) and saliva (r = −0.417, p < 0.001) viral loads for all patients were inversely correlated with the days from symptom onset with statistical significance. Patients with cough, sputum, and headache had significantly higher saliva, but not NPS, viral loads. Higher saliva, but not NPS, viral loads were associated with total lymphopenia, CD3 and CD4 lymphopenia (all p < 0.05), and were inversely correlated with total lymphocyte (r = −0.43), CD3 (r = −0.55), CD4 (r = −0.60), CD8 (r = −0.41), B (r = −0.482), and NK (r = −0.416) lymphocyte counts (all p < 0.05).

Conclusion: Saliva viral load appeared to correlate better with clinical symptoms, hospital length of stay and immunological profiles than NPS viral load. Symptomatic children had higher NPS and saliva viral loads on admission, which predicted longer hospital stay regardless of the antiviral treatment. Saliva viral load correlated well with NPS viral load. Patients with total, CD3, and CD4 lymphopenia were more likely to have higher saliva viral load, but not NPS viral load. Both B lymphocyte counts and IgG levels were predictors of hospital LOS. Larger-scale studies are needed in the future to compare the sensitivity and specificity of using NPS versus saliva viral load for the detection of SARS-CoV-2 in children.

Neeland, MSaffrey, RNat CommunInnate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children17 02 2021AustraliaAustralia48Epidemiology - Disease Burdenhttps://www.nature.com/articles/s41467-021-21414-x

This study, published on 17 February 2021, reports the acute and convalescent immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2 presenting to the Royal Children’s Hospital Melbourne, Australia, between April and August 2020.

Background: Children with SARS-CoV-2 have predominantly mild or asymptomatic infection compared to adults, but any underlying immunological basis for this difference between younger and older age groups is unclear. This study aimed to supply data on the cellular immune response in non-hospitalised children with mild disease, the commonest clinical course of children with COVID-19, compared with the cellular immune response in adults. It also looked at the immune response of children and adults exposed in their households to SARS-CoV-2 infection, but consistently testing PCR negative.

Study population: Participants were families presenting for SARS-CoV-2 testing at the Royal Children’s Hospital Melbourne between April and August 2020, divided into two groups: 1. SARS-CoV-2 positive individuals (27 children and 25 adults), who were non-hospitalised patients with a nasopharyngeal swab positive for SARS-CoV-2 and mild symptoms (including coryza, headache, nausea, fever, cough, sore throat, malaise and myalgia); 2. SARS-CoV-2 exposed individuals (21 children and 45 adults), who had a positive household close contact (defined as having face-to-face contact for more than 15 minutes and sharing a closed space with a confirmed case of COVID-19), but were SARS-CoV-2 PCR negative on repeated nasopharyngeal swabs (up to 5 repeat PCR tests at 5-7 day intervals for 4 weeks). Acute blood samples were collected within 2 weeks of the first positive PCR result and convalescent samples were collected 4-7 weeks from the first positive PCR result. These were not longitudinally collected samples from the same paediatric and adult patients, thus there were 8 groups in the study cohort: children vs adults, SARS-CoV-2-positive vs SARS-CoV-2-negative but exposed to SARS-CoV-2, acute vs convalescent sample. Median age for children in the SARS-CoV-2 positive group was 4.5 yrs (range 1-14) for 11 acute samples and 10 years (range 1-17) for 16 convalescent samples; median age for adults in the SARS-CoV-2 positive group was 35 years (range 19-62) for 17 acute samples and 40 years (range 20-62) for 8 convalescent samples. Median age for children in the SARS-CoV-2 exposed (but repeat PCR negative) group was 9 years (range 3-17) for 7 acute samples and the same age profile for 14 convalescent samples; median age for adults in the SARS-CoV-2 exposed (but repeat PCR negative) group was 38 years (range 21-50) for 21 acute samples and 41 years (range 22-56) for 24 convalescent samples.

Monocytes, dendritic cells and natural killer cells: Children with SARS-CoV-2 infection had low proportions of total monocytes during the acute phase that were restored in convalescence (median 0.67% vs 3.0% of PBMCs, p=0.0031). This was true of all three circulating monocyte subsets, with largest differences between acute and convalescent in the intermediate (CD14+CD16+, median 0.07% vs 0.14%, p=0.005) and non-classical (CD14lowCD16+, median 0.04% vs 0.33%, p=0.0003) subsets. This was also seen in adults for non-classical monocytes (median 0.19% acute vs 1.1% convalescent, p=0.01), but not for classical and intermediate subsets. Children also had a reduction in dendritic cells during the acute phase of infection that were restored in convalescence (median 0.26% vs 0.50%, p=0.0004), but this was not seen in the dendritic cell population of adults. SARS-CoV-2 positive children had reduced natural killer cells during the acute phase compared with SARS-CoV-2-exposed children (median 4.8% vs 8.3% of PBMC, p=0.06); whereas positive adults did not have different proportions of natural killers cells relative to exposed (but PCR negative) adults (median 9.1% vs 8.8%, p=0.99).

CD63+ neutrophil response: Total proportions of neutrophils and eosinophils were not significantly different between groups in children or adults, but there was an increase in the proportion of CD63+ neutrophils in SARS-CoV-2 infected children relative to SARS-CoV-2 exposed children in the acute phase (median 22% vs 1.7%, p=0.0002), which decreased from 22% to 8.1% in convalescence. CD63 is upregulated on the surface of neutrophils after activation and involved in the release of pro-inflammatory mediators as part of the anti-viral immune response. This response was not seen in SARS-CoV-2 infected adults. Other markers of innate cell activation (including HLADR, CD11b and CD11c) were not different between groups.

Low-density immature neutrophils: Children and adults exposed to SARS-CoV-2 but negative on PCR testing displayed increased proportions of low-density immature neutrophils that could be observed up to 7 weeks post-exposure.

Conclusions: In this study comparing the innate immune responses of children and adults with mild SARS-CoV-2 infection, infection in children was characterised by increased activation of neutrophils and low circulating proportions of all monocyte subsets, dendritic cells and natural killer cells, in contrast to infected adults who showed reductions in the non-classical monocyte fraction only. The reduction of innate cell populations in the circulation suggests that these cells may be recruited to sites of infection. This has been demonstrated in previous studies in adults (e.g. a study comparing blood and lung profiles of patients with severe COVID-19, where non-classical monocytes were seen to preferentially migrate from the blood into the lungs during disease). Additionally, this study showed that exposure to SARS-CoV-2 induces changes in the immune response in the absence of virological confirmation of infection, highlighted by the emergence of low-density immature neutrophils up to 7 weeks post-exposure in both children and adults. Longitudinal studies comparing responses from the same patients throughout infection and recovery would provide further insight into the immune mechanisms contributing to age-related differences in severity of disease after infection with SARS-CoV-2. Further investigation of cellular immune responses in adults and children exposed to SARS-CoV-2, but PCR negative, would also cast light on protective immune responses.

Lachassinne, EAupiais, CLancet Child Adolesc Healthwww.thelancet.com/child-adolescent Published online February 8, 2021 https://doi.org/10.1016/S2352-4642(21)00024-9 1 SARS-CoV-2 transmission among children and staff in daycare centres during a nationwide lockdown in France: a cross-sectional, multicentre, seroprevalence study08 Feb 2021FranceEurope327Epidemiology - Transmissionhttps://doi.org/10.1016/S2352-4642(21)00024-9

This is a cross sectional prevalence study in France, assessing prevalence of SarsCov2 antibodies in children of frontline workers who attended day care during initial lockdown (March 15 to May 9 2020) and comparing them to day care worker, and matched adult controls

Methods: Children of essential workers, attending 24 day cares during the initial lockdown were enrolled in a cross sectional study, 4-8 weeks after the end of lockdown. Staff at the day cares were also enrolled. The comparator adult group, was hospital admin and lab staff who kept working during lockdown, but who were not patient facing, and had no regular contact with infants. All had SarsCOV-2 antibody testing by finger prick using Biosynex COVID-19 Ag BSS. Positive and negative serologies were defined respectively as the presence and absence of IgM or IgG, or both. These results were then adjusted for imperfect sensitivity and specificity of the test.

In children, for those whose parents consented, RT -PCR, by NPA and stool swab were also obtained.

Parents working in a hospital underwent Sars-Cov2 antibody testing as part of a local campaign and these results were collected retrospectively.

Data on demographics, and history of symptoms associated with SARSCoV-2 were also collected.

Results : Mean age of children was 1·9 years (SD 0.9), with 167 (51%) male. Mean age of daycare staff was 40 years (SD 12) with 195 (99%) female.

14/327 children, 14/197 daycare centre staff and 9/164 comparator adults were seropositive, resulting in estimated raw seroprevalence rates of 4·3% (95% CI 2·6–7·1) among children and 7·7% (4·2–11·6) among staff and 5.5% (95% CI 2.9-10.1) in comparator adult group.

The corrected seroprevalence rate among daycare centre staff was similar to that in the comparator group (6·8% [95% CrI 3·2–11·5] vs 5·0% [1·6–9·8]). After adjustment for age, sex, and contact with a known COVID-19 case, the odds of a positive serological status for occupational status (ie, being a daycare worker) were 1·5 (95% CI 0·6–3·9).

None of the 197 nasal swabs and none of the 261 stool swabs from the children was positive for SARSCoV-2 PCR.

Conclusions: Authors conclude that there was low seroprevalence of SARSCoV-2 antibodies in a group of young children attending daycare during a national lockdown. Also, the seroprevalence rate among daycare centre staff did not differ from that observed in a group of hospital staff who did not have occupational contact with children or COVID-19-positive patients.

Kim, EJeong, EPediatr Infect VaccineChildren with COVID-19 after reopening of schools, South Korea12 Nov 2020South KoreaAsia127Epidemiology - Transmissionhttps://www.piv.or.kr/search.php?where=aview&id=10.14776/piv.2020.27.e23&code=1153PIV&vmode=PUBREADER

Summary: This study investigated the affect of school reopening in South Korea on paediatric COVID-19 cases. They looked at cases of COVID-19 in children aged 3-18 years who attended kindergarten or school, and analyzed data on exposure and transmission to assess the effect of attending these education settings on COVID-19 rates. They found low rates of transmission in school compared to other settings.

Cohort: All children aged 3-18 years attending kindergarten or school, who were reported to the National Surveillance System with COVID-19 between 1 May (when schools reopened) and 12 July. There were 127 cases reported, with 66% of cases being males, and 36% aged between 7-12 years.

Results: Analysis of SARS-CoV-2 exposure showed the most common form of exposure was from family and relatives – this accounted for 47% of cases. Exposure was attributed to cram schools (not defined) and private lessons in 14% of cases, to multi-use facilities such as churches and karaoke venues in 6% of cases, and to kindergarten/school in just 2% of cases.

Discussion: This study adds to the body of evidence that schools, where infection prevention measures are in place as in South Korea, are relatively low risk settings for SARS-CoV-2 transmission, and supports the call to keep schools open. The findings indicate that settings where infection control measures aren’t applied or aren’t as controlled, present a much greater risk for transmission.

Perramon, ASoler-Palacin, PmedrxivEpidemiological dynamics of the incidence of COVID-19 in children and the relationship with the opening of schools in Catalonia (Spain)17 Feb 2021Spain/CataloniaEurope940000Epidemiology - Transmissionhttps://doi.org/10.1101/2021.02.15.21251781

This pre-print article describes the trends in SARS-CoV-2 transmission in children under 18 in the whole of Catalonia, Spain, from 14 Sept 2020 to 31 Jan 2021. The authors relate these trends to schools opening and closing over autumn and Christmas. Both PCR and rapid antigen tests were used. Around 943,000 tests were performed, and 5.2% were positive overall. As seen elsewhere, incidence was similar to the general population in adolescents aged 12-17, but lower in younger children.

In Catalonia, all schools were closed between March and September 2020. Their data showed that when schools eventually re-opened, the incidence rate among children remained lower than the general population. This was in spite of more testing being done. They describe all the interventions in schools to prevent transmission: mask-wearing for all over 6 years old, natural ventilation, hand hygiene, clustering in bubble groups, and 10-day quarantining of bubble groups following a positive test.

They conclude that kindergarten and primary school-age children ‘…have not played a significant role in SARS-CoV-2 dissemination in Catalonia probably due to their lower susceptibility to the virus and lesser capacity to transmit it’.

This paper has not been peer-reviewed, and there are several potential sources of bias and inaccuracy which may not have been adequately recognised: e.g. differential testing rates, whole population trends, new variants, etc. Temporal association does not always imply cause and effect. As such we should be cautious in drawing firm conclusions from these results

Gold, JVallabhaneni, SMorb Mortal Wkly RepClusters of SARS-CoV-2 Infection Among Elementary School Educators and Students in One School District — Georgia, December 2020–January 202122 02 2021USANorth America32Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7008e4.htm

This study from Georgia, USA, described clusters of SARS-CoV-2 transmission in eight public elementary schools over an 8-week period (December 1st 2020 - January 22nd 2021). Mitigation measures were in place including mandatory in-classroom mask use and placement of plastic dividers between students, but physical distancing was not possible. Community transmission in the local county was high during the study period (cumulative weekly cases rose from 194 to 704 cases per 100,000).

Cases of SARS-CoV-2 were identified either by self-report of by local public health officials. Close contacts of confirmed cases were advised to quarantine and free PCR testing was offered to all contacts within 5-10 days of in-school exposure (60% of identified contacts were tested - the remained could not be reached or declined). For positive contacts, virtual interviews were conducted to assess likelihood of in-school transmission. An estimated 2,600 students and 700 staff attended in person learning during the study period.

A total of 9 clusters were identified, involving 13 educators and 32 students. An educator was the index case in 4 clusters which accounted for 21/31 cases of in school transmission. This included one two cluster with initial educator to educator transmission for followed by educator to student transmission (15/31 cases of in school transmission). A student was the index patient in 1 cluster (2/31 cases of in school transmission) and in the remaining 4 clusters whether the index case was an educator or student could not be determined.

Investigation of in-school transmission events revealed 9/9 clusters were associated with suboptimal physical distancing (students sat <3 feet apart), 7/9 were associated with small group instruction with educators working in close proximity to students, and 5/9 occurred in settings of inadequate mask use. Of household contacts of school-associated cases, 26% (18/69) tested positive for SARS-CoV-2.

These findings demonstrate that educators may play an important role in in-school transmission of SARS-CoV-2, with clusters with an educator index cases accounting for at least two thirds of in-school transmissions. The number of in-school transmission reported here is higher compared to recent reports from elsewhere in the US, possibly owing to the absence of some mitigation measures particularly limitations in mixing between staff (as employed in Wisconsin) or physical distancing and a hybrid model of virtual and in person teaching (as employed in North Carolina). Nonetheless, similar to school studies elsewhere, the incidence of in-school transmissions in this setting is low considering the high rate of transmission in the surrounding community at the time of the study. This study is also limited by the lack of universal testing of contacts, and the lack of viral sequencing to definitively determine direction of transmission.

This study highlights the importance of mitigation measures targeted at preventing SARS-CoV-2 transmission between educators as part of a multi-faceted approach to limit in-school transmission of SARS-CoV-2 in settings with high levels of community transmission. Measures such as limiting in-person adult interactions at school, ensuring mask compliance and physical distancing during essential encounters and (although not a requirement for re-opening schools) vaccination of educators once available have potential to reduce transmission and therefore minimise interruptions to in-person learning.

Al Suwaidi, HAlsheikh-Ali, AClin Microbiol Infect.Saliva for molecular detection of SARS-CoV-2 in school-aged children.10 Feb 2021United Arab EmiratesMiddle East476Epidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S1198743X21000847?dgcid=rss_sd_all

This was a prospective observational diagnostic study looking into the accuracy of saliva samples in paediatrics when tested by RT-PCR. The study notes that diagnostic accuracy of saliva in adults has been well reported but those reporting the accuracy in paediatrics have lacked in power.

Methods: The samples were collected between 1-23rd October 2020 and included 476 paediatrics who presented to a Dubai Health Authority community-based screening centre in the UAE. Indications included contact with confirmed COVID-19 patients, presence of presumptive symptoms or testing for return to school. Both nasopharyngeal and saliva samples were collected at the same time. Saliva samples were collected from each patient after 30+ minutes of abstinence from food and NP samples were collected by a trained HCP. Both samples were sent off to a laboratory for RT-PCR testing within 3 hours. The RT-PCR was used for detection of three gene targets (N, E and RdRp genes) and the cycle threshold of ≤40 was taken as the cut-off for positive result.

Statistical Data: Based on an infection prevalence of 5%, a sample size of 400 participants was required to detect at least a sensitivity of 80% and specificity of 95%. 476 paediatric patients with a mean age of 10.8 years (±3.9SD, range 3-18) were included and 58.1% were male. 9 participants were sampled on two occasions due to discordant results, leading to the testing of 485 pairs of NP swab/ saliva RT-PCR samples. Processing time for samples were similar in both arms (NP 9.62 ± 4.34 vs saliva 10.19±4.74 p=0.06).

Results: Viral detection was present in at least one specimen type in 17.9% of specimen pairs (87/485). Prevalence of COVID-19 diagnosis by NP swab RT-PCR was 16.7% (81/485) and 15.9% (77/485) by saliva RT-PCR. 87 children were positive by either test and 39 (44.8%) of these children had reported symptoms. Most commonly reported symptoms were fever (25/39), cough (16/39) and sore throat (15/39).

With NP swab RT-PCR as a reference, the sensitivity and specificity of saliva RT-PCR was 87.7% (95%CI 78.5-93.9%) and 98.5% (95%CI 96.8-99.5%) respectively. PPV and NPV were 92.2% (95%CI 84.2%-96.3%) and 97.6% (95%CI 95.7-98.6%).

Median cycle threshold (Ct) values for E, RdRP and N gene targets in NP swab were 23.9 (IQR 17.3-31.9), 27.8 (IQR 19.8-35.5) and 26.6 (IQR 21.5-31.1) respectively. In Saliva swabs, Ct values were 27.2 (IQR 19.9-32.0), 29.5 (IQR 23.6-34.1) and 28.2 (IQR19.4-32.0) respectively. Concordance of findings between NP swabs and saliva samples did not differ by age (p=0.67) or gender (p=0.29). However, for those who self-reported symptoms compared to no symptoms, mean CT values for the E gene in both samples and the N gene in saliva samples had statistical significances.

Discussion: Diagnostic accuracy of saliva RT-PCR is comparable to the NP swab RT-PCR in ambulatory school-aged children. The results of this study are also aligned with other studies investigating saliva RT-PCR. Although children with COVID19 are largely asymptomatic, they tend to have similar viral loads comparable to adults and reportedly greater viral loads are present in those under five years old.

Therefore, it is expected that the diagnostic accuracy of saliva in children should be on par or superior when compared to adults. The results of this study found the sensitivity of saliva RT-PCR to be higher than some studies on the adult population.

There are 2 other studies which concluded that saliva RT-PCR was not useful for diagnosing COVID-19 in paediatrics. They found that RT-PCR had a low sensitivity but had very small sample sizes of 18 and 11 and were underpowered to assess diagnostic accuracy. Therefore, the reliability of the studies are questioned (Chong et al., 2020; Han et al., 2020).

The strength of this study included the high power and sample size of participants and the target of RT-PCR towards 3 different genes; E, N and RdRp which was not done in previous studies. Limitations include the collection of data from children who presented at a testing centre for screening. This may not provide a result able to be generalised to the wider population. Further research on the wider population including those under 3 would allow for better generalisability

Rha, BLangley, G J Pediatric Infect Dis SocSevere acute respiratory syndrome coronavirus 2 infections in children: Multicenter surveillance, United States, January-March 202018062020United StatesNorth America5573Epidemiology - Transmissionhttps://academic.oup.com/jpids/article/9/5/609/5859277

This paper reports the findings of a US-based multi-centre surveillance study looking at the number of Covid-19 infections in children at the start of the pandemic (January-March 2020).  The study included children <18 years old who had symptoms of an Acute Respiratory Illness (ARI) as well as asymptomatic controls.  These children were enrolled in pre-existing active, prospective surveillance of paediatric ARI by the New Vaccine Surveillance Network (NVSN) across 7 sites in the US.   Retrospective Covid-19 RT-PCR testing was then performed on existing respiratory specimens from enrolled children.

Study population: The 7 NVSN sites are based in Cincinnati, Seattle, Houston, Kansas City, Pittsburgh, Rochester and Nashville.  Each site recruited patients from 4 potential settings; inpatient, Emergency Department (ED), outpatient clinics and well-child visits.  The eligible age-groups for enrollment varied at each setting.   Children between 14 days and 5 years old were recruited from well-child clinics and served as asymptomatic controls.  All other children who were recruited presented with symptoms of an Acute Respiratory Illness (ARI).  Children less than 18 years were recruited from the inpatient and ED settings whilst only those less than 24 months of age were recruited from outpatient clinics. The following presenting symptoms/events were classified as an Acute Respiratory Illness: fever, cough, earache, nasal congestion, runny nose, sore throat, vomiting after coughing, wheezing, shortness of breath, apnea, apparent life-threatening event or brief resolved unexplained event, or myalgias.

Results: 3261 of 5573 (59%) eligible children were enrolled from January-March 2020.  The median age of all children tested was 19 months (range, 0–17 years).  43% of children were recruited from an inpatient setting, 39% from the Emergency Department, 12% from outpatient clinics and 6% were asymptomatic.  During the surveillance period, only 4 children tested positive for Covid-19 infection (0.1%).  The median age of those who tested positive was 6 months and all were symptomatic with symptoms including fever, cough, nasal congestion and irritability.   All 4 children tested positive between 20-31st March 2020.  Three cases were detected in Seattle and 1 was detected in Cincinnati, Ohio.  Community spread in the Seattle area occurred in late February and the first reported case in Ohio was in March.   No children tested positive in the remaining NVSN sites; the first reported community cases in these sites was between 5-18th March.

Discussion: This study aims to provide a more accurate insight into the prevalence of Covid-19 infections in children  through active surveillance rather than clinician-dependant testing and reporting.  The authors conclude that the low numbers of Covid-19 infection are consistent with previous US reports showing children constitute a small minority of reported COVID-19 cases.  From 12th February to 2nd April 2020, only 1.7% of cases reported to the CDC occurred in children.   They also make note of the study’s limitations which may have led to missed detections (only 59% of eligible children enrolled, differing age groups at different settings).  It is also worth noting that the study was conducted at the start of the pandemic when community transmission was low.  Ongoing active surveillance would therefore be of use.

Mensah, ALadhani, SNJ InfectSARS-CoV-2 infections in children following the full re-opening of schools and the impact of national lockdown: Prospective, national observational cohort surveillance, July-December 2020, England25 Feb 2021EnglandEuropeEpidemiology - Transmissionhttps://www.sciencedirect.com/science/article/pii/S0163445321000931?via%3Dihub

Methods: This prospective epidemiologic study used national and regional surveillance data to monitor age-specific and weekly-trends of SARS-Cov-2 in England from the start of the summer holiday (13th July 2020), until the end of 2020 in school-aged children (27th December 2020). The impact of national restrictions and local lockdown on SARS-Cov-2 infections rates in students and adults during November 2020, was also examined. During the study period, widespread testing for SARS-Cov-2 was available.

SARS-Cov-2 tests were categorised by corresponding school year (i.e., nursery: 2 to 3 years old; pre-school: 3 to 4 years old; reception: 4 to 5 years old, primary school years 1 (5 to 6 years old) to 6 (10 to 11 years old) and secondary school years 7 (11 to 12 years old) to 13 (17 to 18 years old)) and educational settings (preschools: nursery and preschool; primary school: reception and years 1 to 6; secondary school: years 7 to 13).

The infection rates in school-aged children were compared to all ( 18 and 64-years-olds) and young adults (18 to 29-years-old).

Results: Infection rates during summer holidays (13th July to 30th August 2020) were low across all age groups. The infection rates started to increase from August 2020 -before schools were reopened- and continued across all the educational cohorts until the end of the year. These increments occurred initially in young adults, followed by secondary and primary school-aged children, with little change in pre-school-aged children.

Similar trends in SARS-Cov-2 infections in children and adults were detected after the schools reopening in England in September 2020; however, cases in school-aged children lagged adult rates.

Regional infection rates in adults, were examined in low (July 2020) and high (October 2020) national weekly incidence. These rates were correlated with the observed in secondary (R2: 0.8594 and 0.9661) and primary (R2: 0.9221 and 0.9339) and preschool-aged children (R2: 0.8594 and 0.8347).

The schools remained open during the national lockdown in November 2020. During that period, rapid decline in young adult infection rates, followed by secondary and primary school-aged children with one-week lag was noticed. Of interest, the decline in weekly infections was more prominent in regions with high SARS-Cov-2 infection positivity rates and was followed by an increase across all age-groups, which was associated with the spread of SARS-Cov-2 B.1.1.7 variant.

Strengths and limitations: Although this study examined a large volume of regional and national SARS-Cov-2 surveillance data, the role of asymptomatic children and adults is yet to be unveiled, since the cases included for analysis presented to national testing facilities with symptoms consistent with COVID-19. Complementary genomic surveillance once schools reopen in 2021, is paramount to better understand the role of SARS-Cov-2 infection and transmission in schools.

Feldstein, LRandolph,G JAMACharacteristics and Outcomes of US children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19 24 Feb 2021United States North America1116Clinical - PIMS-TShttps://jamanetwork.com/journals/jama/fullarticle/2777026

Introduction : This is case series comparing children and young adults diagnosed with MIS-C with those diagnosed with severe coronavirus disease. 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states were included, with final date of follow-up was January 5, 2021.

Methods : These children were included in the “Overcoming Covid-19” registry, a network across 33 states, that was approved by Boston children’s Hospital ethics, and the CDC which allowed for a consent waiver.

MIS-C criteria was consistent with the CDC definition

Age <21 y, Fever ≥38.0 °C for ≥24 h or report of subjective fever lasting ≥24h, Laboratory evidence of inflammation, Evidence of clinically severe illness requiring hospitalization with multisystem (≥2) organ involvement (cardiac, kidney, respiratory, hematologic, gastrointestinal, dermatologic, or neurological), no alternative plausible diagnoses, Positive for current or recent SARS-CoV-2 infection by RT-PCR, antibody, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 wk prior to the onset of symptoms).

Severe Acute Covid-19 was defined as;

Admitted to the hospital with symptoms suspected to be related to COVID-19, Evidence of infection with SARS-CoV-2 based on a positive RT-PCR test result during current illness, Severe organ system involvement of at least one system, which is listed in detail in the paper.

Comparisons were made between groups including age, sex, race, ethnicity and any underlying conditions.

Results: Of 1116 cases included in the final analysis, 539 (48%) were classified as MIS-C and 577 (52%) as acute COVID-19. In patients with MIS-C, 52% had a positive PCR test result, 45% were antibody positive only, 31% were positive for both, and 19% did not have an antibody test performed. By definition all those with acute COVID-19 were PCR positive.

Compared with patients with COVID-19, those with MIS-C were younger, more likely to be non-Hispanic Black, and less likely to have 1 or more chronic medical conditions.

Presenting symptoms and signs were similar among patients with MIS-C and COVID-19 with the exception of mucocutaneous findings (66.8% MISC-C vs 10.2% Acute COVID-19).

80% of patients with both MIS-C and COVID-19 each had severe respiratory involvement; however, more patients with MIS-C had cardiac involvement (66.7%) compared with COVID-19 (11.8%).

On laboratory testing within 48 hours of admission, patients with MIS-C had a mean CRP level of 152 mg/L vs 33 mg/L, P < .001) and more thrombocytopenia (platelets <150 ×103 cells/μL) than patients with COVID-19 (41% vs 17%, P < .001).

Cardiac complications; In the MIS-C group (n=504), of the 172 patients with MIS-C and depressed LVEF, 91.0% had a normal LVEF by 30 days. 424 of the 504 MIS-C cohort had coronary arterys evaluated. 57 patients had coronary aneurysms, of which 53, were mild, 4 were moderate, and none were large/giant. Aneurysms regressed to normal internal lumen diameter (z score <2.5) in 79.1% of patients by 30 days (based on small numbers, 100% by 90 days.

Ten patients (1.9%) with MIS-C vs 8 (1.4%) with COVID-19 unfortunately died during hospitalisation

Conclusions: This case series found that non-Hispanic Black children and adolescents were more likely than non-Hispanic White patients to have MIS-C than COVID-19, after adjusting for age, sex, geographic region, and underlying conditions, whereas Hispanic patients did not appear to be at a higher risk for MIS-C than COVID-19. Most patients classified as having MIS-C and COVID-19 experienced severe respiratory involvement and it is possible that some patients may have had COVID-19 with cardiovascular involvement.

This series shows that most severe cardiovascular involvement from MIS-C, including left ventricular dysfunction and coronary artery aneurysms, resolved within 30 days. The mortality rate from both severe Covid 19 and MIS-C in children, was similar.

Husby, AKrause, TMedrxivSARS-CoV-2 infection in households with and without young children: Nationwide cohort study02.03.2021DenmarkEurope0Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.28.21250921v1.full-text

This article is a preprint and has not been peer-reviewed.

This study looks at the hypothesis that recent exposure to seasonally spreading human coronaviruses (HCoVs) might result in protection from SARS-CoV-2 infection. It is a large cohort study from Denmark where there is a central database of all residents and nationwide information on all laboratory confirmed cases of SARS-CoV-2 infections and hospitalisations.

