An evidence summary of Paediatric COVID-19 literature

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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:
http://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.

Whilst our project began with written reviews of every paper, as the volume of publication has increased and become more repetitive, we have moved to a selective reviewing process to ensure important, relevant findings are not lost among a large volume of similar publications. This is as of April 17th 2020.

Our process involved a formal literature search, followed by identification of all papers relevant to children/young people, then reading of every article by one of our team of doctors. If the article is felt to be of high enough quality, determined by consensus and involvement of a clinical academic, then we will include a written review. We are keeping a record of all pertinent literature which is available on this page or via the downloadable PDF.

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 [email protected]

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Executive Summary (Updated 29th May)

Epidemiology

Around the world, children make up a minority of confirmed cases of COVID-19, usually contributing to between 1 – 5% of total case numbers. Concerns exist that low case rates reflect selective testing of only the most unwell, however data from South Korea and subsequently Iceland which have undertaken widespread community testing, have also demonstrated significantly lower case numbers in children. This has also been seen in the Italian town of Vo, which screening 70% of its population and found 0 children <10 years positive, despite a 2.6% positive rate in the general population.

More detailed information has emerged into childhood severity of COVID-19. A large number of children appear asymptomatic. Critical illness appears very rare (~1%). In Chinese and USA CDC data, infants appear most likely to be hospitalised, although rates of PICU admission do not appear to be significantly different as yet.

To date, deaths remain extremely rare in children from COVID-19.

 

Transmission

Precise details regarding paediatric transmission cannot be confirmed without widespread sero-surveillance, however important trends are emerging. Low case numbers in children suggest a more limited role than was initially feared. Contact tracing data from Shenzhen in China demonstrated an equivalent attack rate in children as adults, however this has been contradicted by 4 subsequent studies in Japan, Guangzhou, Wuhan and Shanghai, and cities in close proximity to Wuhan. These have all demonstrated a significantly lower attack rate in children. This, coupled with low case numbers would suggest that children are less likely to acquire the disease. The role of children in passing the disease to others is unknown, in particular given large numbers of asymptomatic cases. Notably, the China/WHO joint commission could not recall episodes during contact tracing where transmission occurred from a child to an adult. Studies of multiple family clusters have revealed children were unlikely to be the index case, in Guangzhou, China, and internationally. A SARS-CoV2 positive child in a cluster in the French alps did not transmit to anyone else, despite exposure to over 100 people.

Several studies have now shown that SARS-CoV-2 can be detected by PCR in the stool of affected infants 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. In the absence of widespread community or serological testing, it is 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.

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.

More recently, a hyperinflammatory syndrome resembling Kawasaki shock, which appears to be a delayed immune response to COVID-19 has been described. Published reports from London, Italy and France 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.

 

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. As yet, cord blood, amniotic fluid and placental swabs persistently testing negative for SARS-CoV-2. 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. When tested, breast milk has been negative for SARS-CoV-2 except for on a single occasion. It is unclear if this positive result reflects live, infectious virus, and whether the source was the mother or the infant who subsequently also tested positive for the virus. The vast majority of newborns have not acquired COVID-19 themselves. 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.


Children with comorbidities

There is little clinical data to inform us on the effect of COVID-19 on children with other comorbidities. Some data has been published from a liver transplant unit in Lombardy, Italy, which had 3 cases of COVID-19 in post-transplant patients who all suffered very mild symptoms. A case series of 9 children with inflammatory bowel disease on immunosuppression all suffered a mild course, as did a series of 5 children being treated for malignancy. Studies from PICU admissions in the US and Italy found the majority have some comorbidities, most commonly respiratory or complex neurodisability – groups for whom there is 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. The role of children in transmission is unclear, but consistent evidence is demonstrating a lower likelihood of acquiring infection, and lower rates of children bringing infections into households. Changes in laboratory or radiographic parameters are slightly different to adults, and changes usually mild. There is some evidence of vertical transmission to neonates, however it is unclear is this is perinatal or intrauterine. Evidence suggests both infected mothers and infants are no more severely affected than other groups. There does not appear to be significant increased risk for children with immunosuppression, but further data is needed. Children with respiratory 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 29th May)

de Lusignan, S., J. Dorward, A. Correa, N et al,  “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.

 

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 – 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.

 

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.

 

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.

