Cite this article as:
Boast A, Munro A, Goldstein H. An evidence summary of Paediatric COVID-19 literature, Don't Forget the Bubbles, 2020. Available at: https://doi.org/10.31440/DFTB.24063
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.
Around the world, children have made up a minority of confirmed cases of COVID-19 during the first wave of the pandemic, usually contributing to between 1 – 5% of total case numbers. This almost certainly represents some undercounting of children in total case numbers as many countries have focussed on testing the most unwell. As countries have become better at shielding elderly populations and moved to community testing, the proportion of cases detected in children has increased (although predominantly in older children aged 10 – 19 years).
Countries which have produced representative population seroprevalence studies (including Switzerland, Spain, France, Brazil and the UK) found proportionately far fewer children were infected during the first wave than adults (young children <10 years in particular).
More detailed information has emerged into childhood severity of COVID-19. A significant number of children may be asymptomatic, but the true proportion is unknown. It seems possible up to 50% of cases may develop no symptoms at all, but the data is of low quality for assessing symptomology. Critical illness is very rare (~1%). In data from China, the USA and Europe, there is a “U shaped” risk gradient, with infants and older adolescents appear most likely to be hospitalised and to suffer from more severe disease. Deaths in children remain extremely rare from COVID-19, with only 4 deaths in the UK as of May 2020 in children <15 years, all in children with serious comorbidities.
Transmission
Precise details regarding paediatric transmission are still being ascertained, however important trends are emerging. Low case numbers in children suggest a more limited role than was initially feared. Meta-analyses of contact tracing data from Asia, Europe, Israel and the USA have all demonstrated a significantly lower attack rate in children than adults, including testing of asymptomatic household contacts on both PCR and serology. These findings indicate young children in particular are approximately half as likely as adults to acquire the infection given equivalent exposure.
Children of all ages are infectious and capable of transmitting regardless of symptom status. Determining the relative infectiousness of children as compared to adults is difficult, given unknown numbers of asymptomatic cases which are underrepresented in studies of transmission. Household studies with children as index cases have so far been difficult to interpret due to bias from shared exposure (children and their contacts becoming infected simultaneously), increased exposure of caregiver to their symptomatic children post infection, and underrepresentation of asymptomatic cases.
Contact tracing studies from schools have generally found very low rates of transmission, especially among younger children. There is evidence of larger outbreaks within secondary school age and adolescents, predominantly in schools during period of high community transmission. There is little evidence in the literature of large outbreaks within primary school, or age equivalent educational facilities in periods of low to moderate community transmission.
Studies of viral loads in children have generally found comparable levels of virus to adults, with no consistent or clinically relevant variation by age or symptom burden. Several studies have now shown that SARS-CoV-2 can be detected by PCR in the stool of affected children for several weeks after symptoms have resolved. Studies have confirmed there can also be live virus found in the stool of infected individuals. How much virus is present, and the extent to which faecal-oral transmission may be possible is yet to be confirmed.
Clinical features
A significant proportion of children with COVID-19 do not appear to develop any symptoms, or have subclinical symptoms, but it remains uncertain what this proportion is. The most detailed paediatric population data from China showed 13% of confirmed cases had no symptoms (cases detected by contact tracing). Considering both confirmed and suspected cases, 32% of children aged 6-10yrs were asymptomatic. Data from Italian emergency departments found 21% of SARS-CoV-2 positive children to be asymptomatic. Importantly, these studies did not follow up children to determine if they later developed symptoms, so the true proportion of asymptomatic children is unknown.
Possibly the most reliable data comes from serological screening with symptom surveys, suggesting approximately 50% of children may be asymptomatic, and only 10 – 15% will exhibit symptoms consistent with COVID-19 case definitions (cough, fever, shortness of breath). These studies are subject to recall bias.
Clinical features in symptomatic children are somewhat different to adults. Children tend to have more mild illness. The most common presenting features are cough and fever, occurring in over half of symptomatic patients. Upper respiratory tract symptoms such as rhinorrhoea and sore throat are also relatively common, occurring in 30-40% of patients. It is not uncommon for children to have diarrhoea and/or vomiting (around 10% of cases), even in some cases as their sole presenting features. Several case series of rashes resembling chill blains (often occurring on feet/toes) have been reported from Europe, contemporaneously associated with the COVID-19 outbreak but with few cases simultaneously confirmed to be infected
Blood tests also show slightly different features to adults. Lymphocytopaenia is relatively rare in children, with the majority having normal or sometimes raised lymphocyte counts. Inflammatory markers such as CRP and Procalcitonin are often raised but only very mildly. Slight elevations in liver transaminases appear to be common.
Radiographic features in children are also somewhat different to their adult counterparts. Chest X-rays are often normal, and many CT chest scans are also normal. When present abnormalities are often less severe, however a reasonable number of children have bilateral pneumonia. Changes may be found on CT even in asymptomatic children. Common features in abnormal CT scans include mild, bilateral ground glass opacities, but with less peripheral predominance than is reportedly found in adults.
There appears to be little in the way of clinical signs in children to differentiate COVID-19 from other childhood respiratory virus infections, or other benign childhood illnesses.
PIMS-TS/MIS-C
A new hyperinflammatory syndrome resembling Kawasaki shock, which appears to be a delayed immune response to COVID-19 has been described. It is known as PIMS-TS in Europe and MIS-C in the USA. Published reports from London, Italy, France and the USA in a cohort of children with evidence of past COVID-19 infection have presented with early symptom of abdominal pain, vomiting and diarrhoea, with persistent high-grade fever and commonly progression on to shock with cardiac involvement. High inflammatory markers, myocarditis, macularpapular rashes and non-suppurative conjunctivitis are common. Respiratory involvement is notably absent. Investigations are underway to ascertain a link and mechanism of disease. Most cases recover quickly, but there have been deaths reported.
Consistent with adult literature, children from a Black, Asian and Minority Ethnic (BAME) background seem to be at higher risk of severe disease from acute COVID-19 infection, and are significantly overrepresented in case reports of PIMS-TS
Newborns
A large number of cases of infants born to mothers with COVID-19 have now been reported, including several hundreds from the UK. Mothers and their babies in general appear to do well. There is a small but notable increase in the rates of preterm birth, and signals of increase in rates of foetal loss/stillborn delivery. There have been a few cases of infants delivered to mothers with COVID-19, who had elevated SARS- CoV-2 IgM. This may indicate intrauterine transmission, however swab PCR from these children has been negative and false positives with IgM tests are not uncommon. There have been case reports of newborns and very young infants testing positive including several within 12 hours of age, however they have mostly not suffered any complications of the disease and required minimal respiratory support. Evidence has been found of viral invasion into placenta, indicating possible intrauterine transmission. Vertical transmission however remains rare, occurring in approximately 2% of cases of maternal infection.
When tested, breast milk has usually been negative for SARS-CoV-2, but there have been a small number of instances where it has tested positive. It is unclear if this positive result reflects live, infectious virus, and whether the source was the mother or infants who subsequently also test positive for the virus. The vast majority of newborns have not acquired COVID-19 themselves.
Children with co-morbidities
There is a growing body of evidence reflecting a small increased risk of children with comorbidities to be hospitalised or need intensive care from COVID-19. A pan European consortium found children with chronic lung disease, congenital heart disease, neurological disease or malignancy had 3 times higher odds of needing admission to PICU; whilst this is an increased relative risk, the absolute risk remains small. Studies from PICU admissions in the US and Italy also found the majority have some comorbidities, most commonly respiratory, cardiac or complex neurodisability. These are groups for whom there is already a background increased risk of complications from all respiratory viruses. The rates of complications from SARS-CoV-2 infection do not appear disproportionate to those from other respiratory viruses from this early data.
Conclusion
COVID-19 appears to affect children less often, and with less severity, including frequent asymptomatic or subclinical infection. There is evidence of critical illness, but it is rare. Children can become infected and transmit even when asymptomatic. Contact tracing studies suggest children are approximately half as susceptible to infection as adults, and their relative infectiousness remains difficult to estimate. Changes in laboratory or radiographic parameters are slightly different to adults, and changes usually mild. There is some evidence of vertical transmission to neonates which appears predominantly perinatal but evidence of intrauterine infection does exist. Evidence suggests only a small increased risk to pregnant mothers and newborns compared to other groups. Children with respiratory, cardiac and complex neurodisability appear more likely to suffer complications, however not obviously more than would be expected from infection with other respiratory viruses.
New and Noteworthy (Updated 11 April 2021)
Shamez N Ladhani, Frances Baawuah, Joanne Beckmann et al. SARS-CoV-2 infection and transmission in primary schools in England in June–December, 2020 (sKIDs): an active, prospective surveillance study. Lancet Child and Adolescent Health, March 16th 2021, https://doi.org/10.1016/S2352-4642(21)00061-4
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.”
Hershow RB, Wu K, Lewis NM, et al. Low SARS-CoV-2 Transmission in Elementary Schools — Salt Lake County, Utah, December 3, 2020–January 31, 2021. MMWR Morb Mortal Wkly Rep 2021;70:442–448. DOI: http://dx.doi.org/10.15585/mmwr.mm7012e3
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.
Doyle T, Kendrick K, Troelstrup T et al. COVID-19 in Primary and Secondary School Settings During the First Semester of School Reopening — Florida, August–December 2020. MMWR Morbidity and Mortality Weekly Report 70(12): 437-441 2021 http://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
Volpp, K. G., B. H. Kraut, S. Ghosh and J. Neatherlin (2021). “Minimal SARS-CoV-2 Transmission After Implementation of a Comprehensive Mitigation Strategy at a School – New Jersey, August 20-November 27, 2020.” MMWR Morb Mortal Wkly Rep 70(11): 377-381. http://dx.doi.org/10.15585/mmwr.mm7011a2
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.
Hu, S., Wang, W., Wang, Y. et al. Infectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China. Nat Commun12, 1533 (2021). https://doi.org/10.1038/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.
Cotugno, N., A. Ruggiero, F. Bonfante, M. R. Petrara, etal. Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies. Cell Reports 34 (11) (no pagination) (108852). https://doi.org/10.1016/j.celrep.2021.108852
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.
Niño-Taravilla C, Otaola-Arca H, Lara-Aguilera N, Zuleta-Morales Y, Ortiz-Fritz P. Multisystem inflammatory syndrome in children, Chile, May–August 2020. Emerg Infect Dis. 2021 May https://doi.org/10.3201/eid2705.204591
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.
F MCaribú, R Erra, L Pugni et al. Severe SARS-COV-2 placental infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest. January 26th 2021, https://doi.org/10.1172/JCI145427.
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.
Cooper DM, Messaoudi I, Aizik S, Camplain RL, Lopez NV, Ardo J, et al. SARS-Cov-2 acquisition and immune pathogenesis among school-aged learners in four K-12 schools. medRxiv 2021.03.20.21254035; doi: https://doi.org/10.1101/2021.03.20.21254035
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-γ 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.
Shira Doron, Robin R. Ingalls, Anne Beauchamp, et al. Weekly SARS-CoV-2 screening of asymptomatic students and staff to guide and evaluate strategies for safer in-person learning. medRxiv, March 22nd 2021. https://doi.org/10.1101/2021.03.20.21253976
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.
The studies included in this review are as follows:
Rottenstreich A, Zarbiv G, Oiknine-Djian E, Zigron R, Wolf DG, Porat S. Efficient maternofetal transplacental transfer of anti-SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. medRxiv. 2021 Jan 1.
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 KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, Baez AM, Shook LL, Cvrk D, James K, De Guzman R. COVID-19 vaccine response in pregnant and lactating women: a cohort study. American Journal of Obstetrics and Gynecology. 2021 Mar 26.
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 Y, Prahl M, Cassidy A, Wu AH, Jigmeddagva U, Lin CY, Gonzalez VJ, Basilio E, Warrier L, Buarpung S, Asiodu IV. Immune response during lactation after anti-SARS-CoV2 mRNA vaccine. medRxiv. 2021 Jan 1.
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 Y, Prahl M, Cassidy A, Lin CY, Ahituv N, Flaherman VJ, Gaw SL. COVID-19 mRNA vaccine is not detected in human milk. medRxiv. 2021 Jan 1.
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.
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.
Knight, K. Bunch, N. Vousden et al. Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV 2 infection in the UK: A national cohort study using UK obstetric surveillance system. Nuffield Department of Population Health, UKOSS Publications 11th May 2020, https://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.
Zeng L, Xia S, Yuan W et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatr. Published online March 26, 2020. doi:10.1001/jamapediatrics.2020.0878
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.
Yu, Nan et al Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study, The Lancet Infectious Diseases, Volume 0, Issue 0, Published:March 24, 2020 DOI:https://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.
Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395 :809–15. doi:10.1016/S0140-6736(20)30360-3
This retrospective case series looks at 9 pregnant women who were positive for COVID19 in Wuhan University Hospital between Jan 20th and Jan 31st. They all underwent a caesarean section (between 36 and 39+4 gestation). All newborn babies were well with good APGARS and, importantly, tests from 6 (3 not tested) patients were negative for SARS-CoV-2 in all amniotic fluid, cord blood, neonatal throat swabs, and breastmilk samples. There was no evidence of vertical transmission.
Dong L, Tian J, Songming H et al. Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4621
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 H, Xu C, Fan J, et al. Antibodies in Infants Born to Mothers With COVID-19 Pneumonia. JAMA. Published online March 26, 2020. 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 SARS-CoV-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.
Liu, Yangli et al. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy.Journal of Infection, Volume 0, Issue 0 https://doi.org/10.1016/j.jinf.2020.02.028
This is a small case series of 13 pregnant women with confirmed SARS-CoV-2 infection between December 8 2019 and February 25 2020, in China. Two women were <28 weeks at presentation, the remainder were in the third trimester. One infant was stillborn, the 12 remaining infants (92%) were well at birth with no complications. None were positive for SARS-CoV2 or had ‘serological evidence’ of vertical transmission. The method of testing neonates was not clearly defined. The stillborn neonate had a mother who was severely unwell on Extracorporeal Membrane Oxygenation (ECMO) at the time of delivery.
Five of the 10 patients (50%) were delivered by emergency cesarean section due to pregnancy complications including fetal distress (30%), premature rupture of the membrane (10%) and stillbirth (10%). Interestingly, six patients (46%) had preterm labour between 32- 36 weeks of gestation.
Han, M. S., M. W. Seong, E. Y. Heo, J. H. Park, N. Kim, S. Shin, S. I. Cho, S. S. Park and E. H. Choi (2020). “Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2.” Clin Infect Dis. https://doi.org/10.1093/cid/ciaa447
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.
Groß, C. Conzelmann, J. A. Müller, S. Stenger, K. Steinhart, F. Kirchhoff and J. Münch. Detection of SARS-CoV-2 in human breastmilk. Lancet, May 21st 2020, https://doi.org/10.1016/S0140-6736(20)31181-8
This report is presented as a letter.
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:
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.
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.
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. Further studies will be necessary to attempt to culture virus from breast milk and assess risk of transmission, which to date has seemed low.
Li, M., L. Chen, J. Zhang, C. Xiong and X. Li (2020). “The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study.” PLoS One 15(4): e0230295. https://doi.org/10.1371/journal.pone.0230295
The study explores the presence of Angiotensin-converting enzyme 2 (ACE2) within the placenta and the developing baby. It demonstrates significant expression of RNA coding the for ACE2 protein at several points of the maternal-foetal interface, as well as variable expression in a number of foetal organs. This theoretically provides a potential route for vertical transmission, placental dysfunction and pregnancy complications. The authors call for further clinical analysis to establish this potential.