All adults aged 18-60y living in Denmark on 01.01.2020 were included in the study cohort, and a cohort of SARS-CoV-2 test positive individuals constructed, who were followed up for hospitalisation until 30 days after their test. Cohort members were followed up from 27.2.20 until a positive SARS-CoV-2 test or 15.11 20.

Taking living with young children (10m- 5y) as a proxy for exposure to HCoVs, hazard ratios were calculated for SARS-CoV-2 infection by household type.

Other available data including age, gender, ethnicity, comorbidities, urbanicity and household composition (including older children), were used as study covariates. Details of the statistical analysis are given.

Main Results: There are around 3 million adults age 18-60 living in Denmark, around ½ million (14.6%) of these live in households with young children. More details are in the paper.

The adjusted hazard ratio of risk of SARS-CoV-2 infection in adults in households with young children compared to those without, was 1.05 (95% CI 1.02-1.09). This figure increases with the number of young children in the household.

There was strong evidence of increased risk of SARS-CoV-2 infection among adults where there were older children in the household (adjusted hazard ratio1.31 (95%CI 1.27-135)).

There was a non-statistically significant reduced risk of hospitalisation among adults living with young children compared to those who don’t but analyses were limited by low numbers [146 hospitalised adults amongst 3,039 SARS-CoV-2 test positive adults living with young children v 1,130 hospitalised adults amongst 18,542 SARS-CoV-2 test positive adults living with no young children: adjusted hazard ratio 0.84 95%CI 0.70-1.09].

Discussion: This study produced no evidence that exposure to HCoVs reduces the risk of SARS-CoV-2 infection in adults, thereby suggesting no strong preventive effect of recent exposure to HCoVs against SARS-CoV-2 infection.

This is in line with serological and epidemiological studies which suggest no sterilising cross-reactive immunity.

It is the 1st study of an entire national population and will have captured the vast majority of SARS-CoV-2 infections. However, there was no direct, serological evidence of adult exposure to HCoVs, but living with young children has been taken as a good proxy in other studies.

The authors comment that the slightly increased risk of SARS-CoV-2 infection amongst adults living with young children may be due to the increased social contacts for the adults in taking this age group to nursery etc. or because the young children bring the infection home.

They hope that similar data from other countries might explore the potential effect of HCoV exposure on the severity of SARS-CoV-2 infection (as suggested by hospitalisation rates).

Vella, LAWherry, EJSci Immunol 6(57).Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-1902/02/21USANorth America30Clinical - PIMS-TShttps://immunology.sciencemag.org/content/6/57/eabf7570

This important, highly complex paper will be of interest to expert immunologists and ID specialists. A study of 16 paediatric Covid-19 and 14 MIS-C cases presenting to a US tertiary referral centre between April – June 2020, were studied and compared to an adult population of healthy and Covid-19 patients. Median (range) and M:F split for the paediatric Covid-19 and MIS-C cases were 14yrs (0.15-18yrs) and 8:8, and 9yrs (5-17yrs) and 7:7. Detailed breakdowns of patient characteristics, and treatment and sampling regimes are given. More patients had lymphocyte as opposed to whole blood flow cytometry performed. SARS-CoV-2 infection in children resulted in marked T cell activation and proliferation. The “immune landscape” in paediatric and adult Covid-19 infections was similar but in MIS-C there was an exacerbated T cell activation, particularly for CD8+ T cells, even compared to severely ill adults. A distinct CD8+ T cell subset linked to vascular endothelial damage surveillance was raised in MIS-C, and correlated with the need for vasoactive support, but this finding did not achieve statistical significance after correction for multiple comparisons in this small dataset. Immune activation in paediatric Covid-19 and MIS-C showed differing relationships with some clinical investigations, such as LDH and D-dimer. There was evidence of persistence of SARS-CoV-2 viral RNA in MIS-C cases (12/14), suggesting chronic antigen availability, and possibly chronic inflammatory stimulation.

Lessler, JStuart, EmedRxivHousehold COVID-19 risk and in-person schooling1 Mar 2021USANorth AmericaEpidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.27.21252597v1

This article is a preprint and has not been peer-reviewed.

This preprint, posted on 1st March 2021, uses a large internet-based cross-sectional survey in the United States to analyse the risk of COVID-19 in households with a child attending in-person school and the effect on that risk of school-based mitigation measures, in two time periods of one month each (Nov/Dec 2020 and Jan/Feb 2021).

Background: There are over 130,000 K-12 schools (from age 5 to 18 years) in the US (mostly public schools, with around 28% of students in private or charter schools). As a result of the COVID-19 pandemic, during the 2020-21 school year there has been huge variation in the approaches to schooling across the United States, from total closure of schools to opening with no mitigation measures in place. Most schools open to in-person learning have some measures in place to mitigate transmission of SARS-CoV-2, but there is wide variety in the number and types of measures adopted. Since SARS-CoV-2 infection in children and young people generally causes mild disease, one of the main reasons for a focus on transmission in schools is not the risk to students, but the risk that in-person schooling poses to teachers and family members, as well as its impact on the trajectory of the overall epidemic. This study focuses on the risk of in-person schooling to adult household members.

Data collection: The US COVID-19 Symptom Survey is a cross-sectional survey conducted daily by Carnegie Mellon University (CMU), using Facebook as a platform to recruit participants. Selected Facebook users receive an invitation each day to participate in the survey at the top of their news feed, yielding approximately 500,000 survey responses in the US each week. The survey was developed by public health and survey experts, reviewed and approved by the Institutional Review Boards of CMU and the University of Maryland, and includes questions related to health symptoms, testing, mental health, preventive behaviours and (since late November 2020) the schooling experience of any children in the household. Stratified random sampling within US states is used to provide adequate geographic coverage. Facebook employs a two-stage weighting process to account both for the systematic demographic differences between the Facebook Active User Base (aged 18+ and living in the US) and the US population, and for bias related to non-response and coverage (using age, gender, geographical variables and other user characteristics), so that the survey population is representative of the US population.

Study population: This study analysed data collected over two time periods during the 2020-21 school year: 24 November to 23 December 2020 and 11 January to 10 February 2021 (to exclude the winter school holidays). During these time periods there were 2,142,887 survey respondents in the 50 US states and Washington DC. 576,051/2,142,887 (27%) reported at least one child in school living in their household. 284,789/576,051 (49%) of these reported a child living in the household attending school in person either full- or part-time.

Primary outcomes: 3 different primary outcomes, as reported and experienced by the survey respondents, were considered (to mitigate for bias due to varying relationships between the timeframe of reported behaviours and other exposures): 1. COVID-like illness (CLI), defined as fever, cough, shortness of breath or difficulty breathing in the last 24 hours; 2. Loss of sense of taste or smell in the last 24 hours; 3. Positive SARS-CoV-2 test in the last 14 days.

Risk of living in a household with a child attending in-person school: After adjusting for county-level COVID-19 incidence and other individual- and county-level factors, living in a household with a child in full-time in-person schooling is associated with an increase in the odds ratio of reporting CLI (adjusted odds ratio (aOR) 1.38, 95% CI 1.30-1.47), loss of sense of taste or smell (aOR 1.21, 95% CI 1.16-1.27) and positive SARS-CoV-2 test in the last 14 days (aOR 1.30, 95% CI 1.24-1.35). The association between COVID-19 outcomes and a child in the household in part-time in-person schooling is attenuated but still statistically significant for CLI (aOR 1.21, 95% CI 1.13-1.29), loss of sense of taste or smell (aOR 1.18, 95% CI 1.13-1.24) and positive test (aOR 1.09, 95% CI 1.03-1.14).

Risk stratified by school grade level: Restricting the analysis to households reporting a child/children in a single grade strata in full-time in-person schooling, the strength of the associations with the 3 primary outcomes increase with grade level, from no association in households with only pre-K and Kindergarten students to a substantial positive association in households with only high school aged students. For part-time schooling the association between school grade and COVID-19-related outcomes is less clear.

Mitigation measures reported in school: For students in any form of in-person learning, the most common mitigation measures in school to reduce the risk of transmission of SARS-CoV-2 reported were student mask mandates (88%), teacher mask mandates (80%), restricted entry to school for parents and caregivers (66%) and extra space between desks (63%). A total of 14 possible mitigation measures were reported: the other 10 were student with the same teacher all day, student with the same students all day, some or all outdoor instruction, reduced class sizes, closed cafeteria, closed playground, use of separators (desk shields) in classrooms, no school-based extracurricular activities, no sharing of books/supplies and daily symptom screening. There was a mean of 6.7 (IQR 4-9) mitigation measures in place at any school attended by a household child, with more mitigation measures for children in part-time schooling (mean 7.3) than full-time schooling (mean 6.4), and substantial geographic heterogeneity (households in South Dakota reporting the least (mean 4.6) and Vermont the most (mean 8.9)).

Association between mitigation measures and risk of COVID-19 outcomes: There was a clear association between the number of mitigation measures implemented in schools and the risk of COVID-19 outcomes among adult household members responding to the survey after adjustment for individual and county level factors, including survey respondent age, gender, occupation, masking behaviour, out-of-state travel, reporting of a visit to a bar/restaurant/café or event with 10+ people, use of public transport, household size, number of children, county two-week average attack rate, county population, percentage white population, percentage households in poverty, index of income inequality and metropolitan type. Each mitigation measure implemented was associated with a 9% decrease in the odds of CLI (aOR 0.91, 95% CI 0.89-0.92), an 8% decrease in the odds of loss of sense of taste or smell (aOR 0.92, 95% CI 0.91-0.93) and a 7% decrease in the odds of a recent positive SARS-CoV-2 test (aOR 0.93, 95% CI 0.92-0.94). Regression treating each individual mitigation measure as having an independent effect showed that report of daily symptom screening was clearly associated with greater risk reductions than the average measures, with some evidence that teacher mask mandates and cancelling extra-curricular activities were also associated with larger reductions than average. In contrast, closing cafeterias and playgrounds and use of desk shields were associated with lower risk reductions (or even risk increases). Part-time in-person schooling was not associated with a decrease in the risk of COVID-19-related outcomes compared to full-time in-person schooling once other mitigation measures were accounted for. Looking at respondents with a child attending in-person school at schools with 0, 1-3, 4-6, 7-9 and 10+ mitigation measures in place, the study found that where 7 or more mitigation measures were in place, the risks associated with in-person schooling largely disappeared, with complete absence of increased risk with 10 or more mitigation measures.

Demographic and incidence differences: There were few systematic or statistically significant deviations from the overall estimate of the relative risk associated with full- and part-time schooling when stratified analyses were performed to account for differences between urban, suburban and rural counties, local patterns of COVID-19 incidence or propensity to avoid in-person schooling.

Conclusions: There was a clear association in this study between living with a child attending school in-person and the risk of COVID-19-related outcomes in adult household members. However, school-based mitigation measures were associated with significant reductions in risk, particularly daily symptom screening, teacher mask mandates and closure of extra-curricular activities. With 7 or more mitigation measures in place, the association between in-person schooling and COVID-19-related outcomes all but disappeared. However, in-person schooling and mitigation measures are not distributed at random in the population; for example, households with a student attending in-person school tend to be in counties that are a higher percentage white and contain survey respondents who are more likely to have recently eaten out or gone to a bar. Although the analysis attempted to adjust for local incidence, individual behaviour and other potential confounders, unmeasured factors may be responsible for the observed associations. The study was unable to measure the risk posed by in-person schooling to students themselves, nor how teachers and other school staff are impacted. It provides limited insight into how in-person schooling increases risk and it is possible that classroom transmission plays a minor role, with other school-related activities (such as student pick-up and drop-off, teacher interactions and broader changes in behaviour when school is in session) driving risk. Adjustments were made for county-level measures of socioeconomic status; these factors are known to be associated with COVID-19 risk and attitudes about in-person schooling. Importantly, the study suggests that common, low cost school mitigation measures can greatly reduce the risk of COVID-19-related outcomes in adult household members of children attending in-person school.

Lyngse, FKirkeby, CmedrxivAssociation between SARS-CoV-2 Transmission Risk, 2 Viral Load, and Age: A Nationwide Study in Danish Households05 03 2021DenmarkEurope18194Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.02.28.21252608v1.full.pdf

This article is a preprint and has not been peer-reviewed.

This large national registry-based study from Denmark explores the association between SARS-CoV-2transmission, viral load (measured by PCR cycle threshold (Ct value)) and age.

Methods: All positive SARS-CoV-2 PCR tests performed at community testing facilities (TestCenter Denmark (TCDK)) between August 25th, 2020 and February 10th, 2021 had Ct values determined. Data linkage was used to construct households with 2-6 members, the first household member testing positive was considered the primary case. Subsequent household members testing positive 1-14 days after the primary case were defined as secondary cases (and were presumed to have been infected by the primary case). A household member testing positive on the same day as the primary case was considered a "co-primary" case (rather than a secondary case). Primary cases tested at TCDK were identified up to January 25th; secondary cases were identified from tests performed at TCDK or from hospitals up to February 10th 2021. Associations between Ct value and transmission risk, and age and transmission risk were estimated using non-parametric regression.

Results: Of over 9 million samples analysed at TCDK during the study period (74% of all tests nationally), 66,602 primary cases were identified. Of 213,576 household contacts, 88% were tested 1-14 days following the primary case, 103,389 (48%) tested positive for SARS-CoV-2 and were classified as secondary cases.

Transmission risk was highest with low Ct values (high viral loads) and decreased linearly with increasing Ct value (decreasing viral load). SARS-CoV-2 Ct values were higher in paediatric primary cases aged 0-5 (median 32, mean 31) 5-10 (median 31, mean 31) compared with adults (median 28, mean 28) corresponding with lower viral loads. Adolescent primary cases had similar Ct values (median 29, mean 29) to adults.

In univariate regression analysis, transmission risk was lower in children compared with adults aged 30-35: OR 0.87 (0-5yo), OR 0.75 (5-10yo), OR 0.67 (10-15yo), OR 0.64 (15-20yo). Amongst adults, transmission risk increased with age (OR 4.67 in 80-85yo). In multivariable regression (including Ct value, household size and gender) children 5-20yo had a lower transmission risk, however infants had a slightly elevated risk (OR 1.11) compared with adults aged 30-35. In contact matrices, increase rates of transmission were observed from the youngest children to the elderly rather than to other children, perhaps representing an increased risk of transmission to grandparents due to their increased susceptibility.

Child contacts aged <10 years tested positive less frequently than other age cohorts (9,273/29,569, 31.3%, vs 6,613/10,451, 63% of aged 65 – 75 yrs), possibly indicating reduced susceptibility compatible with findings from other household contact tracing studies.

Conclusion: The findings of this study are consistent with data elsewhere indicating higher viral loads (or lower Ct values) are associated with increased risk of SARS-CoV-2 transmission. Notwithstanding these limitations of the methods used to determine direction of transmission, the results suggest that the risk of SARS-CoV-2 transmission from child primary cases is lower compared to adult primary cases. In multivariate analysis, children aged 0-5 years had a higher risk of transmission, possibly owing to increased close contact with household members or grandparents who are more susceptible, compared with older children. Notably the median viral load was lower in this age group compared with adult primary cases (Ct value 32 vs 28), possibly impacting overall transmission risk in this analysis.

Plumb LNitsch DArch Dis ChildCOVID-19 in children with chronic kidney disease: findings from the UK renal registry19 Feb 2021United KingdomEurope5Epidemiology - Disease Burdenhttp://dx.doi.org/10.1136/archdischild-2020-319903

Every paediatric subspecialty is now reporting Covid-19 infection numbers and outcomes for children affected by chronic diseases. This brief letter adds to the list, with data from all 13 UK paediatric nephrology units from 26 March to 15 July 2020. They report that there were only 5 cases of Covid-19 in children with stage 4 or 5 chronic kidney disease, which includes all those on renal replacement therapy. All we are told is that their mean age was 11 years, 4/5 were male, and none died. This report suffers from a lack of a denominator (5 out of how many?), and no data on severity of illness. However, it was sufficient to allow a relaxation of shielding criteria for children with kidney disease, and this was incorporated into the RCPCH revised recommendations of July 2020, since adopted by the UK government.

Carles Bautista-Rodriguez, Joan Sanchez-de-Toledo, Bradley C. Clark et al, Multisystem Inflammatory Syndrome in Children: An International Survey, Pediatrics Feb 2021, 147 (2) e2020024554; DOI: 10.1542/peds.2020-024554

A retrospective International study of 183 children mean age 7.0 ± 4.7 years (range: 1.2 months–18 years) with MIS-C who were discharged or died with MIS-C between 1st March 2020 and 15th June 2020. The participants came from 33 hospitals in 14 countries in Europe, Asia, N and S America. 109 children (59%) were male, 56 were black (30.6%); and 48 (26.2%) were obese.

All children had a fever, 114 of the 183 had SARS-COV-2 infection, 117 had gastrointestinal symptoms. 78 of 183 presented with shock, 27 fulfilled the criteria of Kawasaki disease, and the remaining 78 had signs of fever and inflammation. The patients with Kawasaki disease were younger and had no shock and fewer gastrointestinal, cardiorespiratory, and neurologic symptoms.

SARS-CoV-2 PCR results were positive in 43 of 114 (37.7%) tested patients, and SARS-CoV-2 serology test results were positive in 95 of 110 (86.3%) tested patients. In total, 114 of 183 (62.3%) patients had evidence of current or recent SARS-CoV-2 infection.

As far as treatment was concerned inotropic support was needed in 72 (39.3%), mechanical ventilation in 43 (23.5%), and extracorporeal in 4 (2.2%). Intravenous immunoglobulin was used in 26 of 27 (96.2%) patients with KD-like illness and in 137 of 156 (87.8%) of the remaining patients. 15

of 27 (55.6%) patients with KD-like illness and 90 of 156 (57.7%) of the remaining patients received steroids. A variety of other therapeutics were used including azithromycin, aspirin, anticoagulation, anakinra, infliximab, and hydroxychloroquine.

Children with Kawasaki type diseases had shorter duration of hospital stay and required less intensive care support. A total of three 1.6% children died. A shorter duration of symptoms before admission was found to be associated with a poor patient outcome and the need for extracorporeal membrane oxygenation and/or death.

The authors concluded “MIS-C has emerged with a wide clinical spectrum at presentation, including KD-like, life-threatening shock and milder forms with mainly fever and inflammation. The risk for worse outcome (ECMO and/or death) is associated with a short time interval between the onset of

symptoms and admission. More studies encompassing larger numbers of patients are needed to better describe this new disease, its optimal treatment, and long-term monitoring.”

This is an interesting paper with important information relating to MIS-C but unfortunately the paper is spoilt by editorial errors. In the summary it is stated that 79 children presented with shock compared with 78 elsewhere in the paper, under treatment it says 26 of 7 children were treated with immunoglobulin.

Bautista-Rodriguez, CFraisse, APeduatricsMultisystem Inflammatory Syndrome in Children: An International Survey1 February 202113 countriesInternational183Clinical - PIMS-TS https://pediatrics.aappublications.org/content/147/2/e2020024554.long
LaRovere, KRandolph, AJAMANeurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome5 March 2021USANorth America1695Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamaneurology/fullarticle/2777392

This study is from USA between March 15, 2020, and December 15, 2020. A surveillance was performed at 61 US hospitals. Case series of patients aged <21 years with positive SARS-CoV-2 test result (PCR and/or Antibody). Patients were excluded if they had asymptomatic SARS-CoV-2 infection or anon–COVID-19–related cause for hospitalization or death.

Results: 1695 patients were identified. 22% from 52 sites had documented neurologic involvement. Neurologic deficits were defined as gross impairment in motor, cognitive, or speech and language functions. Psychiatric sequelae were not included. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 [22%]) compared with those without (113 [8%]). Neurologic signs and symptoms differed by age with seizures or status epilepticus most common in children < 5 years and anosmia and/or ageusia most common in patients between ages 13 and 20 years. Most patients with and without neurologic involvement were discharged alive (351 [96%] and 1322 [99%], respectively. 43 (12%) had life-threatening neurologic involvement associated with COVID-19. Life threatening neurologic conditions included severe encephalopathy (n = 15; 5 with white-matter hyperintensities and splenial lesions), acute ischemic or hemorrhagic stroke (n = 12), acute CNS infection/ADEM (n = 8), acute fulminant cerebral oedema (n = 4), and GBS (n = 4). Eight patients with stroke had underlying risk factors (as arteriovenous malformation). Four patients were previously healthy and did not have stroke risk factors. Children with life-threatening neurologic disease were more likely to undergo lumbar puncture, head CT and MRI. CSF results were unremarkable. Patients with life-threatening vs non–life-threatening neurologic involvement had higher neutrophil-to-lymphocyte ratios, and higher D-dimer. In patients who developed life-threatening neurologic involvement, 11 (26%) died and 17 (40%) were discharged from hospital with new neurologic deficits. Of survivors with new deficits, 16 (94%) were previously healthy, none had prior neurologic disorders, 7 (41%) met MIS-C criteria 14 (82%) required rehabilitative services on discharge.

Association of COVID-19 neurologic involvement with fatality: Fourteen patients with COVID-19 neurologic involvement died in the hospital. Causes included cardiorespiratory disease, cardiac arrest, multiorgan failure, acute fulminant cerebral edema, status epilepticus with cardiac arrest, and severe encephalopathy.

Discussion: 22% of the patients had neurological involvement. Approximately half of patients with and without neurologic involvement were previously healthy. 43 patients (12%) with neurological involvement, developed a range of life-threatening neurologic conditions. 66% of these patients had unfavorable outcomes, including death or new neurologic disability at hospital discharge. Approximately 1 in 4 patients with neurologic involvement presented with altered awareness or confusion. Five previously healthy patients who presented with severe encephalopathy, focal neurologic deficits, and visual hallucinations and had diffuse abnormal T2 hyperintensities and reduced diffusivity involving the white matter and genu or splenium of the corpus callosum on MRI. T. Three patients had unfavorable outcomes (1 died and 2 were discharged with new deficits). Seven patients had probable acute CNS infection.

Limitations: Neurologic involvement were identified only at reporting hospitals and may not accurately reflect the true range and severity of COVID-19 neurologic involvement. Neurologic presentations could be due to exacerbation of underlying neurologic conditions. Not all patients underwent neuroimaging and image acquisition was not standardized. May not have captured certain variables completely, such as the indications for procedures (eg, lumbar puncture). Some neurologic symptoms (eg, anosmia) may be underreported in very young patients. Non-standardized diagnostic workups performed under routine clinical conditions may have missed non–COVID-19–related causes of life-threatening neurological. Standardized and validated assessments of neurologic outcomes at or after hospital discharge were not performed. This is not a prospective cohort study but a case series.

Conclusions: neurologic involvement was common in children and adolescents with COVID-19–related hospitalization and is mostly transient. A spectrum of life-threatening neurologic involvement infrequently occurred and was associated with more extreme inflammation and severe sequelae. Long-term follow-up of paediatric patients with COVID-19–related neurologic involvement is needed to evaluate effects on cognition and development.

Abrams, JBelay, ELancetChildAdolescHealthFactors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study9 Mar 2021USANorth America1080Clinical - PIMS-TShttps://doi.org/10.1016/S2352-4642(21)00050-X
Soriana-Arandes, ASoler-Palacin, PClin. Infect. Dis.Household SARS-CoV-2 transmission and children: a network prospective study,12 mar 2021SpainEurope1040Epidemiology - Transmissionhttps://doi.org/10.1093/cid/ciab228

Introduction : This is a prospective observational study of Covid 19 positive children (<16 years) in the Catalonian region of Spain from July 1st 2020 to October 30th 2020.

Methods : 120 paediatricians across primary, secondary, public and private care recorded data on paediatric Covid 19 cases. Positive cases were by RT-PCR for all of study but RT-PCR and antigen testing during last week of study. Paediatricians enrolled all positive cases seen in their daily practice up to first positive 5 cases per day. Contact tracing was carried out by the study group.

A paediatric index case was when the child was the first symptomatic person in the household. A paediatric secondary case was when someone else in the household had a positive test before the child. A primary paediatric case, was when no other household contact apart from child tested positive. The study period was spilt into summer time (July 1st to Sept 15th 2020) and school time (sept 15th to October 31st).

Results: During the study period, 6.4% (26,665/417,578) of SARS-CoV-2 RT-PCRs in individuals younger than 16 years tested positive in the region. 4.9%, (1309/26,665) of these patients were enrolled, with 1040 with complete, clinical, epidemiological, and microbiological data reported on. 547 occurred during summer, with 493 in school period.

Nearly half the paediatric cases (491/1040) were asymptomatic. 52.8%, (549/1040) had mild symptoms and 2.6% (27) children required hospitalisation.

Across the whole study time period, 72.7% (756/1040) of children were cases secondary to an adult case, and 5.0% (52/1040) were secondary to another child, with 7.7% (80/1040) of children deemed household index cases. The remaining 14.6% (152/1040) were primary cases.

Even during school time, paediatric cases were much more likely to be secondary cases from household transmission (69.4%) rather than index case 8.3%. [Statistical data comparing summer and school periods not shown, raw numbers only]

Conclusions : Similar to previous studies, this study demonstrates that within their households, most paediatric COVID-19 cases were secondary to an adult case. The secondary attack rate was significantly lower in households where children rather than adults had transmitted SARS Cov2, and was even lower during the school period.

Jordan, IGratacos, EClin. Infect. Dis.Transmission of SARS-CoV-2 infection among children in summer schools applying stringent control measures in Barcelona, Spain12 03 2021SpainEurope30Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab227/6168543

In this prospective study from Barcelona, Spain, SARS-CoV-2 transmission at summer schools was assessed during the 5-week period from June 29th to July 31st, 2020.

Study details

All children aged 3-15 y.o. and staff >16 y.o. attending summer schools in Barelona Metropolitan Region were eligible for the study. Transmission mitigation measures were in place at all schools including universal masking (for all >6 y.o.), frequent handwashing, organisation of students into small groups ("bubbles" of 8-14 individuals) and most activities were conducted outdoors. Community transmission was low during the study period. Index cases attending school were identified either through active surveillance with weekly saliva PCR testing (at 22 summer schools) or through the regional (Catalonia) health surveillance symptoms via symptom-based testing or contact tracing from a positive community case (an additional 18 summer schools). Once an index case was diagnosed, all close school contacts were assessed with a COVID-19 symptom questionnaire and nasopharyngeal swabs were tested for SARS-CoV-2 PCR on day 0, 7 & 14. Secondary attack rate was calculated, and effective reproduction number (Re) was determined and compared with Re in the surrounding community.

Findings

Amongst 1905 participants (1509 students) in the 22 summer schools conducting active surveillance, 12 index cases (9 students, 3 staff) were identified. An additional 27 index cases (21 students, 6 staff) were identified through the local health service (960 individuals attending 18 other schools). The number of index cases within individual schools corresponded to the prevalence of SARS-CoV-2 infection in the district surrounding the school.

Of the 39 total index cases (30 students, 9 staff), 253 close contacts were identified of whom 230 (90.1%) consented to participation and provided samples. In total 12/253 (4.7%) contacts were confirmed to have been infected with SARS-CoV-2 infection. There were 9 cases student to student transmission, 1 of student to staff and 2 of staff to student. The Re in summer schools was 0.3, lower than in the general population during the study period where Re ranged from 1.7 to 2.0.

Discussion

The findings here are consistent with data from a large number of other studies that suggest, in the presence of appropriate mitigation measures, transmission of SARS-CoV-2 within schools is low compared to transmission in the surrounding community. A major strength of this study is the repeated PCR testing of all contacts regardless of symptoms, allowing for robust identification of all secondary cases. Interestingly, the authors plan to conduct further analysis of the close contacts in this study using SARS-CoV-2 serology testing of saliva samples at 5 weeks following exposure. The authors highlight the value of organising students into small "bubbles" which facilitated timely and comprehensive contact tracing as well as allowing quarantine of all-contacts with minimal disruption to other students. This study provides further evidence that in-school transmission is not a primary driver of the pandemic and supports policy for schools re-opening with appropriate mitigation measures.

Williamson, EKuper, HMedRxivOpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study08 Mar 2021 EnglandEurope2624353Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.08.21253112v1.full.pdf+html

This article is a pre-print and has not yet been peer reviewed.

This cohort study by Williamson et al., (2020) assessed the association between learning disability and the risk of hospitalisation and mortality from COVID-19 in adults and children in the UK. The primary outcome for this study was COVID-19 related death and COVID-19 related hospitalisation.

Background: Data from the first wave of COVID-19 showed that people with learning disability were at higher risk from mortality when compared to the rest of the population. The Oxford RCGP Research and Surveillance Centre documented an odds ratio of 1.96 (95%CI 1.22-3.18) for mortality in the first wave in the UK for those with learning disabilities compared to those without. Another study also documented that adults with Down syndrome had a hazard ratio of 10.4% (95%CI 7.1-15.2) for COVID death. However, there is a lack of data documenting the risk of COVID-19 related deaths amongst individuals with milder learning disabilities, in both adults and children. The UK national recommendation included those with severe disabilities to be included in the first 6 priority groups for vaccination. However, those with milder learning disabilities were not included.

Methods: This is a two-population observational cohort study conducted in England which included 2,624,353 children under the age of 16 and was conducted in 2 waves. The first wave between 1st March 2020 – 31st August 2020 and the second wave between 1st September 2020 -31 December 2020. These periods of time reflect the two main timeframes in which COVID-19 infection rates were highest in the UK. Participants were recruited from GP surgeries which employed the TPP system for data collection.

Statistical analyses were conducted thoroughly for the adult population. However, data for COVID-19 related deaths in those under 16 was omitted due to smaller number of outcomes.