 

Oberweis, M. L., A. Codreanu, W. Boehm, D. Olivier, C. Pierron, C. Tsobo, M. Kohnen, T. T. Abdelrahman, N. T. Nguyen, K. Wagner and I. de la Fuente Garcia (2020). “Pediatric Life-Threatening Coronavirus Disease 2019 With Myocarditis.” Pediatr Infect Dis J. May 11th 2020, doi: 10.1097/INF.0000000000002744

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.

 

P. Deza Leon, A. Redzepi, E. McGrath, N. Abdel-Haq, A. Shawaqfeh, U. Sethuraman, B. Tilford, T. Chopra, H. Arora, J. Ang and B. Asmar. COVID-19 Associated Pediatric Multi-System Inflammatory Syndrome. J Paediatric Infect Dis Soc, May 22nd 2020, https://doi.org/10.1093/jpids/piaa061

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

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

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

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

 

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”.

 

Tullie, K. Ford, M. Bisharat, T. Watson, et al. Gastrointestinal features in children with COVID-19: an observation of varied presentation in eight children.  Lancet Child Adolesc Health, May 19th 2020, https://doi.org/10.1016/S2352-4642(20)30165-6

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.

 

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.

 

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.

 

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.

 

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.

 

Pain, C. E., S. Felsenstein, G. Cleary, S. Mayell, K. Conrad, S. Harave, P. Duong, I. Sinha, D. Porter and C. M. Hedrich (2020). “Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms.” Lancet Rheumatol. https://doi.org/10.1016/S2665-9913(20)30137-5

This is a case report from Alder Hey Childrens Hospital, Liverpool of previously health 14 year old patient fitting criteria for PIM-TS, successfully treated with Anakinra.

Initial presentation : This patient initially presented with a a 3-day history of fever, abdominal pain, nausea, and vomiting, and no respiratory symptoms. A previous history of mild respiratory symptoms 3 weeks earlier was reported. On initial presentation patient had fever 38.1, was cardiovascularly stable, no respiratory distress, but had a tense abdomen with guarding in right upper and lower quadrant. Initial investigations conducted showed; bloods – lymphopenia (0·14 × 109 cells/L), CRP of 242mg/per L, urine – sterile pyuria (30cells), radiology – normal CXR, normal abdominal ultrasound. Nasopharyngeal Sars CoV2 PCR – sent (subsequently negative). A provisional diagnose of acute appendicitis was made, and patient started on Piperacillin-tazobactam.

Deterioration : Within 24 hours of admission, patient became visually more unwell, was tachycardic, had increased dyspnoea and cough, and developed a widespread maculopapular rash. Further investigations showed; Radiology – Ct chest, showed typical findings of SARS-CoV-2. Bloods showed; lymphopenia, anaemia, thrombocytopenia, raised CRP and Ferritin, raised serum interleukin (IL)-6 (1098 pg/mL [normal range<7]), coagulopathy with raised D Dimers and prolonged PR and APTT, raised increased liver enzymes, hypertriglyceridaemia, ANA negative, raised APL (anticardiolipin IgG 25·5 U/mL [normal range <20] and antiβ2-glycoprotein IgG 28·8 U/mL [normal range <20]) were positive, and low complement levels (C3 0·09 g/L [normal range 0·90–1·88], C4 0·12 g/L [normal range 0·18–0·42]).  Patient also developed mild polyarticular arthritis.

Treatment and ongoing care : Initial oxygen requirement (8 L/min), finally escalating to CPAP ventilation support. IV Bolus for hypertension. Anti-inflammatory treatment with recombinant IL-1 receptor antagonist (Anakinra) was started after multidisciplinary discussion. It was commenced at 4 mg/kg per day s/c but increased to 8 mg/kg per day after 36 hours because patient required inotropic support for hypotension and rising lactate (6 mmol/L). Because of cardiovascular involvement (borderline LV systolic dysfunction, aortic regurgitation, progressive left coronary dilatation, enzyme leak with troponin-T 45 ng/L), aspirin was started (2 mg/kg) for its antithrombotic effects. Patient did not show additional clinical features of Kawasaki disease, and upon discussion IVIG nor corticosteroids were not given.

Outcome : SARS-CoV-2 IgG became positive (borderline day 6, positive day 11). In temporal relation with anakinra treatment, the patient’s respiratory status stabilised and clinical and laboratory variables returned to normal.

 

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.