Top 10 Clinical Papers
Swann Olivia V, Holden Karl A, Turtle Lance, Pollock Louisa, Fairfield Cameron J, Drake Thomas M et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. August 27th 2020, https://doi.org/10.1136/bmj.m3249
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 illness – 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.
This European multicentre cohort study recruited 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 identified cases prior to 1st April and prospectively between 1-24th April. The diagnosis was made based 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 was included from the history, with parents being the suspected 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 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. A 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 included 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 for 25 patients (4%) and ECMO was needed in one 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 older than 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 the end of the study period, 553 patients had made a full recovery and 25 patients had ongoing symptoms.
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)
Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi: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 confirmed contact with a case of COVID-19. Of these, 171 were confirmed to have SARSCoV-2. The 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 hospitalization. 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 their definition 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.
Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi:10.1056/NEJMc2007617
This report covered 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, the authors categorize their patients according to criteria from Dong et. al (see review in theEpidemiology 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 the severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below
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 were 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 a 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 ontological, and 1 metabolic disease.
Of the few patients that required respiratory support (9/100) a significant number had comorbidities (6/9), although the range was broad. This included two 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.
In comparison to Dong et al, the 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 the population cohorts presenting for testing among the different studies – comparison between cohorts is always difficult due to broad differences in the denominators used. There is no apparent difference in severity according to age in this Italian data set, whereas CDC noted increased hospitalization in children <1yr and Dong 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 the presence of significantly milder illness in children with COVID-19, including many asymptomatic children. A note is made of overrepresentation of children with comorbidities in this cohort (similar to the 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.
DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2020.05.007
This is a retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at the Children’s National Hospital, Washington DC US. Children and young adults were detected because of presentation with symptoms at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalized, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features were associated with hospitalization, or critical care.
This hospital served as a regional centre providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. The overall patient age range was from 0.1 – 34.2 years, with a median of 9.6 years. Of the total group 12/177 were > 20 years of age, and 37/177 were between the ages of 15 – 20years.
Age: There was no significant difference in age between the hospitalized and non-hospitalized patients, however in the hospitalized cohort, the critically unwell group were significantly older than the non-critically unwell hospitalized group (17.3 years versus 3.6 years; P =.04)
Sex: There was equal representation (n = 177 52% male, 48% female), as well as in 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 hospitalized patients (7/44 16%), nor of those admitted, or those who were critically unwell (2/9, 22%). Though the numbers were small, specific underlying conditions such as neurological, cardiac, haematological, or oncological issues were more common in the hospitalised cohort than the non hospitalised cohort. They were not more common in the hospitalized 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 a fever or any other specific symptom compared with the non-critically ill cohort.
Critical Care: 9 patients required critical care. This represented 5% (9/177) of the 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 one high flow nasal cannula oxygenation. 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 overrepresented in requiring critical care. Though underlying conditions were more common in hospitalized patients, they were not significantly more common in the hospitalized patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalized patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of the recently described hyperinflammatory state.
de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk 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 study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6
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 a 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.
González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/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.
M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065
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 in-patients 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. The 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). The estimate of the persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab was 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.
Galván Casas, C., Català, A., Carretero Hernández, et al. (2020), Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. Accepted Author Manuscript. doi: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.
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.
Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041
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 children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 months 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 intussusception) 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.
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Please note that whilst all papers have been reviewed for the database and consideration of the overall updates, only selected papers which added new information at the time of publication had a formal review written. The sublists below also include the top ten papers for convenience.
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)
Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi: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.
Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi: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
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.
DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2020.05.007
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.
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.
de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk 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 study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6
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.
Parri, N., A. M. Magistà, F. Marchetti, et al, (2020). “Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks.” Eur J Pediatr: 1-9. https://doi.org/10.1007/s00431-020-03683-8
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 %<5.5×109) and lymphopenia (<1.2×109) 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).
de Ceano-Vivas M, Martín-Espín I, del Rosal T, et al. SARS-CoV-2 infection in ambulatory and hospitalised Spanish children, Arch Dis Child, doi:10.1136 / archdischild-2020-319366
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.
Chen C. Coronavirus Disease-19 Among Children outside Wuhan, China [Internet]. Lancet Child and Adolescent medicine; Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=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.
Garazzino S, Montagnani C, Dona D, et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020; 25(18). https://dx.doi.org/10.2807%2F1560-7917.ES.2020.25.18.2000600
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%) and 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%)
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 39°C) 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.
Zhang C, Gu J, Chen Q, et al. Clinical Characteristics of 34 Children with Coronavirus Disease-2019 in the West of China: a Multiple-center Case Series. doi:10.1101/2020.03.12.20034686
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.
Qiu, Haiyan et al, Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. The Lancet Infectious Diseases, Volume 0, Issue 0 DOI:https:// 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.”
Zheng F, Liao C, Fan Q-H, et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Curr Med Sci 2020;:1–6. doi: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.
PICU Clinical Papers
González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, et al. Pediatric critical care and COVID19. Pediatrics. 2020; doi: 10.1542/peds.2020-1766
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.
González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/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.
Grasselli, G et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. doi:10.1001/jama.2020.5394 Published online April 6, 2020.
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.
Oualha, M., M. Bendavid, L. Berteloot, et al. “Severe and fatal forms of COVID-19 in children.” Archives de Pediatrie, June 4th 2020, https://doi.org/10.1016/j.arcped.2020.05.010
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 coronavirus 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.
This study focuses on 27 children unwell 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.
Lanyon, N., P. du Pré, T. Thiruchelvam, S. Ray, M. Johnson and M. J. Peters (2020). “Critical paediatric COVID-19: varied presentations but good outcomes.” Arch Dis Child. https://dx.doi.org/10.1136/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.”
Clinical Dermatology COVID-19
Colmenero, I., C. Santonja, M. Alonso-Riano, et al. “SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases.” The British journal of dermatology. June 20th 2020, https://doi.org/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
Locatelli AG, Robustelli Test E, Vezzoli P, Carugno A, Moggio E, Consonni L, Gianatti A, Sena P. Histologic features of long-lasting chilblain‐like lesions in a pediatric COVID‐19 patient. Journal of the European Academy of Dermatology and Venereology.09 May 2020. doi: 10.1111/jdv.16617. https://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.
Recalcati, S., T. Barbagallo, L. A. Frasin, F. Prestinari, A. Cogliardi, M. C. Provero, E. Dainese, A. Vanzati and F. Fantini (2020). “Acral cutaneous lesions in the Time of COVID-19.” J Eur Acad Dermatol Venereol.
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, V., I. Neri, C. Filippeschi, T et al (2020). “Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients.” J Eur Acad Dermatol Venereol published online 24th April 2020 https://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.
Radiology Findings COVID-19
Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults [published online ahead of print, 2020 Mar 5]. Pediatr Pulmonol. 2020;10.1002/ppul.24718. doi: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.
Görkem, S. B. and B. Çetin (2020). “COVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT.” Diagn Interv Radiol. June 5th 2020, DOI 10.5152/dir.2020.20361
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 4.01×109, lymphocytes 1.92×109, 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 hydroxychloroquine. 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.
Denina, M., C. Scolfaro, E. Silvestro, G. Pruccoli, F. Mignone, M. Zoppo, U. Ramenghi and S. Garazzino (2020). “Lung Ultrasound in Children With COVID-19.” Pediatrics. 21. https://doi.org/10.1542/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
Li W, Cui H, Li K, Fang Y, Li S. Chest computed tomography in children with COVID-19 respiratory infection [published online ahead of print, 2020 Mar 11]. Pediatr Radiol. 2020;10.1007/s00247-020-04656-7. doi:10.1007/s00247-02004656-7
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.
Liu H, Liu F, Li J, Zhang T, Wang D, Lan W. Clinical and CT Imaging Features of the COVID-19 Pneumonia: Focus on Pregnant Women and Children [published online ahead of print, 2020 Mar 11]. J Infect. 2020;S0163-4453(20)30118-3. doi: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.
Cardiology Papers
Del Barba, P., D. Canarutto, E. Sala, G. Frontino, M. P. Guarneri, C. Camesasca, C. Baldoli, A. Esposito and G. Barera (2020). “COVID-19 cardiac involvement in a 38-day old infant.” Pediatr Pulmonol. June 18th 2020, https://doi.org/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.
Selman Kesici, Hayrettin Hakan Aykan, Diclehan Orhan, Benan Bayrakci, Fulminant COVID-19-related myocarditis in an infant, European Heart Journal, June 12th 2020, ehaa515, https://doi.org/10.1093/eurheartj/ehaa515
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
Trogen, B., F. J. Gonzalez and G. F. Shust (2020). “COVID-19-Associated Myocarditis in an Adolescent.” The Pediatric Infectious Disease Journal. 03. June 3rd 2020, doi: 10.1097/INF.0000000000002788
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.
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.
Ocular Manifestation
Valente, P., G. Iarossi, M. Federici, et al. Ocular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report. J aapos. June 10th 2020, https://doi.org/10.1016/j.jaapos.2020.05.002
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.
Testing/Viral Studies
M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065
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.
Xu, Y, Li X. Zhu, B. et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med (2020). https://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.
Yuan, C., H. Zhu, Y. Yang, X. Cai, F. Xiang, H. Wu, C. Yao, Y. Xiang and H. Xiao (2020). “Viral loads in throat and anal swabs in children infected with SARS-CoV-2.” Emerg Microbes Infect: https://doi.org/10.1080/22221751.2020.1771219
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 1January 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 pos
GI symptoms: 7/37 (19%) TS pos & 6/17 (35%) AS pos
Cough: 16/37 (43%) TS pos & 4/17 (24%) AS pos
Fever: 20/37 (54%) TS pos & 5/17 (29%) AS pos
CT evidence of pneumonia: 25/37 (68%) TS pos & 10/17 (59%) AS pos
Time from positive to negative for PCR assay: 7 days for TS pos & 6 days for AS pos
The viral loads detected on throat swabs and anal swabs showed no difference.
Zhao, W., Y. Wang, Y. Tang, W. Zhao, Y. Fan, G. Liu, R. Chen, R. Song, W. Zhou, Y. Liu and F. Zhang (2020). “Characteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge.” Clin Pediatr,May 28th https://doi.org/10.1177%2F0009922820928057
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<https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25952>. This includes a large cohort of over 200 patients from Korea <https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030> 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<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> 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<https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2765641> 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
Xing Y, Ni W, Wu Q, et al. Prolonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase. doi:10.1101/2020.03.11.20033159
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.
Pandey U, Yee R, Precit M, et al Pediatric COVID-19 in Southern California: clinical features and viral genetic diversity, medRXiv, June 2nd 2020, https://doi.org/10.1101/2020.05.28.20104539
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.
Zachariah, P., K. C. Halabi, C. L. Johnson, S. Whitter, J. Sepulveda and D. A. Green (2020). “Symptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children.” Clin Infect Dis, May 20th 2020, https://doi.org/10.1093/cid/ciaa608
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<https://www.nature.com/articles/s41591-020-0869-5> – 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<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> / 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.
Haematology and Immunology Focus
Odièvre, M. H., C. de Marcellus, H. Ducou Le Pointe, S. Allali, A. S. Romain, J. Youn, J. Taytard, N. Nathan and H. Corvol (2020). “Dramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome.” May 1st 2020, Am J Hematol. https://doi.org/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-α 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.
Tsao HS, Chason HM, Fearon DM. Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics. 2020 May 1. doi: 10.1542/peds.2020-1419. Pre-publication version.
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.
Wu, H., H. Zhu, C. Yuan, C. Yao, W. Luo, X. Shen, J. Wang, J. Shao and Y. Xiang (2020). “Clinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China.” JAMA Netw Open 3(6): e2010895. doi:10.1001/jamanetworkopen.2020.10895
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.
Venturini E, Palmas G, Galli L. Severe neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection. 2020 May 19. doi 10.1016/j.paeds 2020.04.051 [Epub ahead of print]
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.
Chen, J., Z. Z. Zhang, Y. K. Chen, et al (2020). “The clinical and immunological features of pediatric COVID-19 patients in China.” Genes and Diseases. https://doi.org/10.1016/j.gendis.2020.03.008
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.
Other Interesting Clinical Papers
Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041
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.
Li Y, Wang H, Wang F, Du H, Liu X, Chen P, Wang Y, Lu X, Comparison of Hospitalized Patients with pneumonia caused by COVID-19 and influenza A in children under 5 years, International Journal of Infectious Diseases (2020) https://doi.org/10.1016/j.ijid.2020.06.026
This study is from Wuhan children’s hospital, China. It is a retrospective one reviewing the clinical history, radiology and laboratory results of 57children under 5, with confirmed pneumonia on CT or radiography within 72 hours of admission, with COVID-19 diagnosed by detecting SARS-CoV-2 in throat swabs. The comparison group was 59 children aged under 5 who were admitted with influenza A pneumonia. Influenza A was diagnosed by direct immunofluorescence assay.
The 57 COVID-19 pneumonia children were consecutively admitted between 28th January and 11th March 2020; the 59 influenza A pneumonia children were consecutively admitted between 14th December 2019 and 30th February 2020(?).
The median age of the COVID-19 patients was 18.7+/- 16.7 months. The median age of the Influenza A patients was 21.8+/-16.7 months with no statistical difference. There was slightly higher proportion of males in each group 61.4% for COVID-19 vs 66.1% for the influenza A group with no statistical difference.
Clinical features: 31(54.4%) of the COVID-19 patients presented with fever compared to 50(84.7%) influenza A patients, P<0.001. 40(70.2%) of the COVID-19 patients presented with cough compared to 50(84.7%) in the influenza A group, p<0.001. Dyspnoea occurred in only 2(3.5%) COVID-19 patients and 5(8.5%) influenza A patients, p=NS. Gastrointestinal symptoms occurred in 8(14.1%) of the COVID-19 patients and 21(35.6%) of the influenza A patients, p=NS. Convulsions occurred in only 1 COVID-19 child and 3 influenza A children, p=NS. During hospitalization 1 COVID-19 child required supplementary oxygen and two required intensive care, compared to 7 influenza A children requiring supplementary oxygen and 4 intensive care, p=NS.
Radiology: CT chest imaging with ground glass appearance was more commonly found in COVID-19 pneumonia children 42.1% vs15% influenza A pneumonia children, p=0.03. Consolidation was more common in influenza A children (25%) compared to COVID-19 patients (5.2%), P = 0.02.
Haematology and Biochemistry
Haematology investigations showed COVID-19 patients had significantly lower levels of leukocytes and neutrophils but significantly higher lymphocyte levels compared with influenza A patients (7.87 vs. 9.89 ×109/L, P = 0.02; 2.43 vs. 5.16 ×109/L, P < 0.001; 4.58 vs. 3.56 ×109/L; P = 0.006.
Lower levels of C-reactive protein (CRP) were observed in COVID-19 patients than influenza A patients (3.7 vs. 15.1 mg/L, P = 0.001.
There were no significant routine biochemistry differences between the two groups except potassium which was significantly lower in the COVID-19 group.
Significantly lower levels of D-dimer and prothrombin time (PT) were found in COVID-19 patients than influenza A patients (0.34 vs. 1.94, P < 0.001; 10.8 vs. 11.2 mm/h, P = 0.014).
There were no deaths reported in this study.
Conclusion: The authors concluded that children under 5 with COVID-19 pneumonia compared to children with influenza A pneumonia showed milder clinical symptoms and a significantly increased lymphocytosis with a more prevalent ground glass CT chest appearance compared to influenza A pneumonia children under 5. There were no reported deaths or serious complications from COVID-19 in this study.