Results: Among the 2,624,353 children under 16 included in this study, only 9,114 (0.35%) were identified as being on the learning disability register. Only 907/2635 (34%) of those with Down syndrome were registered on the disability register and only 500/4619 (11%) of those with cerebral palsy were registered on the disability register.

The authors document that there were 281 COVID-19 related hospital admissions in the first wave and 292 in the second wave. However, further details including the separation of this data with individual learning disabilities was not possible due to stringent redaction rules applied to protect patient privacy. However, data on hazard ratios for COVID-19 hospital admission among those under 16 was given. The authors found that being on the learning disability register was associated with an increased hazard ratio of COVID-19 related hospital admissions in both wave 1, HR 5.1 (95%CI 1.9-14.0) and in wave 2, HR 8.8 (95%CI 4.9-15.8). The authors also note that the elevated risk in those under 16 with learning difficulties documented has also been reported in the USA.

The authors concluded that the risk seen among those under 16 suggests that vaccination in this age group warrants further consideration. However, further research is needed to confirm this.

Limitations: Due to redacted information, it was not possible to view the data and evidence for each learning disabilities and their own hazard ratios for COVID-19 hospital related admission. In addition to this, it is not possible to identify everyone with a learning disability through medical records alone and therefore, it is likely that the hazard ratios were underestimated. There were also specific pieces of data missing from the study, particularly ethnicity, although it is not known whether this would have had a meaningful impact on the data.

Comments: Although the data of this study did look at the effects on both adults and children, the discussion was very much based towards adults with learning disabilities and less so for children. This may have been due to the smaller number of outcomes for children when assessing COVID-19 related deaths and full adjustments for comorbidities. It was also difficult to determine how many cases of the hospital admissions were due to reoccurrence in those under 16 as a result of the strict redaction rules for patient privacy.

For results on the adult arm of this study, please refer to study paper.

Telle, KKacelnik, OmedRxivSecondary attack rate of COVID-19 in Norwegian families: A nation-wide register-based study08 MAR 2021NorwayEurope14808Epidemiology - Transmissionhttps://doi.org/10.1101/2021.03.06.21252832

BACKGROUND: understanding transmission among family members by parents and children is vital for containment strategies.

AIM: To compare the SAR in family households when the index case is a child to the SAR when the index case is an adult.

METHODS: register-based cohort study. All families in Norway with at least one parent and one child below age 20 years living at same address on March 1st 2020 where one member, the index case, either parent or child had tested positive for SARS-CoV-2 at any time between March 1st 2020 and January 1st 2021. Family members who tested positive within 7 days of the index case were defined as secondary cases. SAR7 = number of non-index family members who tested positive within seven days after the date index tested positive, divided by all non-index family members x 100. Families where 2 members tested positive on the same date were excluded.

Testing: During the first wave, testing capacity was limited but became easily accessible to anyone with symptoms as well as for close contacts of confirmed cases. Percentage tested was calculated as the number of non-index family members who were tested within seven days after the date when the index family member tested positive, divided by all non-index family members.

RESULTS: The families comprised a total of 26991 individuals (12184 parents, 14808 children). There were 7548 index cases of whom 4964 (66%) were parents and 2584 were children (34%). Among children index cases, 8% were in the 0-6 years and 42% were in age band 17-20 years.

SAR7 was higher when a parent was the index case = 24% (95% CI 24 to 25) compared to 14% (95% CI 13 to 15) when the index case was a child.

If the index case was a child, the highest SRA7 was seen in age band 0 – 6y = 24% (95% CI 20 to 28) with 89% of family members tested. SAR7 dropped to 14 for age bands 7 – 12y (CI 95% 12 – 15) and 13 – 16y (CI95% 13-16) with 86% and 85% of family members tested respectively. It was lowest in age band 17 – 20y at 11% (CI 95% 10 – 13), 66% tested.

The SAR7 among parents was higher when a parent was the index case (35%, 95% CI 33 - 36) than when a child was the index case (15%, 95% CI 14 - 16). The same pattern was found, albeit attenuated, of higher SAR7 among children if the index case was a parent: 21% (95% CI 20 to 22) if a parent was the index case, and 12% (95% CI 11 to 13) if a child was the index case.

As testing became more widely available the percentage of family members tested increased from 20% in April to about 80% in December. There was an associated increase in overall SAR7 but this stabilised at around 20% once the percentage being tested rose above 50% reaching around 80% by December 2020.

Discussion

SARS-CoV-2 infection was introduced in families mainly by parents or by the older children. Transmission within the family was more common from parents and preschool children.

Preschool children may display few or no symptoms, may be less likely to be infected or might not be tested as often as older children and parents because they are more difficult to test. If they are true higher transmitters within families this may be due to more physical contact compared to children in the older age bands. Additional data on SAR at 14 days did not significantly differ from SAR7.

COMMENTS: This is a large, population-based study that appears to show that infected preschool children transmit SARS-CoV-2 to the same extent as parents. Secondary cases may be co-index cases particularly if asymptomatic transmission is not looked for, and because the incubation period varies. The figures may have been affected by differential rates of testing and this was shown by a higher percentage of family members tested if the child was the index case than if parent was index case. Testing may have been more relevant to detect potential transmission from other household members to others at school or at work. This may also have been due to younger children being more difficult to test, higher false negatives or not tested because they may have been regarded as unlikely to pass infection if being kept at home.

Cerami CLin JTmedRxivHigh household transmission of SARS-CoV-2 in the United States: living density, viral load, and disproportionate impact on communities of color12 Mar 2021USNorth America78Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.10.21253173v1.full.pdf

This is a prospective observational study carried out in the Piedmont region of North Carolina, southern United States, between April and October 2020. The study aimed to describe the secondary attack rates and risk factors associated with SARS-CoV-2 transmission in household of individuals with a positive qualitative nasopharyngeal swab for SARS-CoV-2, willing to isolate for a 14-day period and living with at least one household contact, aged > 12 months. The assessment of eligibility and enrolment were completed via phone call. A home visit took place on day 1, for the collection of serology, rapid antibody test, nasopharyngeal (NP) swab and participants self-collected nasal mid-turbinate (NMT) swabs. Follow-up visits to measure viral clearance and viral shedding took place on day 7, 14 and 21. In each one of these follow-up visits, participants self-collected NMT swabs. On day 28, blood samples for serology and rapid antibody test were also taken. A daily symptom diary, from onset until 2 days after resolution was filled in.

NP and NMT were tested following the CDC qRT-PCR protocol that targets the N1, N2 and RP regions of the virus. Where the three assays were positive, the viral load was quantified and further genotypic screening for D614G mutation completed. An in-house ELISA with previously reported high sensitivity and specificity was utilised to determine the total Ig binding to the receptor binding domain of the spike protein of SARS-CoV-2. A validated research tool was used to rapidly detect SARS-Cov2-specific IgM and IgG. The bands were read in duplicate by two independent staff members. Discrepancies were resolved through discussion. The primary endpoint was SARS-CoV-2 infection in the household confirmed via real-time PCR of NP and NMT swabs during the follow-up period, or evidence of seroconversion during the study, according to the results of antibody testing. The index case was defined based on a positive qualitative NP swab for SARS-CoV-2 at enrolment, the day of the onset of the symptoms and in some cases, where the latter remained ambiguous, baseline antibody positivity was used as evidence of recent infection. Those with evidence of prior infection were excluded from the analysis. The proportion of household contacts who remained susceptible to SARS-CoV-2 by the end of follow-up was used to calculate the secondary attack rate among household contacts.

Statistical analysis

Data were analysed using a logistic regression model with a random intercept to account for within-household variation to calculate race/ethnicity specific secondary attack rate. The primary analysis assumed that all secondary cases were due to household transmission. Sensitivity analyses excluded secondary cases infected at baseline and those that may have been acquired outside the household, owing to the date of detection (i.e. identified on day 14th or later).

Results

One-hundred and two households were recruited and two were excluded from analysis due to evidence of prior infection in all household members or lack of completion of the baseline questionnaire. The median household size was 3.5 persons. They were enrolled at a median of 6 days (IQR 4 to 7) after the onset of the symptoms of the index case; 52% were females and 42% self-identified as non-white race/ethnicity . Eight percent of the index cases were under 18 years of age (0 to 12 yo: n =2/100; 2%; 13 to 17 yo; n = 6/100; 6%); 46% have completed high school or lower; 28.3% worked in retail/hospitality and 38% had a BMI > 30. Among 204 household contacts, the proportion of females was the same as reported for index cases; 47% self-identified as non-white race/ethnicity; 34.3% were under 18 years of age (0 to 12 yo: 22.5%; 46/204 and 13 to 17 yo: 11.8%; 24/204); 48.5% completed high school or lower; 26.1% worked in retail/hospitality and 32.1 % were reported as having a BMI > 30 Kg/m2.

Those household contacts who tested positive at baseline and had the same environmental exposure than the index case (n = 22) were excluded from the transmission analysis. The overall secondary attack rate was calculated with a denominator of 176 susceptible individuals and reported as 60% (106/176, 95% CI 53%-67%); 73/176 were positive at baseline and classified as secondary cases; 33 additional secondary cases were observed during the follow-up period. Of them, the majority were symptomatic (82%) and occurred within the first 7 days after enrolment. Where the secondary cases were restricted to those that were negative at baseline, the secondary attack rate was 32%; and where the case definition was further limited to those who acquire the infection within the first 13 days post-enrolment, the secondary case ranged between 52 and 57%. Index cases with a high nasopharyngeal viral load at enrolment, were more likely to transmit the virus to their household contacts during the follow-up period (OR 4.9; 95CI 1.3 -18). Although no difference in viral load was observed according to race/ethnicity, compared to white index cases, non-white index cases were more likely to transmit virus within their household (secondary attack rate 70%; 95 CI 59-79%). Other risk factors for household transmission included higher living density or > 3 household members living in a home with less than 6 rooms (OR 5.9, 95% CI 1.3-27; secondary attack rate 91%; 95% CI 71-98%); partner of the index case (OR 4.1, 95% CI 1.3-13) and BMI > 30 Kg/m2 (OR: 5.4, 95% CI 1.4-21)).

Comments

This study is reported to be the largest single site and ethnically diverse prospective observational study on household transmission on SARS-CoV-2, combining weekly PCR testing for 21 days and antibody detection on day 28 post-enrolment. Its findings support previous modelling studies, as a great proportion of cases occur within 7 days of exposure, and also support current 14-day quarantine policies for the entire household (calculated from the day of symptom onset of the index case), as 2/3 of the household contacts were already infected at enrolment and 94% of secondary cases were detected within 14 days from symptom onset of the index case.

In household contacts who self-identified as non-white, risk factors such as obesity and overcrowding were more common than in white counterparts. The number of household contacts positive at baseline with a common exposure as the index case is perhaps higher than reported, but the authors state that according to their experience, a substantial number of these exposures still occur in the immediate household or among family members. Interestingly, households where high viral loads were detected, were more likely to have other members with high viral loads. This may translate in higher risk of disease severity. Although the sample size remained insufficient to investigate the drivers of increased transmission household transmission in non-white households, the contributions of this papers to the understanding of the impact of ethnicity and other social determinants of health on disease transmission should not be overlooked.

Clouser, KAschner, JJ Pediatric Infect Dis SocShort-Term Outcomes After Multisystem Inflammatory Syndrome in Children Treatment19 Nov 2020USANorth America20Clinical - PIMS-TShttps://academic.oup.com/jpids/article/10/1/52/5992300

This paper describes features of 20 patients admitted to hospital in New Jersey and diagnosed with multisystem inflammatory syndrome in children (MIS-C). The study period ran from 15 April to 20 June 2020 and data was collected retrospectively by reviewing medical records.

Study population: The children ranged from <1 year to 18 years with a mean of 7.3 years. 55% were male. 40% were Hispanic, 20% Caucasian, 20% Asian and 15% African American (the degree to which this reflects the local population was not noted)

Clinical features: 50% of patients were admitted to a general paediatric ward and 50% to intensive care. All patients had fever at presentation. 65% had cardiac abnormalities (raised BNP, dilated coronary arteries and/or decreased ejection fraction), 55% had gastrointestinal symptoms, 55% had conjunctivitis and 50% had a rash. 18 of the 20 patients had an initial echocardiogram and findings included pericardial effusion and decreased myocardial function – 50% had normal study. There were no cases of coronary artery dilation on initial scan but 1 patient had developed this on follow up scan.

Treatment: 50% of patients received both corticosteroids and IVIG, 15% received corticosteroid monotherapy and 10% received IVIG monotherapy. The remaining 25% were successfully treated with supportive care only. 25% required vasoactive support.

Short-term outcomes: The mean length of stay was 4.6 days. All but one patient (95%) were discharged home without any activity limitation. One patient required oxygen on discharge, which was discontinued within 30 days. By 30 days after treatment, all patients were described as having returned to normal activity for age.

Discussion: This study highlights the spectrum of severity for MIS-C and is encouraging in its report of 100% recovery to baseline, with no ongoing sequelae (at least in the short-term period analysed).

Bhopal, S Bhopal, RLancet Child Adolesc HealthChildren and young people remain at low risk of COVID-19 mortality10 Mar 2021United kingdomInternational259Epidemiology - Disease Burdenhttps://doi.org/10.1016/S2352-4642(21)00066-3

Summary: This paper reviewed Covid-19 mortality statistics (259 deaths) from children in 7 countries to February 2021; updating the previous published data from the group. Data from the following countries was obtained: USA, UK, Italy, Germany, Spain, France, and South Korea. The group found deaths from COVID-19 in children remained rare up to February, 2021, at 0·19 per 100 000 population, comprising 0·54% of the estimated total mortality from all causes in a normal year. Deaths from COVID-19 were relatively more frequent in older children compared with younger age groups.

They cautioned that differences between countries need careful interpretation due to: small numbers, possible differences in case definition and death reporting mechanisms, and the related condition paediatric inflammatory multisystem syndrome temporally associated with COVID-19, which might not always, be captured in these data.

The highest rate of deaths per 100 000 children was in Spain (0·64 for children aged 0–9 years; 0·53 for children aged 10–19 years) and the lowest in South Korea (0 deaths for children aged 0–9 years and 10–19 years). The UK data showed 7 Covid-19 deaths in children between 0-9 years and 22 10-19 years, representing rates of 0.09 and 0.29 respectively.

Conclusions: Overall, there was no clear evidence of a trend of increasing mortality throughout the period up to February, 2021, but additional deaths have clearly occurred in children and young people during periods of high community transmission, particularly in Spain, Germany, and Italy.

Although COVID-19 mortality data are contemporary and likely to accurately represent the reality in these countries, it is not possible to access such data for other causes of death. The authors used estimates from the Global Burden of Disease 2017 database, which does not account for seasonality or changes in mortality patterns in this pandemic year.

Therefore, the very low mortality described from COVID-19 compared with all-causes is likely to be of the correct magnitude. With the caveat that some children at high risk might be using extreme so-called shielding measures, children are overall not becoming seriously unwell with COVID-19,and data from England show that children are also not requiring intensive care in large numbers.Some of the measures to counteract the devastating impact of the virus on adults are having unintended negative consequences for children. They continue to caution that the virus is likely to change over time, and that these conclusions should be kept under review.

Cordery, RSriskandan, SPreprint in medRxivTransmission of SARS-CoV-2 by children attending school. Interim report on an observational, longitudinal sampling study of infected children, contacts, and the environment09 Mar 2021United KingdomEurope55Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.08.21252839v1

This article is a preprint and has not been peer-reviewed.

This is an interim report providing a descriptive analysis of the initial TraCK (Transmission of Coronavirus-19 in Kids) study findings from October-December 2020. This is an observational study conducted in nurseries and schools in London, UK looking at SARS-CoV-2 transmission by children in their school and home environments. It aims to provide a more detailed analysis on transmission risk and possible mechanisms by intercepting individual cases and performing longitudinal sampling of cases, contacts and their environment.

For context, at the time of the study, schools throughout England were operating under additional Covid-19 prevention measures such as social distancing and mask-wearing in certain schools. Any child who tested positive for SARS-CoV-2 had to self-isolate from school for 14 days, as did their close classroom contacts. Household contacts of cases were also required to remain at home in quarantine during this period. In early years and primary school, close contacts consisted of the whole class. In secondary school, close contacts were defined according to proximity and duration of contact.

Methods : From October 2020, nurseries and schools within the London region that reported a new case of SARS-CoV-2 infection in a pupil were asked to take part in the study. Cases, their households and contacts at school were recruited by gaining consent from parents/guardians. The study included children aged 2-18 years. There were 4 categories of participants: 1) Cases - children who tested positive for SARS-CoV-2 infection. 2) Bubble contacts - children who were in close contact.i.e the same “bubble” as the Case and had to isolate from school for 14 days. 3) School contact - children in a class within the same school that was adjacent in terms of age-group or proximity. These children remained at school. 4) Household contacts. Cases and contacts underwent regular RT-PCR testing including nose and throat swabs (14 days for cases and 28 days for contacts). Swabs were taken from multiple surfaces at home and school and air sampling was conducted at both sites. Environmental samples were performed weekly for up to 28 days and tested using RT-PCR.

Results : From October-December 2020, 5 cases of SARS-CoV-2 were recruited to the study from 5 different schools. The median age of the children who tested positive was 11 years old. In addition to these 5 Cases, the study included 13 Bubble contacts, 29 School contacts and 23 Household contacts (8 children and 15 adults). Importantly, there was no onward transmission of the virus to Bubble contacts detected in the study. There was also no evidence of more widespread transmission of the virus amongst other School contacts who remained at school. In one secondary school, a cluster of 3 asymptomatic school contacts was unexpectedly detected in week 2. The cluster was considered unlikely to be related to the study’s index case as they had previously had negative tests in week 1 of the study. Among household contacts, 3 adults and 1 child tested positive in week 1 with adults in these households considered to be the index case. One adult tested positive in week 2 and this was felt to be the only evidence of child-to-adult transmission within any of the households studied. There was also one case of child-to-child transmission in which a teenager, who was sharing a bedroom with the index case, tested positive. Environmental sampling showed limited contamination of the virus within the school environment but did show surface contamination amongst household items in households where children had the highest viral loads, particularly on digital equipment and electronic toys.

Discussion: In the context of the Covid-19 prevention measures at the time, this study did not detect transmission of the virus to contacts within the school environment. There was also no evidence of significant environmental contamination within the school setting. Although small, the detailed nature of this study may help inform future policies and interventions. The authors note the difficulties with participation and recruitment, particularly of Bubble contacts, which may have resulted in missed transmission events

Rottenstreich, APorat, SmedRxivEfficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination11 Mar 2021IsraelMiddle East20Neonatalhttps://doi.org/10.1101/2021.03.11.21253352

This prospective single-centre study, based at the Hadassah Medical Center in Jerusalem, Israel investigated 20 parturient-mother/newborn dyads. Women who were admitted for delivery in Feb 2021 and who had received two doses of SARS-CoV-2 BNT162b2 mRNA (Pfizer) vaccine during the third trimester of pregnancy were recruited. The median maternal age was 32 years, with a median gestational age of 393/7 weeks at the time of delivery. The median time intervals between the first and second doses of vaccine administration and delivery was 33 [IQR 30-37] and 11 [IQR 9-15] days, respectively. Spike protein S1/S2 IgG, RBD- specific IgG levels and SARS-CoV-2 IgM were measured in maternal and cord blood sera.

All women and infants were found to be positive for anti S- and anti-RBD-specific IgG. SARS-CoV-2 IgM antibodies were detected in 6 (30.0%) parturients and were not detected in any of the infants. The median placental transfer ratios of anti-S and anti-RBD specific IgG were 0.44 [IQR 0.25-0.61] and 0.34 [IQR 0.27-0.56], respectively. SARS-CoV-2 anti-S and anti-RBD-specific IgG levels in maternal sera were positively correlated with their respective concentrations in cord blood (P<0.001 and P <0.001, respectively. The levels of both SARS-CoV-2 anti-S and anti-RBD specific IgG titres in cord blood directly correlated with the time interval between the first vaccine dose and delivery, which is in accord with studies of respiratory syncytial virus vaccine.

The authors comment that the placental transfer ratios were lower than those reported in studies of vaccine-elicited antibodies to influenza, pertussis, measles, rubella and hepatitis B, in which transfer ratios ranging from 0.8 to 1.7 have been reported. The finding is consistent with those of another recent study of pregnant women who had contracted covid-19, in which low placental transfer of anti–SARS-CoV-2 IgG [9] was reported.

The authors further speculate that, given the observed kinetics of the immunoglobulin response both in pregnant women infected with the SARS-CoV-2 virus and in non-pregnant recipients of SARS-CoV-2 mRNA vaccines, vaccination early in the second trimester might be the optimal time to provide “adequate” immunity to both mother and neonate.

Gray, KEdlow, AmedRxivCOVID-19 vaccine response in pregnant and lactating women: a cohort study07 Mar 2021USANorth America10Neonatalhttps://doi.org/10.1101/2021.03.07.21253094

A prospective cohort study conducted at Massachusetts General Hospital and Brigham and Women’s Hospital, working in conjunction with Harvard Medical School, Boston, has evaluated the immunogenicity and “reactogenicity” of covid-19 mRNA vaccination in pregnant and lactating women, comparing the results with those of 37 pregnant women who had been diagnosed with covid-19 infection 4-12 weeks prior to recruitment to the study.

The study population comprised 131 women who appear to have been primarily healthcare workers from the participating hospitals. The majority were White, non-Hispanic and in their mid-30s; 84 pregnant, 31 lactating, and 16 non-pregnant subjects were enrolled. Either the Pfizer or the Moderna vaccine was administered to each of the participants, with an approximately 50-50 split between the two vaccines. In the pregnant subjects 46% received the vaccine during the second trimester and 40% during the third trimester. Titres of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at the following timepoints: baseline, prior to the 2nd vaccine dose, 2-6 weeks post 2nd vaccine and, for the pregnant group, at the time of delivery. “Reactogenicity” was evaluated by means of a questionnaire which recorded information about vaccine side effects after each dose, such as injection site soreness, injection site skin reaction/rash, headache, myalgias, fatigue, fever and chills. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups. Of the pregnant participants, the mean gestational age at first vaccine dose was 23.2 weeks but the inter-quartile ranges were 16.3 - 32.1 weeks.

The main outcomes were that vaccine-induced immune responses were equivalent in the serum of pregnant, lactating and non-pregnant women and that all titres were higher than those induced by SARS-CoV-2 infection during pregnancy. A significant rise in IgG, IgM and IgA to all antigens was observed between pre-vaccination serum samples and those taken prior to the second vaccine dose. A further rise in IgG levels following the second vaccine dose but there was no additional rise in IgM and IgA. Similar responses were observed in the breast milk of lactating women. Vaccine-generated antibodies were present in all umbilical cord blood samples. No differences were noted in reactogenicity across the groups.

The authors concluded that “robust” humoral immunity, which is greater than the response to natural infection, is generated by these covid-19 mRNA vaccines in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Further, immune transfer to neonates occurred via both the placenta and breastmilk. The authors acknowledge that potential risks to the fetus of the vaccine were not evaluated and that further studies in larger populations, across gestational ages, are required.

Golan, YGaw, SmedRxivImmune response during lactation after anti-SARS-CoV2 mRNA vaccine09 Mar 2021USANorth America0Neonatalhttps://doi.org/10.1101/2021.03.09.21253241

A prospective study from the University of California measured maternal and neonatal SARS-CoV-2 antibody levels in maternal serum (anti-SARS-CoV-2 IgG and IgM), and breast milk (anti-SARS-CoV-2 RBD IgA), after vaccination with anti-covid-19 mRNA-based vaccines during lactation. Pylon 3D automated immunoassay was used for IgG and IgM measurements and ELISA assay was used for IgA. The subjects were 23 “lactating individuals”, 9 of whom were vaccinated with the mRNA-1273 vaccine (Moderna) and 14 with the BNT162b2 (Pfizer) vaccine. Demographic details of the subjects, and information concerning the duration of lactation prior to vaccination, are not given. The number of plasma samples assayed were: 7 pre-vaccine, 12 post first vaccine and 14 post second vaccine; it is not clear how many of these samples were taken from subjects vaccinated with the Moderna vaccine and how many were taken from those vaccinated with the Pfizer. The breast milk assays used ELISA and similar sample numbers to the plasma assays at each time point seem to have been assayed, but for each of the two vaccines. In addition, three milk samples collected from “lactating individuals” who had previously contracted SARS-CoV-2 virus infections were assayed. Information concerning the timing of these infections prior to milk sample collection is not given.

The findings were that the levels of both IgG and IgM were significantly increased in maternal plasma samples on the day of the second vaccine dose when compared with pre-vaccine samples but only plasma IgG levels were significantly higher when comparing those taken prior to the second dose with those taken four weeks after the second dose. With regard to breast milk, anti-SARS-CoV2-RBD IgA antibodies were present 3-4 weeks after administration of both the Moderna and the Pfizer vaccines. The levels of anti-SARS-CoV2-RBD IgA antibody in milk of vaccinated individuals were not significantly different from those measured in the breast milk taken from the three participants who had a previous history of SARS-CoV-2 infection.

The authors concluded that the administration of anti-covid-19 mRNA vaccines during lactation leads to increased anti-SARS-CoV2 IgM and IgG levels in the plasma of lactating mothers and increased anti-SARS-CoV2-RBD IgA levels in human milk. They recommend that, pending long-term outcome studies, lactating women who receive the vaccine should continue breastfeeding their infant human milk to allow continuing transfer of anti-SARS-CoV-2 IgA antibodies to the neonate.

Golan, YGaw, SmedRxivCOVID-19 mRNA vaccine is not detected in human milk05 Mar 2021USANorth America0Neonatalhttps://doi.org/10.1101/2021.03.05.21252998

A second study from the group based at the University of California studied breast milk samples collected from six lactating women at intervals varying between four and 48 hours after they had received a dose of an mRNA covid-19 vaccine – five Pfizer and one Moderna. No demographics for the population sample are given. Of the 15 samples tested, two were taken prior to a first vaccination, 11 were taken 4-48 hours after a first vaccination and two were taken following a second vaccination. RT-qPCR was performed in triplicate using specific primers targeting the vaccines’ mRNA for SARS-CoV-2 spike protein. Pre-vaccine breast milk samples spiked with mRNA-1273 (Moderna) vaccine acted as positive controls and non-spiked pre-vaccine samples served as negative controls.

The study detected no evidence of vaccine mRNA in any of the post-vaccine breast milk samples. The authors conclude that these findings support international guideline recommendations that lactating individuals who receive the anti-covid-19 mRNA-based vaccine should continue to breastfeed their infants uninterrupted. The authors also acknowledge that the number of specimens tested was small and that studies using larger population sizes are required.

M Hall March 2021

References

1. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ 2020;370:m3320.

2. FIGO Statement: COVID-19 Vaccination for Pregnant and Breastfeeding Women

https://www.figo.org/covid-19-vaccination-pregnant-and-breastfeeding-women

Doyle, TBlackmore, CMMWR Morb Mortal Wkly RepCOVID-19 in Primary and Secondary School Settings During the First Semester of School Reopening — Florida, August–December 202026 Mar 2021USANorth America170Epidemiology - Transmissionhttp://dx.doi.org/10.15585/mmwr.mm7012e2

This Early Release Report was posted on the MMWR website of the USA Department of Health and Human Services / Centers for Disease Control and Prevention on 19 March 2021. It is an analysis of data collected by the Florida Department of Health, relating to school-related cases and outbreaks of COVID-19 following the resumption of in-person instruction.

In the 2020–21 school year, 2,809,553 students were enrolled in 6,800 schools in Florida. All schools in the state suspended in-person instruction by 20 March 2020 and began to re-open in August 2020.

COVID-19 cases were identified using nucleic acid amplification or antigen detection of SARS-CoV-2, in symptomatic or asymptomatic people. School-based outbreaks were defined as two or more epidemiologically linked school-related cases.

Between 10 August and 21 December 2020, 63,654 cases of COVID-19 were identified in young people aged 5–17 years. During the same time- period, 34,959 school-related COVID-19 cases were reported: 25,094 (72%) in students and 9,630 (28%) in staff. Therefore, 39.4% of all cases reported in school-age children, were school-related. School-related cases in children occurred in <1% (25,094 of 2,809,553) of all registered students.

The median age of the children with COVID-19 was 13 years (IQR 9–15 years). Higher case rates were reported in school students from counties with the lowest population, districts re-opening schools earlier in August 2020 and those districts that did not mandate mask-wearing.

Analysis of a subset of 562 of the 695 school-based outbreaks, identified activities outside the classroom setting as being associated with 20% of the outbreaks. These activities included sports, social gatherings and transportation.

Of the school-related cases, 101 children required hospital admission and there were no deaths. 219 school staff were admitted to hospital and there were 13 deaths. Of these, 9 deaths occurred in staff with “additional risk factors” including obesity (7), age >60 years (4) and other chronic conditions (4).

The authors conclude that resumption of in-person schooling can be achieved without causing a rapid spread of COVID-19. Alongside this they emphasise that community-level and school-based measures are essential to reduce SARS-CoV-2 transmission in school settings.