 

Russell, M. R., N. J. Halnon, J. C. Alejos, M. M. Salem and L. C. Reardon (2020). “COVID-19 in a pediatric heart transplant recipient: Emergence of donor-specific antibodies.” J Heart Lung Transplant. https://doi.org/10.1016/j.healun.2020.04.021

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.

 

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:

  1. The breast milk of one of the mothers tested positive for SARS­CoV­2 RNA at 10-13 days after birth. Testing of breast milk from the other mother was negative.
  2. Quantification using Ct values corresponded to 1∙32 × 10⁵ copies per mL in whole milk and 9∙48 × 10⁴ copies per mL in skimmed milk.
  3. An 89∙2% reduction in recovery rate in whole milk and 51∙5% in skimmed milk, suggesting that the actual viral loads in whole milk of the mother could be even higher than detected.

This study provides the first report of the detection of viral RNA in human breast milk collected from a mother who had clinical signs of Covid-19 confirmed by PCR testing of swabs. This does not provide evidence that the RNA was indicative of infectious virus or that transmission of the virus to the baby occurred via breastmilk. Further studies will be necessary to attempt to culture virus from breast milk and assess risk of transmission, which to date has seemed low.

 

Cook, K Harman, B. Zoica et al. Horizontal transmission of severe acute respiratory syndrome coronavirus 2 to a premature infant: multiple organ injury and association with markers of inflammation. Lancet Child and Adolescent Health. 19th May 2020, https://doi.org/10.1016/S2352-4642(20)30166-8

This is a single case report of an ex-27 week preterm male infant, who presented on the 30/03 to King’s College Hospital, London at 8 weeks of age (35 weeks CGA). He had a relatively stable NICU course requiring 3 days of ventilation and had been discharged 10 days prior to presentation. Household members were asymptomatic and there were no cases of COVID 19 prior or post his discharge from NICU. Symptoms (not specified) had commenced 2 days prior to admission. At presentation he was in presumed septic shock with unrecordable BP, lactic acidosis and respiratory distress and was intubated and commenced on 4 antibiotics and acyclovir. Investigations on admission included a CXR (bilateral airspace opacification), nasopharyngeal swab (positive for SARS COV2) and blood culture (grew Staph. epi). Urine, CSF and respiratory secretions were negative and subsequent 2 blood cultures were negative. 2 further nasopharyngeal swabs on day D7 and D15 of admission continued to be positive. On D8 there was respiratory deterioration (repeat CXR showing worsening bilateral opacification) and he was commenced on HFOV with iNO. Remdesivir was also commenced at this time and continued for a 10 day course. Ferritin and LDH peaked just before D8 and IL6 and IL10 were the highest on D8 (no levels available prior to D8). CRP was highest on admission and had quickly declined, with no rise associated with the respiratory deterioration. He was switched back to conventional ventilation on D16, extubated to Highflow on D22 and off all respiratory support on D24. He was discharged from PICU to the general paediatric ward on D25 to continue weaning off sedation (no neurological sequalae reported). There was evidence of liver (raised AST and GGT) and renal (raised creatinine with peak around D7) impairment along with bone marrow dysfunction (drop in platelet and WCC) initially which improved during the admission. There was no change in the viral load between admission and D16-17 of admission.

This case report is the first to chart the clinical course of a SARS COV 2 related hyperinflammatory state in a baby with a background of being born very preterm. The timing from NICU discharge to symptom onset makes it likely that the SARS COV 2 infection was acquired post discharge. The report does not explain why the ETT is barely visible/not present on the second CXR. It is not possible to say whether the IL6 and IL10 peaks were on the day of deterioration or whether this may have preceded it (as was the case in LDH and ferritin levels), since there were no interleukin levels prior to D8. Unlike ferritin and LDH, interleukin levels are not routinely tested outside tertiary centres. Therefore, the former two markers are a more feasible option for purposes of basing day to day clinical decision-making but may not be specific to SARS COV2 related hyperinflammation. CRP levels did not correspond to the respiratory deterioration. It is unclear whether the drop in all WCC lines and platelets suggestive of the marrow suppression and the acute renal and liver dysfunction were secondary to the shock at presentation or part of the hyperinflammatory state. It would have been helpful to know about the coagulation and fibrinogen status in this case. It is also noteworthy that Remdesivir did not change the viral load during the acute period of the admission. Therefore, it stands to reason that administration of this antiviral did not contribute to the clinical improvement, as suggested by the authors.