The study shows COVID-19 pneumonia is milder than influenza A pneumonia in a series children under 5. The influenza A patients were not typed and came from a different but overlapping time period during the winter months. Comorbidities were also not mentioned in either group.
Lu, Y., Y. Li, W. Deng, M. Liu, Y. He, L. Huang, M. Lv, J. Li and H. Du (2020). “Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan.” The Pediatric infectious disease journal. 05. doi: 10.1097/INF.0000000000002729
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-α. 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.
Xiao, Z., X. Xie, W. Guo, Z. Luo, J. Liao, F. Wen, Q. Zhou, L. Han and T. Zheng (2020). “Examining the incubation period distributions of COVID-19 on Chinese patients with different travel histories.” Journal of infection in developing countries 14(4): 323-327. doi:10.3855/jidc.12718
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.
Zhang, B., S. Liu, Y. Dong, L. Zhang, Q. Zhong, Y. Zou and S. Zhang (2020). “Positive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19).” Journal of Infection April 23rd 2020, https://doi.org/10.1016/j.jinf.2020.04.023
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.
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 39°C). 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 with fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.
Wu, Q., Y. Xing, L. Shi, W. Li, Y. Gao, S. Pan, Y. Wang, W. Wang and Q. Xing (2020). “Co-infection and Other Clinical Characteristics of COVID-19 in Children.” Pediatrics. May 1st 2020, DOI: https://doi.org/10.1542/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.
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.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775
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.
There were only 59 patients under 10yo, and 15 patients between 10-20 years of age in this study.
The results below unless specified are for patients of all ages.
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 34 patients under 18 age group out of those who had reached discharge end point. There were still 25 patients under 20 years hospitalised at the time of the paper.
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.
Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. Published online May 11, 2020. doi:10.1001/jamapediatrics.2020.1948
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%)
Lazzerini, Marzia et al, Delayed access or provision of care in Italy resulting from fear of COVID-19, The Lancet Child & Adolescent Health, Volume 0, Issue 0, Published April 9th 2020, https://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.
Preßler, J., S. Fill Malfertheiner, M. Kabesch, H. Buntrock-Döpke, S. Häusler, A. Ambrosch and S. Wellmann (2020). “Postnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study.” Pediatr Allergy Immunol. 9th June 2020, https://doi.org/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 15May 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).
Small cohort <10 children and Single Case Reports
Ji L, Chao S, Want Y et al. Clinical features of pediatric patients with COVID-19: a report of two family cluster cases. World J Pediatr. 2020 Mar 16. doi: 10.1007/s12519-020-00356-2. [Epub ahead of print] https://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.
Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med 2020;:NEJMc2003717. doi: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.
Pan X, Chen D, Xia Y, et al. Asymptomatic cases in a family cluster with SARS-CoV-2 infection, The Lancet Infectious Diseases, 2020, https://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.
Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang Z. Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. Published online February 14, 2020. doi: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.
Jiehao Cai, Jing Xu, Daojiong Lin et al, A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features, Clinical Infectious Diseases, ciaa198, https://doi.org/10.1093/cid/ciaa198
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.
Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series BMJ 2020; 368 :m606
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.
Kai-Qian Kam, Chee Fu Yung, Lin Cui et al, A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load, Clinical Infectious Diseases, ciaa201, https://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.
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 Published Online First: 17 March 2020. doi:10.1093/infdis/jiaa113
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.
Paret M, Lighter J, Pellett Madan R, Raabe VN, Shust GF, Ratner AJ. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress [published online ahead of print, 2020 Apr 17]. Clin Infect Dis. 2020;ciaa452. doi: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.
Zhu, L., J. Wang, R. Huang, L. Liu, H. Zhao, C. Wu and C. Zhu (2020). “Clinical characteristics of a case series of children with coronavirus disease 2019.” Pediatr Pulmonol 8th April 2020 https://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.
Canarutto, D., A. Priolo, G. Russo, M. Pitea, M. C. Vigone and G. Barera (2020). “COVID-19 infection in a paucisymptomatic infant: Raising the index of suspicion in epidemic settings.” Pediatr Pulmonol. https://doi.org/10.1002/ppul.24754
This early single case report from Milan, Italy describes an infant with 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.
Shen Q, Guo W, Guo T, Li J, He W, Ni S, Ouyang X, Liu J, Xie Y, Tan X, Zhou Z. Novel coronavirus infection in children outside of Wuhan, China. Pediatric pulmonology. 2020 Apr 7.p1-6 DOI: 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.
Han, Y. N., Z. W. Feng, L. N. Sun, X. X. Ren, H. Wang, Y. M. Xue, Y. Wang and Y. Fang (2020). “A comparative-descriptive analysis of clinical characteristics in 2019-Coronavirus-infected children and adults.” J Med Virol. 6th April 2020. https://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.
Kamali Aghdam M, Jafari N, Eftekhari K. Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report [published online ahead of print, 2020 Apr 1]. Infect Dis (Lond). 2020;1–3. doi:10.1080/23744235.2020.1747 634 Accessed from: https://www.tandfonline.com/doi/full/10.1080/23744235.2 020.1747634 on 4th April
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).
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.
Su L, Ma X, Yu H, et al. The different clinical characteristics of coronavirus disease cases between children and their families in China – the character of children with COVID-19. Emerg Microbes Infect. 2020;9(1):707–713. doi:10.10 80/22221751.2020.1744483
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.
Lou XX, Shi CX, Zhou CC, et al. Three children who recovered from novel coronavirus 2019 pneumonia. J Paediatr Child Health Published Online First: 22 March 2020. doi: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.
Top Papers on Co-morbidities
Mixed co-morbidities
Issitt R, Booth J, Bryant W, Spiridou A, Taylor A, DuPre P, Ramnarayan P, Hartley J, Borja MC, Moshal K, Dunn H. Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population. medRxiv. 2020 Jan 1. Doi https://doi.org/10.1101/2020.05.20.20107904
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
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.
Oncology
Gampel, B. Troullioud Lucas, AG. Broglie, T. et al. (2020 Jun 26). “COVID-19 disease in New York City pediatric hematology and oncology patients.” Pediatr Blood Cancer: e28420. June 26th 2020, https://doi.org/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
Ferrari, A., M. Zecca, C. Rizzari, F. et al (2020). “Children with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy.” Pediatr Blood Cancer: e28410.
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.
Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in Children With Cancer in New York City. JAMA Oncol. Published online May 13, 2020. doi:10.1001/jamaoncol.2020.2028
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.
Cesaro, S., F. Compagno, D. Zama, L. Meneghello, N. Giurici, E. Soncini, D. Onofrillo, F. Mercolini, R. Mura, K. Perruccio, R. De Santis, A. Colombini, A. Barone, L. Sainati, V. Baretta and M. G. Petris (2020). “Screening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy.” Pediatr Blood Cancer: e28466, https://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 V, Miranda R, Merino L, et al. SARS-CoV-2 infection in children with febrile neutropenia [published online ahead of print, 2020 Jun 12]. Ann Hematol. 2020;1-2. doi:10.1007/s00277-020-04115-1
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.
Sieni, E. Pegoraro, F. Casini, T. Tondo, A. Bortone, B. Moriondo, M. Azzari, C. Galli, L. Favre, C. Favourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression. British Journal of Haematology. 2020 May 5. https://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.
Hrusak, O., T. Kalina, J. Wolf, A. et al. (2020). “Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.” European Journal of Cancer 132: 11-16. https://doi.org/10.1016/j.ejca.2020.03.021
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.
D’Antiga L. (2020), Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl. Accepted Author Manuscript. doi: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.
Balduzzi, A, Brivio, E, and Rovelli, A et al, Lessons 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, Italy. Estote Parati. (Be Ready.) (3/19/2020). Available at SSRN: https://ssrn. com/abstract=3559560 or https://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.
Cardiac disease
Lee, H., B. S. Mantell, M. E. Richmond, S. P. Law, W. A. Zuckerman, L. J. Addonizio, T. M. Lee and I. D. Lytrivi (2020). “Varying Presentations of COVID-19 in Young Heart Transplant Recipients: A Case Series.” Pediatr Transplant: e13780. https://doi.org/10.1111/petr.13780
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 pandemic
Hospital/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.
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.
Respiratory disease
Poli, P., S. Timpano, M. Goffredo, R. Padoan and R. Badolato. “Asymptomatic case of Covid-19 in an infant with cystic fibrosis.” Journal of Cystic Fibrosis, April 14th 2020, https://doi.org/10.1016/j.jcf.2020.03.017
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.
Inflammatory Bowel Disease
Turner D, Huang Y, Martín-de-Carpi J, et al. COVID-19 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto group of ESPGHAN [published online ahead of print, 2020 Mar 31]. J Pediatr Gastroenterol Nutr. 2020; doi: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.
Brenner, E. J., R. C. Ungaro, R. B. Gearry et al “Corticosteroids, but not TNF Antagonists, are Associated with Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results from an International Registry.” Gastroenterology https://doi.org/10.1053/j.gastro.2020.05.032
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.
Renal disease
Schwierzeck, V., J. C. Konig, J. Kuhn, A. Mellmann, C. L. Correa-Martinez, H. Omran, M. Konrad, T. Kaiser and S. Kampmeier (2020). “First reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit.” Clin Infect Dis, https://doi.org/10.1093/cid/ciaa491
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.
Transplant related disease
Lagana SM, De Michele S, Lee MJ, Emond JC, Griesemer AD, Tulin-Silver SA, Verna EC, Martinez M, Lefkowitch JH. COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation. Archives of Pathology & Laboratory Medicine. 2020 Apr 17. doi: 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.
Angeletti, A., A. Trivelli, A. Magnasco, S. Drovandi, F. Sanguineri, M. Santaniello, G. Ferrando, R. Forno, G. Cipresso, G. Tripodi, L. V. Riella, P. Cravedi and G. M. Ghiggeri (2020). “Risk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study.” Clin Transplant. 2020 May 12. doi: 10.1111/ctr.13889. [Epub ahead of print]
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.
Morand, A., B. Roquelaure, P. Colson, S. Amrane, E. Bosdure, D. Raoult, J. C. Lagier and A. Fabre (2020). “Child with liver transplant recovers from COVID-19 infection. A case report.” Archives de Pediatrie. https://doi.org/10.1016/j.arcped.2020.05.004
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.
Other co-morbidities
Genovese, G., Colonna, C. and Marzano, A.V. (2020), Varicella‐like exanthem associated with COVID‐19 in an 8‐year‐old girl: A diagnostic clue?. Pediatr Dermatol. Accepted Author Manuscript. doi: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.
Top 10 Epidemiological Papers on Transmission
Yung, C. F., Kam, K., Nadua, K. D. et al. Novel coronavirus 2019 transmission risk in educational settings. Clinical Infectious Diseases. https://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.
Heavey, L., G. Casey, C. Kelly, D. Kelly and G. McDarby (2020). “No evidence of secondary transmission of COVID-19 from children attending school in Ireland, 2020.” Euro Surveill 25(21). May 28th 2020, https://doi.org/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.
Somekh, E., A. Gleyzer, E. Heller, M. Lopian, L. Kashani-Ligumski, S. Czeiger, Y. Schindler, J. B. Lessing and M. Stein (2020). “The Role of Children in the Dynamics of Intra Family Coronavirus 2019 Spread in Densely Populated Area.” Pediatr Infect Dis J. doi: 10.1097/INF.0000000000002783
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.
Qin-Long Jing, Ming-Jin Liu, Jun Yuan et al, Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study, The Lancet, June 17th 2020, https://doi.org/10.1016/S1473-3099(20)30471-0
This is study from Guangzhou, China documenting the attack rate amongst 1964 close contacts and 134 secondary or tertiary cases of 215 confirmed COVID-19 cases from January 7th to February 18th 2020.
There were 103 non-primary cases amongst 784 household contacts giving an attack rate of 13.1% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.2%. In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.23, 95% CI 0.11-0.46)
Only 10/215 (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 keeping with other reports from Asia (Zhang), Israel (Somekh) and the USA (Rosenberg).
Eli S Rosenberg, Elizabeth M Dufort, Debra S Blog et al. New York State Coronavirus 2019 Response Team, COVID-19 Testing, Epidemic Features, Hospital Outcomes, and Household Prevalence, New York State—March 2020, Clinical Infectious Diseases, ciaa549, https://doi.org/10.1093/cid/ciaa549
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.
This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghai) 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.
Li, W., B. Zhang, J. Lu, S. Liu, Z. Chang, P. Cao, X. Liu, P. Zhang, Y. Ling, K. Tao and J. Chen (2020). “The characteristics of household transmission of COVID-19.” Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 17. https://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.
Wang, Z., W. Ma, X. Zheng, G. Wu and R. Zhang (2020). “Household Transmission of SARS-CoV-2.” The Journal of infection. 10. https://doi.org/10.1016/j.jinf.2020.03.040
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.
Zhu Y, Bloxham CJ, Hulme KD, et al. Children are unlikely to have been the primary source of household SARS-CoV-2 infections. medRxiv 2020;:2020.03.26.20044826. doi: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.
Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study, Lancet Infectious Disease, April 27th 2020, https://doi.org/10.1016/S1473-3099(20)30287-5
This was a fairly impressive study looking at contact tracing of 1286 contacts of 391 patients with COVID-19. Only 20 (5.1%) of the initial 391 cases were children, of which 2/3 were asymptomatic. They discovered a secondary attack rate of 15% for household contacts and 9.6% overall. The most important finding is that the rate of infection in children <10 years (7.4%) was similar to the population average (7.9%). The findings of this study suggested that children were becoming infected at a similar rate to adults but were much less likely to be asymptomatic. As no repeat testing was performed, it is unclear if these children were truly asymptomatic, or presymptomatic. Subsequent studies have consistently shown lower attack rates in children, and the reason for this discrepancy is unknown.
Top Epidemiological Papers on Disease Burden
Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al. Prevalence of SARSCoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 2020. https://doi.org/10.1016/ S0140-6736(20)31483-5
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-CoV-2 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.
Gabriele Pagani, Federico Conti, Andrea Giacomelli et al, Seroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA). medRxiv June 24th 2020, https://doi.org/10.1101/2020.06.24.20138875
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.
Stringhini, S., A. Wisniak, G. Piumatti, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study.” Lancet. June 11th 2020, https://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.
Lavezzo, E., Franchin, E., Ciavarella, C. et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’. Nature (2020). https://doi.org/10.1038/s41586-020-2488-1
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). It should be noted the definition of symptoms was restricted to ECDC definitions of COVID-19 related symptoms, and given the wide variation of non-classic symptoms which have been described (rashes, malaise, joint aches, rhinorroea, GI symptoms etc), this likely significantly undercounts the number of patients who truly developed symptoms.
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.
Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, Melsted P, Norddahl GL, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med, Published April 14th 2020, doi: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.
Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 April 2020. DOI: https://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.
Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics 2020:e20200702. doi:10.1542/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.
Top 10 PIMS-TS / MIS-C Papers
Felstein, L.R. et al (2020) Multisystem Inflammatory Syndrome in U.S. Children and Adolescents, NEJM. epub 29 June 2020, DOI:10.1056/NEJMoa2021680.
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.
Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. DOI: 10.1056/NEJMoa2021756.
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.
Kaushik, S., S. I. Aydin, K. R. Derespina et al, “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection: A Multi-institutional Study from New York City.” J Pediatr. https://doi.org/10.1016/j.jpeds.2020.06.045
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 ³ 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.
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
Capone, C. A., A. Subramony, T. Sweberg, J. et al. “Characteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection.” J Pediatr. https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.044
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.
Whittaker, E., A. Bamford, J. Kenny, et al. “Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2.” Jama. doi:10.1001/jama.2020.10369
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.