This report includes no analysis of socio-economic, or racial and heritage factors associated with infection risk. The authors also offer no further conclusions about the substantial infection rate and death toll in the school staff

Doron, SCiaranello, APre-printWeekly SARS-CoV-2 screening of asymptomatic students and staff to guide and evaluate strategies for safer in-person learning30 Mar 2021United StatesNorth America2403Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.20.21253976v1

This pre-print article reports the results of a Covid-19 screening programme conducted in one school district in Massachusetts, US in the autumn of 2020. The study was conducted at a time when schools in the district were operating hybrid learning in which the school week was divided between in-person and remote learning. Schools had also adopted Covid-19 prevention measures and community testing for those with symptoms was in place. The study aimed to evaluate the incidence of asymptomatic COVID-19 in schools and the risk of in-school transmission through widespread screening.

Students and staff from one middle school and one high school were invited to participate. Students were aged 11-18 years and of the 2403 eligible students, 58-77% participated weekly. 73-83% of the 921 eligible staff participated. Weekly pooled PCR testing of saliva was performed for 18 weeks. Participant numbers varied on a weekly basis due to reasons such as school absence and forgotten samples. Individual diagnostic testing (RT-PCR) was performed to confirm positive cases and contact tracing was then conducted.

Rates of COVID-19 in the Massachusetts district increased from 5 to 32/100,000/day during the 18-week period. During the study, there were 126 positive cases of Covid-19 infection in the participating schools. 37 were identified through the screening program with the rest identified through outside testing. There was only one cluster of in-school transmission identified in the program and this was amongst 4 staff members. In another week, 7 positive asymptomatic cases in non-close contacts were identified in one school. In both cases, risk factors for transmission within the schools were identified whilst early measures to prevent further spread were implemented. In the cluster case, risk factors included lack of social distancing in staff areas whilst eating as well as high-traffic areas and shared offices.

They study concludes that in-school transmission is rare as long as infection prevention measures are adhered to. They add that widespread screening can help early identification of cases and that their implementation could further support the safe operation of schools during the pandemic. They acknowledge the limitations of screening programs such as the significant associated costs and the need for participation and acceptance from students and staff.

The Efficacy and Safety of Covid-19 mRNA Vaccines Administered During Pregnancy and Lactation

A review of four recent publications

Pregnancy and lactation were specified as exclusion criteria for recruitment to all of the clinical trials of covid-19 vaccines which have, to date, been approved by the MRHA, the EMA and the FDA. However, while recognising the gap in knowledge concerning the efficacy and safety of covid-19 vaccines in pregnancy and lactation, these regulatory bodies have all recommended that the covid-19 vaccines should be offered to those pregnant individuals who are either at high risk of exposure to SARS-CoV-2 virus or who are at high risk of complications from the disease, preferably after discussion with their health care providers.

Over the past few months evidence has been accumulating that covid-19 infection presents an increased risk of morbidity and mortality to pregnant women and an increased risk of preterm delivery and NICU admission to their babies.1 On 2nd March 2021, the International Federation of Gynecology and Obstetrics (FIGO), having gained some reassurance from animal studies and from a preliminary report that a US Study of covid-19 vaccination in 20,000 pregnant women had identified “no alarming signs”, issued the following position statement: “It is now established that pregnant women are at increased risk of severe COVID-19-associated illness compared with non-pregnant women…… FIGO, therefore, considers that there are no risks – actual or theoretical – that would outweigh the potential benefits of vaccination for pregnant women. We support offering COVID-19 vaccination to pregnant and breastfeeding women”.2

Notwithstanding this recommendation, there is still a need to convert the expectation of efficacy and safety of vaccination in pregnancy and lactation into evidence. A number of recently-published papers, all relating to mRNA vaccines, have reported on studies which were designed to help fill these knowledge gaps. The studies are mostly of small sample size and some lack detail concerning aspects such as study population and methodology but, when combined, they appear to provide some reassurance concerning short-term safety issues relating to vaccination during both pregnancy and lactation, together with evidence of positive immunological benefits for mother, fetus and baby.

A summary of the main findings of these papers is as follows:

1. Both the Moderna and the Pfizer vaccines induced IgG, IgM and IgA antibodies to SARS-CoV-2 receptor-binding domains (RBD) and to the viral spike proteins when the vaccine was administered to pregnant mothers, irrespective of the trimester of pregnancy.

2. IgG, but not IgM or IgA, concentrations showed a further increase after the second dose of the vaccine.

3. There was a positive correlation between maternal serum antibody and cord blood antibody concentrations.

4. For both vaccines, there was a positive correlation between the concentrations of SARS-CoV-2 IgG titres in cord blood and the time interval between the first vaccine dose and delivery.

5. Both vaccines induced anti-SARS-CoV-2 RBD-specific IgA antibodies in the breast milk of lactating mothers and spike-specific IgG, IgM and IgA antibodies. Only IgG showed a further increase following the second vaccine.

6. No evidence of vaccine mRNA was found in a small study of lactating women who received either the Moderna or the Pfizer vaccines.

7. Placental transfer ratios of SARS-CoV-2 antibodies may be lower than those of some other vaccines.

Different laboratory methodologies were used in these studies and different units of measurement of antibody concentrations were used which precludes a direct comparison of the measurements. The papers have not yet been subject to peer review and this must be borne in mind when interpreting the validity of the reported findings. None of the studies report on longer term outcomes.

Volpp, KNeatherlin, JMMWRMinimal SARS-CoV-2 Transmission After Implementation of a Comprehensive Mitigation Strategy at a School - New Jersey, August 20-November 27, 2020.19 03 2021USANorth America775Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7011a2.htm

This study was done in a private boarding school for Grade 9-12 students (age 14-18y) in the USA: there were 520 boarding pupils, 255 commuter students and 405 staff.

The mitigation strategy was comprehensive and included:

Testing and Screening: Quarantine for 2 weeks before travelling to school + proof of negative RT-PCR result, monitor for symptoms daily and 2X daily temperature checks throughout, 2X weekly RT-PCR test for all staff and pupils, rapid antigen testing if anyone had symptoms and they were quarantined until confirmatory RT-PCR

Distancing/ Physical barriers: Student numbers in the classroom reduced by a rotated proportion learning online, masks worn at all times outside of bedrooms, meals eaten outside, enhanced ventilation systems in communal areas, proximity tracing devices worn at all times

Compliance: all students and staff had to agree to comply with the mitigation strategies, encouraged by ongoing educational and motivating messages, breaking of the rules resulted in a sanction. 10 students received 3 sanctions and were sent home for 2 weeks.

Results: 8,955 RT-PCR on staff salivary samples, 17 (0.18%) positive (+2 positive in off-site testing). 12,494 RT-PCR on student nasal swab specimens, 8 (0.6%) positive. 66 antigen tests performed for COVID-19 like symptoms: all negative. Case investigation of the 27 positive tests showed an off-campus contact as the likely source for 25 of these infections; 2 were in boarding pupils were plausibly caused by secondary transmission on campus as no other source of infection was found. All contacts (from proximity tracing device data) of the 27 cases were quarantined for 14 days and none tested positive suggesting that the mitigation strategies were effective. During the study period the incidence of COVID-19 in the local area was increasing.

This study demonstrates that SARS-CoV-2 transmission can be considerably reduced by the measures implemented.

The authors themselves note that the costs of the proximity tracing devices and of the testing and management programme are probably not affordable in many settings. Though physical distancing, mask wearing and hand hygiene is already known to be effective, teenagers, who have no sanctions to fear, may be less likely (even unlikely) to abide by these rules and so it is difficult to know how far the results of the study are useful for most schools and communities.

Cotugno, NPalma, PCell Reports 34 (11) (no pagination) (108852). Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies16 Mar 2021ItalyEurope66Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S2211124721001662

This paper studied humoral and cellular immune responses in 66 SARS-CoV-2 infected children (mean age (SD) 6.8y (5.4); 41 male), presenting to a single centre in Italy between March-April 2020, and compared them to 11 non-infected controls admitted with Covid-like symptoms who tested negative on 2 consecutive NP samples.

Blood samples were taken at admission and after approximately 48hrs and 7 days. NPS for viral load was taken every 48hrs until undetectable. The presence (37/66) or absence (29/66) of neutralizing antibodies (NAbs) did not correlate with disease severity at presentation. There was an inverse correlation between SARS-CoV-2 IgG and NAbs and viral load, time taken to clear the virus and in vitro viral replication. Evidence is presented for specific B and T cell responses in NAb+ cases compared to NAb-. Serum proteomic analysis showed 2 proteins associated with lymphocyte activation were raised in NAb+ cases. The important findings in this study are that not all children develop NAbs but those that do carry a lower viral load, achieve viral clearance sooner and may be less infective, as measured in vitro.

Hershow, RChu, VMorb. Mortal. Wkly. Rep.Low SARS-CoV-2 Transmission in Elementary Schools — Salt Lake County, Utah, December 3, 2020–January 31, 202119 03 2021USANorth America40Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7012e3-H.pdf

In this study, led by the Centre for Disease Control in the US, transmission of SARS-CoV-2 was assessed in 20 elementary schools (kindergarten - grade 6) in Salt Lake County, Utah from December 3rd, 2020 to January 31st, 2021. Community transmission in the region was high during the study period with 290 - 670 new weekly cases per 100,000 people. Of the 10,000 students, more than 80% were attending school in person. Mask use in schools was high, but distancing between students' seats in class was 3 ft (less than the previously recommended 6 ft). Other mitigation measures including cohorting of students, staggered mealtimes and limits on extra-curricular activities and large group gatherings were also in place.

All school contacts of identified index cases answered a symptom questionnaire, and were offered RT-PCR saliva SARS-CoV-2 testing, performed 5-10 days after exposure. All close school contacts (within 6ft of index patient for >15 minutes in a day) up to December 17th were ordered to quarantine, close contacts following this date were only quarantined if masking was inadequate during interaction with the index case. Household members of school contacts were interviewed and also offered testing. Whole genome sequencing (WGS) was performed for all available positive specimens to confirm source and direction of transmission. School contacts with a positive test were considered to have a school-associated case unless illness preceded first school exposure, a household member had an illness in the 14 days preceding or WGS demonstrated a non-school related lineage.

A total of 51 index cases were identified across 48 classrooms: 40 students and 11 staff. One third of index cases were asymptomatic. Of 1041 susceptible school contacts (133 staff and 908 students), testing was completed in 735 (71%) of whom 12 were positive (11 students, 1 teacher). There were five cases classified as school-associated (following exclusion of four cases with epidemiological evidence of acquisition of infection outside of school and three cases in whom WGS demonstrated a non-school related lineage). The secondary attack rate amongst school contacts was 0.7%; no outbreaks (>2 school-associated cases linked to an index case) were documented. Six of eight household members of school-associated cases subsequently tested positive for SARS-CoV-2.

The findings here add to the body of evidence that, with appropriate mitigation measures, SARS-CoV-2 transmission within schools is uncommon, even in the setting of high-community transmission. A major strength of this study is the high proportion of contacts who received PCR testing, regardless of symptoms. The low transmission despite the inability to maintain distancing of 6 feet between students suggest that 3 feet of distancing may be adequate in elementary schools in the context of other mitigation measures including high usage of masks. Similarly, the modified criteria for quarantining close contacts (only if mask use is inadequate during interaction with index case) may be adequate to prevent school-associated transmission, whilst limiting missed days of in-person learning.

Cooper, DMUlloa, EmedRxivSARS-CoV-2 Acquisition and Immune Pathogenesis Among School-Aged Learners in Four K-12 Schools26 Mar 2021USANorth America320Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.03.20.21254035v1

Methods

This prospective observational study carried out in four schools in Orange County, California USA aimed to test the assumption that school-aged children would be less susceptible to SARS-CoV-2 infections if they avoided onsite learning. The study was conducted in schools deemed to represent the socio-demographic diversity of this area, during a period of relatively low level of community transmission of SARS-CoV-2 (early fall 2020, COVID-19 incidence: 3 to 4 cases/100,000) and 6 to 8 weeks after, amidst a surge of COVID-19 in the community (fall-winter, COVID-19 incidence: 40 cases/100,000). A total of 320 learners aged between 7 to 17 years old (mean 10.5 ± 2.1 SD) and 99 school staff aged ≥ 18 years old were enrolled across three public (school A, B, C) and one private school (school D). Schools A and B served economically disadvantaged Hispanic children; school C special needs learners and school D, middle and upper-middle income White learners. As opposed to school D, remote learning predominated in public schools.

The study involved two-testing cycles in which every participant completed a COVID-19 symptom screening. Anterior nasal swabs for the detection of SARS-CoV-2 and co-circulating respiratory viruses via RT-qPCR were collected, and an optional phlebotomy for SARS-CoV-2 specific IgG and IgM, neutralising antibodies, immunologic markers, and lipid screening (the latter only for the cycle 2) was offered. The fidelity of face covering and physical distancing mitigation in schools were measured using momentary time sampling techniques in classroom, recess, communal dining and physical education classes by trained observers, who visited the schools between 3 and 5 times.

Results: seventeen out of 320 learners (5.31%, mean age 9.9 ± 2.1 years old), and six out of 99 staff (6.1%) had positive RT-qPCR during the second cycle of testing. No evidence of RSV or influenza was reported. No statistically significant differences in the rates of SARS-CoV-2 infections were described between onsite and remote learners across the study settings (95% CI was not provided in this pre-print). School A had the highest number and proportion of SARS-CoV-2 infected learners (9/70) and the highest proportion of infected staff (3/25); the differences in the results of RT-qPCR among the schools may reflect the differences in neighbourhood infection rates. Learners with documented SARS-CoV-2 infection were more likely to have symptoms consistent with COVID-19. They also showed SARS-CoV-2 neutralising antibodies, detectable SARS-CoV-2 specific IgM and IgG, detectable SARS-CoV-2 specific IFN- secreting CD4 T cells following exposure to SARS-CoV-2 antigens, as well as low levels of circulating monocytes, NK cells and several inflammatory immune mediators. The results of the lipid screening suggested that either low HDL or high LDL were more commonly seen in socioeconomically disadvantaged learners (schools A and B), and 26% of learners with low HDL, had a positive test for SARS-CoV-2. High levels of face covering and physical distancing compliance in classrooms, and an expected reduction of face covering and physical distancing during communal dining was also reported.

Comments: successful mitigation strategies to prevent local SARS-CoV-2 transmissions in schools are achievable yet related with socioeconomic factors and regional transmission of SARS-CoV-2. Remote learning did not avert SARS-CoV-2 infections in school-aged children. Mild symptoms of COVID-19 might be explained by strong humoral and cellular immune responses, coupled with a reduced number of circulating monocytes and inflammatory immune mediators.

Caribú, FNuciforo, PJ Clin Invest.Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission26 Jan 2021ItalyEurope37Neonatalhttps://www.jci.org/articles/view/145427

This is a cohort study of 37 pregnant women who were admitted to a hospital in Milan, Italy between 12/03/2020- 23/04/2020. They all underwent nasopharyngeal SARS-CoV-2 PCR testing on admission, some of whom also had COVID symptoms. 21 were positive on these swabs. Following delivery, placental tissue was collected and all the newborns underwent nasopharyngeal PCR testing. The placental tissue underwent quantitative RT-PCR for SARS-CoV-2, in-situ hybridisation (ISH) and a study of gene expression. Lung samples taken post-mortem from individuals who had died from COVID in Basel, Switzerland was used as controls.

All neonates born to these mothers had a negative PCR swab result for SARS-CoV-2. One woman (Patient 1) underwent an emergency c-section 1 week and 5 days after the positive PCR test for reduced fetal movement. The baby had suffered a perinatal asphyxia event and required mechanical ventilation and underwent therapeutic hypothermia. 10 out of the 21 women had positive quantitative PCR on their placental tissue; Patient 1 had a higher viral load detected with 14 PCR cycles compared to the median of 32 (IQR 31-35) from the other placentas. The placenta from Patient 1 was significantly different from all other placentas investigated and showed similarity to the lung specimens. It showed massive fibrin deposition and necrosis of syncytiotrophoblast on histology, intense positivity of perivillious trophoblast with extensive apoptosis of infected cellular compartment on ISH similar to the lung sample and a gene expression profile which was similar to the control lung specimens.

This study is useful in understanding the placental injury (and therefore the effect on the fetus) following placental exposure to high viral load of SARS-COV-2. The similarities between patient 1’s placenta on those of the lung specimen controls does offer sufficient cause for concern in this group of women. However, this is a single example of this magnitude of placental injury. Despite the nasopharyngeal swab and placental quantitative PCR positivity, the finding of negative nasopharyngeal PCR swabs in all neonates does raise the possibility that the placenta acts as an efficient barrier for vertical transmission. There was however no umbilical cord sampling or any other form of testing for antibodies in the neonate and therefore vertical transmission cannot be ruled out. It is also a single centre study with a majority white ethnic background.

Niño-Taravilla, COrtiz-Fritz, PEmerging Inf Dis JMultisystem Inflammatory Syndrome in Children, Chile, May–August 20201 May 2021ChileSouth America26Clinical - PIMS-TShttps://wwwnc.cdc.gov/eid/article/27/5/20-4591_article

Introduction and Method: Few COVID-19 articles on children and MIS-C have reviewed cases in Latin America. The authors here describe the clinical characteristics, treatment, and results of a cohort of children (26) admitted to the paediatric intensive care unit (PICU) with MIS-C in a tertiary hospital in Chile.

They collected demographic data, medical history, clinical symptoms, and physical examination findings, also results of imaging, cardiac, and laboratory tests conducted during the patient’s stay in the emergency room and PICU. Data on treatment, complications, outcome, and length of PICU and total hospital stay was analysed.

Results: Of the 33 patients with SARS-COV-2 who were hospitalized in the PICU during the study period, 26 met the definition for MIS-C.16/26 (61.5%) patients met the criteria for Kawasaki disease. Their median age was 6.5 years (IQR 2–10.5 years); 15 (57.7%) patients were male. Only 1 patient had a chronic underlying condition.

In total, 22 (84.6%) patients tested positive for SARS-CoV-2 infection, 7 (26.9%) by reverse transcription PCR and 15 (57.6%) by serologic assay. The other 4 (15.3%) patients tested negative for SARS-CoV-2 but had a COVID-19 exposure. The most frequent symptoms were fever (26, 100%), shock (24, 92.3%), abdominal pain (17, 65.4%), diarrhoea (16, 61.5%), vomiting (12, 46.2%), rash (16, 61.5%), and conjunctivitis (15, 57.7%).

Ten (38.5%) patients required mechanical ventilation for a median duration of 4 days (IQR 2.5–5 days). Only 1 (3.8%) patient met the criteria for acute respiratory distress syndrome; that patient had an oxygenation index of 25. Half (13, 50.0%) of the patients required vasoactive drugs. We used high-flow hemofiltration as salvage therapy for refractory shock in 1 patient. No patients required extracorporeal membrane oxygenation (ECMO). In total, 20 (76.9%) patients received intravenous immunoglobulin; 2 (9.1%) received a second dose. We treated 23 (88.5%) patients with corticosteroids; 1 (3.8%) required a larger dose. We prescribed immunomodulatory agents for 4 (15.4%) patients: tocilizumab for 3 patients and infliximab for 1.

In total, 18 (69.2%) patients had echocardiographic abnormalities, including 5 (19.2%) patients who met the criteria for Kawasaki disease with coronary artery abnormalities. The median duration of PICU stay was 5 days (IQR 2–7 days). None of the patients died.

Conclusions: The authors described 26 children with MIS-C in Chile. Their findings were similar to those reported in other countries. Most patients had echocardiographic abnormalities, and half required vasoactive drug support. We administered immunomodulatory therapy to most patients. Clinical trials and long-term follow-up are needed to elucidate the mechanisms of various treatments and potential sequelae of this condition.

Ladhani, SRamsay,MLancet Child Adolesc HealthSARS-CoV-2 infection and transmission in primary schools in England in June–December, 2020 (sKIDs): an active, prospective surveillance study16 Mar 2021EnglandEurope6727Epidemiology - Transmissionhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00061-4/fulltext

A prospective surveillance study undertaken in school aged children in England between June 2020 and December 2020. There were two groups in the study, one had weekly swabs for a minimum of 4 weeks, the other group had blood tests on four occasions, at the start of the study in June 2020, in July 2020, in September 2020 and in December 2020.

There was a total of 11,966 participants. 6,727 students, (49% male, 42.6% aged 4-6, 23.1%, aged 7-9 and 34.6% aged 10-12). There were 4,628 staff (84.8% female, age range 20 to ≥60 years), and 611 in whom the status of the participant was unknown (staff or student). A total of 40,501 swabs were taken in 131 schools. In 45 of these schools, blood sampling was also taken.

In June 2020 the weekly SARS-CoV-2 infection rates, as determined by swab, were 4·1 per 100,000 for students and 12·5 per 100,000 for staff.

At recruitment in June 2020, in 45 schools, 91 of 816 students and 209 of 1,381 staff members were positive for SARS-CoV-2 antibodies. Antibody positivity varied across the different English regions and between students and staff but was similar to the regional seroprevalence during the same week. A school clustering effect was significant for staff members but not students. For both students and staff, seropositivity was associated with non-White ethnicity and health-care workers in the household. There was no association between seropositivity and school attendance during lockdown. In July 2020 603 of 816 students and 1015 of 1381 staff members were still participating in the surveillance, and five (four students, one staff member) had seroconverted. By December 2020, 55 of 1085 participants who were seronegative at recruitment had seroconverted, including 19 of 340 students and 36 of 745 staff members.

The authors found very low rates of symptomatic or asymptomatic SARS-CoV-2 infection in students and staff following partial and full reopening of primary schools in England in June 2020. Community SARS-CoV-2 infection rates were low during the summer half-term and high during the autumn term. The authors conclude “the results indicate that primary schools were not sites of significant transmission before the emergence of new variants of SARS-CoV-2 in the UK. Further work is needed to understand the effect of new variants within educational settings.”

Hu, SYu, HNature CommunicationsInfectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China09 Mar 2021ChinaAsia00000000000000Epidemiology - Transmissionhttps://www.nature.com/articles/s41467-021-21710-6

Many publications have described transmission patterns of SARS-CoV-2 within populations, but this report is more authoritative than most. It includes people of all ages, but there are some important messages relating to children. It comes from the Chinese province of Hunan, which has a population of 67 million, and is adjacent to Hubei province, where the pandemic began. They were able to rapidly institute an effective test, track and trace system, and they record here how the virus spread, between 13th January and 2nd April 2020.

Much of it confirms what we already knew, but with bigger numbers and more reliable data. Starting with a cohort of 1178 people who were PCR positive (1019 symptomatic, 159 asymptomatic), they traced 15648 potential contacts. Of these, 471 tested PCR positive. Mean generation time between contact and positivity was 5.7 days, with infectiousness peaking at 1.8 days. Presymptomatic transmission has been a defining feature of this pandemic, and their rate was 59% - greater than some other reports have suggested. There was no significant difference in onward transmission rates between symptomatic and asymptomatic people. 831/1178 index cases were epidemiologically linked, in 210 identified ‘clusters’. In pairs where a single infector could be linked to a specific infectee, in 14% the infectee’s symptoms preceded those of their infector.

There are more data in this report than can be summarised here, but some points relevant to children include:

- Susceptibility to infection (not transmission) increased with age (under 15 vs over 15 years)

- Transmissibility did not differ significantly between these age groups: lower virus carriage rates in children may have been compensated for by more individual contacts, at least while still in school

- Fewer PCR-positive under-15s had symptoms, and in this age group almost as many were asymptomatic as symptomatic.

- Household contacts carried highest risk of transmission

- First generation of contacts carried higher risks of onward transmission than subsequent contacts

- Comparing the periods before and after 23rd January, the mean serial interval increased from 4 days to 7 days: this may reflect more intensive tracing and isolation.

This is important confirmatory evidence of the potential for children to transmit the virus significantly, even if largely asymptomatic. However, much has changed since April 2020 and new variants of the virus, as well as changing public health policies, may reduce the generalisability of these findings.

Belay, EGodfred-Cato, SJAMA PediatrTrends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic06 APR 2021USANorth America1733Clinical - PIMS-TShttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2778429

This is a retrospective study of 1733 children with MIS-C (PIMS-TS), who were notified to the Centers for Disease Control and Prevention surveillance database in the USA, between March 2020 and January 2021. Data from these patients were analysed for temporal and geographic trends.

Case definition: Age < 21y AND Fever, laboratory evidence of inflammation and admitted to hospital AND Involvement of ≥2 organs (cardiac, renal, respiratory, haematological, gastrointestinal, dermatological, or neurological) AND No alternative plausible diagnosis AND Either laboratory confirmation of SARS-CoV-2 infection OR known COVID-19 exposure before symptom onset.

Demographics: The median age of patients was 9 years (IQR 5–13) and 57.6% were male.

71.3% were either Hispanic or non-Hispanic Black (39% of children in the USA come from Hispanic and non-Hispanic Black backgrounds).

Clinical features: Of the 1733 children who met the criteria for MIS-C, 1567 (90.4%) had involvement of at least 4 organ systems. The most common signs and symptoms, in addition to fever, were abdominal pain (66.5%), vomiting (64.3%), rash (55.6%), diarrhoea (53.7%) and conjunctival injection (53.6%). Cough, shortness of breath and chest pain were reported in less than 30%. Hypotension occurred in 50.8% and 36.8% developed shock. Cardiac dysfunction was reported in 31.0%, pericardial effusion in 23.4%, myocarditis in 17.3% and coronary artery dilatation or aneurysms in 16.5%.

Younger children aged 0-4 years had less multiple organ involvement. Older patients, aged 18-20 years, were more likely to have myocarditis and ARDS. Of the total cohort, 1009 (58.2%) were admitted to intensive care and 24 (1.4%) died.

Temporal trends: Three peaks for MIS-C were identified, in early May, early August, and December. The first 2 peaks followed the peaks for the COVID-19 pandemic by 2 to 5 weeks. The third peak also appears to be following a rise in paediatric COVID-19 cases.

Geographic trends: The incidence of MIS-C ranged from 0.2 to 6.3 for states reporting children with MIS-C. The incidence of MIS-C was highest in the Northeast of the USA, while most of the states with high paediatric COVID-19 rates were in the West and Midwest.

Conclusions: The authors conclude that the geographic and temporal occurrence of MIS-C in close as- sociation with the COVID-19 pandemic is consistent with the hypothesis that the emergence of MIS-C is due to delayed immunologic responses to infection by SARS-CoV-2. MIS-C disproportionately affects Hispanic and Black children and adolescents, most probably due to long-standing inequities in the social determinants of health.

Pierce, CHerold, BJCI InsightNatural mucosal barriers and COVID-19 in children06 Apr 2021USANorth America12Clinical - Clinical Features https://insight.jci.org/articles/view/148694
Paul, ABuchan, SmedRxiv Pediatric household transmission of SARS-CoV-2 infection31/03/2021 CanadaNorth America9861Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.03.29.21254565v1.full#ref-22
Dawson, PSalzer, JMorb Mortal Wkly RepPilot Investigation of SARS-CoV-2 Secondary Transmission in Kindergarten Through Grade 12 Schools Implementing Mitigation Strategies — St. Louis County and City of Springfield, Missouri, December 202026 03 2021USANorth America24Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7012e4.htm?s_cid=mm7012e4_x

In this study from Missouri, USA, transmission of SARS-CoV-2 in K-12 schools in Springfield and St Louis County was assessed from December 7th-18th, 2020. SARS-CoV-2 incidence in the surrounding community was high during the study period (cumulative 711 cases per 100,000 population).

Mitigation measures were in place in all schools, including mask mandates (100%) spacing of desks >3ft (100% - including 27% of schools with >6 ft spacing), physical barriers between teachers and students (98%) and increased ventilation (98% - predominantly opening windows, use of fans and decreased occupancy of closed spaces). During the study period 70% of students (21,342 / 30,588) attended in-person schooling at least part-time.

All students and staff who tested positive for SARS-CoV-2 during the study period and attended school whilst potentially infectious and associated close contacts were approached to participate. Close contacts were followed for 14 days with SARS-COV-2 PCR saliva testing at 5-8 days after last exposure. In St Louis, all close contacts were instructed to quarantine according to CDC guidelines. In Springfield, close contacts were only required to quarantine if there was prolonged close physical contact with a case, contact outside of the classroom or a breach in mask use.

Of 56 index cases with SARS-CoV-2 infection, 37 (66%) agreed to participate along with 156 of 270 (58%) close contacts. Students made up 65% (24/37) of index cases and 88% (137/156) of close contacts. Of 156 contacts, 54 declined PCR testing; of 102 tested close contacts, only 2 had a positive PCR for SARS-CoV-2. Both episodes (one student to student, one teacher to student) were deemed "probable" school transmission events based on symptom onset and epidemiology; one case was confirmed by whole genome sequencing. Both contacts had been instructed to quarantine (one because of prolonged close physical contact with a case and one because of contact outside of the classroom). There were no school outbreaks identified.

In Springfield, 51% (41/82) of participating close contacts met criteria for exemption from quarantine. None returned a positive SARS-CoV-2 test result (21 of 41 tested).

This study provides further evidence that, in the presence of mitigation measures, in school transmission of SARS-CoV-2 is rare, even in settings with high levels of community transmission. In this case incidence of cases due to in-school transmission was almost 100-fold lower than in the general community (~8 vs 711 per 100,000 persons). The follow up of contacts using modified criteria for quarantine suggest that in school learning may be able to continue for some close school contacts, thereby minimising disruptions, but this approach requires further study.

Mo, HHu, KPediatr NeonatolDetectable antibodies against SARS-CoV-2 in newborns from mothers infected with COVID-19 at different gestational ages26 Mar 2021ChinaAsia6Neonatalhttps://doi.org/10.1016/j.pedneo.2021.03.011

AIM: to understand changes in the antibody levels to SARS-CoV-2 in newborns after maternal infection at different gestational ages.