Future studies need to look at whether the specific inflammatory markers delineated in this case report could be used to predict which infant is susceptible to hyperinflammatory state and help steer the early course of management (e.g. early switch to HFOV).

 

Baergen, R. N., & Heller, D. S. (2020). Placental Pathology in Covid-19 Positive Mothers: Preliminary Findings. Pediatric and Developmental Pathology23(3), 177 180.  https://doi.org/10.1177/1093526620925569

This is a rapid communication letter in a pathology journal describing 20 placentas of Sars-Cov-2 positive mothers at Weill Cornell Medical Center, New York. Clinical details of both mothers and infants are also described.  This hospital screened all expectant mothers for Sars-COV-2 by RT PCR. These are results of the examination of the first 20 placentas received by the pathology department

Clinical features; 4 woman were symptomatic peripartum; 2 had fever on presentation, 1 had been admitted with hypoxia and pneumonia but discharged pre delivery, 1 was re-admitted day 3 postpartum for hypoxia and shortness of breath, the rest were asymptomatic. Mothers were aged median 31 years (13.5 years) 4 women had pre-existing conditions ( 1 sickle trait, 1 chronic diabetes, 1 hypertension, 1 hypothyroid). No woman required ICU admission.

There was 19 singletons, and 1 set of twins. No infant tested positive for Sars CoV-2. Five infants were born at 32 – <37, and the rest from 37 weeks gestation. All infants had 5-minute Apgars of 8 or 9, were admitted to the well-baby nursery, and discharged home.

Pathology Features; Placental tissue was not tested for Sars Cov 2. Nine placenta (45%) had evidence of fetal vascular malperfusion. In three cases this was intramural fibrin deposition it one or two areas; in two cases there was foci of stromal-vascular karyorrhexis, and in the other four there was widespread foci of stromal-vascular karyorrhexis. In all cases vascular malperfusion was graded as mild. In one woman who had pneumonia and acute hypoxia, placenta showed evidence of ascending infection with acute chorioamnionitis and acute funisitis. Four other cases showed chronic villitis though its relationship to SArs COV 2 is unclear.

Conclusion; Authors conclude that Sars Cov2 in mothers, may be associated with a propensity for thrombosis in fetal circulation. However, they caution this might also be unrelated and further work is needed.

 

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 Dishttps://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:

  1. The breast milk of one of the mothers tested positive for SARS­CoV­2 RNA at 10-13 days after birth. Testing of breast milk from the other mother was negative.
  2. Quantification using Ct values corresponded to 1∙32 × 10⁵ copies per mL in whole milk and 9∙48 × 10⁴ copies per mL in skimmed milk.
  3. An 89∙2% reduction in recovery rate in whole milk and 51∙5% in skimmed milk, suggesting that the actual viral loads in whole milk of the mother could be even higher than detected.

This study provides the first report of the detection of viral RNA in human breast milk collected from a mother who had clinical signs of Covid-19 confirmed by PCR testing of swabs. This does not provide evidence that the RNA was indicative of infectious virus or that transmission of the virus to the baby occurred via breastmilk. 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

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 SARS-CoV-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 denominators 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.

 

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.

The paper provides reasonably clear definitions of Mild, Moderate, Severe and Critical illness, with asymptomatic patients identifying as Mild. For this cohort, 28% of patients were asymptomatic, with Moderate cases more likely to have fever of 38degC 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 further analyse their cohort as 1-5yo and 5-16yo, in general noting that the older children were more likely to be lymphopaenic and would shed virus for a longer period (11 vs 9 days).

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.”

 

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%).

 

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/). Three points are worth noting at this stage:

  • 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 syndrome
  • It 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 illness
  • Reports 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%)

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.

 

Julie Toubiana, Clement Poirault, Alice Corsia et al. Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France medRxiv 2020.05.10 doi: https://doi.org/10.1101/2020.05.10.20097394

As a pre print this study should be interpreted with caution until it has undergone peer review.

This retrospective cohort study looks at a cluster of patients diagnosed with Kawasakis disease at a hospital in Paris between April 27th and May 7th. During this time they admitted 17 children with a diagnosis of Kawasakis or incomplete Kawasakis, with a mean age of 7.5yr and 10/17 (59%) female.