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.
Cheung EW, Zachariah P, Gorelik M, et al. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. JAMA. Published online June 08, 2020. doi:10.1001/jama.2020.10374
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.
Belot, A., D. Antona, S. Renolleau, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020.” Euro Surveill 25(22). June 4th 2020, https://doi.org/10.2807/1560-7917.ES.2020.25.22.2001010
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.
Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, Auriau J, Grimaud M, Oualha M, Beghetti M, Wacker J. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020 May 17. doi: 10.1161/CIRCULATIONAHA.120.048360
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.
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”.
Toubiana Julie, Poirault Clément, Corsia Alice, Bajolle Fanny, Fourgeaud Jacques, Angoulvant François et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study BMJ 2020; 369 :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.
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.
Paediatric COVID data
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Parri, N
Buonsenso, D
NEJM
Children with Covid-19 in Pediatric Emergency Departments in Italy
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
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, H
Fearon, D
Pediatrics
Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics
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, C
Teachey, D
Blood Advances
Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.
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, M
Tulus, K
Archdischild
COVID-19 in children treated with immunosuppressive medication for kidney diseases
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, M
Launes, C
jinf
Low Impact of SARS-CoV-2 infection among Paediatric Acute Respiratory Disease Hospitalisations
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, C
Segura, O
PIDJ
Clinical and epidemiological analysis of COVID-19 children cases in colombia PEDIACOVID
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, M
Goss, J
Paediatric Transplantation
The pediatric solid organ transplant experience with COVID‐19: An initial multi‐center, multi‐organ case series
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, S
Garg, A
J Am Acad Dermatol
Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children
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, J
Ludvigsson, J
Acta Paediatr
Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19
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, H
Ramsi, M
BMJ
Clinical course of COVID-19 among immunocompromised children a clinical case series
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, L
Pandey, A.K
Int J Pediatr Otorhinolaryngol
Loss of smell and taste in COVID-19 infection in adolescents
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, G
Kearns, P
Br J Cancer
Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project
10 Dec 2020
United Kingdom
Europe
54
Clinical - Clinical Features
https://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, C
Campbell, JR
jpids
A Surge in Pediatric Coronavirus Disease 2019 Cases: The Experience of Texas Children's Hospital from March to June 2020
10 Dec 2020
USA
North America
1215
Clinical - Clinical Features
https://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, A
Alghounaim, M
J Infect Public Heal
Characteristics and outcomes of coronavirus disease2019 (COVID-19) in critically ill paediatric patients admitted to the intensive care unit: a multi-center retrospective cohort study.
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, A
Gaur, S
Pediatr Infect Dis J
Pediatric COVID-19 and Appendicitis: A Gut Reaction to SARS-CoV-2
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, B
Segal, E
Nat. Commun
Longitudinal symptom dynamics of COVID-19 infection
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, R
Brodie,M
Journal of Cystic Fibrosis
Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.
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, M
Ceyhan, M
Pediatr Pulmonol
Diagnostic Value of Lung Ultrasonography in Children with COVID-19
21 Oct 2020
Turkey
Europe and Asia
40
Clinical - Clinical Features
https://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, MC
Wheeler, SE
J Pediatric Infect Dis Soc
Immunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center
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, M
Garazzino, S
Pediatr Infect Dis J
Sequelae of COVID-19 in Hospitalized Children: A 4-Months Follow-Up
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, D
Koumans, E
CDC MMWR
SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020
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, DM
Rapp, JB
Paediatr Radiol
Imaging of children with COVID-19: experience from a tertiary children’s hospital in the United States
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.
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, C
Thoon, K
Clin Infect Dis
Saliva is not a useful diagnostic specimen in children with Coronavirus Disease 2019
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, G
Linguraru, GM
Pediatr Pulmonol
PEDIATRIC LUNG IMAGING FEATURES OF COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS
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, MS
Chang, SH
JAMA Paediatr
Clinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea
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).
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, L
Fasano, A
jpeds
Pediatric SARS-CoV-2: Clinical Presentation, Infectivity and Immune Responses
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, M
Shankar-Hari
Nat Med
Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection
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, O
Semple, M
BMJ
Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study
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, X
Chen, J
J Infect Dis
Clinical and epidemiological features of 46 children under 1 year old with coronavirus disease 2019 (COVID-19) in Wuhan, China: a descriptive study
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%).
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, T
Kociolek, LK
JAMA Paediatr
Age-Related Differences in Nasopharyngeal SevereAcute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) Levels in Patients With Mild toModerate Coronavirus Disease 2019 (COVID-19)
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.B
Yassky, E
EJACI
SARS‐CoV‐2 receptorACE2 protein expression in serum is significantly associated with age
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, C
Tagarro, A
Clinical infectious Diseases
Multi-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain
25 Jul 2020
Spain
Europe
252
Clinical - Clinical Features
https://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, A
Cunha, A
J Pediatr (Rio J)
Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study
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, M
Lorry, GR
Pediatrics
Early Experience of COVID-19 in a US Children's Hospital
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, KR
Medar, SS
J Pediatr
Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with COVID-19 in New York City.
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, L
Madhi, F
J Clin Med 9(7)
Epidemiology and Clinical Presentation of Children Hospitalized with SARS-CoV-2 Infection in Suburbs of Paris
14 Jul 2020
France
Europe
192
Clinical - Clinical Features
https://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.
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, D
Wenbin,G
Front Pediatr
Clinical Characteristics of Children With COVID-19: A Meta-Analysis
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.”
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, Q
Xing, Q
Pediatrics
Co-infection and Other Clinical Characteristics of COVID-19 in Children
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, O
Hacohen, Y
JAMA Neurol
Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children
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, J
Dai, X
J Med Internet Res
Identification of Symptoms Prognostic of COVID-19 Severity: Multivariate Data Analysis of a Case Series in Henan Province
30 Jun 2020
China
Asia
12
Clinical - Clinical Features
https://www.jmir.org/2020/6/e19636/pdf
Acker, K
Han, J
Clin Pediatr (Phila)
Infectious Diseases Diagnoses of Children Admitted With Symptoms of Coronavirus Disease 2019 During an Outbreak in New York City
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, F
Tebruegge, M
Lancet
COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study
25 Jun 2020
Europe (Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the UK)
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 Pulmonology
Clinical Characteristics of Acute Respiratory Syndrome with SARS-CoV-2 Infection in Children in South China.
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, J
Kaicker, S
Pediatric Blood and Cancer
SARS‐CoV‐2 infection in two pediatric patients with immune cytopenias: A single institution experience during the pandemic
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, N
Martinez, M
Paediatr Transplant
A Case of an Infant with SARS-CoV-2 hepatitis early afterLiver Transplantation
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 Pulmonol
COVID-19 cardiac involvement in a 38-day old infant
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, LB
Kociolek, LK
j.peds
SARS-CoV-2 Infection in Infants Less than 90 Days Old
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.”
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.
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 dermatology
Chilblains in children in the time of Covid‐19: new evidence with serology assay
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, QL
Yu, ZJ
Transbound Emerg Dis
Clinical course and treatment efficacy of COVID-19 near Hubei Province, China: a multicentre, retrospective study
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 Y
Liu Y H
Clin Infect Dis.
Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019 - a multi-centre observational study.
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.
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, W
Q. Li
J Infect Public Health
Persistence of SARS-CoV-2 virus RNA in feces: A case series of children
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, M
Jpn J Radiol
Clinical and radiological characteristics of pediatric patients with COVID-19: focus on imaging findings
Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York
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,N
Lazzerini,M
Eur J Pediatr
Characteristic of Covid-19 infection in paediatric patients: early findings from two Italian Pediatric Research Networks
03 Jun 2020
Delayed access or provision of care in Italy resulting from fear of COVID-19
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 U
Dien Bard J
MedRxIV
Pediatric COVID-19 in Southern California: clinical features and viral genetic diversity
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, C
Bamford A
Pediatrics
Infant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir
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).
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, OY
Shnakhova, LM
Dermatol Ther
Cutaneous manifestations in COVID‐19: a skin rash in a child
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
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, A
Serrano-Gonzalez, A
Pediatr Crit Care Med
Children in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital
Features of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
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, E
Balla, U
Eur Rev Med Pharmacol Sci
Lung ultrasound cannot be used to screen for Covid-19 in children
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, E
Galli, L
J Paediatr
Severe neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection
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 X
Tam, P
Gut
Comparative study of the clinical characteristics and epidemiological trend of 244 COVID-19 infected children with or without GI symptoms
Acute inflammation and elevated cardiac markers in a two-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with cardiac symptoms
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, B
Turel, O
Dermatol Ther
Appearance of Skin Rash in Pediatric Patients with COVID-19: Three Case Presentations
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, K
Li, C
PIDJ
Clinical analysis of 25 Novel Coronavirus Infections in Children
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, J
Medar, S
J. 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
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, N
Zheng, X
Transl Pediatr
Analysis and suggestions for the preview and triage screening of children with suspected COVID-19 outside the epidemic area of Hubei Province
10 May 2020
China
Asia
36
Clinical - Clinical Features
http://dx.doi.org/10.21037/tp.2020.03.08
Andina, D.
Torello, A.
Paediatric Dermatology
Chilblains in children in the setting of COVID-19 pandemic
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, GR
Kwolek, CJ
International Journal of Pediatric Otorhinolaryngology
Asymptomatic COVID-19 infection in a child with nasal foreign body
Protective humoral immunity in SARS-CoV-2 infected pediatric patients
07 May 2020
China
Asia
6
Clinical - Clinical Features
https://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, A
Varrassi, G
Pain Ther
Images in Practice: Painful Cutaneous Vasculitis in a SARS-Cov-2 IgG-Positive Child
Are 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 Wuhan
Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan
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 Therapy
Chilblain-like lesions in pediatrics dermatological outpatients during the COVID-19 outbreak
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, X
Ciu, L
VirusRes
Co-infection with respiratory pathogens among COVID-2019 cases
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 neonate
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, V
Bassi, A
Journal of the European Academy of Dermatology and Venereology
Chillblain-like lesions during COVID-19 pandemic: a preliminary study on 63 patients
24 Apr 2020
Italy
Europe
63
Clinical - Clinical Features
https://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, S
Fantini, F
J Eur Acad Dermatol Venereol
Acral cutaneous lesions in the time of COVID-19
24 Apr 2020
Italy
Europe
11
Clinical - Clinical Features
https://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, N
Aguirre, T
International Journal of Dermatology
Chillblain-like lesions on feet and hands during the COVID-19 pandemic
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, L
Zhou, J
Clin Imag
Initial CT imaging characters of an imported family cluster of COVID-19
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, H
Xu, Q
J Infect
The Profile of Peripheral Blood Lymphocyte Subsets and Serum Cytokines in Children With 2019 Novel Coronavirus Pneumonia
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, S
Davidson, K
JAMA network
Presenting Characteristics, Comorbidities and Outcomes among 5700 patients hospitalized with COVID-19 in the New York City area
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, H
Xu, J
Journal of Medical Virology
Positive result of SARS-CoV-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu, China
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.
JMV
Detection of SARS‐CoV‐2 by RT‐PCR in anal from patients who have recovered from coronavirus disease 2019
Delayed access of provision of care in Italy resulting from fear of COVID-19
09 Apr 2020
Italy
Europe
12
Clinical - Clinical Features
https://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, C
Zhu, L
Pediatric Pulmonology
Clinical characteristics of a case series of children with coronavirus disease 2019
08 Apr 2020
China
Asia
10
Clinical - Clinical Features
https://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, J
Liu, L
Clinical Infectious Diseases
PCR assays turned positive in 25 discharged COVID-19 patients
08 Apr 2020
China
Asia
6
Clinical - Clinical Features
https://doi.org/10.1093/cid/ciaa398
Shen, Q
Zhou, Z
Pediatric Pulmonology
Novel coronavirus infection in children outside of Wuhan, China
07 Apr 2020
China
Asia
9
Clinical - Clinical Features
https://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, P
Jiao, J
Journal of X-ray Science and Technology
Clinical and computed tomographic (CT) images characteristics in the patients with COVID-19 infection: what should radiologists need to know?
A comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults
06 Apr 2020
China
Asia
7
Clinical - Clinical Features
https://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, G
Pasenti, A
JAMA
Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy
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, W
Liu, J
Pediatr Radiol
Computed tomography of the lungs in novel corona virus (COVID-19) infection
06 Apr 2020
China
Asia
2
Clinical - Clinical Features
https://doi.org/10.1007/s00247-020-04664-7
Canarutto, D
Barera, G
Pediatric Pulmonology
COVID-19 infection in a paucisymptomatic infant: raising the index of suspicion in epidemic settings
06 Apr 2020
Italy
Europe
1
Clinical - Clinical Features
https://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, L
Shan, H
Gut
Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection
Journal of Microbiology, Immunology and Infection.
Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019
28 Mar 2020
China
Asia
3
Clinical - Clinical Features
https://dx.doi.org/10.1016%2Fj.jmii.2020.03.021
Yin X
Li H
Radiology of Infectious Diseases
A mild type of childhood COVID-19 - a case report
27 Mar 2020
China
Asia
1
Clinical - Clinical Features
https://doi.org/10.1016/j.jrid.2020.03.004
Qui, H
Lancet: Infectious Diseases
Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study
25 Mar 2020
China
Asia
36
Clinical - Clinical Features
https://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, L
Gai, Z
Emerging Microbes and Infections
The different clinical characteristics of corona virus disease cases between children and their families in China - the character of children with COVID-19
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, F
Jin, R
Current Medical Science
Clinical characteristics of children with coronavirus disease 2019 in Hubei, China
24 Mar 2020
China
Asia
25
Clinical - Clinical Features
https://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, X
Tian, Y
Journal of Paediatrics and Child Health
Three children who recovered from novel coronavirus 2019 pneumonia
22 Mar 2020
China
Asia
3
Clinical - Clinical Features
https://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 H
Lan W
Journal of Infection
Clinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children
21 Mar 2020
China
Asia
4
Clinical - Clinical Features
https://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.
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, Y
Zha, Y
Journal of Infectious Diseases
A 55-day-old female infant infected with 2019 novel coronavirus disease: presenting with pneumonia, liver injury, and heart damage
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, C
Zhou, X
MedRxIV
Clinical characteristics of 34 children with coronavirus disease-2019 in the West of China: a multiple-center case series
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, L
Jian, R
World Journal of Pediatrics
Clinical features of pediatric patients with COVID-19: a report of two family cluster cases
16 Mar 2020
China
Asia
2
Clinical - Clinical Features
https://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, Y
Gong, S
Nature Medicine
Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding
13 Mar 2020
China
Asia
10
Clinical - Clinical Features
https://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, Y
Xing, Q
medRxiv
Prolonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase
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, W
Liu, Y
NEJM
Detection of COVID-19 in children in early January 2020 in Wuhan, China
12 Mar 2020
China
Asia
6
Clinical - Clinical Features
https://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, W
Li, S
Pediatric Radiology
Chest computed tomography in children with COVID-19 respiratory infection
11 Mar 2020
China
Asia
5
Clinical - Clinical Features
https://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, X
Quantit Imag Med and Surg
CT imaging of one extended family cluster of corona virus disease 2019 (COVID-19) including adolescent patients and "silent infection"
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, W
Hu, D
Pediatric Pulmonology
Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults
05 Mar 2020
China
Asia
20
Clinical - Clinical Features
https://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.