METHOD: At delivery and monthly for 6 months, throat swab and blood samples were taken from 6 affected women and their babies. The swabs were tested for viral nucleic acid and blood antibody levels to SARS-CoV-2 were measured using either qualitative or quantitative detection.

RESULTS: Maternal infection, confirmed by nucleic acid testing, occurred in the 2nd trimester in one woman (17 weeks and 5 days) and in the third trimester in 5 (28 weeks and 4 days, 29 weeks and 5 days, 34 weeks and 1 day, 36 weeks and 1 day and 37 weeks and 2 days). Viral shedding had a median duration of 29.0 days (range 18.8 – 42.3) in the

All newborns were born at term ranging from 37 weeks and 5 days to 40 weeks and 5 days.

Three women delivered during the acute phase of COVID-19. The other three women delivered 37, 56, and 111 days after recovery from COVID-19. Although 3 women are said to have been delivered during the acute phase of infection, none of the six women, nor their babies tested positive for PCR after delivery, nor did they have any symptoms of COVID-19.

The 3 mothers who had COVID-19 at 17 to 29 weeks gestation had evidence of IgG but not of IgM at birth. Their IgG was still detectable at more than 4 times the cut off value at 6 months. Their infants didn’t have any IgM at birth but had IgG levels persisting for 5 months in 1 and 6 months in the other 2. The 3 mothers with COVID-19 at 34 weeks or later had IgM and IgG. There was IgM detectable until 60 days and 90 days but in the third mother in this group there was no detected IgM at 30 days. Their IgG lasted 120 days in two and 150 days in the third mother. In their infants the IgG lasted 60 days in one and 120 days in the other two.

DISCUSSION: After delivery, women with COVID-19 between 17 and 29 weeks and their babies had a longer duration of detectable IgG than women with COVID-19 at 34 weeks or later and their babies. It is not clear what level of antibody in infants confers protection against infection.

COMMENTS: this is a small study which confirms previous findings of placental passive transmission of maternal IgG antibodies to their babies which last several months. They seemed to last longer in babies born to mothers who had had COVID-19 earlier in pregnancy (at 17, 28 and 29 weeks) compared to babies whose mothers had COVID-19 closer to term. This may be explained by these mothers in the second group not having reached peak production of IgG by the time their babies were born. The Supplementary file for the maternal and neonatal clinical details did not contain the relevant material on clinical features in mothers and babies. Women were wrongly described as being in the second trimester if the gestational age at infection was 28 and 29 weeks. No details were given on nucleic acid testing of swabs. There were contradictory statements regarding the presence of COVID-19 symptoms or positive PCR at birth: all negative but 3 mothers were described as being in the active phase of infection at the time of delivery.

Haapanen, MKuitunen, IeclinmThe impact of the lockdown and the re-opening of schools and day cares on the epidemiology of SARS-CoV-2 and other respiratory infections in children - A nationwide register study in Finland.30 03 2021FinlandEurope40535Epidemiology - Transmission https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00087-0/fulltext

This is a retrospective study of data in the Finnish national registry. The incidence of 9 respiratory pathogens in children, including SARS-CoV-2 (age 0-19 for SARS-CoV-2, 0-14 for the others) is plotted by week from January to late August 2020. This includes their first school closures as part of COVID-2 reduction measures (weeks12-20) and their school summer holidays (week 23-33). Incidence by age group is presented. The incidence of respiratory pathogens, other than SARS-CoV-2, in 2020, is also compared with 2017-19.

All the cases had positive PCR tests on nasopharyngeal swabs, taken on a clinical basis. Many were in 2o care but some for Influenza A/B and RSV were taken in 1o care.

Results: As expected, the numbers of respiratory pathogen infections (other than SARS-CoV-2) generally reduced following the closure of the schools and by more than the expected seasonal fall shown by the figures from previous years (exception rhinovirus).

However, the incidence of SARS-CoV-2 infections seems to continue to rise during the 1st 2 weeks of school closure then plateau, only showing a sustained fall from week 18. This may not reflect the true picture as the testing was increasing from a very low level. The level of SARS-CoV-2 infections seem to start to rise before the return to school (week 33).

Limitations: Testing for SARS-CoV-2 was extremely limited at the beginning and only used for children with quite severe symptoms and known exposure: it gradually increased through the year. By August, any child with even mild URTI symptoms was tested leading to backlogs and results taking up to a week.

Asymptomatic children were only tested in some special circumstances.

It is unclear how far “nasopharyngeal swabs, taken on a clinical basis” will reflect the true incidence of respiratory infections in the population.

The COVID-2 restrictions were less strict than elsewhere with gatherings of up to 10 people allowed, possibly indoors (not clear from the paper). Mask wearing was not introduced until week 33.

Comment: The authors stated aim was to describe the effect of implementing and easing broad restrictions on the epidemiology of respiratory pathogens in the nationwide paediatric population of Finland. The data does not seem robust enough to attribute all the changes described to opening and closing schools and day care.

Sermet-Gaudelus, IEloit, MEuro Surveill 26(13)Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 202001 Apr 2021FranceEuropeClinical - Clinical Featureshttps://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.13.2001782

Seasonal coronavirus (HCoV) antibodies in 69 children seen or admitted at a French tertiary centre for reasons other than Covid (but including 15 with a multisystem inflammatory syndrome - MISC) between 01/04-01/06/21 but subsequently found to have SARS-CoV-2 antibodies, were compared to 115 sex/age matched controls. Median age 9.6 (SD 5.1), range 0-18 years. Past infection with seasonal coronaviruses did not seem to protect against SARS-CoV-2 infection or MISC. Neither was the SARS-CoV-2 antibody response any different between those with or without evidence of past HCoV infection. Given that reinfection with seasonal coronaviruses is well recognized, this study not only suggests that past HCoV infection is unlikely to prevent SARS-CoV-2 infection but also that the concept of herd immunity from vaccination or natural SARS-CoV-2 infection may not occur. This study does not examine any possible effect of past HCoV infection on severity of SARS-CoV-2 disease.

Beharier OKovo MmedRxivEfficient Maternal to Neonatal transfer of SARS-CoV-2 and BNT162b2 antibodies6 Apr 2021IsraelMiddle East213Neonatalhttps://www.medrxiv.org/content/10.1101/2021.03.31.21254674v1

This study is a pre-print and has not yet been peer reviewed

Methods: Observational study carried out in eight centres across Israel between April 2020 and March 2021. The study evaluated the maternal production and placental transfer of SARS-Cov-2 antibodies in gravidae immunised with BNT162b2 mRNA-based vaccine during pregnancy, versus unvaccinated pregnant women with a history of COVID-19 during pregnancy confirmed via a positive nasopharyngeal swab RT-PCR test. These groups were matched to unvaccinated parturients according to clinical features. Pregnant women younger than 18 years old or with active COVID-19 disease at delivery were not eligible for this study. Maternal and foetal blood samples were collected prior to delivery and from the umbilical cord after delivery, respectively. Serum specific SARS-Cov-2 IgG and IgM were detected using a multiplex assay.

Results: The cohort involved 1094 pregnant women: 105 had been vaccinated; 94 unvaccinated with a history of COVID-19 and 895 unvaccinated without prior history of COVID-19. Among the latter, 66 were selected as controls (matched comparison group) based on clinical characteristics. Matched maternal cord blood serology results were available for 213 mothers and their newborns; 86 vaccinated; 65 unvaccinated with a history of past SARS-CoV-2 positive RT-PCR and 62 non-infected, unvaccinated. Maternal age was lower in the group with past RT-PCR positive for SARS-CoV-2, compared to unvaccinated/non-infected and vaccinated mothers (95% CI not provided. Kruskal- Wallis one way ANOVA p = 0.0011). Other clinical maternal and newborn parameters of interest did not differ among the study groups.

Transfer rates of IgG to S1, S2, RBD and N were higher in participants infected before week 30 (n =25/65) compared to those who had a positive PCR after week 30 of gestation (n = 21/65) (95% CIs unavailable; Wilcoxon rank sum test S1 p = 0.0013; S2 p = 0.0231; RBD p = 0.0010; N p = 0.0003). A subset of participants in the control group were identified as serologically positive for N, S1, S2 and RBD (n = 9/62); a subgroup of vaccinated pregnant women were identified as positive for N (n = 7/86). A rapid IgG response to S1, S2 and RBD but not N, resulting in high titres by day 15 post-vaccination was detected in participants receiving a first dose of BNT162b2, with further increase following the second dose. Compared to women with past RT-PCR positive for SARS-CoV-2, foetal IgG for S2 and N were significantly lower in cord bloods of vaccinated women (p < 0.0001; p < 0.0001 respectively; no confidence intervals are available), but no difference was found between foetal IgG for S1 and RBD (p = 0.70017, p = 0.6887 respectively; no confidence intervals are available). Significant positive correlations between foetal and maternal antibodies were found for all groups and antigens, and no difference in the correlation slopes of SARS-Cov-2 infected/non-vaccinated versus the vaccinated group in any type of antibodies were also detected. Foetal IgM response to BNT162b2 was negligible. Within the PCR positive group, 4/65 newborns had robust SARS-Cov-2 specific IgM responses to all antigens and 1/65 neonates showed a “partial” immune response which may indicate compromised placenta barrier or potential vertical transmission.

Comment: Maternal IgG humoral response to BNT162b2 mRNA-based vaccine appears to be robust in non-infected participants. These antibodies transfer across the placenta to the foetus and are detectable within 15 following the first dose. Self-reporting time of the positive RT-PR among those in the SARS-Cov-2 (recall bias) as well as enrolment of participants during the day (selection bias) are potential limitations of this study. Regarding the latter, it appears unlikely that those women admitted in the evening mounted a different immune response to vaccination or SARS-Cov-2 infection. No RCTs on the efficacy of mRNA-based vaccines against SARS-Cov-2 infections included pregnant women. Although this study shows sounded evidence regarding the immune response elicited by BNT162b2 in the dyad mother-newborn, safety trials focusing on maternal immunisation are warranted.

Gettings, JVallabhaneni, SClin Infect DisSARS-CoV-2 transmission in a Georgia school district - United States, December 2020-January 202117 Apr 2021USANorth America5300Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab332/6232104

Summary: This epidemiological prospective cohort study assessed in-school SARS-CoV-2 transmission in a public school district in Georgia, USA, which included elementary, middle and high schools. This district serves an ethnically and socioeconomically diverse population of 8,500 students and employs 1,400 staff members. The study period was from December 1st 2020 to Jan 22nd 2021 and included a 16-day holiday. Notably, the local COVID-19 incidence (7-day cumulative number of new cases/100,000 persons) increased from 192 cases on December 1st 2020 to a peak of 705 cases on January 13th 2021.

SARS-CoV-2 transmission was assessed using contact testing and cluster analysis and analysed by school setting, index case role, symptom status, and month of transmission. In-school transmission was highest when the index case was a staff member, had symptoms or index case contact occurred in an indoor sports setting. More than half of contacts who tested positive were asymptomatic. Recommendations include caution with respect to indoor sports, measures to reduce staff infection (e.g. education, vaccination) and testing of contacts irrespective of symptom status.

Methods: SARS-CoV-2 index case identification and contact tracing was carried out by public health and school officials. Investigators approached in-school contacts for consent to RT-PCR testing (5-10 days post-exposure or at symptom onset) and surveillance of symptoms. RT-PCR testing was offered to family members of study participants with positive tests. Secondary attack rate (SAR) was calculated as positive contacts/number of contacts tested for different scenarios. Whole genome sequencing (WGS) was used to identify clusters (index case epidemiologically linked with ≥ 2 positive contacts in school) and assess likelihood of in-school transmission.

Results/Discussion: Approximately 5,300 students attended school in-person over the study period. Of 98 index cases identified, 86 cases were assessed (33 staff, 53 students), generating 1,119 contacts. Of 688 (63.1%) contacts who were tested, 59 contacts tested positive attributable to in-school transmission, and overall SAR was 8.7% (95% confidence interval [CI]: 6.8–10.9). Fifteen (17.4%) of the index cases were associated with clusters. Of 55 index cases with symptom data, 31 (56.4%) were asymptomatic. SARs were highest for indoor sports settings (23.8%, 95% CI 12.7, 33.3) and staff interactions (18.2%, CI 4.5–31.8). The SAR was higher for elementary (9.5%, CI 6.5–12.5) than high school classrooms (1.6 %, CI 0.0-4.7), although in-person attendance for high school students was lower. For high school students, most positive contacts (93.7%) and all clusters were linked with sports.

SAR was higher for staff (13.1%, CI 9.0–17.2) than student (5.8%, CI 3.6–8.0) index cases, and for symptomatic (10.9%, CI 8.1-13.9) than asymptomatic (3.0%, CI 1.0-5.5) index cases. Outside of sports settings, the majority of positive staff contacts (87.5%) and positive students contacts (72.2%) were linked with a staff index case. Disproportionately more staff members were identified as index cases (40% index cases vs. 20% in-school population).

Siegel, MDanyluk, GMMWR Morb Mortal Wkly Rep Notes from the Field: SARS-CoV-2 Transmission Associated with High School Football Team Members — Florida, September–October 202019 Mar 2021USANorth America0000000000Epidemiology - Transmissionhttps://www.cdc.gov/mmwr/volumes/70/wr/mm7011a3.htm#suggestedcitation

This is one of what appears to be a series of short reports from the American Centers for Disease Control (CDC), intended to warn educators, health professionals and the public about the potential for SARS-CoV-2 transmission in school settings. This one focuses on football (presumably American football, not soccer). In September 2020, a single player at a Florida high school tested positive. All 49 fellow players and coaches were then quarantined, but in spite of this, three days later, 6 additional players tested positive. Health officials investigated, and ultimately a further 19 cases were linked to this index case: 12 fellow players, 2 coaches, 2 classroom contacts and 3 home contacts. Seven were asymptomatic.

They established that immediately preceding the outbreak, the team had held regular practices, and 3 matches against other schools. This involved frequent close contact, including indoor exercises with ‘infrequent’ mask use. Other risks included shared bus transport, shared drinking vessels, and poor locker-room disinfection. There were no confirmed cases amongst the other schools’ teams. The consequences of this one case were the quarantining of 267 students, and the loss of 2243 person-days of school attendance.

Rather belatedly, they make recommendations for limiting virus transmission in school sports.

Shlomai, AEventov-Friedman, SPaediatricsNeonatal SARS-CoV-2 Infections in13 Apr 2021IsraelMiddle East55Neonatal https://pediatrics.aappublications.org/content/early/2021/04/09/peds.2020-010918
Haag, LArmann, JmedRxivPrevalence and Transmission of SARS-CoV-2 in Childcare Facilities: A Longitudinal Study18 Apr 2021GermanyEurope318Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.16.21255616v1

This article is a pre-print and therefore has not yet been peer reviewed.

This longitudinal study by Haag et al., (2021) was conducted to gain further knowledge on prevalence, transmission and spread of SARS-CoV-2 among preschool children aged 1-6 years, their parents and caretakers.

Background: Since the beginning of the SAR-CoV-2 pandemic, school and childcare closures were one of the main strategies to limit the transmission of the virus and it was assumed that children had a similar role in transmitting the virus as they do in transmitting influenza. It was therefore assumed that the closure of schools and childcare was effective in lowering the overall transmission rate. Many studies in the UK, Norway and Germany noted a lower proportion of cases in children compared to their population size and very limited spread in primary and secondary schools.

Method: Children, parents and childcare workers in 14 childcare facilities in Dresden, Germany were invited to participant in the study. Adults had 5mL of peripheral venous blood collected for serological testing for IgG-antibodies against SARS-CoV-2. Stool samples were collected from children by the parents every two weeks. The stool samples were tested using PCR. All samples were collected between July 2020 and January 2021. Participants with detectable antibodies in at least two assays were considered seropositive. The study period was divided into a low-prevalence and a high-prevalence period (15th July 2020 – 15th November 2020 and 16th November 2020 – 31st January 2021 respectively). Only children with at least two donated stool samples were included in the study: 232/318 (73.0%) in the low prevalence phase and 222/318 (69.8%) in the high prevalence phase. No positive stool samples were excluded by these criteria.

Results:

Low Prevalence Period: At baseline, no participants were SARS-CoV-2 seropositive. During the low-prevalence phase, 2 study participants, one childcare worker (1/154 – 0.7%) and one parent (1/196 – 0.5%) became seropositive. Both were confirmed via PCR and they did not attend the same childcare facility. During this time, there were 2 positive stool samples (2/232 – 0.9%). The two children attend different childcare facilities.

High Prevalence Period: During the high prevalence phase, 25/236 (10.6%) parents and 23/187 (12.3%) childcare workers were seropositive. There was no statistical significance between the two groups (p=0.64). Parents whose children were in emergency childcare reported higher seroprevalence than parents whose children were not in childcare during that time (12/64 – 18.8% vs 13/152 – 8.6% respectively). Seroprevalence in childcare workers assigned to administrative work was significantly higher than those with mainly childcare related duties (10/48 – 20.8% vs 8/99 – 8.1% respectively)

SARS-CoV-2 Positive Children: 15/222 children in the second study period had at least one positive stool sample. These occurred at 8 different institutions. In 4 childcare facilities, a possible epidemiological link between a maximum of 3 children each could be identified. In 6 cases, there was no connection to other children.

Conclusion: This study strengthened the hypothesis that childcare facilities are not a major source of uncontrolled clusters of SARS-CoV-2. Around 50% of SARS-CoV-2 infections in children could not be connected to a secondary case within the study population. The higher rate of seropositivity in parents whose children attended emergency childcare may have been a result of their working environment. The fact that administrative staff had a significantly higher rate of seropositivity compared to those with mainly childcare duties suggests that transmission between adults may occur more frequently than between children.

Comments: Strengths of the study included the use of antibody testing instead of PCR testing in parents and childcare workers to reduce the possibility of missed undetected SARS-CoV-2 cases. The use of stool testing instead of NP swabs may have been a strength as viral excretion in stool is thought to be longer than in the upper airway, therefore being more sensitive.

Armann, JBerner, RBMJ Paediatrics openSARS-CoV-2 transmissions in students and teachers seroprevalence follow-up study in a German secondary school in November and December 202024 March 2021GermanyEurope247Epidemiology - Transmissionhttps://bmjpaedsopen.bmj.com/content/5/1/e001036

A study undertaken in 302 subjects (247 students and 55 teachers) in Dresden, Germany in November and December 2020. The students median age was 15years (14-17) 53% of whom were female, and the teachers 51 years (44-56) 23% female. Blood samples were taken in November from these 302 subjects to determine the number who were seropositive. These numbers represent 53% of all students in grades 8–12 and 79% of teachers in the school.

Five students had detectable antibodies against SARS-CoV-2 in at least two different assays and were therefore considered seropositive, indicating a seroprevalence of 1.7% (0.3%–3.3%). While one of the seropositive participants reported to have no knowledge of a previous SARS-CoV-2 infection, the other four seropositive students reported to have been tested positive for SARS-CoV-2 previously by PCR. The ratio of undetected to detected cases was therefore 0.25.

6 weeks later 219 of these subjects (180 students and 39 teachers) had repeat blood testing and an additional 17 students and one teacher were sampled for the first time. These sample numbers represent 42% of students and 57% of teachers.

16 participants were seropositive, including the five seropositive students from the initial visit. Six seropositive participants reported a previous SARS-CoV-2 infection diagnosed by PCR and nine reported a SARS-CoV-2-positive household contact, leading to a ratio of undetected to detected cases of 0.33. The seroprevalence rate was 6.8% (3.8%–10.1%) representing a fourfold rise in seroprevalence within 6 weeks. Since 4 out of the 16 seropositive students were only sampled at the second visit, the authors also analysed the group of participants with two blood samples (n=219) separately. This showed a 2.4-fold seroprevalence increase, from 2.3% (0.5%–4.6%) to 5.5% (2.3%–8.7%). Fifty participants reported to have been in an officially mandated quarantine at least once between the two visits. Five (10%) out of those quarantined newly developed SARS-CoV-2 antibodies, three of these newly seropositive participants reported to have been tested SARS-CoV-2 positive by PCR and one reported a SARS-CoV-2-positive household contact leading to a ratio of undetected to detected cases of 0.25 in this subsample.

In summary the seroprevalence increased from 1.7% (0.3–3.3) to 6.8% (3.8–10.1) during the study period. This mirrored the increase of officially reported SARS-CoV-2 infections during this time. The ratio of undetected to detected SARS-CoV-2 infections ranged from 0.25 to 0.33.

The especially important conclusion of the authors was “We could not find evidence of relevant silent, asymptomatic spread of SARS-CoV-2 in schools neither in a low prevalence setting nor during the second wave of the pandemic, making it unlikely that educational settings play a crucial role in driving the SARS-CoV-2 pandemic.”

Chmielewska, BKhalil, ALancet Glob HealthEffects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis31 Mar 2021Global - systematic reviewGlobal - systematic reviewEpidemiology - Transmissionhttps://doi.org/10.1016/S2214-109X(21)00079-6

The evidence to date indicates that, when SARS-CoV-2 is contracted during pregnancy, there is an increase in potential adverse outcomes for those pregnancies, including the risk of the mother requiring intensive care with a possible increase in maternal mortality, and the pregnancy ending in preterm delivery1. However, the global effect of the Covid-19 pandemic and of the population control measures introduced to mitigate its effects, on maternity outcomes for all pregnant women – both infected and non-infected - is less clear. This systematic review conducted by academic clinicians based in the UK and Turkey and published in Lancet Global Health has sought to address this issue.

The aim of the study is stated in the introduction section as being “to assess the collective evidence on the effects on maternal, fetal and neonatal outcomes of the pandemic” and in the abstract as “to assess the collateral effects on maternal, fetal, and neonatal outcomes of the global COVID-19 pandemic”. A more precise understanding of the research question can be found in the study protocol registered on Prospero in October 2020 where the elements of the PICO framework which was used to direct the literature search were specified as follows:

P (Population) - the whole obstetric population, not limited to those women infected with COVID 19

I (Intervention) - the COVID-19 pandemic and subsequent healthcare service restructuring

C (Comparator(s)/Control(s)) - the equivalent population in the period preceding the pandemic

O (Outcome) – Primary: stillbirth:

Secondary: preterm birth, pregnancy hypertension, gestational diabetes caesarean

section, neonatal death and morbidity and maternal mortality or severe

morbidity

This was, therefore, a systematic review of studies which reported on population, rather than specific patient, outcomes which were recorded “before and after” the COVID-19 pandemic. The literature databases which were used to identify relevant studies were confined to Medline and Embase; studies published between January 202 and January 2021 were eligible for inclusion, with no language restrictions. In addition the Oxford COVID-19 Government Response Tracker was used to identify national government-level interventions which were introduced in the countries in which the studies originated. The search terms used reflected the listed outcomes. Details relating to the process of the literature do not seem to have been provided. Standard Covidence software was used for data extraction and analysis.

The literature search identified 40 studies which met the inclusion criteria. Meta-analysis was performed on the 21 outcomes for which two or more studies reported data. The main findings were that:

- there was a statistically significant increase in both maternal deaths and stillbirths associated with the pandemic

- there was no overall change in the prevalence of preterm births when both high-income countries (HICs) and low-income and middle-income countries (LMICs) were combined in the analysis

- there was a decrease in preterm births <37 weeks gestation (but not <34, 32 or 28 weeks) of all causes in HICs and specifically in spontaneous (rather than iatrogenic) preterm births

- mean Edinburgh Postnatal Depression Scale scores were higher during the pandemic

- there was an increase in surgically-managed ectopic pregnancies.

No effect of the pandemic was found on maternal gestational diabetes, hypertensive disorders of pregnancy, labour induction, post-partum haemorrhage, mode of delivery, low birthweight (<2500 g) or neonatal death.

For the outcomes of stillbirths and preterm birth the number of pregnancies included in the meta-analyses was ~170,000 for both, and studies from both HICs and LMICs were included; the observed changes, therefore, may be representative of global trends. For 17 of the other 19 outcomes, however, fewer than 10 studies were available for meta-analysis and the only two studies reporting maternal deaths were from LMICs; this limits the ability to extrapolate or generalise the findings among diverse global settings.

In their discussion of the outcomes of the review the authors suggest that the increased rate of adverse outcomes was driven primarily by the inefficiency of health-care systems and their inability to cope with the pandemic, rather than by the restrictions imposed by pandemic mitigation measures. The possible reduction in preterm births appeared to apply to those which were spontaneous, rather than iatrogenic, and the authors conclude that It is more likely that changes in health-care delivery and population behaviours were the more important contributing factors to the reduction in preterm births rather than changes in obstetric management.

The authors acknowledge a number of limitations to interpretation of the reported outcomes, including possible publication bias, the retrospective design of the included studies, heterogeneity of the study populations and differences in definitions and measurement of outcomes.

A final comment is that, given the population-based approach of this study, the inclusion of measurements of maternal morbidities such as depression and anxiety, and speculation in the discussion section about the impact of domestic violence on pregnancy outcomes, I wonder whether, if the study were to be repeated, a broader range of literature databases might be used, to include those which focus on epidemiology, mental health and social sciences in addition to the medically-focused Embase and Medline.

1. Pregnant People. At increased risk for severe illness from COVID-19.

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnant-people.html

Preston, LGoodman, AJAMACharacteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-1909 Apr 2021USA North America20714Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347

Introduction: The authors conducted a cohort study to estimate adjusted associations between demographic and clinical characteristics and severe COVID-19 among hospitalized pediatric patients.

Methods: Discharge data from 869 medical facilities that contributed inpatient and emergency department encounters to the Premier Healthcare Database Special COVID-19 Release (PHD-SR) database capturing approximately 20% of US hospitalizations, were used to describe patients 18 years or younger who had an inpatient or emergency department encounter with a primary or secondary COVID-19 discharge diagnosis from March 1 through October 31.Severe COVID-19 was defined as care requiring treatment in an intensive care unit or step-down unit, involving use of invasive mechanical ventilation, or resulting in death. Race/ethnicity was defined by information in patient medical records in the PHD-SR.Adjusted odds ratios (AORs) and 95% CIs for severe COVID-19 were calculated using a multivariable generalized estimating equations model adjusting for within-facility correlation, age, sex, race/ethnicity, insurance type, and presence of chronic conditions. The a priori significance level was set at P = .05; all hypothesis testing was 2-sided.

Results: Among 20 714 pediatric patients with COVID-19, 10 950 (52.9%) were girls, 11 153 (53.8%) were aged 12 to 18 years, 8148 (39.3%) were Hispanic or Latino individuals, 5054 (24.4%) were non-Hispanic Black individuals. Among these patients with COVID-19, 6047 (29.2%) had 1 or more chronic conditions.

Among the cohort of 2430 pediatric patients (11.7%) who were hospitalized with COVID-19, 756 (31.1%) experienced severe COVID-19. An increased association of severe COVID-19 was observed among patients with 1 or more chronic conditions vs those with none (AOR, 3.27; 95% CI, 2.44-4.37); in children aged 2 through 5 years or 6 through 11 years vs those aged 12 through 18 years (AORs, 1.53; 95% CI, 1.11-2.13 and 1.53; 95% CI, 1.04-2.23, respectively); and in male vs female patients (AOR, 1.52; 95% CI, 1.26-1.83). There was no statistically significant association between race/ethnicity or insurance type and severe COVID-19.

Discussion: In this cohort study, nearly one-third (756 [31.1%]) of hospitalized pediatric patients with COVID-19 experienced severe COVID-19, which is consistent with previous findings. Analysis revealed an increased association of severe COVID-19 in younger children (those aged 2-11 years) compared with older children (those aged 12-18 years). Although admission to an intensive care unit for younger children may indicate an abundance of caution by clinicians or facility and administrative requirements rather than disease severity, this finding has important clinical and resource planning implications for facilities and clinicians.

The results suggest that existing chronic conditions and male sex are independently associated with severe COVID-19. Consistent with previous reports, non-Hispanic Black and Hispanic or Latino children with COVID-19 were overrepresented compared with all pediatric patients in the PHD-SR. The authors found no statistically significant association between severe disease and race/ethnicity among hospitalized patients when controlling for covariates.

Although most children with COVID-19 experience mild illness, some children develop serious illness that leads to hospitalization, use of invasive mechanical ventilation, and death. Understanding factors associated with severe COVID-19 disease among children could help inform prevention and control strategies.

Lugon, PBrasil, PPediatricsSARS-CoV-2 Infection Dynamics in Children and Household Contacts in a Slum in Rio de Janeiro01 Apr 2021BrazilSouth America377Epidemiology - Transmissionhttps://pediatrics.aappublications.org/content/early/2021/04/14/peds.2021-050182

This prospective study, conducted in Brazil from May to September 2020, examined rates of SARS-CoV-2 infection, measured by nasopharyngeal and rectal swab PCR and IgG serology, in children under 14 years and their household contacts, over a series of home visits, to evaluate the direction of transmission of infection.

Study population: 323 children under 14 years of age who visited a primary healthcare clinic in northern Rio de Janeiro for any reason, including accompanying relatives, and additional children in this age group who shared the same residential address, were recruited. The clinic provides primary care and immunisation services to Manguinhos, an impoverished urban slum (favela) lacking sanitation and electricity. Following enrolment, children and their household contacts (54 adolescents aged 14-19 years and 290 adults older than 19 years of age) were visited at home at 1, 2 and 4 weeks after enrolment, then quarterly. Recruitment and follow-up took place between 18 May and 24 September 2020; 259 households were studied.