Clinical features: All children presented with persistent fever and with initial GI symptoms (vomiting and diarrhoea) with nearly half fulfilling complete KD criteria (8/17, 47%). The majority were irritable (11/17, 65%) and myocarditis was common (12/17, 71%). Coronary artery dilation was seen in 5/17 but no aneurysms seen. 6/14 who had chest imaging had lung changes.

Bloods: Inflammatory markers were significantly raised, with a median CRP of 219, PCT 23.3 and IL-6 218. Interestingly mean platelet count was 432 (but up to 838). Median troponin 136 and D dimer 4762 (up to 19330). Ferritin not reported.

COVID-19 status: 7/17 tested positive on swab and 15/17 had positive serology

Treatment: All were given IVIg, following which 5/17 still had fever 36hrs afterwards. They were given a second dose of IVIg and steroids. 10/17 required inotropic support and the same number 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.

 

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.

 

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.

 

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.

 

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.

 

Top 10 Epidemiological Papers

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:

  • Asymptomatic: no symptoms at all
  • Mild: Primarily URTI symptoms with or without fever
  • Moderate: Pneumonia, frequent fever, and cough, +/- wheeze, but not hypoxaemic OR none of these but an abnormal CT (worth noting)
  • Severe: Above symptoms but more severe, usually with accompanying hypoxaemia
  • Critical: ARDS, shock, organ failure

So what did they find? 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.

 

Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 April 2020. DOI: http://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 exposure 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. PICU 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 did 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.

 

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 yo tested in the targeted testing cohort, 6.7% (38) were positive – compared with 13.7% of persons >10 yo
– of 848 children <10 yo tested in the population screening cohort, 0% (0) were positive – compared with 0.8% of persons >10yo

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 yo 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 SARS-CoV-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.

 

Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA Published Online First: 17 March 2020. doi:10.1001/jama.2020.4344

This is a helpful one page summary of data around COVID-19 numbers in Italy as of 15th March 2020. Of note, there have been 22,512 cases of COVID-19 with 2026 (9%)  being health care workers. There have been 1625 deaths (7.2%) of cases in Italy, which is a higher case fatality than rates from China and other countries so far. Below are two of the charts below which depict the age range and severity of COVID-19 infections. From a paediatric perspective, 1.2% of cases have been in patients <18 years old and remarkably there have been 0 deaths under 30yrs of age so far

Enrico Lavezzo, Elisa Franchin, Constanze Ciavarella, et. al, Suppression of COVID-19 outbreak in the municipality of Vo, Italy, medRxiv 2020.04.17.20 doi: https://doi.org/10.1101/2020.04.17.20053157

A pre-print, this article should be interpreted with caution until it has undergone peer review.

This paper outlines the strategy of a small town in Italy which immediately shutdown for 14 days following their first death from COVID-19 on Feb 21st 2020. They subsequently screened 86% of the population for SARS-CoV-2 using nasopharyngeal swabs, then screened again 2 weeks later (71.5% of the population).

At the start of the lockdown 2.6% (95% CI 2.1 – 3.3%) of the population tested positive, but 0 of 217 children aged 0 – 10 tested positive (0%), and only 3/250 aged 11 – 20 (1.2%) tested positive. By the end of the lockdown, 0/157 (0%) children aged 0 – 10 tested positive, and 2/210 (1%) children aged 11- 20 tested positive. Many of the children aged 0 -10 lived with infected individuals. They also noted >40% of people who tested positive were asymptomatic. They note a significant number of infections appeared to have come from asymptomatic individuals during contact tracing. They also note these asymptomatic individuals never developed symptoms, and had similar viral loads to symptomatic patients (as determined by the cycle threshold from RT-PCR).

This study has relatively small numbers, but again appears to provide evidence for several important features of paediatric infection: primarily that children appear significantly less likely to become infected than adults. It presents evidence for asymptomatic transmission, and against the theory of viral load correlation with symptom burden.

 

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.

 

Mizumoto K, Omori R, Nishiura H. Age specificity of cases and attack rate of novel 1 coronavirus disease (COVID-19) 2. doi:10.1101/2020.03.09.20033142

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

This is a series of the 313 domestically acquired cases of COVID-19, in Japan, up until March 7th 2020. It looks at the ages of patients who acquired the disease and compares this to those exposed (n=2496) to estimate attack rates.