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, K
Thoon, KC
Clinical Infectious Diseases
A well infant with coronavirus disease 2019 with high viral load
28 Feb 2020
Singapore
Asia
1
Clinical - Clinical Features
https://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, J
Zeng, M
Clinical Infectious DIseases
A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features
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, C
Wang, F
Lancet pre-print server
Coronavirus disease-19 among children outside Wuhan, China
25 Feb 2020
China
Asia
31
Clinical - Clinical Features
http://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, XW
Li, LJ
BMJ
Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: a retrospective case series
19 Feb 2020
China
Asia
2
Clinical - Clinical Features
https://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, M
Liu, Y
JAMA
Novel coronavirus infection in hospitalized infants under 1 year of age in China
14 Feb 2020
China
Asia
9
Clinical - Clinical Features
https://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, N
Masi, S
Pediatrics
COVID-19 in 17 Italian Pediatric Emergency Departments
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, G
Moscatelli, A
Acta Paediatr
Clinical course of COVID‐19 in children with pre‐existing medical conditions
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, B
Jacobson, K
Intnl J of Inf Dis
Severe COVID-19 Infection and Pediatric Comorbidities: A Systematic Review and Meta-Analysis.
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, D
BSJ
Favourable perioperative outcomes for children with SARS‐CoV‐2
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 M
single author
Ped Allergy Immunology
Shielding against SARS‐Cov‐2 infection is not justified in children with severe asthma
05 Aug 2020
Europe
Europe
0
Clinical - Comorbidities
https://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.
Screening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy
15 Jun 2020
Italy
Europe
282
Clinical - Comorbidities
https://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, V
Lenica A, C
Ann Hematol.
SARS-CoV-2 infection in children with febrile neutropenia
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, C
Lopez, M
J Laparoendosc Adv Surg Tech A .
Thoracoscopic Bullectomy for Persistent Air Leak in a 14-Year-Old Child With COVID-19 Bilateral Pulmonary Disease
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, A
Balduzzi, A
Pediatr Blood Cancer
Children with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy
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, RW
Sebire, NJ
medRxiv
Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population
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
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, Z
SN Comprehensive Clinical Medicine
Pediatric Asthma & Coronavirus (COVID-19)-Clinical Presentation in an Asthmatic Child—Case Report
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, M
Tullus K
Lancet Child Adolesc Health
The severity of COVID-19 in children on immunosuppressive medication
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, RA
Kneidinger, N
American Journal of Transplantation
SARS-CoV-2 infection in two patients following recent lung transplantation
Corticosteroids but not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Pateitns with Inflammatory Bowel Disease: Results from an International Registry.
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, T
Perez-Martinez, A
Pediatric Blood and Cancer
COVID-19 Infection in children and adolescents with cancer in Madrid
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, X
Marsal, S.
Med archives
Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs
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, M
Perez-Beltran, V
Ped Nephrol
SARS-CoV-2 infection in Spanish children with chronic kidney pathologies
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, A
Turkmen Karaagac, A
Indian Pediatrics
COVID-19 in a Young Girl with Restrictive Cardiomyopathy and Chronic Lung Disease
30 Apr 2020
Turkey
Western Asia, Southeastern Europe
1
Clinical - Comorbidities
https://www.indianpediatrics.net/june2020/577.pdf
Russell M.
Reardon L
The Journal of Heart and Lung Transplantation
COVID-19 in a paediatric heart transplant recipient: Emergence of donor-specific antibodies
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, A
Rev Esp Cardiol (Engl Ed).
Fatal outcome of COVID-19 disease in a 5-month infant with comorbidities
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, Y
Huang, K
Diabetes Care
Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication
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, O
Schrappe, M
Eur J Cancer
Flash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment
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, A
Biondi, A
Lancet pre-print server
Lessons 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, Italy
02 Apr 2020
Italy
Europe
5
Clinical - Comorbidities
https://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, SM
Lefkowitch, JH
Archives of Pathology & Laboratory Medicine
COVID-19 associated hepatitis complicating recent living donor liver transplantation
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, D
Russel, R
Journal of Pediatric Gastroenterology and Nutrition
COVID-19 and paediatric inflammatory bowel diseases
31 Mar 2020
International
International
8
Clinical - Comorbidities
https://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, L
Liver transplantation
Coronaviruses and immunosuppressed patients: the facts during the third epidemic
20 Mar 2020
Italy
Europe
3
Clinical - Comorbidities
https://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, S
Farber, D
Nat Immunol
Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.
5 Nov 2020
USA
North America
47
Clinical - PIMS-TS
https://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, A
González Cortés, R
Crit Care 24(1): 666
Severe 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 Spain
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, E
Hensley, S
JPIDS
SARS-CoV-2 antibody responses in children with MIS-C and mild and severe COVID-19
02 Dec 2020
USA
North America
29
Clinical - PIMS-TS
https://doi.org/10.1093/jpids/piaa161
Lucio Verdoni, MD
Lorenzo D'Antiga, MD
The Lancet
An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study
13th May 2020
Italy
Europe
10
Clinical - PIMS-TS
https://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, LM
Blazquez, D
Clin Microbiol Infect
Cardiovascular magnetic resonance imaging in children with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and heart dysfunction
10 Oct 2020
Spain
Europe
5
Clinical - PIMS-TS
https://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, P
Singh, R
Clinical Pediatrics
Cardiac Findings in Pediatric Patients With Multisystem Inflammatory Syndrome in Children Associated With COVID-19
25 Sep 2020
USA
North America
33
Clinical - PIMS-TS
https://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, J
Breuer, J
Pediatrics
SARS-CoV-2 Polymorphisms and Multisystem Inflammatory Syndrome in Children (MIS-C)
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 S
Stern K
Jpeds
Longitudinal Echocardiographic Assessment of Coronary Arteries and Left Ventricular Function Following Multisystem Inflammatory Syndrome in Children (MIS-C)
Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2
30 Jul 2020
USA
North America
20
Clinical - PIMS-TS
https://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, PY
Son, MBF
J Clin Invest 2020
Distinct clinical and immunological features of SARS-COV-2- induced multisystem inflammatory syndrome in children
23 Jul 2020
USA
North America
28
Clinical - PIMS-TS
https://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, K
Kwan, M
Diagnostic Microbiology and Infectious Disease
False-positive SARS-CoV-2 serology in 3 children with Kawasaki disease
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, P
Ramnarayan, P
Lancet
Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study
09 Jul 2020
UK
Europe
78
Clinical - PIMS-TS
https://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, E
Zucker, H
NEJM
Multisystem Inflammatory Syndrome in Children in New York State
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, LR
Randolph, AG
NEJM
Multiststem Inflammatory Syndrome in U.S. Children and Adolescents
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, L
Randolph, A
NEJM
Multisystem Inflammatory Syndrome in U.S. Children and Adolescents
Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19.
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, M
Pediatr Cardiol.
Kawasaki Disease Features and Myocarditis in a Patient with COVID-19
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, K
Tang, JWT
Journal of Medical Virology
COVID-19 Multisystem Inflammatory Syndrome in Three Teenagers with Confirmed SARS-CoV-2 Infection
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.
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, A
Molho-Pessach, V
J Eur Acad Dermatol Venereol
Introductory histopathologic findings may shed light on COVID19 pediatric hyperinflammatory shock syndrome
Paediatric Inflammatory Multisystem Syndrome: Temporally Associated with SARS-CoV-2 (PIMS-TS): Cardiac Features, Management and Short-Term Outcomes at a UK Tertiary Paediatric Hospital
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, A
Melki, I
Ann Rheum Dis
Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort
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 E
Ducou le Pointe H
Radiology
Cardiac MRI of Children with Multisystem Inflammatory Syndrome (MIS-C) Associated with COVID-19: Case Series
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, E
Milner, J
JAMA
Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City
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, E
Levin, M
JAMA
Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2
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, J
Allali, S
BMJ
Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study
03 Jun 2020
France
Europe
21
Clinical - PIMS-TS
https://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, M
Oualha, M
Annals of Intensive care
Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children.
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, Andrea
Zuccotti, Gianvincenzo
Lancet Child Adolescent Health 2020
Acute myocardial injury: a novel pattern in children with Covid-19
01 Jun 2020
Italy
Europe
9
Clinical - PIMS-TS
https://doi.org/10.1016/s2352-4642(20)30168-1
Greene, A
Sinert, R
AJEM
Toxic shock-like syndrome and COVID-19: A case report of multisysteminflammatory syndrome in children (MIS-C)
Gastrointestinal 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 cases
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, K
John, A
J Pediat Inf Dis Soc
Multisystem Inflammatory Syndrome in Children during the COVID-19 pandemic: a case series
26 May 2020
America
North America
8
Clinical - PIMS-TS
https://doi.org/10.1093/jpids/piaa069
Chang, A
Hicar, M
medRxiv
Kawasaki Disease serum responses against SARS-CoV-2.
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, T
Gill, P
Am J Emerg Med
Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department
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.
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, L
Curry, J
The Lancet. Child & adolescent health
Gastrointestinal features in children with COVID-19: an observation of varied presentation in eight children
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,F
Montin, D
Pediatrics
SAR-Cov2-Induced Kawasaki -Like Hperinflamatory Syndrome: A novel Covid Phenotype in Children
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, C
Hedrich, C
Lancet Rheumatol
Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms
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, M
Serrano-Gonzalez, A
Pediatr Infect Dis J
Severe SARS-CoV-2 Infection in Children With Suspected Acute Abdomen: A Case Series From a Tertiary Hospital in Spain
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, V
Mathew, R
Hospital Pediatrics
COVID-19 and Kawasaki Disease: Novel virus and novel case
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, O
Davidovitch, N
Arch Dis Child.
COVID-19 infections following physical school reopening.
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, E
Reilly, K
JAMA Netw Open
Race/Ethnicity Among Children With COVID-19-Associated Multisystem Inflammatory Syndrome.
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, LC
Forrest CB
JAMA Peds
Assessment of 135 794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States
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, C
Waterfield, T
Lancet Infect Dis
Kinetics and seroprevalence of SARS-CoV-2 antibodies in children
19 Nov 2020
United Kingdom
Europe
849
Epidemiology - Disease Burden
https://doi.org/10.1016/S1473-3099(20)30884-7
Oved, K
Lustig, Y
j.eclinm
Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation
19 Nov 2020
Isreal
Middle East
688
Epidemiology - Disease Burden
https://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, I
Somekh, E
Clin Infect Dis
Reopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.
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, I
Somekh, E
Clin Infect Dis
Reopening Schools and the Dynamics of SARS-CoV-2 Infections in Israel: A Nationwide Study.
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 A
van der Klis F R M
J Epidemiol Community Health
Nationwide seroprevalence of SARS-CoV-2 and identification of risk factors in the general population of the Netherlands during the first epidemic wave
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, M
Chen, W
J. Paediatr. Child Health
Epidemiological characteristics and transmission dynamics of paediatric cases with coronavirus disease 2019 in Hubei province, China
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, H
Tsolia, M
Pediatr Infect Dis J
Children and Adolescents With SARS-CoV-2 Infection: Epidemiology, Clinical Course and Viral Loads
01 DEC 2020
Greece
Europe
203
Epidemiology - Disease Burden
https://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, Z
Frischer, T
Pediatr Allergy Immunol
Lessons from low seroprevalence of SARS-CoV-2 antibodies in schoolchildren: a cross-sectional study
29 JAN 2021
Austria
Europe
2069
Epidemiology - Disease Burden
https://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, L
Pollock, N
J Clin Microbiology
Comparison of upper respiratory viral load distributions in asymptomatic and symptomatic children diagnosed with SARS-CoV-2 infection in pediatric hospital testing programs.
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, D
Valentini, P
medRxiv
SARS-CoV-2 infections in Italian schools: preliminary findings after one month of school opening during the second wave of the pandemic
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, RT
Lozier M
Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report (MMWR)
COVID-19 Trends Among School-Aged Children — United States, March 1–September 19, 2020
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, E
Kubiak, J
Eur J Clin Microbiol Infect Dis
Children were less frequently infected with SARS-CoV-2 than adults during 2020 COVID-19 pandemic in Warsaw, Poland
28 Sep 2020
Poland
Europe
904
Epidemiology - Disease Burden
https://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, A
Kriemler, S
medRxiv
Variation in SARS-CoV-2 seroprevalence in school-children across districts, schools and classes
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, M
Fernández-Cañadas Morillo, A
Pediatr Infect Dis J
Maternal, Perinatal and Neonatal Outcomes With COVID-19: A Multicenter Study of 242 Pregnancies and Their 248 Infant Newborns During Their First Month of Life
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, K
Yung, C
medRxiv
SARS-CoV-2 Viral RNA Load Dynamics in the Nasopharynx of Infected Children
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 M
Chan, D K
JAMA Pediatr
Prevalence of SARS-CoV-2 Infection in Children Without Symptoms of Coronavirus Disease 2019
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, J
John, C
Cureus
Prevalence of Asymptomatic SARS-CoV-2 Infection in Children and Adults in Marion County, Indiana
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, L
Garg, S
MMWR Morb Mortal Wkly Rep
Hospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-Confirmed COVID-19 - COVID-NET, 14 States, March 1-July 25, 2020
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.
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, S
Pezzotti,
Pediatr
COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy
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, M
Yotti, R
Lancet
Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study
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, N
Danis, K
Lancet Child Adolescent Health
Emergence of Kawasaki Disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic:a time-series analysis
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 Nasopharynge
An evidence summary of Paediatric COVID-19 literature
Boast A, Munro A, Goldstein H. An evidence summary of Paediatric COVID-19 literature, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24063
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)
Epidemiology
Around the world, children have made up a minority of confirmed cases of COVID-19 during the first wave of the pandemic, usually contributing to between 1 – 5% of total case numbers. This almost certainly represents some undercounting of children in total case numbers as many countries have focussed on testing the most unwell. As countries have become better at shielding elderly populations and moved to community testing, the proportion of cases detected in children has increased (although predominantly in older children aged 10 – 19 years).
Countries which have produced representative population seroprevalence studies (including Switzerland, Spain, France, Brazil and the UK) found proportionately far fewer children were infected during the first wave than adults (young children <10 years in particular).
More detailed information has emerged into childhood severity of COVID-19. A significant number of children may be asymptomatic, but the true proportion is unknown. It seems possible up to 50% of cases may develop no symptoms at all, but the data is of low quality for assessing symptomology. Critical illness is very rare (~1%). In data from China, the USA and Europe, there is a “U shaped” risk gradient, with infants and older adolescents appear most likely to be hospitalised and to suffer from more severe disease. Deaths in children remain extremely rare from COVID-19, with only 4 deaths in the UK as of May 2020 in children <15 years, all in children with serious comorbidities.
Transmission
Precise details regarding paediatric transmission are still being ascertained, however important trends are emerging. Low case numbers in children suggest a more limited role than was initially feared. Meta-analyses of contact tracing data from Asia, Europe, Israel and the USA have all demonstrated a significantly lower attack rate in children than adults, including testing of asymptomatic household contacts on both PCR and serology. These findings indicate young children in particular are approximately half as likely as adults to acquire the infection given equivalent exposure.
Children of all ages are infectious and capable of transmitting regardless of symptom status. Determining the relative infectiousness of children as compared to adults is difficult, given unknown numbers of asymptomatic cases which are underrepresented in studies of transmission. Household studies with children as index cases have so far been difficult to interpret due to bias from shared exposure (children and their contacts becoming infected simultaneously), increased exposure of caregiver to their symptomatic children post infection, and underrepresentation of asymptomatic cases.
Contact tracing studies from schools have generally found very low rates of transmission, especially among younger children. There is evidence of larger outbreaks within secondary school age and adolescents, predominantly in schools during period of high community transmission. There is little evidence in the literature of large outbreaks within primary school, or age equivalent educational facilities in periods of low to moderate community transmission.