Testing for SARS-CoV-2: At enrolment and during subsequent home visits, PCR assays (on nasopharyngeal and rectal swabs, and some saliva samples) and IgG serology were performed on all children and their household contacts, regardless of symptoms. A participant was defined as positive if any of their serial samples collected during the study was positive. 45/323 children under 14 years were PCR positive (13.9%). Higher rates were seen in children under 1 year old (25%) and 11-13 year olds (21%). 13.2% of contacts aged 14 years or older were positive. Of those who had IgG serology performed, 32.6% of children under 14 years old and 31.2% of older household contacts were positive. The 11-13 year age group had the highest proportion of IgG positivity, followed by over 60 year olds. Asymptomatic infection was more prevalent in children under 14 years of age (74.3%) than those 14 years and older (51.1%). Median CT values for PCR-positive children under 14 years of age were not significantly different between naso-oral, saliva and rectal samples, nor between different age groups or household sizes. There were no severe cases of COVID-19 among the children and their household contacts, including siblings.

Infection dynamics: These were assessed by looking at PCR-positive children under 14 years of age to see if they had an adult contact who was IgG positive or had a clinical history suggestive of past COVID-19, defined as a recent respiratory illness accompanied by anosmia or ageusia. Of the 45 children who were PCR-positive, 26 had an adult contact who provided specimens for testing; all 26 were either PCR or IgG positive. The remaining 19 adult contacts had a clinical history of suspected COVID-19. The assumption was that this indicated that transmission was primarily from adults and adolescents to children.

Conclusions: All children with PCR-positive SARS-CoV-2 infection had an adult or adolescent household contact with suspected or confirmed SARS-CoV-2 infection before the child’s diagnosis, compatible with the hypothesis that the children were infected after or concurrently with household contacts, mostly their parents, implying that children were not the primary source of infection in the household. Of note, schools remained closed during the study period, while adults continued to work outside the home. Approximately one-third of children and their household contacts in the study were IgG positive, indicating that they had already been exposed to SARS-CoV-2 by August 2020, which is a higher prevalence of infection than that reported for the general population of Rio de Janeiro during that time period (7.5%). The study was limited by the logistical challenges of enrolment and home visits in this community.

Bark, DChoi, AmedRxivSARS-CoV-2 transmission in K-12 schools in the Vancouver Coastal Health Region: a descriptive epidemiologic study18 May 2021CanadaNorth America517Epidemiology - Transmissionhttps://doi.org/10.1101/2021.05.15.21257271

This article is a pre-print and has not yet been peer reviewed.

It is an analysis of data from the Vancouver Health Coastal Region’s electronic COVID-19 case and contact management platform, comparing school-related cases and outbreaks of COVID-19 to those in the general population between the 10th of September and 18th December 2020.

Schools in the region under study reopened following the summer holidays on 10 September 2020. There were 699 COVID-19 cases identified in schools during the study period. There were 71 school clusters comprising 251 of these cases. There was school-based transmission of SARS-CoV-2 in 26 of the clusters (37%), resulting in 55 secondary and 10 tertiary cases. School staff accounted for 54% of the index cases (14/26) and 25% of secondary cases (14/55).

The weekly incidence of SARS-CoV-2 infection in the school population rose and peaked at 6.6 per 10,000 in the 10 weeks following school reopening. This compared with a peak weekly incidence of 9.4 per 10,00 of the population as a whole at the same time. The incidence of new cases in schools and in the population as a whole followed similar trends over the time of the study, although incidence was always lower in the schools. The authors conclude that schools are not a significant driver of SARS-CoV-2 transmission and where school-based transmission occurs, the number of secondary cases is limited.

Bellon, MEckerle, I Clin Infect DisSARS-CoV-2 viral load kinetics in symptomatic children, adolescents and adults5 May 2020SwitzerlandEurope279Epidemiology - Transmissionhttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab396/6265276

This study looks at the Covid-19 transmission risk posed by symptomatic children by using viral load as a surrogate for the presence of infectious disease. The study analysed the samples of symptomatic individuals of all ages who were diagnosed via a positive Covid-19 RT-PCR specimen in one institution in Switzerland. The samples were taken between the spring and winter of 2020 (exact months unspecified). The viral load (SARS-CoV-2 RNA load) of each specimen was measured and analysed in relation to the onset and number of symptoms of the tested individual. They aimed to use this data on viral shedding kinetics to compare how infectious children and adolescents were compared to adults in the first week of illness.

In total, 8027 positive specimens were included (279 children aged 0-13 years, 639 adolescents aged 14-19 years and 7109 adults). For all age-groups, a peak in viral load was seen in 1-3 days after symptom onset. 58% of children and 61% of adolescents had viral loads above the threshold for infectious virus presence at the time of diagnosis. This number was significantly higher in adults compared to children. The mean viral load was slightly lower in children than adolescents and adults although the small effect size means it may not be of practical significance.

Ultimately, the authors conclude that symptomatic children and adolescents are able to transmit Covid-19 infection for the majority of their first week of illness but that they may have slightly lower viral loads and be infectious for a shorter time than adults. These findings should be taken into context with the study’s limitations as recognised by the authors. The study includes symptomatic children only although we know a large proportion of children are asymptomatic. It relies on pooled data from multiple individuals to reach conclusions about infectiousness over time rather than performing consecutive swabs on the same individual. Finally, it assumes that viral load is the main driver of transmission and does not include other factors such as behaviour and environment.

Mossong, JWilmes, PBMC Infect DisSARS-CoV-2 transmission in educational settings during an early summer epidemic wave in Luxembourg, 202004 MAY 2021LuxembourgEurope390Epidemiology - Transmissionhttps://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06089-5#:~:text=Transmission%20of%20SARS%2DCoV%2D2,mitigating%20transmission%20within%20educational%20settings.

Background: Several studies have reported a limited role for children in transmission of COVID-19 however, epidemiological data of transmission within educational settings are scarce. All schools in Luxembourg were closed on 19th March with a gradual return to in person teaching during the first week of May. Luxembourg reunited all classes to normal sizes, despite experiencing an early second wave of infections in June-July 2020 and social distancing and face masks were made mandatory. An epidemiological analysis of the second wave of infections were conducted by comparing the incidence of infections in school-age children and teachers to that of the general working population. The study also estimated the number of secondary transmissions occurring at schools.

Methods: All positive SARS-CoV-2 infections were detected by RT-PCR and reported to the health directorate. COVID-19 surveillance data was linked to national database and therefore details including employers and school class identifiers were retrieved. Determination of the source of transmission was conducted manually by epidemiologists. If contact with a known positive case occurred within an incubation interval of less than 14 days, this case was considered as the probable source. Sources were categorised as family, school, friends, or others (sports or multiple probable sources). Complex cases with more than two probable sources were reviewed by two independent epidemiologists.

Results: During the first wave in March-April 2020, the incidence of SARS-CoV-2 infection was substantially lower in school-age children when compared to the older adult population. Data during the peak week of March 23-29 found that the incidence was 28 per 100,000 for those aged 0-19 years old compared to 208 per 100,000 for the rest of the population (Incidence rate ratio (IRR) 0.13, 95%CI 0.09-0.19, p<0.001). During the peak week of the second wave of COVID-19 infections (July 20-26) , there was no difference in incidence observed between school-aged children and other adults.

Incidence rates of SARS-CoV-2 infection in teachers and the general working population were similar during the first wave but slightly lower in teachers during the second wave. Incidence was significantly lower in pupils compared to teachers during the first wave (IRR 0.20, 95% CI 0.12-0.34, p<0.001) but was higher during the second wave.

Incidence rates were significantly lower in pre-primary school pupils (IRR 0.18, 95%CI 0.04-0.76, p<0.05) and in primary school pupils (IRR 0.21 95%CI 0.08-0.55, p<0.001) than in high school pupils during the first wave, but these differences were less marked during the second wave. (IRR 0.61, 95%CI 0.32-1.16, p<0.05) and (IRR 0.72, 95%CI 0.46-1.14, p<0.05) respectively.

Data collected between 4th May- 25th July 2020 identified 390 cases of confirmed SARS-CoV-2 infection in pupils and 34 cases in teachers. 37.5% of cases had no identifiable cause. The most frequent observed source of infection was family/household (42.5%) followed by school transmission (11.6%). For 123 (29%) cases, there was no data available to ascertain whether the individuals were present at school, while 73 cases (17.2%) were not present at school and therefore posed no infection risk.

Of the 228 cases present at school, 150 did not give rise to any secondary cases, while 29 cases gave rise to a total of 49 secondary cases. Of these 49 cases, 38 (78%) were pupil-to-pupil transmission, seven (14%) teacher-to-pupil, three (6%) pupil-to-teacher and one was teacher-to-teacher transmission.

In total, 179 positive cases who went to school were estimated to have transmitted SARS-CoV-2 infection to 49 secondary cases, which corresponded to an effective reproductive rate of 0.27 when considering only the school setting.

Comments: This study agrees with the view that currently COVID-19 outbreaks in educational settings appear uncommon and that the incidence of infections in educational settings is correlated with that of the general population.

Toh, Z QLicciardi, P VEmerg Infect DisPersistence of SARS-CoV-2-Specific IgG in Children 6 Months After Infection, Australia20 May 2021AustraliaAustralasia22Clinical - Clinical Features https://wwwnc.cdc.gov/eid/article/27/8/21-0965_article

This research letter describes a study looking at humoral immune response to SARS-CoV-2 infection in children (and adults) over time. It showed seroconversion in around 80% of children by 6 weeks, despite all being asymptomatic or having mild disease, and this seropositivity persisted at 6 months.

Participants and their family members were recruited after testing positive for SARS-CoV-2 infection by rt-PCR at Melbourne Children’s Hospital, Australia. All had mild disease or were asymptomatic, none were hospitalised. The study included 22 children, median age of 4 years (0-18 years).

At 6 weeks, 79% of children (15/19) had seroconverted and this IgG response persisted at 3 months and 6 months (14/17 children, 82%). Seropositivity rates were similar in the adult cohort.

Participant numbers were small and the time period limited to 6 months, but the findings of good and lasting humoral responses after mild disease, at least in the medium term, is encouraging.

Lyngse, FKirkeby, CmedRxivIncreased Transmissibility of SARS-CoV-2 Lineage B.1.1.7 by Age and Viral Load: Evidence from Danish Households19 Apr 2021DenmarkEurope1214Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.16.21255459v1

This article is a pre-print and has not yet been peer reviewed.

Introduction: The B.1.1.7 lineage was first identified in the southeast of England in September 2020. In Denmark, B.1.1.7 was first detected on November 14, 2020, and by March 2021 comprised more than 90% of the circulating lineages. The aim of this study was to estimate the household transmissibility SARS-CoV-2 for lineage B.1.1.7 compared with other lineages, by age and viral load and to estimate any multiplicative effect.

Methods: Data from the Danish register was assessed from January 11th to February 7th 2020. This register included the full population of Denmark, all RT-PCR tests for Sars-Cov-2 and all positive tests which has whole genome sequencing (approx. 70% of samples), CT value, and presumed Sars-cov-2 lineage. The Danish civil registration number was linked to a national register of address codes, to analyse presumed household transmission.

Results: 8,093 household primary cases were identified, of which 82% (6,632) were selected for WGS, and 65% (5,241) generated a high-quality SARS-CoV-2 genome. Lineage B.1.1.7 was found in 15% (808) of these genomes. The primary cases lived in households comprising 2-6 persons with a total of 16,612 potential secondary cases, of which 4,133 tested positive. This implies an attack rate of 25% (4,133/16,612).

The age specific transmissibility followed a U-shaped pattern with the lowest transmission from primary cases in the 10 to 30 years age range, higher from younger children, and highest from elderly casesIn households where the primary cases were infected with B.1.1.7, the attack rate was 38%, compared with 27% when the primary cases were infected with other lineages.

Discussion: Sars Cov 2 lineage B.1.1.7 had a household transmissibility 1.5-1.7 times higher compared with other lineages even after adjusting for CT values. Sars Cov 2 lineage B.1.1.7 generally follows the pattern of other lineages, where teenagers are the least transmissible within households. However, B.1.1.7 was consistently more transmissible per age group compared with other lineages.

This paper adds to the data for Sars Cov 2 lineage B.1.1.7 being more transmissible than other previous lineages, and may have public health implications, ie contact tracing for variable with higher transmissibility should be prioritised. This data implies that any model that is used as a tool for decision makers on further public health interventions must take into account the predominant lineage in the population and its transmissibility.

Galow, LArmann, JJ InfectLower household transmission rates of SARS-CoV-2 from children compared to adults27 04 2021GermanyEurope17Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(21)00209-7/fulltext

In this seroprevalence study from Dresden, Germany, transmission between individuals with confirmed SARS-CoV-2 infection and their household contacts was assessed. PCR-positive SARS-CoV-2 individuals identified by the local public health office from June 2020 were invited to participate. SARS-CoV-2 seropositive individuals identified in a separate seroprevalence study in schools were also invited. All household members of confirmed cases were tested for SASR-CoV-2 IgG antibodies and information on infection prevention measures implemented within households was collected.

A total of 150 households were included; 139 based on a SARS-CoV-2 PCR-positive household member and 11 based on a seropositive member. Serostatus was available on 88% (414/470) of all household members. Over half (51%, 211/414) were seropositive. The secondary attack rate (SAR) was 0.35 overall. SAR was significantly lower for the 17 child index cases (0.15 (95% CI 0.05-0.27)) compared with the 126 adult index cases (0.38 (95% CI 0.32-0.45)). Avoiding shared spaces (employed in 42% of households) and masking of the index case (14% of households) both significantly reduced risk of household transmission.

A strength of this study is the use of SARS-CoV-2 serostatus to assess household transmission, thereby minimising the likelihood of under-detection of secondary cases. This study is however limited by the lack of longitudinal data to accurately determine direction of transmission, with the first case identified by PCR or antibody testing determined to be the index case. Notwithstanding this, the results of a significantly lower household SAR for children compared with adults, along with the small number of paediatric index cases, is consistent with existing evidence that children are less susceptible to and less likely to transmit SARS-CoV-2 compared with adults.

Say, DTosif, SLancet Child AdolescPost-acute COVID-19 outcomes in children with mild and asymptomatic disease20 04 2021AustraliaAustralia171Epidemiology - Disease Burdenhttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00124-3/fulltext
Somekh ISomekh EJAMA Netw. OpenComparison of COVID-19 Incidence Rates Before and After School Reopening in Israel26 Apr 2021IsraelMiddle East148564Epidemiology - Disease Burdenhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778940

Aim: to understand whether school reopening was associated with SARS-CoV-2 infection in children aged 0 to 9 years of age.

Methods: national data from Israel obtained from the Ministry of Health to calculate SARS-CoV-2 age group–specific weekly incidence rates and test positivity rates for the following age groups: 0-9 years, 10-19 years, 20-39 years, 40-59 years and 60 years and older. These rates were adjusted for the number of tests performed and for the proportion of each age group in the general population. Using adjusted incidence rate ratios (IRRS) and test positivity rate ratios (RRs)s the rates were compared between the 3 weeks in September 2020 following reopening of the schools on the 1st September and the last week in August. An infection surge led to schools being closed on 14th September. Rates were compared between November through to December with that from the last week in October following schools being reopened on 1st November 2020. Linear regression was used to look at how the incidence rate varied during the first 3 weeks in September.

Results: data were analysed from 47260 children aged 0 – 9 years, 101 304 youths aged 10 to 19 years, 151 295 adults aged 20 to 39 years, 103 056 adults aged 40 to 59 years, and 63 438 adults aged 60 years and older. Children aged 0 – 9 years had the lowest increase in IRRS (p<0.001) and RRs in September and in Nov-Dec 2020 (p<0.001).

Age group Sept 2020 IRR (incidence rate ratio) Nov-Dec 2020 IRR (incidence rate ratio) Sept 2020 RR (test positivity rate ratio) Nov-Dec 2020 RR (test positivity rate ratio)

0 to 9 years 1.1 (95%CI, 1.0-1.14) 1.34 (95%CI, 1.23-1.45) 0.77 (95%CI, 0.7-0.8) 0.75 (95%CI, 0.7-0.8)

10-19 years 3.1 (95%CI, 2.96-3.3) 1.9 (95%CI, 1.74-2.06) 1.5 (95%CI, 1.4-1.6) 0.97 (95%CI, 0.95-1.1)

20-39 years 3.2 (95%CI, 2.96-3.4) 2.5 (95%CI, 2.3-2.7) 1.6 (95%CI, 1.5-1.66) 1.3 (95%CI, 1.25-1.4)

40-59 years 3.1 (95%CI, 2.9-3.3) 2.43 (95%CI, 2.3-2.6) 1.5 (95%CI, 1.45-1.6) 1.28 (95%CI, 1.2-1.4)

≥60 years 2.2 (95%CI, 2.0-2.3) 2.95 (95%CI, 2.6-3.3) 1.1 (95%CI, 1.0-1.2) 1.48 (95%CI, 1.35-1.6)

The youngest age group also had the lowest slope when plotting incidence rate versus week in September.

Authors’ Conclusions: These analyses suggest that children in this age group do not have substantial rates of SARS-CoV-2 infection during school attendance and are unlikely to play a substantial role in the spread of infection.

Comments: The study suffers from a number of limitations, e.g. there is no information on extent of symptomatic and asymptomatic testing. No raw data were provided, only ratios, there was little detail on statistical analyses. The labelling of parameters in the figures did not correspond to those in the methodology. The pattern of results could be explained by other factors such as differential testing, by differences in social behaviour not considered by the authors.

Chua, GKwan, MJAMAClinical Characteristics and Transmission of COVID-19 in Children and Youths During 3Waves of Outbreaks in Hong Kong03 May 2021Hong KongAsia397Epidemiology - Transmissionhttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779416

Methodology: A cross-sectional study of individuals under the age of 18 years with PCR confirmed SARS-CoV-2 in Hong Kong. Data was collected from 9 paediatric wards over 3 waves of COVID-19; January 23rd to March 21st, 2020, March to July 4th, 2020 and July 5th to December 2nd 2020. Information on study participants was prospectively captured in a central database by physicians included in a territory-wide paediatric COVID-19 study. Retrospective analysis of demographics, clinical characteristics and close contacts aimed to compare clinical features across the three COVID-19 waves of infection and determine the most common sources of infection.

Results: 397 children and youths were identified between January 23rd and December 2nd 2020, of which 14 were confirmed in wave 1, 118 were confirmed in wave 2 and 265 were confirmed in wave 3. 55.4% (220) of participants were males and the mean (SD) age was 9.95 (5.34). 51.4% (204) of infections within this cohort were contracted locally.

394 (99.2%) of individuals within the cohort only developed mild symptoms. Only 4.3% (17) had anosmia and 3.5% (14) ageusia in the cohort. Across the 3 waves, fever and cough was more common in the first wave (fever 71.4% (10), cough 42.6% (6)) than the second (fever 18.5% (22), cough 12.7%(15)) and third (fever 37.0% (98), cough 19.6% (52). 3 individuals demonstrated COVID-19 manifestations including toe chilblains, multisystem inflammatory syndrome (MIS-C) and steroid-dependent autoimmune haemolytic anaemia, all of which were treated successfully. No patients within the cohort developed pneumonia nor did they need oxygen or intensive care treatment.

Imported cases were more common in wave 1 (78.6%) and wave 2 (93.2%), however, in wave 3 local infections were more common (72.8%). Of the 91.2% (186) local cases who reported close contact with another COVID-19 case, 90.0% reported family members with COVID-19. Overall, 68.8% (273) of individuals reported close contact with a confirmed case of COVID-19, and of these 98.9% (270) reported family members as their close contacts. 3 individuals in the first wave, 6 individuals in the second wave and 3 individuals in the third reported close contact with an COVID-19 confirmed schoolmate. Unknown contact history was common. Within wave 1 and part of wave 2, full school closures were implemented, half school closures were implemented in part of wave 2 and parts of wave 3 and full school opening were implemented in part of wave 3.

Comment: Children and youth captured within this cross-sectional study in Hong Kong demonstrated mild illness in majority of cases. Complications namely MIS-C, chilblains and steroid-dependent autoimmune haemolytic anaemia were rare, occurring in only 3 cases that were treated successfully. Evaluation of close-contacts showed that a COVID-19 positive family member was significantly more common than classmates, however school closures were apparently for most of the study period.

Aguilera-Alonso, DCalvo, CArch Dis ChildPrevalence of thrombotic complications in children with SARS-CoV- 230 April 2021SpainEurope537Clinical - Comorbiditieshttps://adc.bmj.com/content/early/2021/05/24/archdischild-2020-321351.info

Methods: Epidemiological multicentre prospective cohort study in Spain. Included children less than 18 years with active SARS-CoV-2 or MIS-C and attended at 49 hospital from 1 March to 30 September 2020.

Thrombotic complications were defined as any radiologically confirmed thrombosis, arterial or venous, occurring close to the diagnosis of SARS-CoV-2 infection (up to 3 weeks).

Results: 537 children diagnosed with SARS-CoV-2. 368 (68.5%) were hospitalised. 58 (10.8%) cases required PICU. Forty-seven (8.8%) cases were diagnosed with MIS-C. Anticoagulant drugs (heparin in all cases) were administered to 29 (5.4%) patients: as prophylaxis in 24 (82.8%) cases, and as treatment in 5 (17.2%) cases. Most of the patients on thromboprophylaxis had severe COVID-19. Four cases (0.7%) out of the global cohort, developed thrombotic complications. Three out of these four patients were adolescent girls. None of the cases was diagnosed with MIS-C. Two patients (patients 1 and 2) had several significant thrombotic risk factors. Patients 3 and 4 did not have any previous personal or family risk factors for thrombosis. However, patient 3 was diagnosed later with lupus anticoagulant. The only patient receiving thromboprophylaxis before thrombosis was patient 2. D-dimer levels were severely increased in patients 1 and 4. All cases had thrombosis affecting the limbs, with cerebral venous sinus thrombosis and pulmonary embolism in one of them. All patients were treated with heparin and discharged without sequelae.

Discussion: Prevalence of thrombosis is slightly higher than that previously described in hospitalised children without COVID-19. Only two of our four cases had significant thrombotic risk factors, highlighting the difficulty of predicting thrombotic complications in children with COVID-19 to initiate anticoagulant prophylaxis.

Thrombosis is very uncommon in patients under 18 years old, and systemic anticoagulant prophylaxis may have adverse events that outweigh its benefit.

The authors conducted a systematic search to review reported paediatric patients diagnosed with COVID-19 infections with any thrombotic complication. Ten cases were found; one of them is already included in this cohort. Three (3.8%) and four (2.2%) cases diagnosed with MIS-C from two other national cohorts developed a venous thrombosis.

In this cohort, 8 of 169 (40.2%) had a D-dimer value >1500 μg/L. However, only 2 of 68 (2.9%) cases developed a thrombotic complication. Therefore, the use of the D-dimer value is not specific enough to make decisions regarding anticoagulant prophylaxis in children.

In the authors opinion, other factors, such as the age, coexistence of risk factors, or MIS-C diagnosis, should be considered when initiating anticoagulant prophylaxis in children with COVID-19.

Limitations: As some children were diagnosed on basis of serology rather than PCR, it is unclear if these cases were related acute infection. On patient was both negative on PCR and serology, so it is unclear on which basis the diagnosis was made. Additionally, since ultrasound was not routinely performed in all patients, subclinical thrombosis may not have been diagnosed.

Conclusion: Except in the MIS-C, unlike adults, thrombotic complications seem very uncommon in children with SARS-CoV-2. Adolescence and previous thrombotic risk factors may be considered when initiating thromboprophylaxis in children with COVID-19.

Thielecke, MMockenhaupt, FPEur J Public HealthSARS-CoV-2 infections in kindergartens and associated households at the start of the second wave in Berlin, Germany - a cross sectional study6 May 2021GermanyInternational155Epidemiology - Transmissionhttps://academic.oup.com/eurpub/advance-article/doi/10.1093/eurpub/ckab079/6270920

Methods: Cross-sectional study carried out in Berlin between September 28 and October 2, 2020. Twelve out > 2700 kindergartens were randomly chosen to assess the prevalence of SARS-Cov-2 infections and IgG seropositivity among preschool children, educators and household contacts, during the beginning of the local second wave of the COVID-19 pandemic. For the selection of the study sites, each local district was stratified by socioeconomic status. From each stratum, two districts were randomly selected, and from them two kindergartens were randomly chosen. Where feasible, 20 children and 5 staff were recruited from each kindergarten; their household contacts were also invited to participate.

Research staff visited each study site, interviewed and examined the study participants, collected finger prick blood samples, as well as swabs from the nasal vestibules and oropharynx. Household contacts self-collected their swabs and took them to mobile clinics set up off the kindergartens for this study. Five self-reported ill participants were visited at home.

Results; Seven-hundred and twenty participants were assessed (155 pre-school children, 78 educators and 487 household members). The children’s age ranged between 1 and 6.3 years old (median 4.4 years old); 40% were female (60/150); 24.2% (4/152) had one or more current symptoms suggestive of COVID-19, and 57.0% (73/128) had at least one symptom compatible with this illness in the previous two weeks. Educators were mostly females 86.8% (66/76), aged between 18 and 78 years old (median: 44 years old).A third of them had current signs and/or symptoms of COVID-19 (28.9%; 22/76) and 74.6% (50/67) a history of symptoms of this disease in the previous two weeka. Household members were aged between 0 and 90 years (median: 36 years old); 58.4% (215/368) had a history of any symptoms in the preceding two weeks, but none were symptomatic at enrolment. Physical distance between staff (8/12) and between staff and parents (11/12), obligatory facemask wearing by staff for contacts (5/12) and for contacts among colleagues (1/12) were implemented in accordance with local regulations. Daily training on good hygiene practices against COVID-19 were reported in most facilities, and attendance irrespective of upper respiratory symptoms was allowed in ¾ of the surveyed centres.

While IgG antibodies against SARS-Cov-2 were detected in one kindergarten worker (1 /672 samples) who denied a current or past history consistent with COVID-19 infection, no nasal and oropharyngeal swabs were positive for SARS-Cov-2 (samples were collected from 152/155 children; all educators and 471/487 household contacts).

Comment: during the study period no SARS-Cov-2 infections were detected in kindergarten children during the beginning of the second wave of community transmission in Berlin. Although there was no evidence of SARS-Cov-2 transmission within these schools at the time of the assessment, outbreaks in these and similar settings may occur. These findings reinforce the importance of good hygiene and other transmission mitigation practices, frequent testing and vaccination of educators and school staff.

Fontanet, AHoen, BEuropean communicable disease bulletinSARS-CoV-2infection in Schools in a Northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 202015 April 2021FranceEurope749Epidemiology - Transmission https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.15.2001695

This retrospective observational study undertaken in Northern France in early 2020 involved 664 participants from a high school and 1,340 participants from 6 primary schools. This was a time when there was unsuspected SARS-CoV-2 circulating in the general population and there were limited control measures. 239 children from the high school (8 <12 years of age, 235 age 12-17years) and 510 children from the six primary schools in the region had blood taken for serological analysis. Serological investigations were also undertaken in staff from the schools (80 high school staff and 69 primary school) and parents and relatives (345 high school, 761 primary school).

All school staff, as well as pupils and their parents and relatives were invited to complete a questionnaire covering symptom history since 13 January 2020.

In the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils’ parents and relatives (p < 0.001).

In the primary school, infection attack rates were 8.8% (45/510), 7.3% (3/41) and 3.6% (1/28), in pupils, teachers and none teaching staff respectively vs 11.8% (76/642) and 7.1% (1/14) in the pupils’ parents and relatives (p>0.1).

In the primary schools overall, antibody prevalence in pupils sharing classes with symptomatic cases was higher than in pupils from other classes: 15/65 (23.1%) vs 30/445 (6.7%) (p < 0.001). Among 46 SARS-CoV-2 seropositive pupils < 12 years old, 20 were asymptomatic. There was no evidence that past HKU1 and OC43 seasonal coronavirus infection protected against SARS-CoV-2 infection in 6–11 year olds.

In the authors discussion of their results, they make several comments. Firstly, while the high school experienced a noticeable outbreak of symptomatic infections, the circulation of the virus in the primary schools was partly silent, with a large proportion (43.5%) of asymptomatic infections among children under 12 years old.

Secondly, parents and relatives of infected pupils were more likely to be infected compared with those of non-infected pupils, particularly for families of primary school pupils.

Thirdly, infected children less than 12 years of age experienced mild forms of disease, with no specific symptoms, or were asymptomatic, whilst teenagers and adults experienced similar forms of disease. Adults and children developed neutralising antibodies at a similar rate, with a higher proportion of those with neutralising antibodies among symptomatic compared with non-symptomatic participants.

Finally, past infection with seasonal coronavirus HKU1 and OC43 was very common (>95% of primary school-aged children), precluding the possibility of studying any effect of past infection with these two coronaviruses on the risk of acquiring SARS-CoV-2 infection.

The authors conclusions are “Our investigations identified SARS-CoV-2 circulation in both a high school and primary schools at the very early onset of the pandemic, in a context of unsuspected circulation in the community and absence of control measures. Decisions to reopen or close schools should be considered carefully in the context of the extent of transmission in the wider community. Ongoing monitoring for possible resurgence in infections would be needed, as well as strategies to limit transmission in the school setting, including testing of all those with symptoms, rapid isolation of cases and quarantine and testing of contacts, hand hygiene, physical distancing, respiratory etiquette, cohorting of classes, and the wearing of masks for older pupils.”