Of note, there was a significantly lower attack rate in children (7.2% in males and 3.8% in females) than in the older populations (up to 22% in 50 – 59yr olds). This attack rate in children is similar to that observed in Shenzen, but much lower than observed in older adults in Japan. This suggests children are much less likely to acquire the disease than adults if exposed. This is at odds with the findings from Shenzen, and the reason for this disparity is unclear.

 

Qin-Long Jing, Ming-Jin Liu, Jun Yuan et al, Household Secondary Attack Rate of COVID-19 and Associated Determinants, medRxiv, 11th April 2020, https://doi.org/10.1101/2020.04.11.20056010

A pre-print, this article should be interpreted with caution until it has undergone peer review.

This is study from Guangzhou, China documenting the attack rate amongst 2075 close contacts of 212 confirmed COVID-19 cases from January 7th to February 17th 2020.

There were 97 non-primary cases amongst 770 household contacts giving an attack rate of 12.6% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.3%.
In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.27 for close contacts and OR 0.23 for household contacts)
Only 10/217 (5%) of primary cases were children.

Although the criteria for testing contacts in this study are not entirely clear, the results suggests that children are less susceptible to SARS-CoV-2 infection compared with adults with similar exposure. This is in contrast to earlier data from Shenzhen, China suggesting similar attack rates in children, but is in keeping with more recent epidemiological data from Iceland and Italy.

 

Zhang J, Litvinova M, Liang Y, et al, Changes in contact patterns shape the dynamics of the COVID-19 outbreak in ChinaScience, 29th April 2020, DOI: 10.1126/science.abb8001

This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghai) using 3 arms:

  1. 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
  2. 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).
  3. Finally using the above data they estimated the effects of non-pharmaceutical interventions on reducing spread of COVID-19. They found that closing schools was likely to significantly impact the R0 but not enough 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://doi.org/10.1093/cid/ciaa450

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.

 

Paediatric COVID data

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About 

Alison is a paediatric registrar in Australia, currently embarking on her PhD in bone and joint infections. She is passionate about teaching and making the world just that little bit more organized with the help of washi tape.

About 

Alasdair is a Paediatric registrar in the UK, currently working as a Clinical Research Fellow in Paediatric Infectious Diseases. His interests include evidence based medicine, diagnostics and antimicrobial resistance.

@apsmunro | Ally's DFTB posts

About 

A Paediatric Trainee based in Queensland, Australia, Henry is passionate about Adolescent Medicine & General Paediatrics, with a strong interest in Medical Education & Clinical Teaching. An admitted nerd & ironman with a penchant for Rubik's Cubes & 'Dad jokes'.

@henrygoldstein | + Henry Goldstein | Henry's DFTB posts

Author: Alison Boast Alison is a paediatric registrar in Australia, currently embarking on her PhD in bone and joint infections. She is passionate about teaching and making the world just that little bit more organized with the help of washi tape.

54 Responses to "An evidence summary of Paediatric COVID-19 literature"

  1. Jo Mannion
    Jo Mannion 3 months ago .Reply

    Thanks for collating this Alisdair and Alison
    Really useful

    • Dr. Vicki Burneikis
      Dr. Vicki Burneikis 3 months ago .Reply

      The prolonged faecal shedding is worrying- should grandparents wear PPE to change nappies?

  2. Kylie Stark
    Kylie Stark 3 months ago .Reply

    You guys never fail to deliver
    Thankyou

  3. Claire Lundy
    Claire Lundy 3 months ago .Reply

    Absolutely brilliant thanks so much

  4. Dr Rajiv Uttam
    Dr Rajiv Uttam 3 months ago .Reply

    Very useful information
    Thanks

  5. Dr P
    Dr P 3 months ago .Reply

    Thanks. An amazing effort once again.

  6. veronica giordano
    veronica giordano 3 months ago .Reply

    Thank you so much, brilliant

  7. Shermina
    Shermina 3 months ago .Reply

    Thanks for doing this work – really helpful

  8. Johhn Kopsidas
    Johhn Kopsidas 3 months ago .Reply

    Thank you!

  9. Kelly
    Kelly 3 months ago .Reply

    We need risk and recommendation commentary on special needs paediatric population; particularly those of school age (and whose parents/Carers are front line such as health care workers)

    • Katie
      Katie 3 months ago .Reply

      Echoing your request; this cohort needs timely guidance based on what evidence we can glean. Thanks DFTB once again for educational content.