Studies of viral loads in children have generally found comparable levels of virus to adults, with no consistent or clinically relevant variation by age or symptom burden. Several studies have now shown that SARS-CoV-2 can be detected by PCR in the stool of affected children for several weeks after symptoms have resolved. Studies have confirmed there can also be live virus found in the stool of infected individuals. How much virus is present, and the extent to which faecal-oral transmission may be possible is yet to be confirmed.
Clinical features
A significant proportion of children with COVID-19 do not appear to develop any symptoms, or have subclinical symptoms, but it remains uncertain what this proportion is. The most detailed paediatric population data from China showed 13% of confirmed cases had no symptoms (cases detected by contact tracing). Considering both confirmed and suspected cases, 32% of children aged 6-10yrs were asymptomatic. Data from Italian emergency departments found 21% of SARS-CoV-2 positive children to be asymptomatic. Importantly, these studies did not follow up children to determine if they later developed symptoms, so the true proportion of asymptomatic children is unknown.
Possibly the most reliable data comes from serological screening with symptom surveys, suggesting approximately 50% of children may be asymptomatic, and only 10 – 15% will exhibit symptoms consistent with COVID-19 case definitions (cough, fever, shortness of breath). These studies are subject to recall bias.
Clinical features in symptomatic children are somewhat different to adults. Children tend to have more mild illness. The most common presenting features are cough and fever, occurring in over half of symptomatic patients. Upper respiratory tract symptoms such as rhinorrhoea and sore throat are also relatively common, occurring in 30-40% of patients. It is not uncommon for children to have diarrhoea and/or vomiting (around 10% of cases), even in some cases as their sole presenting features. Several case series of rashes resembling chill blains (often occurring on feet/toes) have been reported from Europe, contemporaneously associated with the COVID-19 outbreak but with few cases simultaneously confirmed to be infected
Blood tests also show slightly different features to adults. Lymphocytopaenia is relatively rare in children, with the majority having normal or sometimes raised lymphocyte counts. Inflammatory markers such as CRP and Procalcitonin are often raised but only very mildly. Slight elevations in liver transaminases appear to be common.
Radiographic features in children are also somewhat different to their adult counterparts. Chest X-rays are often normal, and many CT chest scans are also normal. When present abnormalities are often less severe, however a reasonable number of children have bilateral pneumonia. Changes may be found on CT even in asymptomatic children. Common features in abnormal CT scans include mild, bilateral ground glass opacities, but with less peripheral predominance than is reportedly found in adults.
There appears to be little in the way of clinical signs in children to differentiate COVID-19 from other childhood respiratory virus infections, or other benign childhood illnesses.
PIMS-TS/MIS-C
A new hyperinflammatory syndrome resembling Kawasaki shock, which appears to be a delayed immune response to COVID-19 has been described. It is known as PIMS-TS in Europe and MIS-C in the USA. Published reports from London, Italy, France and the USA in a cohort of children with evidence of past COVID-19 infection have presented with early symptom of abdominal pain, vomiting and diarrhoea, with persistent high-grade fever and commonly progression on to shock with cardiac involvement. High inflammatory markers, myocarditis, macularpapular rashes and non-suppurative conjunctivitis are common. Respiratory involvement is notably absent. Investigations are underway to ascertain a link and mechanism of disease. Most cases recover quickly, but there have been deaths reported.
Consistent with adult literature, children from a Black, Asian and Minority Ethnic (BAME) background seem to be at higher risk of severe disease from acute COVID-19 infection, and are significantly overrepresented in case reports of PIMS-TS
Newborns
A large number of cases of infants born to mothers with COVID-19 have now been reported, including several hundreds from the UK. Mothers and their babies in general appear to do well. There is a small but notable increase in the rates of preterm birth, and signals of increase in rates of foetal loss/stillborn delivery. There have been a few cases of infants delivered to mothers with COVID-19, who had elevated SARS- CoV-2 IgM. This may indicate intrauterine transmission, however swab PCR from these children has been negative and false positives with IgM tests are not uncommon. There have been case reports of newborns and very young infants testing positive including several within 12 hours of age, however they have mostly not suffered any complications of the disease and required minimal respiratory support. Evidence has been found of viral invasion into placenta, indicating possible intrauterine transmission. Vertical transmission however remains rare, occurring in approximately 2% of cases of maternal infection.
When tested, breast milk has usually been negative for SARS-CoV-2, but there have been a small number of instances where it has tested positive. It is unclear if this positive result reflects live, infectious virus, and whether the source was the mother or infants who subsequently also test positive for the virus. The vast majority of newborns have not acquired COVID-19 themselves.
Children with co-morbidities
There is a growing body of evidence reflecting a small increased risk of children with comorbidities to be hospitalised or need intensive care from COVID-19. A pan European consortium found children with chronic lung disease, congenital heart disease, neurological disease or malignancy had 3 times higher odds of needing admission to PICU; whilst this is an increased relative risk, the absolute risk remains small. Studies from PICU admissions in the US and Italy also found the majority have some comorbidities, most commonly respiratory, cardiac or complex neurodisability. These are groups for whom there is already a background increased risk of complications from all respiratory viruses. The rates of complications from SARS-CoV-2 infection do not appear disproportionate to those from other respiratory viruses from this early data.
Conclusion
COVID-19 appears to affect children less often, and with less severity, including frequent asymptomatic or subclinical infection. There is evidence of critical illness, but it is rare. Children can become infected and transmit even when asymptomatic. Contact tracing studies suggest children are approximately half as susceptible to infection as adults, and their relative infectiousness remains difficult to estimate. Changes in laboratory or radiographic parameters are slightly different to adults, and changes usually mild. There is some evidence of vertical transmission to neonates which appears predominantly perinatal but evidence of intrauterine infection does exist. Evidence suggests only a small increased risk to pregnant mothers and newborns compared to other groups. Children with respiratory, cardiac and complex neurodisability appear more likely to suffer complications, however not obviously more than would be expected from infection with other respiratory viruses.
New and Noteworthy (Updated 11 April 2021)
Shamez N Ladhani, Frances Baawuah, Joanne Beckmann et al. SARS-CoV-2 infection and transmission in primary schools in England in June–December, 2020 (sKIDs): an active, prospective surveillance study. Lancet Child and Adolescent Health, March 16th 2021, https://doi.org/10.1016/S2352-4642(21)00061-4
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.”
Hershow RB, Wu K, Lewis NM, et al. Low SARS-CoV-2 Transmission in Elementary Schools — Salt Lake County, Utah, December 3, 2020–January 31, 2021. MMWR Morb Mortal Wkly Rep 2021;70:442–448. DOI: http://dx.doi.org/10.15585/mmwr.mm7012e3
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.
Doyle T, Kendrick K, Troelstrup T et al. COVID-19 in Primary and Secondary School Settings During the First Semester of School Reopening — Florida, August–December 2020. MMWR Morbidity and Mortality Weekly Report 70(12): 437-441 2021 http://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
Volpp, K. G., B. H. Kraut, S. Ghosh and J. Neatherlin (2021). “Minimal SARS-CoV-2 Transmission After Implementation of a Comprehensive Mitigation Strategy at a School – New Jersey, August 20-November 27, 2020.” MMWR Morb Mortal Wkly Rep 70(11): 377-381. http://dx.doi.org/10.15585/mmwr.mm7011a2
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.
Hu, S., Wang, W., Wang, Y. et al. Infectivity, susceptibility, and risk factors associated with SARS-CoV-2 transmission under intensive contact tracing in Hunan, China. Nat Commun 12, 1533 (2021). https://doi.org/10.1038/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:
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.
Cotugno, N., A. Ruggiero, F. Bonfante, M. R. Petrara, etal. Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies. Cell Reports 34 (11) (no pagination) (108852). https://doi.org/10.1016/j.celrep.2021.108852
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.
Niño-Taravilla C, Otaola-Arca H, Lara-Aguilera N, Zuleta-Morales Y, Ortiz-Fritz P. Multisystem inflammatory syndrome in children, Chile, May–August 2020. Emerg Infect Dis. 2021 May https://doi.org/10.3201/eid2705.204591
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.
F MCaribú, R Erra, L Pugni et al. Severe SARS-COV-2 placental infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest. January 26th 2021, https://doi.org/10.1172/JCI145427.
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.
Cooper DM, Messaoudi I, Aizik S, Camplain RL, Lopez NV, Ardo J, et al. SARS-Cov-2 acquisition and immune pathogenesis among school-aged learners in four K-12 schools. medRxiv 2021.03.20.21254035; doi: https://doi.org/10.1101/2021.03.20.21254035
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-γ 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.
Shira Doron, Robin R. Ingalls, Anne Beauchamp, et al. Weekly SARS-CoV-2 screening of asymptomatic students and staff to guide and evaluate strategies for safer in-person learning. medRxiv, March 22nd 2021. https://doi.org/10.1101/2021.03.20.21253976
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.
The studies included in this review are as follows:
Rottenstreich A, Zarbiv G, Oiknine-Djian E, Zigron R, Wolf DG, Porat S. Efficient maternofetal transplacental transfer of anti-SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. medRxiv. 2021 Jan 1.
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 KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, Baez AM, Shook LL, Cvrk D, James K, De Guzman R. COVID-19 vaccine response in pregnant and lactating women: a cohort study. American Journal of Obstetrics and Gynecology. 2021 Mar 26.
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 Y, Prahl M, Cassidy A, Wu AH, Jigmeddagva U, Lin CY, Gonzalez VJ, Basilio E, Warrier L, Buarpung S, Asiodu IV. Immune response during lactation after anti-SARS-CoV2 mRNA vaccine. medRxiv. 2021 Jan 1.
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 Y, Prahl M, Cassidy A, Lin CY, Ahituv N, Flaherman VJ, Gaw SL. COVID-19 mRNA vaccine is not detected in human milk. medRxiv. 2021 Jan 1.
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.
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
Top 10 Neonatal Papers
Knight, K. Bunch, N. Vousden et al. Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV 2 infection in the UK: A national cohort study using UK obstetric surveillance system. Nuffield Department of Population Health, UKOSS Publications 11th May 2020, https://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.
Zeng L, Xia S, Yuan W et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatr. Published online March 26, 2020. doi:10.1001/jamapediatrics.2020.0878
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.
Yu, Nan et al Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study, The Lancet Infectious Diseases, Volume 0, Issue 0, Published:March 24, 2020 DOI:https://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.
Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395 :809–15. doi:10.1016/S0140-6736(20)30360-3
This retrospective case series looks at 9 pregnant women who were positive for COVID19 in Wuhan University Hospital between Jan 20th and Jan 31st. They all underwent a caesarean section (between 36 and 39+4 gestation). All newborn babies were well with good APGARS and, importantly, tests from 6 (3 not tested) patients were negative for SARS-CoV-2 in all amniotic fluid, cord blood, neonatal throat swabs, and breastmilk samples. There was no evidence of vertical transmission.
Dong L, Tian J, Songming H et al. Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4621
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 H, Xu C, Fan J, et al. Antibodies in Infants Born to Mothers With COVID-19 Pneumonia. JAMA. Published online March 26, 2020. 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 SARS-CoV-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.
Liu, Yangli et al. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy.Journal of Infection, Volume 0, Issue 0 https://doi.org/10.1016/j.jinf.2020.02.028
This is a small case series of 13 pregnant women with confirmed SARS-CoV-2 infection between December 8 2019 and February 25 2020, in China. Two women were <28 weeks at presentation, the remainder were in the third trimester. One infant was stillborn, the 12 remaining infants (92%) were well at birth with no complications. None were positive for SARS-CoV2 or had ‘serological evidence’ of vertical transmission. The method of testing neonates was not clearly defined. The stillborn neonate had a mother who was severely unwell on Extracorporeal Membrane Oxygenation (ECMO) at the time of delivery.
Five of the 10 patients (50%) were delivered by emergency cesarean section due to pregnancy complications including fetal distress (30%), premature rupture of the membrane (10%) and stillbirth (10%). Interestingly, six patients (46%) had preterm labour between 32- 36 weeks of gestation.
Han, M. S., M. W. Seong, E. Y. Heo, J. H. Park, N. Kim, S. Shin, S. I. Cho, S. S. Park and E. H. Choi (2020). “Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2.” Clin Infect Dis. https://doi.org/10.1093/cid/ciaa447
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.
Groß, C. Conzelmann, J. A. Müller, S. Stenger, K. Steinhart, F. Kirchhoff and J. Münch. Detection of SARS-CoV-2 in human breastmilk. Lancet, May 21st 2020, https://doi.org/10.1016/S0140-6736(20)31181-8
This report is presented as a letter.
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:
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. Further studies will be necessary to attempt to culture virus from breast milk and assess risk of transmission, which to date has seemed low.
Li, M., L. Chen, J. Zhang, C. Xiong and X. Li (2020). “The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study.” PLoS One 15(4): e0230295. https://doi.org/10.1371/journal.pone.0230295
The study explores the presence of Angiotensin-converting enzyme 2 (ACE2) within the placenta and the developing baby. It demonstrates significant expression of RNA coding the for ACE2 protein at several points of the maternal-foetal interface, as well as variable expression in a number of foetal organs. This theoretically provides a potential route for vertical transmission, placental dysfunction and pregnancy complications. The authors call for further clinical analysis to establish this potential.
Top 10 Clinical Papers
Swann Olivia V, Holden Karl A, Turtle Lance, Pollock Louisa, Fairfield Cameron J, Drake Thomas M et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. August 27th 2020, https://doi.org/10.1136/bmj.m3249
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 illness – 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.
Götzinger, F., B. Santiago-García, A. Noguera-Julián, et al. “COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.” Lancet Child Adolesc Health.
This European multicentre cohort study recruited 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 identified cases prior to 1st April and prospectively between 1-24th April. The diagnosis was made based 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 was included from the history, with parents being the suspected 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 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. A 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 included 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 for 25 patients (4%) and ECMO was needed in one 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 older than 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 the end of the study period, 553 patients had made a full recovery and 25 patients had ongoing symptoms.
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)
Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi: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 confirmed contact with a case of COVID-19. Of these, 171 were confirmed to have SARSCoV-2. The 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 hospitalization. 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 their definition 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.
Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi:10.1056/NEJMc2007617
This report covered 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, the authors categorize their patients according to criteria from Dong et. al (see review in theEpidemiology 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 the 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 were 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 a 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 ontological, and 1 metabolic disease.
Of the few patients that required respiratory support (9/100) a significant number had comorbidities (6/9), although the range was broad. This included two 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.
In comparison to Dong et al, the 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 the population cohorts presenting for testing among the different studies – comparison between cohorts is always difficult due to broad differences in the denominators used. There is no apparent difference in severity according to age in this Italian data set, whereas CDC noted increased hospitalization in children <1yr and Dong 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 the presence of significantly milder illness in children with COVID-19, including many asymptomatic children. A note is made of overrepresentation of children with comorbidities in this cohort (similar to the 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.
DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2020.05.007
This is a retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at the Children’s National Hospital, Washington DC US. Children and young adults were detected because of presentation with symptoms at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalized, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features were associated with hospitalization, or critical care.
This hospital served as a regional centre providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. The overall patient age range was from 0.1 – 34.2 years, with a median of 9.6 years. Of the total group 12/177 were > 20 years of age, and 37/177 were between the ages of 15 – 20years.
Age: There was no significant difference in age between the hospitalized and non-hospitalized patients, however in the hospitalized cohort, the critically unwell group were significantly older than the non-critically unwell hospitalized group (17.3 years versus 3.6 years; P =.04)
Sex: There was equal representation (n = 177 52% male, 48% female), as well as in 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 hospitalized patients (7/44 16%), nor of those admitted, or those who were critically unwell (2/9, 22%). Though the numbers were small, specific underlying conditions such as neurological, cardiac, haematological, or oncological issues were more common in the hospitalised cohort than the non hospitalised cohort. They were not more common in the hospitalized 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 a fever or any other specific symptom compared with the non-critically ill cohort.