Osmanov, I. M.Munblit, DMedrxivRisk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study.26 Apr 2021RussiaAsia518Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.04.26.21256110v1

This article is a pre-print and has not yet been peer reviewed.

Telephone follow up study of persisting symptoms in 518 children from a cohort of 853 SARS-CoV-2 RT PCR positive cases admitted to a tertiary hospital in Moscow, Russia, between 02/04/20-26/08/20. Median age (IQR), 10.4 years (3-15.2). 55.2% female. Median interval (IQR) to the follow up call, 256 days (223-271). Parents of 24.3% of the children reported persisting symptoms. The commonest were fatigue (10.6%), sleep disturbance (7.2%), sensory problems (6.2%), GI disturbance (4.4%) and non-eczematous dermatological problems (3.6%). 8.5% reported symptoms from >1 category, of which the commonest combination was fatigue and sleep disturbance. Multivariate logistic regression of demographic features, pre-existing conditions and features of the initial Covid illness identified age 6-11 years or 12-18 years and allergic disease as significant predictive factors for persisting symptoms. The most significant weaknesses of this study is the lack of any matched control data on persisting symptoms in non-Covid cases admitted to hospital, since hospitalization itself can trigger psychological/psychosomatic features in children.

Kushner L EMathew RHosp. Pediatr.“For COVID” or “With COVID”: Classification of SARS-CoV-2 Hospitalizations in Children18 May 2021USANorth America117Epidemiology - Disease Burdenhttps://hosppeds.aappublications.org/content/hosppeds/early/2021/05/18/hpeds.2021-006001.full.pdf

This short reports aims to assess the impact of incidental findings of SARS-CoV-2 positivity on hospital metrics for “hospitalisations” of children with COVID-19. They set out to establish a method of characterising admissions as being “likely”, or “unlikely” to have COVID-19

The authors also wondered what the interrater differences might be in both the existing hospitalisation categorisations and their novel “likely” and “unlikely” to have COVID-19 categorisation they advance.

They retrospectively assessed children hospitalised to the Santa Clara County Department of Public Health (DPH), a quaternary care children’s hospital in Northern California, during the period May 10, 2020 to February 10, 2021 and who had undergone universal testing for SARS-CoV-2 including children readmitted after 90 days of the first admission and children negative to SARS-CoV-2 at admission but who became ill or deteriorated with it later on the ward.

The hospital established infection by a positive result of SARS-CoV-2 RNA via real-time reverse transcriptase polymerase chain reaction (rtPCR).

The authors then looked at the previously published categorization system that classified patients as either asymptomatic, mild/moderate, severe, critical, or the Centers for Disease Control and Prevention (CDC) definition of multisystem inflammatory syndrome in Children(MIS-C). Using information from the children’s admission notes and discharge notes, the authors recategorized each of the above stems into “likely” or “unlikely” to have required admission based on severity of SARS-CoV-2 infection.

They gathered 117 children in the cohort most of whom were Hispanic/LatinX 83(70.9%), followed by White Non-Hispanic 13(11.1%) and Asian 11(9.4%) and a few Native Hawaiian/ Pacific Islander (3) and Black/African American (2). There were about equal numbers of boys and girls and the age range was 1.5years to 18 years.

By the previously published categorisation for SARS-CoV-2, the authors found that 15(12.8%) were critical cases with nearly 100% interrater agreement that SARS-CoV-2 infection was correct (one case in critical care for respiratory failure after cardiac surgery, asymptomatic for SARS-CoV-2 at admission but positive later with worsening symptoms while hospitalised). 14 cases(12%) were SARS-CoV-2 MIS-C cases with 100% interrater agreement, 9(7.7%)severe cases, 33(28.2%) mild / moderate cases. There were 46(39.3%) asymptomatic admissions with interrater agreement of just below 95% (kappa 0.85%).

On the “likely/unlikely” to have SARS-CoV-2 yardstick for admitting the children to hospital, they found SARS-CoV-2 should have likely been the cause of admission in 64 (54.7%, 95% CI 45.2 – 63.9%) patients and unlikely in 53 (45.3%, 95% CI 36.1 – 54.8%) patients.

Using this method of determining necessity of admission for SARS-CoV-2, a number of cases would have been overlooked. 5/33 (15%) of the mild/moderate cases admitted for SARSCoV-2 would have been counted as admitted for other than SARS-CoV-2, 3/9 (30%) of severe cases but 44/46(96%) of asymptomatic cases would have been excluded from those admitted due to SARS-CoV-2 infection. The researchers’ interrater agreement was 89% (kappa 0.78). Examples of causes of interrater differences occurring included brief resolved unexplained respiratory episodes (BRUES), new/worsening seizures, and SARS-CoV-2 negative at admission but symptomatic while hospitalised.

The authors conclude that both the existing and the possible novel hospitalisation categorisations are adequate even if not perfect. They however acknowledge that more and more is being learnt about clinical manifestations of SARS-CoV-2 (specificity may thus be achieved in the future). The authors also point to clinical symptoms common between SARS-CoV-2 and other diagnoses possibly contributing to the blurring of differentiation of SARS-CoV-2 as reason for admission when “likely”/ “unlikely” to have SARS-CoV-2 were applied as admission category for this cohort.

This report is seeking a more accurate and fair enumeration of SARS-CoV-2 disease burden in children that does not socially and educationally disadvantage them. However, there are limitations in the report for a number of reasons. Firstly, the likely /unlikely to have SARS-CoV-2 categorisation would currently have to be applied with hindsight. Secondly, this report was a situation analysis and the sample size was small. The results give an indication that incidental findings of SARS-CoV-2 positivity in hospital admissions may be an important consideration in interpreting hospitalisation metrics. The methods utilised by the authors for determining this may not be generalizable to others settings.

Verberk, JBruijning-Verhagen, PMedRxivTransmission of SARS-CoV-2 within households: a prospective cohort study in the Netherlands and Belgium – Interim results26 Apr 2021Belgium and NetherlandsEurope00000000000Epidemiology - Transmissionhttps://www.medrxiv.org/content/10.1101/2021.04.23.21255846v1.full

This pre-print report describes a detailed study of selected households in the second wave of the pandemic, in September-December 2020. Whenever there was a positive PCR test for SARS-CoV-2, all other household members underwent serial testing with PCR swabs, and dried blood-spot antibody testing. Infants under 2 also had stool PCR tests. Symptoms were also reported daily. This continued for about 40 days. They were thus able to estimate secondary attack rates (SAR) for their community.

They recruited 117 households (20 in Belgium, 97 in the Netherlands), involving 117 index cases and 265 household members. Some interesting results emerged, confirming what has been found elsewhere. From the index cases, 74 secondary infections were confirmed, giving a household SAR of 44%. Of these, 20 (27%) were detected by seroconversion only without PCR, and 13 (18%) were asymptomatic. Not surprisingly, index cases with acute respiratory symptoms were more infectious to their co-habitees (SAR 52%, vs SAR 22% for those with mild symptoms). Transmission occurred early, with 2/3 household contacts being already infected at recruitment. More transmission occurred in larger households.

Of more significance to paediatricians was the confirmation that children were much less infectious than adults: child-to-parent SAR was only 9%, compared to parent-to-child SAR of 28%, and adult-to-spouse SAR of 36%.

With near-universal antibody testing, they were able to establish that only 78% of those with PCR-confirmed infection developed antibodies: which raises doubts about how much protection is afforded by natural infection, and is further confirmation that vaccination is required for everybody.

There are some potential flaws to this study, which has not yet been peer-reviewed. The families may not have been typical: many were health-care workers; specimens were taken by families and may have been unreliable; the index cases may in fact have been secondary, with the true index undetected initially; some may have been infected outside the household.

Most importantly, this study was done before either the arrival of new variants that are known to be far more transmissible, or the introduction of mass vaccination, therefore the generalisability of the findings may be limited.

Rosen HYinon YJ Clin MedFetal and Perinatal Outcome Following First and Second Trimester COVID-19 Infection: Evidence from a Prospective Cohort Study16 May 2021IsraelMiddle East29Neonatalhttps://doi.org/10.3390/jcm10102152

There have been a number of published studies, including systematic reviews, reporting on the outcomes for mother and foetus of pregnancies in which the mother contracted Covis-19 infection. In these studies a large proportion of the infections were diagnosed in the last trimester of pregnancy. This paper from Israel reports on a prospective, single-tertiary-centre, study of pregnant women who developed evidence of SARS-CoV-2 infection in the first two trimesters of pregnancy.

The majority of women were identified either because they had symptoms of SARS-CoV-2 infection or they were contacts of cases; three were diagnosed as a result of routine testing prior to amniocentesis. The diagnosis of SARS-CoV-2 infection was based on a positive result on real-time reverse-transcriptase polymerase chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens.

The study protocol included serial sonographic examinations every 4–6 weeks to assess foetal well-being, growth, placental function, foetal anomalies and signs of foetal infection; amniocentesis was offered to assess amniotic fluid SARS-CoV-2-PCR (polymerase chain reaction) and foetal brain magnetic resonance imaging (MRI) was offered at 30–32 weeks gestation. Perinatal outcomes were recorded. Demographic, obstetric and neonatal data were collected from history intake, medical charts or by telephone survey.

The study recruited 55 pregnant women with laboratory-proven SARS-CoV-2 infection contracted prior to 26 weeks gestation; 51 of the pregnancies were singleton pregnancies and four were twin. The mean maternal age was 29.6 +/-6.2 years. The infection was diagnosed in the first trimester in 28 of the women and in the second trimester in 27. The clinical illness severity was classified as “asymptomatic “or “mild” in 54, although six developed respiratory symptoms which led to hospital admission for observation. One woman developed severe myocarditis after recovery from the SARS-CoV-2 and was reported to have made a full recovery from the myocarditis.

Of the 22 who underwent amniocentesis none had evidence of SARS-CoV-2 in the amniotic fluid. Serial targeted sonographic scans were performed in 38 women and major fetal anomalies were identified in two; it was not possible to determine whether these resulted from SARS-CoV-2 infection. Five MRI scans were performed, all of which were reported to be normal.

A summary of the main finding of the study is as follows:

- there was no evidence of vertical SARS-COV-2 transmission from amniotic fluid PCR testing or cord blood serology at delivery

- there was no evidence of adverse foetal effects on serial ultrasound anatomy scans

- no increased rates of obstetric complications were found

- most deliveries occurred at term and birthweights were appropriate for gestational age

- neonatal outcome was overall reassuring.

-there was no significant difference for the above outcome measures when comparing first to second trimester infections.

While the outcome data from this study are reassuring, the sample size is small and only 29 of the pregnancies had reached term at the time of submission for publication. More precise estimates of the risks associated with maternal Covid-19 contracted during the first two trimesters of pregnancy must await the completion of larger-scale studies which are currently in progress.

Loenenbach, ABuchholz, UMedrxivSusceptibility and infectiousness of children and adults with SARS-CoV-2 variant B.1.1.7 deduced from three daycare centre outbreaks and related household situations; Germany, 202117 MAY 2021Germany Europe47Epidemiology - Transmissionhttps://doi.org/10.1101/2021.05.12.21256608

The authors investigated three SARS-CoV-2 variant B.1.1.7 kindergarten outbreaks in Germany and related household situations, a total 47 out of 171 children were affected. Despite group cohorting, cases occurred in almost all groups, i.e. also among persons without close contact. Secondary attack rates (SAR) of children were similar to adults (day care: 23% vs. 30%; p=0.15; households: 32% vs. 39%; p=0.27), and also child-induced household outbreaks led to similar SAR compared to adults.

In summary, the author’s investigation confirms increased transmissibility of B.1.1.7. In addition, the data presented suggest that both susceptibility and infectiousness of children 1-5-years-old is substantially higher compared to the pre-Variant of concern era, and may be converging to those among adults.

Angelidou, A Belfort, MJAMA Network Open.Association of Maternal Perinatal SARS-CoV-2 Infection With Neonatal Outcomes During the COVID-19 Pandemic in Massachusetts23 Apr 2021USANorth America250Neonatal https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779051
Havers, FTaylor, CMMWRHospitalization of Adolescents Aged 12–17 Years with Laboratory-Confirmed COVID-19 — COVID-NET, 14 States, March 1, 2020–April 24, 202111 Jun 2021USANorth America376Epidemiology - Disease Burdenhttp://dx.doi.org/10.15585/mmwr.mm7023e1

This Early Release Report is an analysis of data collected by the Coronavirus Disease 2019 - Associated Hospitalization Surveillance Network (COVID-NET), relating to hospital admissions of young people aged 12-17 years with COVID-19. In this report, data from 1 January 2021 to 31 March 2021 are analysed in detail and then compared to data and trends from 1 March 2020 to 24 April 2021.

Between 1 January and 31 March 2021, 376 adolescents with a positive SARS-CoV-2 test result were hospitalised and notified to the COVID-NET registry, which covers 14 US states and approximately 10% of the population of that country. Of these, 172 (45.7%) were analysed separately because their primary reason for admission was not directly COVID-19–related.

Among the 204 patients who were admitted primarily for COVID-19–related illness 52.5% were female, 31.4% were of Hispanic heritage and 35.8% were of non-Hispanic Black heritage. 31.4% of these patients required ICU admission and 4.9% required mechanical ventilation. There were no deaths.

Among the patients admitted primarily for COVID-19–related illness, 70.6% had one or more underlying medical conditions, which included obesity (35.8%) chronic lung disease including asthma (30.9%) and neurologic disorders (14.2%).

Between March 2020 and April 2021, weekly COVID-19–associated hospitalisation rates among adolescents, peaked at 2.1 per 100,000 in early January 2021, declined to 0.6 in mid-March, and then rose again to 1.3 in April. The overall rate was 12.5 times lower than in adults aged over 18 years, but higher than in children aged less than 12 years.

Rates of COVID-19–associated hospitalisation among adolescents were also 2.5–3.0 times higher than rates of seasonal influenza-associated hospitalisation during comparable periods.

The authors conclude that although COVID-19–associated hospitalisation rates in adolescents in the USA are lower than in adults, nevertheless severe disease does occur, including that requiring ICU admission and mechanical ventilation. They point out the frequent occurrence of underlying illness in these hospitalised adolescents. They also emphasise that two thirds of adolescents hospitalised with COVID-19 were of Hispanic or non-Hispanic Black heritage, although they do not identify reasons for the disparity in hospitalisation rates between different ethnic groups.

This authors also point out that the Pfizer-BioNTech COVID-19 vaccine was administered to some adolescents aged 16–17 years during this study period, which may have modified hospitalisation rates amongst adolescents in that age band, as well as the overall hospitalisation rate for all adolescents.

Lu, LTambayah, P AJ Infect DisRole of Asymptomatic Children in Community Severe Acute Respiratory Syndrome Coronavirus 2 Transmission16 Mar 2021SingaporeAsia16Epidemiology - Transmissionhttps://academic.oup.com/jid/article/223/10/1834/6174435

This Singapore-based study investigated the role of children in the transmission of SARS-CoV-2 and found no evidence of children acting as a community reservoir of infection.

The authors recruited SARS-CoV-2 positive families with asymptomatic children (within which they included symptomatic children who had a negative swab). Families were designated as “linked” households, being those with confirmed epidemiological links to other cases, or “unlinked” households, being those with no discernible link to other cases after contact tracing. The authors hypothesised an excess of SARS-CoV-2 positive children in the “unlinked” households, if children were acting as a community reservoir of infection.

The study included 16 children from 12 households, all under 12 years. These comprised 9 “linked” households and 3 “unlinked”. All were tested for SARS-CoV-2 infection by pharyngeal swab PCR as well as having convalescent serology at least 3 weeks after index case diagnosis. The 2 groups were well matched other than that the time between index case diagnosis and serological testing was significantly longer in the “linked” vs “unlinked” households.

8 of 9 “linked” households had children who tested positive for SARS-CoV-2 (either on PCR or serology). None of the children in the “unlinked” households tested positive. The data in this study suggests children were not acting as a community reservoir of infection. The findings are encouraging in this respect, although limited by sample size.

Snapiri, OBilavsky, EPediatr Infect Dis JTransient Cardiac Injury in Adolescents Receiving the BNT162b2 mRNA COVID-19 Vaccine20 May 2021IsraelMiddle East7Clinical - Clinical Features https://journals.lww.com/pidj/abstract/9000/transient_cardiac_injury_in_adolescents_receiving.95800.aspx

Israel led the world in instituting mass vaccination early in 2021, using mainly the Pfizer BioNtech mRNA vaccine BNT162b2. The population vaccinated included those aged 16-18 years. This case series describes 7 cases of perimyocarditis, all in Jewish boys aged 16-18, all temporally related to receiving BNT162b2 vaccination 1-3 days before onset of symptoms. Data were gathered through an informal network of paediatricians at 3 centres, rather than any formal surveillance.

All cases were mild, and none had symptoms typical of Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Covid-19 infection itself can rarely cause peri/myocarditis, but all these had repeatedly negative SARS-CoV-2 PCR swabs. In 6/7 the symptoms began after their 2nd dose. All had chest pain, and some also had cough, dyspnoea and/or nausea. 6/7 had ECG features (ST segment elevations), and 3/7 had pericardial effusions on echocardiogram. CRP was at least mildly raised in all, and all had a raised troponin, markedly so in 4/7. Full investigation for other causes proved negative in all. They were all admitted to hospital, with length-of-stay ranging from 3-6 days. None required intensive care, and all appeared to make a full recovery.

All 7 were diagnosed in Jan-Feb 2021 during which time nearly 200,000 16-19-year-olds in Israel had received at least one dose, so assuming all cases were identified, the prevalence of this association must be very low. However, it seems to be higher than the background level: the same centres saw only two 16-18-year-olds, and only 11 children of any age, with peri/myocarditis in the whole of 2020, before vaccination started.

So, is there any plausible biological mechanism for this association? A number of older vaccines have been associated with rare cases of myocarditis, but all these were based on live or attenuated organisms: it seems less likely that mRNA, which should not disseminate beyond the injection site, could provoke an inflammatory response in a remote organ. No putative mechanism is suggested here.

Nonetheless there have been a number of reports of similar associations in recent months, mostly in young adult men and with good outcomes (doi:10.1001/jamacardio.2021.2821). In the US, the CDC has acknowledged a possible association but in the UK the MRHA are still monitoring the situation (doi: 10.1136/bmj.n1635). It may become a factor in the JCVI’s difficult decision on vaccinating secondary school-age children.

Kompaniyets, LGoodman, AJAMA Network OpenUnderlying medical Conditions Associated with Severe COVID-19 Disease07 06 2021USANorth America43465Clinical - Comorbiditieshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780706

This is a large cross-sectional study done by the US CDC. The sample was 43,465 children (aged18 and under) presenting to an Emergency Department or treated as an inpatient, with a diagnosis of COVID-19 illness from a database collecting data from 872 hospitals, between March 2020 and January 2021. Demographic data is given. Outcomes considered were i) hospitalisation and ii) severe illness when hospitalised (ICU treatment, mechanical ventilation or death). The study assessed 2 exposures of interest a) specific underlying medical conditions b) medical complexity.

Result: The presence of chronic disease was significantly associated with hospitalisation and severe disease, and complex chronic disease even more so.

The cross-sectional analysis showed that children with type1 DM, cardiac and circulatory congenital anomalies, obesity, essential hypertension, epilepsy, neuro-psychiatric disorders and asthma, as well as children with chronic disease were at an increased risk of hospitalisation or severe COVID-19 illness. Over half the children were 12-18 and sub analyses of different age groups give different results eg prematurity being associated with increased risk of hospitalisation or severe disease in children of 1 or under. 28.7% of the sample had 1 or more underlying conditions but this rose to 62.9% of the hospitalised children.

Asthma was the most frequent diagnosed condition significantly associated with hospitalisation (risk ratio 1.23) but not severe disease. Thus, the role of asthma in severity of infection both in adults and children remains unclear.

Comment: Previous small studies have suggested that being younger than 1 year, or having an underlying health condition such as congenital heart disease, asthma, obesity, diabetes or neurological conditions are risk factors for more severe COVID-19 disease. This study, with its large sample, provides strong evidence of many of these risk factors.

Interestingly it finds neuro-psychiatric conditions (including ADHD, autism, anxiety, depression) carry a higher risk of hospitalisation but not severe disease and the authors speculate that this may be for family support or lack of other input during the pandemic.

Race/ethnicity data was collected but no associations are commented on.

The authors list the limitations of this study:

• misclassifications or underestimations may have occurred (e.g., 2.5% of the sample and 10.2% of hospitalised children had an obesity diagnosis but 18.5% of children in US are obese).

• The only indicator of socio-economic status was payer type

• Only children presenting to a hospital were included in the sample, and so are not representative of all children with COVID-19

• This analysis was limited to frequent chronic conditions which may have led to the omission of acute or rare conditions that are risk factors for severe COVID-19 illness

Brotons P Muñoz-Almagro CClin Infect DisSusceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Children and Adults: A Seroprevalence Study of Family Households in the Barcelona Metropolitan Region, Spain15 June 2021SpainEurope672Epidemiology - Transmissionhttps://academic.oup.com/cid/article/72/12/e970/5979490

This is a cross-sectional seroprevalence study conducted in Barcelona, Spain assessing the susceptibility of household contacts to SARS-CoV-2 infection. The study was conducted between 28th April and 3rd June 2020 when there was a strict home quarantine order in place in Barcelona.

The study included 381 volunteer households who reported an adult index case (SARS-CoV-2 positive on RT-PCR) during the study period. Within these households, there were 672 child contacts (under 15 years) and 412 adult contacts. Participants had serology tests (lateral flow assays) performed 3–12 weeks after the first-reported case.

Based on this household serological study, children appear to have similar susceptibility to SARS-CoV-2 infection as adults. 17.5% of children and 18.7% of adult contacts tested positive for SARS-CoV-2 antibodies. The vast majority (99.9%) of positive child contacts reported no or very mild symptoms.

This study has the advantage that contacts were confined to their houses, therefore, both adult and child participants experienced similar conditions and exposure to infection. One limitation is the relatively low sensitivity of lateral flow assays which were chosen for ethical and pragmatic reasons.

Somekh, ISomekh, EPediatr. Infect. Dis. J.INTRAFAMILIAL SPREAD AND ALTERED SYMPTOMATOLOGY OF SARS-COV-2, DURING PREDOMINANT CIRCULATION OF LINEAGE B.1.1.7 VARIANT IN ISRAEL10 06 2021IsraelEurope72Epidemiology - Transmissionhttps://journals.lww.com/pidj/Abstract/9000/INTRAFAMILIAL_SPREAD_AND_ALTERED_SYMPTOMATOLOGY_OF.95798.aspx

This study measured the secondary attack rate (SAR) of SARS-CoV-2 in household clusters in Bnei Brak, a "young and crowded" city in Israel from January-February 2021 (during which time B 1.1.7 had become the predominant circulating variant locally). All household members of a positive case underwent PCR testing regardless of symptoms.

The study included 15 family clusters: 11 with an adult index case, 4 with a child index case (17.5 yo, 13.5 yo, 13yo and a 6yo). Of 98 household contacts, 76 (78%) were infected. The SAR was highest in adults contacts (90.4%) followed by children 6-17 yo (75%) and children 0-5yo (72%). The SAR in these 2021 clusters was higher than the SAR amongst 37 clusters in the same region during April-May 2020 (59% in adults, 32.5% in 6-17yo and 11.8% in 0-5yo). Infection was either mild (53%) or asymptomatic (47%) in children 0-17yo (n=68).

The results of this small study are consistent with data from the UK and elsewhere, demonstrating that the increased transmissibility of the B 1.1.7 variant across all age groups, including children. The higher SAR seen in young children in this setting compared with data from the UK may be due to the crowded living conditions in Bnei Brak. Reassuringly all infections in children in this study were mild or asymptomatic.

Fraley, ABradley, TCell. Mol. Immunol.Cross-reactive antibody immunity against SARS-CoV-2 in children and adults31 May 2021USANorth America86Clinical - Clinical Featureshttps://doi.org/10.1038/s41423-021-00700-0

Previous studies have provided some evidence that children may have a higher degree of pre-existing cross-reactive immunity to SARS-CoV-2 which protects them from severe infection. This study aimed to explore whether children have a higher pre-existing cross-reactive immunity to SARS-CoV-2 compared to adults.

METHODS: IgG antibody responses to SARS-CoV-2 nucleocapsid protein (NP) and three spike protein subunits (S1, S2 and receptor binding domain (RBD)) were measured.

Subjects:

44 adults of diverse age, sex and race/ethnicity, mostly Hispanic who had a positive SARS-CoV-2 PCR test in the previous 2-133 days, none of whom had been hospitalised.

44 healthy adults recruited in early 2019 not previously exposed to SARS-CoV-2, all female, ethnicity unknown.

86 children recruited in 2016 / 2017 prior to the COVID-19 outbreak: 17 aged 0-1 year, 37 aged 2-10 years and 32 aged 11-15 years.

Detection threshold was defined as 230 MFI (sum of the average and standard deviation of the highest negative control beads without antigen). When comparing pre-existing immunity in the different age groups the average MFI values in the non-exposed group plus the standard deviation was used for each viral antigen. High resolution mapping of antibody epitopes was carried out using overlapping peptide microarrays covering fully the SARS-CoV-2 spike protein.

RESULTS:

SARS-CoV-2 PCR positive group: All had positive IgG to S2 and RBD, 38 also to NP and 41 also to S1.

SARS-CoV-2 non-exposed adults and children: 41/44 adults and 57/86 children had detectable IgG antibodies against the SARS-CoV-2 spike S2 subunit. 41 adults and 46 children had detectable antibodies to NP. Pre-existing immunity to the S1 antigen was rarely detectable (1 adult and 3 children). Levels of SARS-CoV-2 antibodies in adults and children were, on average, an order of magnitude lower than those soon after natural infection.

Age comparisons of pre-existing immunity in non-exposed: 6% (1/17) aged 0-1 year had IgG-RBD antibodies, there were no other positive responses to S1, S2 or NP. Adults and children aged 2 and over had similar positivity rates: in adults between 13.6% and 18.3% for the S1, S2, and RBD and NP antigens, in children between 16% and 12.8% for S2 and RBD but a lower frequency of antibodies to S1 and to NP (averaged 3.2%).

High resolution of antibody epitopes: this was carried out in 14 SARS-CoV-2 PCR positive adults at an average of 25 days after a PCR positive result, 7 non-exposed adults and 7 non-exposed children.

Immunodominant regions in the S1 subunit, S2 subunit and RBD were found in both SARS-CoV-2 PCR positive group and the non-exposed individuals. The sequences of these peptides are conserved among closely related and emergent group B coronaviruses such as SARS-CoV-1 but not group C beta-coronaviruses such as Middle Eastern Respiratory Syndrome (MERS).

11 peptides were found with significantly higher binding in the SARS-CoV-2 PCR positive group compared to the non-exposed group. 28 other peptides showed significantly higher binding in the non- exposed group compared to the SARS-CoV-2 PCR positive group.

CONCLUSIONS: SARS-CoV-2 non-exposed adults and children above the age of 2 years had similar detectable IgG cross-reactive antibodies to SARS-CoV-2 viral antigens, with the highest responses to S2, RBD, and NP and rare responses to the S1 subunit. Infants aged 0–1 year old did not have detectable cross-reactive antibodies. These results identified regions in the spike protein that are commonly recognized by antibodies from SARS-CoV-2-infection or SARS-CoV-2 cross-reactive antibodies in non-exposed individuals and could serve as a guide for future vaccine design.

Comments: the report of pre-existing cross-reactive antibodies to SARS-CoV-2 was interesting. These were found in broadly similar proportions in unexposed children and adults. This finding did not support their hypothesis that these might exist preferentially in children, protecting them from severe COVID-19 disease. This could have been addressed more fully in the discussion of their results. There was instead some conjectural discussion on the potential use of the epitopes found in the high resolution peptide array for vaccine development, which probably falls outside the scope of the study as there were no data related to their role in protection from infection or from severe disease.

Gandini, SScorrano, LLancet Reg Health Eur 5: 10009A cross-sectional and prospective cohort study of the role of schools in the SARS-CoV-2 second wave in Italy26 Mar 2021ItalyEurope7376698Epidemiology - Transmission https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(21)00069-7/fulltext

A cross-sectional prospective study of SARS-Cov-2 infections in schools in Veneto region, between 30/09/20 and 28/02/21, during Italy’s 2nd wave of SARS-CoV-2, covering 7976 schools, 7.4M students, 0.77M teachers and 0.2M non-teaching staff. SARS-CoV-2 incidence was lower amongst students than the general population, whereas incidence in teachers was similar. Secondary cases occurred after 1% of school cases and were more likely if the case was a teacher. Clusters of ≥2 secondary cases occurred in 5-7% of schools. In 2 regions, school closures preceded other measures to contain the 2nd wave but this did not affect the rise in cases when compared to regions which closed schools later. This study does not support a role for schools as a driver for the 2nd Covid-19 wave in a large region of Italy.