    • Steph D
      Steph D 3 months ago .Reply

      I am a NHS front line worker with a child who has severe & complex needs and recurring chest infections. Currently isolated pseudomonas in the chest. Desperate for information.

      • CER
        CER 3 months ago .Reply

        Me too. My daughter has bronchiectasis but is currently well.

      • Steph D
        Steph D 3 months ago .Reply

        Massive thanks to you all for this. Keep up the good work 🙂

    • Sarah Mudge
      Sarah Mudge 3 months ago .Reply

      Much appreciated for collating this information. Frontline ICU Nurse and Cerebral Palsy parent.

  10. Angela Luangrath
    Angela Luangrath 3 months ago .Reply

    Very appreciative of you work. Thank you!

  11. Amelia
    Amelia 3 months ago .Reply

    This is amazing – thanks!! Paeds Reg on mat leave with a newborn here. Have been wanting to look into this but too tired to tackle – I am so appreciative.

    • Annika
      Annika 3 months ago .Reply

      Me too, 6 week old daughter, father neurologist in emergency department in Germany. Thank you for summarizing!!

  12. Dr Jacinta Coleman
    Dr Jacinta Coleman 3 months ago .Reply

    Great to have some clarity about presentation in these paediatric case studies. Thank you!

  13. Larry Budd
    Larry Budd 3 months ago .Reply

    With Mycoplasms noted more than just once do Symptomatic cases earn Azithromycin or other atypical therapy while waiting for results? Would the CXR / CT chest findings be consistent with Mycoplasms?

  14. Genevieve
    Genevieve 3 months ago .Reply

    Thank you! This is great summary of really useful studies. Keep up the good work!

  15. Dave Watkin
    Dave Watkin 3 months ago .Reply

    CT’s on asymptomatic children? Why?

  16. Shilpa Shah
    Shilpa Shah 3 months ago .Reply

    this is fabulous work. you all deserve an OBE 🙂

  17. Sarah C
    Sarah C 3 months ago .Reply

    Well done, very concise

  18. Saqib
    Saqib 3 months ago .Reply

    thank you – interesting that they have unilateral opacities on some CXR considering all I knew previously was that it was bilateral ground glass – makes me wonder about the kid I sent home recently with coamox as the XR changes were unilateral…however he has not come back so I assume he is ok! no harm, no foul.

  19. sabine Hennel
    sabine Hennel 3 months ago .Reply

    thank you so much for doing this – great work !!

  20. Konstantina Karanasiou
    Konstantina Karanasiou 3 months ago .Reply

    Thank you

  21. Pilar
    Pilar 3 months ago .Reply

    Thanks! Very useful

  22. Paola
    Paola 3 months ago .Reply

    Thanks a lot for doing this excellent work. These data are confirmed in Italy. Up to Now few children admittedto the hospital, mild symptoms, NO admission di intensive care. Keep fingers crossed. Very important to apply prevention policy and . isolation. Infection rate is starting to decrease in the area where the isolation was perforned rigorously (North East of Italy meaning Veneto and Friuli Venezia Giulia where I work. Good luck to all of you and keep safe

  23. Nick Thies
    Nick Thies 3 months ago .Reply

    Thanks for a brilliant review. You deserve a koala stamp!

  24. Jose Manuel
    Jose Manuel 3 months ago .Reply

    Thank you for this useful review.

  25. Sanaa
    Sanaa 3 months ago .Reply

    Thank you so much . This is a great summary , and such a positive look at paediatric covid cases , so we can somehow reassure the panicked mothers!

  26. Simon Chiles
    Simon Chiles 3 months ago .Reply

    Thank you, really interesting

  27. Rob Millar
    Rob Millar 3 months ago .Reply

    Good to know COVID in kids is relatively mild. However, do we know anything about numbers of paediatric HCWs becoming infected?

  28. OKUYAT ROBERT
    OKUYAT ROBERT 3 months ago .Reply

    Nice good info

  29. ILHAAM Abbas
    ILHAAM Abbas 3 months ago .Reply

    Interesting read. Thank you for sharing

  30. Aurora, R
    Aurora, R 3 months ago .Reply

    Thank you for this much needed information.

  31. Angela Freydag
    Angela Freydag 2 months ago .Reply

    Dear DFTB Team, thank you for this very helpful summary!