Critical Care: 9 patients required critical care. This represented 5% (9/177) of the 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 one high flow nasal cannula oxygenation. 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 overrepresented in requiring critical care. Though underlying conditions were more common in hospitalized patients, they were not significantly more common in the hospitalized patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalized patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of the recently described hyperinflammatory state.
de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk 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 study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6
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 a 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.
González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/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.
M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065
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 in-patients 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. The 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). The estimate of the persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab was 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.
Galván Casas, C., Català, A., Carretero Hernández, et al. (2020), Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. Accepted Author Manuscript. doi: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.
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.
Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041
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 children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 months 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 intussusception) 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.
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Please note that whilst all papers have been reviewed for the database and consideration of the overall updates, only selected papers which added new information at the time of publication had a formal review written. The sublists below also include the top ten papers for convenience.
Larger Cohort Clinical Papers
Götzinger, F., B. Santiago-García, A. Noguera-Julián, et al. “COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.” Lancet Child Adolesc Health. https://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)
Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi: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.
Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi: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.
DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2020.05.007
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.
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.
de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk 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 study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6
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.
Parri, N., A. M. Magistà, F. Marchetti, et al, (2020). “Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks.” Eur J Pediatr: 1-9. https://doi.org/10.1007/s00431-020-03683-8
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 %<5.5×109) and lymphopenia (<1.2×109) 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).
de Ceano-Vivas M, Martín-Espín I, del Rosal T, et al. SARS-CoV-2 infection in ambulatory and hospitalised Spanish children, Arch Dis Child, doi:10.1136 / archdischild-2020-319366
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.
Chen C. Coronavirus Disease-19 Among Children outside Wuhan, China [Internet]. Lancet Child and Adolescent medicine; Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=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.
Garazzino S, Montagnani C, Dona D, et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020; 25(18). https://dx.doi.org/10.2807%2F1560-7917.ES.2020.25.18.2000600
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%) and 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 39°C) 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.
Zhang C, Gu J, Chen Q, et al. Clinical Characteristics of 34 Children with Coronavirus Disease-2019 in the West of China: a Multiple-center Case Series. doi:10.1101/2020.03.12.20034686
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.
Qiu, Haiyan et al, Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. The Lancet Infectious Diseases, Volume 0, Issue 0 DOI:https:// 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.”
Zheng F, Liao C, Fan Q-H, et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Curr Med Sci 2020;:1–6. doi: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.
PICU Clinical Papers
González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, et al. Pediatric critical care and COVID19. Pediatrics. 2020; doi: 10.1542/peds.2020-1766
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.
González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/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.
Grasselli, G et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. doi:10.1001/jama.2020.5394 Published online April 6, 2020.
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.
Oualha, M., M. Bendavid, L. Berteloot, et al. “Severe and fatal forms of COVID-19 in children.” Archives de Pediatrie, June 4th 2020, https://doi.org/10.1016/j.arcped.2020.05.010
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 coronavirus 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.
This study focuses on 27 children unwell 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.
Lanyon, N., P. du Pré, T. Thiruchelvam, S. Ray, M. Johnson and M. J. Peters (2020). “Critical paediatric COVID-19: varied presentations but good outcomes.” Arch Dis Child. https://dx.doi.org/10.1136/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.”
Clinical Dermatology COVID-19
Colmenero, I., C. Santonja, M. Alonso-Riano, et al. “SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases.” The British journal of dermatology. June 20th 2020, https://doi.org/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
Locatelli AG, Robustelli Test E, Vezzoli P, Carugno A, Moggio E, Consonni L, Gianatti A, Sena P. Histologic features of long-lasting chilblain‐like lesions in a pediatric COVID‐19 patient. Journal of the European Academy of Dermatology and Venereology.09 May 2020. doi: 10.1111/jdv.16617. https://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.
Recalcati, S., T. Barbagallo, L. A. Frasin, F. Prestinari, A. Cogliardi, M. C. Provero, E. Dainese, A. Vanzati and F. Fantini (2020). “Acral cutaneous lesions in the Time of COVID-19.” J Eur Acad Dermatol Venereol.
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, V., I. Neri, C. Filippeschi, T et al (2020). “Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients.” J Eur Acad Dermatol Venereol published online 24th April 2020 https://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.
Radiology Findings COVID-19
Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults [published online ahead of print, 2020 Mar 5]. Pediatr Pulmonol. 2020;10.1002/ppul.24718. doi: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.
Görkem, S. B. and B. Çetin (2020). “COVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT.” Diagn Interv Radiol. June 5th 2020, DOI 10.5152/dir.2020.20361
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 4.01×109, lymphocytes 1.92×109, 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 hydroxychloroquine. 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.
Denina, M., C. Scolfaro, E. Silvestro, G. Pruccoli, F. Mignone, M. Zoppo, U. Ramenghi and S. Garazzino (2020). “Lung Ultrasound in Children With COVID-19.” Pediatrics. 21. https://doi.org/10.1542/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
Li W, Cui H, Li K, Fang Y, Li S. Chest computed tomography in children with COVID-19 respiratory infection [published online ahead of print, 2020 Mar 11]. Pediatr Radiol. 2020;10.1007/s00247-020-04656-7. doi:10.1007/s00247-02004656-7
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.
Liu H, Liu F, Li J, Zhang T, Wang D, Lan W. Clinical and CT Imaging Features of the COVID-19 Pneumonia: Focus on Pregnant Women and Children [published online ahead of print, 2020 Mar 11]. J Infect. 2020;S0163-4453(20)30118-3. doi: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.
Cardiology Papers
Del Barba, P., D. Canarutto, E. Sala, G. Frontino, M. P. Guarneri, C. Camesasca, C. Baldoli, A. Esposito and G. Barera (2020). “COVID-19 cardiac involvement in a 38-day old infant.” Pediatr Pulmonol. June 18th 2020, https://doi.org/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.
Selman Kesici, Hayrettin Hakan Aykan, Diclehan Orhan, Benan Bayrakci, Fulminant COVID-19-related myocarditis in an infant, European Heart Journal, June 12th 2020, ehaa515, https://doi.org/10.1093/eurheartj/ehaa515
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
Trogen, B., F. J. Gonzalez and G. F. Shust (2020). “COVID-19-Associated Myocarditis in an Adolescent.” The Pediatric Infectious Disease Journal. 03. June 3rd 2020, doi: 10.1097/INF.0000000000002788
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/μL, 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.
Ocular Manifestation
Valente, P., G. Iarossi, M. Federici, et al. Ocular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report. J aapos. June 10th 2020, https://doi.org/10.1016/j.jaapos.2020.05.002
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.
Testing/Viral Studies
M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065
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.
Xu, Y, Li X. Zhu, B. et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med (2020). https://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.
Yuan, C., H. Zhu, Y. Yang, X. Cai, F. Xiang, H. Wu, C. Yao, Y. Xiang and H. Xiao (2020). “Viral loads in throat and anal swabs in children infected with SARS-CoV-2.” Emerg Microbes Infect: https://doi.org/10.1080/22221751.2020.1771219
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 pos
GI symptoms: 7/37 (19%) TS pos & 6/17 (35%) AS pos
Cough: 16/37 (43%) TS pos & 4/17 (24%) AS pos
Fever: 20/37 (54%) TS pos & 5/17 (29%) AS pos
CT evidence of pneumonia: 25/37 (68%) TS pos & 10/17 (59%) AS pos
Time from positive to negative for PCR assay: 7 days for TS pos & 6 days for AS pos
The viral loads detected on throat swabs and anal swabs showed no difference.
Zhao, W., Y. Wang, Y. Tang, W. Zhao, Y. Fan, G. Liu, R. Chen, R. Song, W. Zhou, Y. Liu and F. Zhang (2020). “Characteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge.” Clin Pediatr,May 28th https://doi.org/10.1177%2F0009922820928057
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<https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25952>. This includes a large cohort of over 200 patients from Korea <https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030> 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<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> 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<https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2765641> 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
Xing Y, Ni W, Wu Q, et al. Prolonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase. doi:10.1101/2020.03.11.20033159
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.
Pandey U, Yee R, Precit M, et al Pediatric COVID-19 in Southern California: clinical features and viral genetic diversity, medRXiv, June 2nd 2020, https://doi.org/10.1101/2020.05.28.20104539
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.
Zachariah, P., K. C. Halabi, C. L. Johnson, S. Whitter, J. Sepulveda and D. A. Green (2020). “Symptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children.” Clin Infect Dis, May 20th 2020, https://doi.org/10.1093/cid/ciaa608
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<https://www.nature.com/articles/s41591-020-0869-5> – 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<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> / 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.
Haematology and Immunology Focus
Odièvre, M. H., C. de Marcellus, H. Ducou Le Pointe, S. Allali, A. S. Romain, J. Youn, J. Taytard, N. Nathan and H. Corvol (2020). “Dramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome.” May 1st 2020, Am J Hematol. https://doi.org/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-α 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.
Tsao HS, Chason HM, Fearon DM. Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics. 2020 May 1. doi: 10.1542/peds.2020-1419. Pre-publication version.
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.
Wu, H., H. Zhu, C. Yuan, C. Yao, W. Luo, X. Shen, J. Wang, J. Shao and Y. Xiang (2020). “Clinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China.” JAMA Netw Open 3(6): e2010895. doi:10.1001/jamanetworkopen.2020.10895
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.
Venturini E, Palmas G, Galli L. Severe neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection. 2020 May 19. doi 10.1016/j.paeds 2020.04.051 [Epub ahead of print]
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.
Chen, J., Z. Z. Zhang, Y. K. Chen, et al (2020). “The clinical and immunological features of pediatric COVID-19 patients in China.” Genes and Diseases. https://doi.org/10.1016/j.gendis.2020.03.008
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.
Other Interesting Clinical Papers
Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041
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.
Li Y, Wang H, Wang F, Du H, Liu X, Chen P, Wang Y, Lu X, Comparison of Hospitalized Patients with pneumonia caused by COVID-19 and influenza A in children under 5 years, International Journal of Infectious Diseases (2020) https://doi.org/10.1016/j.ijid.2020.06.026
This study is from Wuhan children’s hospital, China. It is a retrospective one reviewing the clinical history, radiology and laboratory results of 57children under 5, with confirmed pneumonia on CT or radiography within 72 hours of admission, with COVID-19 diagnosed by detecting SARS-CoV-2 in throat swabs. The comparison group was 59 children aged under 5 who were admitted with influenza A pneumonia. Influenza A was diagnosed by direct immunofluorescence assay.
The 57 COVID-19 pneumonia children were consecutively admitted between 28th January and 11th March 2020; the 59 influenza A pneumonia children were consecutively admitted between 14th December 2019 and 30th February 2020(?).
The median age of the COVID-19 patients was 18.7+/- 16.7 months. The median age of the Influenza A patients was 21.8+/-16.7 months with no statistical difference. There was slightly higher proportion of males in each group 61.4% for COVID-19 vs 66.1% for the influenza A group with no statistical difference.
Clinical features: 31(54.4%) of the COVID-19 patients presented with fever compared to 50(84.7%) influenza A patients, P<0.001. 40(70.2%) of the COVID-19 patients presented with cough compared to 50(84.7%) in the influenza A group, p<0.001. Dyspnoea occurred in only 2(3.5%) COVID-19 patients and 5(8.5%) influenza A patients, p=NS. Gastrointestinal symptoms occurred in 8(14.1%) of the COVID-19 patients and 21(35.6%) of the influenza A patients, p=NS. Convulsions occurred in only 1 COVID-19 child and 3 influenza A children, p=NS. During hospitalization 1 COVID-19 child required supplementary oxygen and two required intensive care, compared to 7 influenza A children requiring supplementary oxygen and 4 intensive care, p=NS.
Radiology: CT chest imaging with ground glass appearance was more commonly found in COVID-19 pneumonia children 42.1% vs15% influenza A pneumonia children, p=0.03. Consolidation was more common in influenza A children (25%) compared to COVID-19 patients (5.2%), P = 0.02.
Haematology and Biochemistry
Haematology investigations showed COVID-19 patients had significantly lower levels of leukocytes and neutrophils but significantly higher lymphocyte levels compared with influenza A patients (7.87 vs. 9.89 ×109/L, P = 0.02; 2.43 vs. 5.16 ×109/L, P < 0.001; 4.58 vs. 3.56 ×109/L; P = 0.006.
Lower levels of C-reactive protein (CRP) were observed in COVID-19 patients than influenza A patients (3.7 vs. 15.1 mg/L, P = 0.001.
There were no significant routine biochemistry differences between the two groups except potassium which was significantly lower in the COVID-19 group.
Significantly lower levels of D-dimer and prothrombin time (PT) were found in COVID-19 patients than influenza A patients (0.34 vs. 1.94, P < 0.001; 10.8 vs. 11.2 mm/h, P = 0.014).
There were no deaths reported in this study.
Conclusion: The authors concluded that children under 5 with COVID-19 pneumonia compared to children with influenza A pneumonia showed milder clinical symptoms and a significantly increased lymphocytosis with a more prevalent ground glass CT chest appearance compared to influenza A pneumonia children under 5. There were no reported deaths or serious complications from COVID-19 in this study.
The study shows COVID-19 pneumonia is milder than influenza A pneumonia in a series children under 5. The influenza A patients were not typed and came from a different but overlapping time period during the winter months. Comorbidities were also not mentioned in either group.
Lu, Y., Y. Li, W. Deng, M. Liu, Y. He, L. Huang, M. Lv, J. Li and H. Du (2020). “Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan.” The Pediatric infectious disease journal. 05. doi: 10.1097/INF.0000000000002729
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-α. 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.
Xiao, Z., X. Xie, W. Guo, Z. Luo, J. Liao, F. Wen, Q. Zhou, L. Han and T. Zheng (2020). “Examining the incubation period distributions of COVID-19 on Chinese patients with different travel histories.” Journal of infection in developing countries 14(4): 323-327. doi:10.3855/jidc.12718
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.
Zhang, B., S. Liu, Y. Dong, L. Zhang, Q. Zhong, Y. Zou and S. Zhang (2020). “Positive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19).” Journal of Infection April 23rd 2020, https://doi.org/10.1016/j.jinf.2020.04.023
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.
Nathan, N., B. Prevost and H. Corvol (2020). “Atypical presentation of COVID-19 in young infants.” The Lancet 395(10235): 1481. https://doi.org/10.1016/S0140-6736(20)30980-6
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 39°C). 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 with fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.
Wu, Q., Y. Xing, L. Shi, W. Li, Y. Gao, S. Pan, Y. Wang, W. Wang and Q. Xing (2020). “Co-infection and Other Clinical Characteristics of COVID-19 in Children.” Pediatrics. May 1st 2020, DOI: https://doi.org/10.1542/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<https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001444> in children is well recognised; similarly in interpreting serology, false positives<https://onlinelibrary.wiley.com/doi/full/10.1111/j.1469-0691.2004.00993.x> 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.
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775
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.
There were only 59 patients under 10yo, and 15 patients between 10-20 years of age in this study.
The results below unless specified are for patients of all ages.
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 34 patients under 18 age group out of those who had reached discharge end point. There were still 25 patients under 20 years hospitalised at the time of the paper.
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.
Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. Published online May 11, 2020. doi:10.1001/jamapediatrics.2020.1948
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%)
Lazzerini, Marzia et al, Delayed access or provision of care in Italy resulting from fear of COVID-19, The Lancet Child & Adolescent Health, Volume 0, Issue 0, Published April 9th 2020, https://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.
Preßler, J., S. Fill Malfertheiner, M. Kabesch, H. Buntrock-Döpke, S. Häusler, A. Ambrosch and S. Wellmann (2020). “Postnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study.” Pediatr Allergy Immunol. 9th June 2020, https://doi.org/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).
Small cohort <10 children and Single Case Reports
Ji L, Chao S, Want Y et al. Clinical features of pediatric patients with COVID-19: a report of two family cluster cases. World J Pediatr. 2020 Mar 16. doi: 10.1007/s12519-020-00356-2. [Epub ahead of print] https://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.
Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med 2020;:NEJMc2003717. doi: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.
Pan X, Chen D, Xia Y, et al. Asymptomatic cases in a family cluster with SARS-CoV-2 infection, The Lancet Infectious Diseases, 2020, https://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.
Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang Z. Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. Published online February 14, 2020. doi: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.
Jiehao Cai, Jing Xu, Daojiong Lin et al, A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features, Clinical Infectious Diseases, ciaa198, https://doi.org/10.1093/cid/ciaa198
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.
Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series BMJ 2020; 368 :m606
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.
Kai-Qian Kam, Chee Fu Yung, Lin Cui et al, A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load, Clinical Infectious Diseases, ciaa201, https://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.
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 Published Online First: 17 March 2020. doi:10.1093/infdis/jiaa113
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.
Paret M, Lighter J, Pellett Madan R, Raabe VN, Shust GF, Ratner AJ. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress [published online ahead of print, 2020 Apr 17]. Clin Infect Dis. 2020;ciaa452. doi: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.
Zhu, L., J. Wang, R. Huang, L. Liu, H. Zhao, C. Wu and C. Zhu (2020). “Clinical characteristics of a case series of children with coronavirus disease 2019.” Pediatr Pulmonol 8th April 2020 https://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.
Canarutto, D., A. Priolo, G. Russo, M. Pitea, M. C. Vigone and G. Barera (2020). “COVID-19 infection in a paucisymptomatic infant: Raising the index of suspicion in epidemic settings.” Pediatr Pulmonol. https://doi.org/10.1002/ppul.24754
This early single case report from Milan, Italy describes an infant with 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.
Shen Q, Guo W, Guo T, Li J, He W, Ni S, Ouyang X, Liu J, Xie Y, Tan X, Zhou Z. Novel coronavirus infection in children outside of Wuhan, China. Pediatric pulmonology. 2020 Apr 7.p1-6 DOI: 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.
Han, Y. N., Z. W. Feng, L. N. Sun, X. X. Ren, H. Wang, Y. M. Xue, Y. Wang and Y. Fang (2020). “A comparative-descriptive analysis of clinical characteristics in 2019-Coronavirus-infected children and adults.” J Med Virol. 6th April 2020. https://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.
Kamali Aghdam M, Jafari N, Eftekhari K. Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report [published online ahead of print, 2020 Apr 1]. Infect Dis (Lond). 2020;1–3. doi:10.1080/23744235.2020.1747 634 Accessed from: https://www.tandfonline.com/doi/full/10.1080/23744235.2 020.1747634 on 4th April
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.
Su L, Ma X, Yu H, et al. The different clinical characteristics of coronavirus disease cases between children and their families in China – the character of children with COVID-19. Emerg Microbes Infect. 2020;9(1):707–713. doi:10.10 80/22221751.2020.1744483
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.
Lou XX, Shi CX, Zhou CC, et al. Three children who recovered from novel coronavirus 2019 pneumonia. J Paediatr Child Health Published Online First: 22 March 2020. doi: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.
Top Papers on Co-morbidities
Mixed co-morbidities
Issitt R, Booth J, Bryant W, Spiridou A, Taylor A, DuPre P, Ramnarayan P, Hartley J, Borja MC, Moshal K, Dunn H. Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population. medRxiv. 2020 Jan 1. Doi https://doi.org/10.1101/2020.05.20.20107904
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.
Oncology
Gampel, B. Troullioud Lucas, AG. Broglie, T. et al. (2020 Jun 26). “COVID-19 disease in New York City pediatric hematology and oncology patients.” Pediatr Blood Cancer: e28420. June 26th 2020, https://doi.org/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
Ferrari, A., M. Zecca, C. Rizzari, F. et al (2020). “Children with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy.” Pediatr Blood Cancer: e28410.
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.
Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in Children With Cancer in New York City. JAMA Oncol. Published online May 13, 2020. doi:10.1001/jamaoncol.2020.2028
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.
Cesaro, S., F. Compagno, D. Zama, L. Meneghello, N. Giurici, E. Soncini, D. Onofrillo, F. Mercolini, R. Mura, K. Perruccio, R. De Santis, A. Colombini, A. Barone, L. Sainati, V. Baretta and M. G. Petris (2020). “Screening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy.” Pediatr Blood Cancer: e28466, https://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 V, Miranda R, Merino L, et al. SARS-CoV-2 infection in children with febrile neutropenia [published online ahead of print, 2020 Jun 12]. Ann Hematol. 2020;1-2. doi:10.1007/s00277-020-04115-1
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.
Sieni, E. Pegoraro, F. Casini, T. Tondo, A. Bortone, B. Moriondo, M. Azzari, C. Galli, L. Favre, C. Favourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression. British Journal of Haematology. 2020 May 5. https://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.
Hrusak, O., T. Kalina, J. Wolf, A. et al. (2020). “Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.” European Journal of Cancer 132: 11-16. https://doi.org/10.1016/j.ejca.2020.03.021
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.
D’Antiga L. (2020), Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl. Accepted Author Manuscript. doi: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.
Balduzzi, A, Brivio, E, and Rovelli, A et al, Lessons 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, Italy. Estote Parati. (Be Ready.) (3/19/2020). Available at SSRN: https://ssrn. com/abstract=3559560 or https://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.
Cardiac disease
Lee, H., B. S. Mantell, M. E. Richmond, S. P. Law, W. A. Zuckerman, L. J. Addonizio, T. M. Lee and I. D. Lytrivi (2020). “Varying Presentations of COVID-19 in Young Heart Transplant Recipients: A Case Series.” Pediatr Transplant: e13780. https://doi.org/10.1111/petr.13780
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 pandemic
Hospital/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.
Respiratory disease
Poli, P., S. Timpano, M. Goffredo, R. Padoan and R. Badolato. “Asymptomatic case of Covid-19 in an infant with cystic fibrosis.” Journal of Cystic Fibrosis, April 14th 2020, https://doi.org/10.1016/j.jcf.2020.03.017
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.
Inflammatory Bowel Disease
Turner D, Huang Y, Martín-de-Carpi J, et al. COVID-19 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto group of ESPGHAN [published online ahead of print, 2020 Mar 31]. J Pediatr Gastroenterol Nutr. 2020; doi: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.
Brenner, E. J., R. C. Ungaro, R. B. Gearry et al “Corticosteroids, but not TNF Antagonists, are Associated with Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results from an International Registry.” Gastroenterology https://doi.org/10.1053/j.gastro.2020.05.032
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.
Renal disease
Schwierzeck, V., J. C. Konig, J. Kuhn, A. Mellmann, C. L. Correa-Martinez, H. Omran, M. Konrad, T. Kaiser and S. Kampmeier (2020). “First reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit.” Clin Infect Dis, https://doi.org/10.1093/cid/ciaa491
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.
Transplant related disease
Lagana SM, De Michele S, Lee MJ, Emond JC, Griesemer AD, Tulin-Silver SA, Verna EC, Martinez M, Lefkowitch JH. COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation. Archives of Pathology & Laboratory Medicine. 2020 Apr 17. doi: 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.
Angeletti, A., A. Trivelli, A. Magnasco, S. Drovandi, F. Sanguineri, M. Santaniello, G. Ferrando, R. Forno, G. Cipresso, G. Tripodi, L. V. Riella, P. Cravedi and G. M. Ghiggeri (2020). “Risk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study.” Clin Transplant. 2020 May 12. doi: 10.1111/ctr.13889. [Epub ahead of print]
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.
Morand, A., B. Roquelaure, P. Colson, S. Amrane, E. Bosdure, D. Raoult, J. C. Lagier and A. Fabre (2020). “Child with liver transplant recovers from COVID-19 infection. A case report.” Archives de Pediatrie. https://doi.org/10.1016/j.arcped.2020.05.004
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.
Other co-morbidities
Genovese, G., Colonna, C. and Marzano, A.V. (2020), Varicella‐like exanthem associated with COVID‐19 in an 8‐year‐old girl: A diagnostic clue?. Pediatr Dermatol. Accepted Author Manuscript. doi: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.
Top 10 Epidemiological Papers on Transmission
Yung, C. F., Kam, K., Nadua, K. D. et al. Novel coronavirus 2019 transmission risk in educational settings. Clinical Infectious Diseases. https://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.
Heavey, L., G. Casey, C. Kelly, D. Kelly and G. McDarby (2020). “No evidence of secondary transmission of COVID-19 from children attending school in Ireland, 2020.” Euro Surveill 25(21). May 28th 2020, https://doi.org/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.
Somekh, E., A. Gleyzer, E. Heller, M. Lopian, L. Kashani-Ligumski, S. Czeiger, Y. Schindler, J. B. Lessing and M. Stein (2020). “The Role of Children in the Dynamics of Intra Family Coronavirus 2019 Spread in Densely Populated Area.” Pediatr Infect Dis J. doi: 10.1097/INF.0000000000002783
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.
Qin-Long Jing, Ming-Jin Liu, Jun Yuan et al, Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study, The Lancet, June 17th 2020, https://doi.org/10.1016/S1473-3099(20)30471-0
This is study from Guangzhou, China documenting the attack rate amongst 1964 close contacts and 134 secondary or tertiary cases of 215 confirmed COVID-19 cases from January 7th to February 18th 2020.
There were 103 non-primary cases amongst 784 household contacts giving an attack rate of 13.1% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.2%.
In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.23, 95% CI 0.11-0.46)
Only 10/215 (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 keeping with other reports from Asia (Zhang), Israel (Somekh) and the USA (Rosenberg).
Eli S Rosenberg, Elizabeth M Dufort, Debra S Blog et al. New York State Coronavirus 2019 Response Team, COVID-19 Testing, Epidemic Features, Hospital Outcomes, and Household Prevalence, New York State—March 2020, Clinical Infectious Diseases, ciaa549, https://doi.org/10.1093/cid/ciaa549
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.
Zhang J, Litvinova M, Liang Y, et al, Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China, Science, 29th April 2020, DOI: 10.1126/science.abb8001
This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghai) 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.
Li, W., B. Zhang, J. Lu, S. Liu, Z. Chang, P. Cao, X. Liu, P. Zhang, Y. Ling, K. Tao and J. Chen (2020). “The characteristics of household transmission of COVID-19.” Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 17. https://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.
Wang, Z., W. Ma, X. Zheng, G. Wu and R. Zhang (2020). “Household Transmission of SARS-CoV-2.” The Journal of infection. 10. https://doi.org/10.1016/j.jinf.2020.03.040
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.
Zhu Y, Bloxham CJ, Hulme KD, et al. Children are unlikely to have been the primary source of household SARS-CoV-2 infections. medRxiv 2020;:2020.03.26.20044826. doi: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.
Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study, Lancet Infectious Disease, April 27th 2020, https://doi.org/10.1016/S1473-3099(20)30287-5
This was a fairly impressive study looking at contact tracing of 1286 contacts of 391 patients with COVID-19. Only 20 (5.1%) of the initial 391 cases were children, of which 2/3 were asymptomatic. They discovered a secondary attack rate of 15% for household contacts and 9.6% overall. The most important finding is that the rate of infection in children <10 years (7.4%) was similar to the population average (7.9%). The findings of this study suggested that children were becoming infected at a similar rate to adults but were much less likely to be asymptomatic. As no repeat testing was performed, it is unclear if these children were truly asymptomatic, or presymptomatic. Subsequent studies have consistently shown lower attack rates in children, and the reason for this discrepancy is unknown.
Top Epidemiological Papers on Disease Burden
Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al. Prevalence of SARSCoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 2020. https://doi.org/10.1016/ S0140-6736(20)31483-5
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-CoV-2 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.
Gabriele Pagani, Federico Conti, Andrea Giacomelli et al, Seroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA). medRxiv June 24th 2020, https://doi.org/10.1101/2020.06.24.20138875
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.
Stringhini, S., A. Wisniak, G. Piumatti, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study.” Lancet. June 11th 2020, https://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.
Lavezzo, E., Franchin, E., Ciavarella, C. et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’. Nature (2020). https://doi.org/10.1038/s41586-020-2488-1
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). It should be noted the definition of symptoms was restricted to ECDC definitions of COVID-19 related symptoms, and given the wide variation of non-classic symptoms which have been described (rashes, malaise, joint aches, rhinorroea, GI symptoms etc), this likely significantly undercounts the number of patients who truly developed symptoms.
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.
Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, Melsted P, Norddahl GL, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med, Published April 14th 2020, doi: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.
Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 April 2020. DOI: https://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.
Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics 2020:e20200702. doi:10.1542/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.
Top 10 PIMS-TS / MIS-C Papers
Felstein, L.R. et al (2020) Multisystem Inflammatory Syndrome in U.S. Children and Adolescents, NEJM. epub 29 June 2020, DOI:10.1056/NEJMoa2021680.
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.
Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. DOI: 10.1056/NEJMoa2021756.
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.
Kaushik, S., S. I. Aydin, K. R. Derespina et al, “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection: A Multi-institutional Study from New York City.” J Pediatr. https://doi.org/10.1016/j.jpeds.2020.06.045
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 ³ 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/mL (8450-14,400), lymphocytes 1,100/mL (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 mg/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
Capone, C. A., A. Subramony, T. Sweberg, J. et al. “Characteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection.” J Pediatr. https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.044
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.
Whittaker, E., A. Bamford, J. Kenny, et al. “Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2.” Jama. doi:10.1001/jama.2020.10369
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.
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.
Cheung EW, Zachariah P, Gorelik M, et al. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. JAMA. Published online June 08, 2020. doi:10.1001/jama.2020.10374
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.
Belot, A., D. Antona, S. Renolleau, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020.” Euro Surveill 25(22). June 4th 2020, https://doi.org/10.2807/1560-7917.ES.2020.25.22.2001010
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.
Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, Auriau J, Grimaud M, Oualha M, Beghetti M, Wacker J. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020 May 17. doi: 10.1161/CIRCULATIONAHA.120.048360
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”.
Toubiana Julie, Poirault Clément, Corsia Alice, Bajolle Fanny, Fourgeaud Jacques, Angoulvant François et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study BMJ 2020; 369 :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.
Riphagen, Shelley et al., Hyperinflammatory shock in children during COVID-19 pandemic, The Lancet, May 7th 2020, https://doi.org/10.1016/S0140-6736(20)31094-1
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.
Paediatric COVID data
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.
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.
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.
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.
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.
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.
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”
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.
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.
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.”
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.
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.
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.
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
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.
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.
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.”
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.
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.
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.
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.
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.
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.
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 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.
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).
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.
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.
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.
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.
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%).
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.
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.
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
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.
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.
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.
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.
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.
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.
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.”
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
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.
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.
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.
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).
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.
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
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.
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.
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.”
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.
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
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.
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.
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.
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.
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).
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.
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).
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.
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
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.
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.
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.
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.
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.
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.
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%).
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.
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.
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.
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.
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.
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.
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.
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.
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)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.”
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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”.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%).
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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 Nasopharynge