Cendejas-Bueno ESARS-CoV-2 Working GroupJ InfectLower nasopharyngeal viral loads in pediatric population. The missing piece to understand SARS-CoV-2 infection in children? 13 Jun 2021SpainEurope126Epidemiology - Transmissionhttps://www.journalofinfection.com/article/S0163-4453(21)00289-9/fulltext

This retrospective study compared the relative viral loads of SARS-Cov-2 in positive nasopharyngeal swabs from children under 17 years old, and adults. The samples were obtained between July and December 2020, during the second and third waves of the COVID-19 pandemic in Madrid, Spain. The samples were re-tested by RT-PCR and the comparative DCt method. They corrected their results dependent on the amount of human RNAse P in the sample – a measure of human tissue which allows comparison depending on sample quality (more nasal epithelial cells present imply a higher quality sample).

One-hundred and twenty-seven samples from adults, and 126 from children (35 from 0 to 5 years old;36 from 6 to 11 years old and 55 from 12 to 17 years old) were recovered. The average viral load was lower in the samples from paediatric patients, compared to those obtained in adults. One fourth of the children had viral loads lower than the fifth percentile of the adult population.

Of note – the levels of RNAse P were much more consistent across the paediatric samples than adult samples, showing that sampling was performed better in children than adults. The authors suggest this might be due to the smaller size of childrens nasal passages compared to adults, allowing swabs to spend more time in contact with the mucosal lining. This provides evidence contrary to the common opinion that lower rates or viral loads are sometimes found in paediatric samples due to poor quality sampling.

Because most of the samples were sent from primary care centres, the authors did not have access to clinical records. Furthermore, most of these patients were followed -up by their primary care providers and therefore, it was assumed that they had mild to moderate symptoms or were asymptomatic.

Ladhani, SRamsay, M.EClinialMedicineSARS-CoV-2 infection, antibody positivity and seroconversion rates in staff and students following full reopening of secondary schools in England: A prospective cohort study, September–December 202009/06/2021EnglandEurope1189Epidemiology - Transmissionhttps://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00228-5/fulltext?rss=yes#seccesectitle0001

Introduction: This is a prospective cohort study of secondary school students and teachers across geographical locations in England, who had SarsCoV2 PCR and antibody testing in September 2020 (Round1) and December 2020 (Round 2). These two time frames represented the start and end of new school term.

Methods: Schools were recruited where a paediatric investigation team could be assembled: Derbyshire, West London, East London, Greater Manchester, Hertfordshire and Birmingham. Schools were open for in person schooling with national guidance for infection control measures, including reducing in after school activities, and mask wearing in communal areas, but not in classrooms. Consent was taken from students, parents and staff. Participants completed a questionnaire, head teachers provided information on school bubbles etc. participants had a nasal swab and a blood test taken.

Results: In round 1, there were 1,825 participants, 948 (51.9%) students and 877 (48.1%) staff. In round 2, 367 participants did not return for their second test (239 [25.2%] students, 128 14.6%] staff) and 384 new participants (241 students, 143 staff) were enrolled, resulting in 1,842 participants (950 [51.6%] students, 892 [48.4%] staff) in round 2.

PCR positivity rates were not significantly different between students and staff between Round 1 (5/948; [0.53%] vs. 2/876 [0.23%]; p = 0.46) or round two (10/948 [1.05%] vs. 7/886 [0.79%];p = 0.63), and were similar to national prevalence at corresponding times.

Overall, antibody prevalence was 11.0% (193/1754; 95%CI: 9.612.6) in round 1 and 13.3% (234/1765; 95% CI: 11.714.9;p = 0.041) in round 2.

In round 1, antibody positivity was higher in students (114/893 [12.8%], 95% CI: 10.615.1) than staff (79/861 [9.2%], 95% CI: 7.311.3; p = 0.016), but similar in round 2 (students: 117/893 [13.1%], 95% CI: 11.015.5; staff: 117/872 [13.4%], 95% CI: 11.215.9; p = 0.85).

In round 1 antibody positivity in students was associated with school area, year group and additional children in the household. In round 2, antibody positivity was associated with Black ethnicity and the number of positive cases in the school.

Discussion: This prospective cohort study showed that antibody seroprevalence rates in students and staff were generally similar to regional community rates, both at the start and end of the Autumn term. Among participants who were seronegative at the start of the autumn term, seroconversion rates were 6.6% in students and 8.7% in staff by the end of term. This study adds to the body of evidence that, with appropriate infection control measures, the risk of transmission of SARS COV2 is low within the school setting.

Of note this study was conducted prior to the widespread prevalence of variants of concern.

MillerFmedRxivPrevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales02 Jun 2021England & WalesEurope4678Epidemiology - Disease Burdenhttps://www.medrxiv.org/content/10.1101/2021.05.28.21257602v1

Methodology: Household cohort study (VirusWatch) across England and Wales consisting of 47,813 individuals of 23,059 households recruited by a range of methods including social media, SMS and letters sent to households. 4,78 of children were included as part of this study to assess the prevalence of any new symptoms that persisted for ≥ 4 weeks. Data was collected from mid- June 2020 to mid-March 2021 from children ≤ 17 years who completed one of two surveys sent via VirusWatch requesting information about persistent symptoms, 1) one of the monthly surveys (17th of February) specifically asking about persistent symptoms, 2) at least 3 weekly surveys within a 5-week period capturing participant symptoms before the 20th of January. Participants were asked “In the last year (since February 2020) have any of the household members experienced any new symptoms that have lasted for four or more weeks even if these symptoms come and go, and that are not explained by something else (eg, pre-existing chronic illness or pregnancy)?”

A history of SARS-CoV-2 was determined by a positive PCR test or positive SARS-CoV-2 IgG. Testing may have occurred as part of the VirusWatch active surveillance program or for other reasons not specified.

The prevalence of persistent symptoms was determined in children with a history of SARS-CoV-2 as well as all children who completed the persistent symptoms survey according to age, sex and presence of a chronic condition. Mixed effects logistic regression models were applied, setting risk factors as the independent variables and unique households as the intercept.

Results: 4,678 children were included in the cohort and the overall prevalence of persistent symptoms was 1.7% (80/4678). 4.6% (8/175) of children with persistent symptoms has a history of SARS-CoV-2. These children either tested positive via PCR testing (62.9%, 110/175) or via serological testing (26.9%, 47/175). Seven children had positive PCR testing attributable to the VirusWatch swabbing programme. 476 children within the cohort reported at least one chronic condition, of which 385 (80.9%) reported clinician-diagnosed asthma. Children 12 – 17 year old, less deprived children and those living in the Eastern regions of England were over-represented within the cohort.

Children with a history of SARS-CoV-2 as well as females, teenagers and children with a chronic health condition were more likely to report persistent symptoms within the cohort.

The most common category of persistent symptoms was respiratory, ENT and general symptoms. Fatigue was the most common general symptoms as reported by 22.5% (18/80) children.

Of the 18 who reported start and end dates, 46 days was the medium duration of symptoms. Severity of symptoms was not discussed within this study.

These results are similar to a number of recent studies looking at the prevalence of persistent symptoms after acute COVID-19 infection in children. A major strength is the inclusion of a comparator group to put the results in context. A limitation is that despite the large total cohort size, the number of children with a COVID-19 diagnosis was not very large, meaning there will be some uncertainty around the estimates provided.

Oliveira, EOliveira, MLancet Child AdolescClinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database10 Jun 2021BrazilSouth America11613Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00134-6/fulltext

Oliviera et al., 2021 Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database

Introduction: Since the emergence of COVID-19 in January 2020, Brazil has been one of the countries most severely affected. Epidemiological evidence has consistently documented less severe disease in paediatrics when compared to adults. It has also been highlighted that there is a greater impact of paediatric COVID-19 fatality in low-income and middle-income countries. The article states that at the time of writing, there is a lack of studies investigating the risk factors associated with severe COVID-19. The authors searched databases that described outcomes of children with COVID-19 and data available on the effects of ethnicity, comorbidities, social inequalities and health disparities on outcomes in children infected with SARS-COV-2 from middle- or low-income countries were scarce.

Methods: All cases of RT-PCR confirmed SARS-COV-2 in children and adolescents aged <20 years and recorded in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe), a nationwide database for the surveillance of severe acute respiratory infections were included. SIVEP-Gripe is the main source of information on COVID-19 related hospital admissions in Brazil and receives information from both public and private hospitals. The analysis was conducted between February 16, 2020 to January 9, 2021. The demographic patient data included age, sex, ethnicity, and geopolitical macroregion (There are historical differences in social, economic, health system capacity and coverage between the different macroregions). 82,055/1,124,689 (7.3%) reported cases of severe acute respiratory illness were <20 years old. Of these, 70442 (85.8%) were excluded as a result of negative SARS-COV-2 RT-PCR test, awaiting test result, not tested or those with inconclusive results. The final sample size was 11,613 patients with positive SARS-COV-2 RT-PCR results.

Results: The median age at admission was 5.1 years (IQR 1.0-14.3) and evenly distributed among three age groups (<2 years, 2-11 years and 12-19 years). The competing risks multivariate survival analysis showed that risk of death was increased in infants younger than 2 years (hazard ratio 2.36 [95% CI 1.94–2.88]) or adolescents aged 12–19 years (2.23 [1.84–2.71]) relative to children aged 2–11 years.

There was a small predominance of COVID-19 infections in boys (52% 6032/11600) and Black or Brown patients accounted for 63.5% of the infections (5784/9109). Compared with White patients, children of Black or Brown ethnicity (HR 1.30 [1.11–1.53]) and Indigenous ethnicity (HR 3.27 [2.17–4.93]) were also at increased risk of death.

COVID-19 cases were most prevalent in the North and Central-West regions, 330.4 cases per million and 330.0 cases per million, respectively. Using the Fine and Gray model, risk of death was increased in patients from the poorest regions, the Northeast region (HR 2.03 [1.72–2.38]) and North region (HR 1.53 [1.25–1.87]) relative to those from the Southeast region

8352 (71.9%) of patients had no pre-existing medical conditions, 2780 (23.9%) had one comorbidity, and 481 (4.1%) had two or more pre-existing comorbidities. Most common pre-existing conditions were asthma (7.5%), neurological disorders (6.1%), malignancies (5%), and heart disease (3.3%). Risk of death was increase in those with one (2.96 [2.52–3.47]), two (4.96 [3.80–6.48]), or three or more (7.28 [4.56–11.6]) pre-existing medical conditions relative to those with none.

Median time from symptom onset to hospitalisation was 3 days (IQR 1-6). 2759 patients (23.8%) were admitted to ICU. Fever (74.5%), cough (67.4%), dyspnoea (57.6%), respiratory distress (54.4%) and <95% O2 Saturations (41.1%) were the most common symptoms. With respect to signs and symptoms at presentation, the presence of respiratory distress (2.78 [2.35–3.29]) and oxygen saturation below 95% (3.66 [3.11–4.30]) were strongly associated with death, whereas fever, cough, and gastrointestinal symptoms were not associated with death.

Comments: The authors had no access to hospital data records to allow for inclusion of information regarding pharmacotherapies, laboratory results or the detailed clinical course of each patient. Complete data were not available for all variables, especially ethnicity and symptoms at presentation, so denominators differ between analyses. Mild cases of COVID-19 in which patients were not hospitalised were not included in the registry, therefore there are concerns around the limitation of the results. Data from the nationwide database showed that death was associated with age younger than 2 years or 12-19 years, indigenous ethnicity, living in the poorest macroregions, and the presence of pre-existing medical conditions.

Carolin, KArmann, JBMJSARS-CoV-2 seroprevalence in students and teachers: a longitudinal study from May to October 2020 in German secondary schools10 Jun 2021GermanyEurope1538Epidemiology - Transmissionhttps://bmjopen.bmj.com/content/11/6/e049876

The authors’ study aimed to quantify the number of SARS-CoV-2 infections in secondary schools in Saxony, Germany after their reopening in May 2020.

Method : The researchers undertook a repeated SARS-CoV-2 seroprevalence study after the reopening of schools and 4 months later. The schools were 13 secondary schools in Dresden, Germany chosen by the state office randomly without the authors input. 1538 students’ grades 8–12 and 507 teachers from 13 schools took part in the study.

The study involved serial blood sampling (5ml each visit) and SARS-CoV-2 IgG antibody assessment. In addition, participants were asked to complete a questionnaire on age, household size, previously diagnosed SARS-CoV-2 infections in themselves or their household contacts, comorbidities and regular medication. Students were also asked about regular social contacts outside their household or classroom

The authors measured seroprevalence of SARS-CoV-2 antibodies in study population and the number of undetected cases.

Results : 1538 students and 507 teachers were initially enrolled and 1334 students and 445 teachers completed both study visits. The seroprevalence for SARS-CoV-2 antibodies was 0.6% in May/June and the same in September/October. Even in schools with reported COVID-19 cases before the lockdown of 13 March, no clusters could be identified. Of 12 persons with positive serology five had a known history of confirmed COVID-19; 23 out of 24 participants with a household history of COVID-19 were seronegative.

Conclusions : The authors concluded schools do not play a crucial role in driving the SARS-CoV-2 pandemic in a low-prevalence setting. Transmission in families occurs very infrequently, and the number of unreported cases is low in this age group. These observations do not support school closures as a strategy fighting the pandemic in a low-prevalence setting.

Harwood RViner RM medRxiv preprintWhich children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis 8 July 2021Global All regions21412Clinical - Comorbiditieshttps://doi.org/10.1101/2021.06.30.21259763

Background: This comprehensive meta-analysis aims to identify the potential risk factors for severe disease in children and young people (CYP) with COVID-19 and PIMS-TS globally. Although well-described for adults, there is less available data on the subject for CYP. Addressing this question now is timely as it provides evidence for which groups of CYP are vulnerable and should be prioritised for vaccination and shielding policies.

Methods: Four major databases were searched between 1st January 2020 to 21st May 2021. Studies involving children hospitalised with SARS-COV-2 or PIMS-TS that provided information on risk factors and outcomes according to the eligibility criteria were included.

Results: 57 studies with a total of 21,412 children were included in the meta-analysis with 22 studies providing Individualised Patient Data (IPD). The studies were conducted in Asia (9), Europe (15), Africa (1), North America (21) and South America (8). Meta-analyses were performed on aggregate study-level data as well as on IPD. The study analysed the odds and risk of severe disease and death associated with sex, age and comorbidities in children hospitalised with SARS-COV-2 or PIMS-TS.

There was no association between sex and outcome. Teenagers were more vulnerable to severe disease and death from COVID-19 and PIMS-TS compared to other age groups. The presence of pre-existing conditions was the strongest risk factor for critical care admission and death for both COVID-19 and PIMS-TS, although the absolute risk compared to CYP without comorbidities was still small. One comorbidity increased absolute risk of critical care admission by 3.6% and death by 1.5% in COVID-19. In particular, cardiac and neurological conditions were associated with increased risk whilst asthma was not. In addition, Trisomy 21, with or without cardiovascular disease, and obesity, independent of other conditions, increased risk of death in COVID-19.

Strengths & limitations: The authors note the limitations of comparing studies of mixed quality from multiple countries with differing practices and resources. Most included studies were open to substantial bias such as publication bias of more severe cases and misclassification of comorbidities. Unfortunately, the data did not allow for the impact of ethnicity and socioeconomic background to be assessed which would be of value given its association with outcomes in adults with COVID-19. Despite its limitations, this meta-analysis offers an impressive global overview of current evidence on the subject and highlights areas of knowledge gaps where future research should focus.

Smith, CFraser, LResearch SquareDeaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data07 07 2021UKEurope61Epidemiology - Disease Burdenhttps://www.researchsquare.com/article/rs-689684/v1

This study examines all deaths in children due to SARS-CoV-2 in England between March 1st, 2020, to February 28th, 2021, comparing characteristics of children who died due to SARS-CoV-2 with those of children who died from all other causes.

Data on all deaths was obtained from the National Child Mortality Database (NCMD), a mandatory system that records all deaths in children <18yo including limited demographic data including age and ethnicity. NCMD data was matched with Public Health England SARS-CoV-2 testing data over the study period. All children who died and had a positive SARS-CoV-2 test (at any time) were included; including post-mortem testing in sudden unexpected deaths. In addition, possible cases of PIMS-TS identified by the NCMD coding team were included. Data on comorbidities was attained by linking NCMD data to national admissions data over the preceding 5-years using established ICD-10 codes with co-morbidities classified according to body system.

For all reported deaths in children with a positive SARS-CoV-2 test, further review of clinical data, by three consultant paediatricians, was conducted to determine if SARS-CoV-2 contributed to death. All cases where SARS-CoV-2 was clearly implicated, probably contributed or possibly contributed to death were included as deaths due to SARS-CoV-2 infection. Infection fatality rate was calculated using the estimated number of children infected with SARS-CoV-2 based on PHE modelling data, to account for likely lack of testing during the first wave.

A total of 3105 children died of all causes during the 12-month study period; 61 had a positive SARS-CoV-2 test. SARS-CoV-2 was the cause of death in 25 (41%) of the 61 children; 22 due to acute COVID-19 and 3 due to PIMS-TS. Overall case fatality rate for SARS-CoV-2 was 5 per 100,000. Mortality rate was 2 per million population, compared with 255 per million for all other causes of death during the study period. The majority of SARS-CoV-2 deaths occurred in children >10yo (72%) including all 3 deaths due to PIMS-TS. Children of Asian (36% vs 16%) and Black (20% vs 8%) ethnicity comprised a higher proportion of SARS-CoV-2 deaths compared to deaths from all other causes.

Six (24%) SARS-CoV-2 related deaths occurred in previously healthy children and 19/25 (76%) in children with underlying comorbidities. The most common comorbidity was an underlying complex neurological condition (13/25, 52% including 8/25 (32%) with neurological as well as respiratory comorbidity) followed by chronic respiratory disease (12/25, 48%). Over half (15/25, 60%) of children who died of SARS-CoV-2 had an underlying life-limiting condition. No deaths due to SARs-CoV-2 occurred in children with isolated cystic fibrosis, asthma, Trisomy 21, epilepsy, or type 1 diabetes.

Major strengths of this study include the use of comprehensive national mortality and testing data as well as the assessment of individual cases of death in children with a positive SARS-CoV-2 test to determine if infection contributed to death. The findings highlight the low mortality rate due to SARS-CoV-2 in children particularly in those without an underlying co-morbidity as well as the higher risk in older children and children with underlying complex neurological and respiratory conditions. These data are important for guiding policy on vaccination and other mitigation strategies in order to prioritise protection of children at highest risk from SARS-CoV-2 infection.

Preston, LGoodman, AJAMACharacteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-1909 Apr 2021USA North America20714Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347
Liu, DZeng, CAmerican Journal of RoentgenologyPregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: A preliminary analysis07 Mar 2020ChinaAsia11Neonatalhttps://www.ajronline.org/doi/full/10.2214/AJR.20.23072
Li, YSheng, JEmerging Infectious DiseasesLack of Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, China05 Mar 2020ChinaAsia1Neonatalhttps://doi.org/10.3201/eid2606.200287
Liu, YGuo, YJournal of InfectionClinical manifestations and outcome of SARS-CoV-2 infection during pregnancy04 Mar 2020ChinaAsia13Neonatalhttps://doi.org/10.1016/j.jinf.2020.02.028
Wang, XChen, XClinical Infectious DiseasesA Case of 2019 Novel Coronavirus in a Pregnant Woman With Preterm Delivery28 Feb 2020ChinaAsia1Neonatalhttps://doi.org/10.1093/cid/ciaa200

This brief report outlines the case of a mother in Suzhou, China, who became symptomatic and tested positive for SARS-CoV-2 in sputum whilst 30/40 pregnant. She had recently travelled to Wuhan. She had an emergency caesarean performed 6 days after presentation for worsening clinical status and concerns for the foetus due to reduced movements and foetal heart rate variability on CTG.

The infant was born in good condition and immediately isolated from the mother. Samples of amniotic fluid, cord blood, placental swabs, infant gastric secretions and throat swabs all tested negative for SARS-CoV-2. Repeat swabs from the infant on day 3 of life were still negative. Mother and baby both recovered well with uneventful postpartum and neonatal course.

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Chen, HZhang, YLancetClinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records12 Feb 2020ChinaAsia9Neonatalhttps://doi.org/10.1016/S0140-6736(20)30360-3
Zhu, HZhou, WTranslational PediatricsClinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia10 Feb 2020ChinaAsia10Neonatalhttps://doi.org/10.21037/tp.2020.02.06

This is a retrospective series of 10 neonates (including a set of twins) born to 9 mothers in Hubei province who were confirmed to have COVID-19.

4 mothers had symptoms prior to delivery, 2 mothers on the day of delivery, and 3 mothers after delivery. 7 mothers delivered via caesarean section and 2 by vaginal delivery. There was intrauterine distress recorded in 6 cases.

Of the babies, 8 were male and 2 female, 4 born at term and 6 preterm (twins at 31/40, and 4 babies around 34 – 35/40). APGARS were good for all babies. 6/10 developed some respiratory symptoms, one had some vomiting and one developed shock with DIC and multiple organ failure, who later passed away. All neonates tested negative for SARS-CoV-2, as did placental swabs.

It is hard to know what to make of this study. There is little information about how/why babies were delivered prematurely, and it would seem most symptoms are related to their early arrival. None were positive for the virus, and there was no evidence of vertical transmission. It seems contradictory to other evidence of babies delivered to mothers with COVID-19 who did well. Interpret with great caution.

Lindan, CPalasis, SLancetNeuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.15 Dec 2020https://doi.org/10.1016/S2352-4642(20)30362-X

This multicentre case series reports on the neuroradiological findings in 38 children from 13 countries who had neurological disease in association with SARS-CoV-2 infection. Cases were reported retrospectively between 30/04–08/09/20. Four children died, all of whom had CNS co-infections. Two were left with significant neurodisability. The commonest neuroradiological findings were an “ADEM-like” picture (n=16), myelitis (n=8), and neural enhancement (n=13). Splenial lesions (n=7) and myositis (n=4) were predominantly found in children with MIS-C. Demographic data incomplete. M:F ratio 21:17. Age range 0.17-16years. No information given on longer term outcomes.

Moreira, AMoreira, AEur J Pediatr (2021)Demographic predictors of hospitalization and mortality in US children with COVID-19.20 Jan 2021USANorth Americahttps://doi.org/10.1007/s00431-021-03955-x

This study is from the USA between March 2, 2020, and July 16, 2020. The Centers for Disease Control and Prevention COVID-19 associated hospitalization surveillance network “CDC COVID-NET” is a population-based system that captures laboratory-confirmed COVID-19 cases in over 250 US acute-care hospitals. The database was searched for the variables including demographics (age stratified as 0-19 and 10 – 19(, other medical conditions and outcomes (hospitalisation / death). Patients with missing data were excluded from this report.

Results: Of the total number of children (27,045), 70.0% between the ages of 10 and 19 years with a similar gender distribution. 39% had an underlying medical condition. 4.7% required hospitalization, with higher odds in children < 10 years of age who were Black or of mixed race/ethnicity, and with a medical condition. Mortality data was available for 20,096 (74.3%) individuals that were hospitalized, and death occurred in 0.19% (more in black, non-Hispanic and those with an underlying medical condition)

Discussion/Conclusion: Black, non-Hispanic and Hispanic children were 2.5 times more likely than White children to be hospitalized and 5 times more likely to die after infection. The reasons suggested by the authors included parents (act as infection vectors) who work in high “viral-contact” jobs are more likely to be minorities. Poverty is more common among minority groups (lower socioeconomic status is intricately linked to larger household sizes, crowding, and therefore more cross-infection.) A past medical history of an underlying condition was the strongest risk factor for poor outcome in US children with COVID-19.

Limitations: Although the data is derived from 14 states, it only represents 10% of the US Population. Missing data was common in the database which decreased the overall sample size from 229,052 children to 27,045 paediatric cases.

Author

  • Alison is a paediatric registrar in Australia, currently embarking on her PhD in bone and joint infections. She is passionate about teaching and making the world just that little bit more organized with the help of washi tape. Alasdair is a Paediatric registrar in the UK, currently working as a Clinical Research Fellow in Paediatric Infectious Diseases. His interests include evidence based medicine, diagnostics and antimicrobial resistance. Henry is a paediatric trainee based in Queensland, Australia, Henry is passionate about Adolescent Medicine & General Paediatrics, with a strong interest in Medical Education & Clinical Teaching. An admitted nerd & ironman with a penchant for Rubik's Cubes & 'Dad jokes'.

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61 thoughts on “An evidence summary of Paediatric COVID-19 literature”

  1. “Our search criteria […]only those felt to be of exceptional quality”

    Selection criteria, based on feelings ?

    Sorry this cannot be taken as a serious meta study which must be based on objective selection criteria.
    No wonder, all selected studies fit a single narrative: “open the schools”.

  2. Has there been anything said about that the children are not going out so wouldn’t be the primary source of the disease (adults doing food shop)? Also, they would rarely be the care giver if a member of household became ill, so less chance of transmission there too.

  3. Dear Alison, Alasdair and Henry, I´ve been following your updates for weeks now. Very helpful. Great work, very much appreciated! Way to go!

  4. Dear Alison, Alasdair and Henry, I was looking for a nice summary of pediatrics literatures and I found yours to be very comprehensive and well organized. Thank you so much!

  5. Pratik Patel M.D.

    Dear Don’t Forget the Bubbles,

    I wanted to make you aware of a critically ill previously healthy pediatric patient who we had in Atlanta (USA) in late March who had concern for hyperinflammation and was successfully treated with a variety of COVID as well as hyperinflammation treatments (remdesivir and tocilizumab). We published our case and it is available online at Pediatrics in case you were interested in including it in your future summaries/posts! https://pediatrics.aappublications.org/content/pediatrics/early/2020/04/30/peds.2020-1437.full.pdf

    Thanks,
    Pratik

  6. Cui Y, Tian M, Huang D, et al. A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis
    Concerning the elevated troponin: we see a slightly elevated troponin in all our young babies (newborn and older), without any clinical or echographic signs of cardiac involvement

  7. Thanks for this wonderful tool. Just one important remark? If you sort according to the date of publication, it is no in a chronological order. It might work if you put the year first, than the month and than the day.
    Best, Tilmann

  8. Dr Luke Jeremijenko Emergency Physician

    Thanks team. Wonderful resource. Avidly reading through the papers. Question to the DFTB brains trust. I ran Dr Ben Symons simulation today and was asked (appropriately) is there a viral filter available for the F&P airvo 2? How are people running HFNP outside a negative pressure room?

    1. We are trying to see what the evidence is, or at least find some expert consensus on this, so watch this space. I’m not a fan of the idea at the moment so we are advocating for starting it in the place it is going to b ultimately used. You don’t want to push a patient on HF through the hospita.l

  9. Kgomotso Lovey Sanyane

    What a wonderful post. Absolutely valuable information in these trying times. I’m a paediatrician in South Africa and we are experiencing an increasing amount of COVID-19 cases

  10. Paeds medical nurse practitioner here, amazing job on the delivery of such valuable information. Great work. Your time & effort greatly appreciated.

  11. Thank you so much for putting this together. Great Work. Faecal shedding is interesting and worrysome at the same time

  12. Thank you for reviewing these papers a friend who is a
    Paediatric nurse sent me this information. What is interesting is that a lot of studies note fecal shedding of virus or detection of virus in fecal samples is still there after oral/nasal tests are negative for virus. This is interesting as it seems coronavirus have evolved and originated in bats and bats shed these virus in fecal matter.

  13. Thank you. As a paediatric anaesthetist I’m trying to keep up with all the latest information and this is a great summary and am very grateful you’ve done this review.

  14. Dear DFTB Team, thank you for this very helpful summary!

    Please note: In Cui Y, Tian M, Huang D, et al. , A 55- day old female.. the authors write at the end of the first paragraph:
    “The nasopharyngeal swab obtained from the infant also tested positive for severe acute respiratory syndrome coronavirus (SARS-CoV-2) on real-time reverse transcription–polymerase-chain-reaction (RT-PCR) assay.”
    I find this reassuring and would like to recommend to correct this part of your summary.
    Sincerely, Angela

    1. Thank you for pointing out this omission – we will correct this immediately. We appreciate you taking the time to comment and help us improve the post.

  15. Good to know COVID in kids is relatively mild. However, do we know anything about numbers of paediatric HCWs becoming infected?

  16. Thank you so much . This is a great summary , and such a positive look at paediatric covid cases , so we can somehow reassure the panicked mothers!

  17. Thanks a lot for doing this excellent work. These data are confirmed in Italy. Up to Now few children admittedto the hospital, mild symptoms, NO admission di intensive care. Keep fingers crossed. Very important to apply prevention policy and . isolation. Infection rate is starting to decrease in the area where the isolation was perforned rigorously (North East of Italy meaning Veneto and Friuli Venezia Giulia where I work. Good luck to all of you and keep safe

  18. thank you – interesting that they have unilateral opacities on some CXR considering all I knew previously was that it was bilateral ground glass – makes me wonder about the kid I sent home recently with coamox as the XR changes were unilateral…however he has not come back so I assume he is ok! no harm, no foul.

  19. With Mycoplasms noted more than just once do Symptomatic cases earn Azithromycin or other atypical therapy while waiting for results? Would the CXR / CT chest findings be consistent with Mycoplasms?

  20. This is amazing – thanks!! Paeds Reg on mat leave with a newborn here. Have been wanting to look into this but too tired to tackle – I am so appreciative.

  21. We need risk and recommendation commentary on special needs paediatric population; particularly those of school age (and whose parents/Carers are front line such as health care workers)

    1. Echoing your request; this cohort needs timely guidance based on what evidence we can glean. Thanks DFTB once again for educational content.

    2. I am a NHS front line worker with a child who has severe & complex needs and recurring chest infections. Currently isolated pseudomonas in the chest. Desperate for information.

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