    Please note: In Cui Y, Tian M, Huang D, et al. , A 55- day old female.. the authors write at the end of the first paragraph:
    “The nasopharyngeal swab obtained from the infant also tested positive for severe acute respiratory syndrome coronavirus (SARS-CoV-2) on real-time reverse transcription–polymerase-chain-reaction (RT-PCR) assay.”
    I find this reassuring and would like to recommend to correct this part of your summary.
    Sincerely, Angela

    • Alasdair Munro
      Alasdair Munro 2 months ago .Reply

      Thank you for pointing out this omission – we will correct this immediately. We appreciate you taking the time to comment and help us improve the post.

  32. jogender Kumar
    jogender Kumar 2 months ago .Reply

    Excellent work. Very useful, precise and to the point information.

  33. Katie
    Katie 2 months ago .Reply

    thank you so much for this summary!

  34. Judith morgan
    Judith morgan 2 months ago .Reply

    Thank you. As a paediatric anaesthetist I’m trying to keep up with all the latest information and this is a great summary and am very grateful you’ve done this review.

  35. Karen Bartholomew
    Karen Bartholomew 2 months ago .Reply

    Thanks for the excellent work from another paediatric anaesthetist

  36. Yamila Gurovich
    Yamila Gurovich 2 months ago .Reply

    Thank you for reviewing these papers a friend who is a
    Paediatric nurse sent me this information. What is interesting is that a lot of studies note fecal shedding of virus or detection of virus in fecal samples is still there after oral/nasal tests are negative for virus. This is interesting as it seems coronavirus have evolved and originated in bats and bats shed these virus in fecal matter.

  37. Narinder Kaur
    Narinder Kaur 2 months ago .Reply

    Thank you so much for putting this together. Great Work. Faecal shedding is interesting and worrysome at the same time

  38. Robert S. Greenberg MD
    Robert S. Greenberg MD 2 months ago .Reply

    Great work….linked to from PedsAnesthesia.Net
    #teamsport

  39. Sarah Berwick
    Sarah Berwick 2 months ago .Reply

    Paeds medical nurse practitioner here, amazing job on the delivery of such valuable information. Great work. Your time & effort greatly appreciated.

  40. Kgomotso Lovey Sanyane
    Kgomotso Lovey Sanyane 2 months ago .Reply

    What a wonderful post. Absolutely valuable information in these trying times. I’m a paediatrician in South Africa and we are experiencing an increasing amount of COVID-19 cases

  41. Dr Luke Jeremijenko Emergency Physician
    Dr Luke Jeremijenko Emergency Physician 2 months ago .Reply

    Thanks team. Wonderful resource. Avidly reading through the papers. Question to the DFTB brains trust. I ran Dr Ben Symons simulation today and was asked (appropriately) is there a viral filter available for the F&P airvo 2? How are people running HFNP outside a negative pressure room?

    • Andrew Tagg
      Andrew Tagg 2 months ago .Reply

      We are trying to see what the evidence is, or at least find some expert consensus on this, so watch this space. I’m not a fan of the idea at the moment so we are advocating for starting it in the place it is going to b ultimately used. You don’t want to push a patient on HF through the hospita.l

  42. Tilmann Schober
    Tilmann Schober 2 months ago .Reply

    Thanks for this wonderful tool. Just one important remark? If you sort according to the date of publication, it is no in a chronological order. It might work if you put the year first, than the month and than the day.
    Best, Tilmann

  43. Paul Van Laer
    Paul Van Laer 2 months ago .Reply

    Cui Y, Tian M, Huang D, et al. A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis
    Concerning the elevated troponin: we see a slightly elevated troponin in all our young babies (newborn and older), without any clinical or echographic signs of cardiac involvement

  44. Pratik Patel M.D.
    Pratik Patel M.D. 4 weeks ago .Reply

    Dear Don’t Forget the Bubbles,

    I wanted to make you aware of a critically ill previously healthy pediatric patient who we had in Atlanta (USA) in late March who had concern for hyperinflammation and was successfully treated with a variety of COVID as well as hyperinflammation treatments (remdesivir and tocilizumab). We published our case and it is available online at Pediatrics in case you were interested in including it in your future summaries/posts! https://pediatrics.aappublications.org/content/pediatrics/early/2020/04/30/peds.2020-1437.full.pdf

    Thanks,
    Pratik

  45. Khallad
    Khallad 2 weeks ago .Reply

    Great work … !!

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