Sep, 2021

Early Impact of SARS-CoV-2 on Pediatric Clinical Research: A Pan-European and Canadian Snapshot in Time


Authors: O L. Mantha, F. Flamein, M. Turner, R. M. Fernandes, R. Hankard, the Network of National Networks Study Group

Published in: The Journal od Pediatrics



The article is meant to capture the early effects of the SARS-CoV-2 pandemic on pediatric clinical research.

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Aug, 2021

Causes of Microcephaly in the Zika Era in Argentina: A Retrospective Study


Authors: G Berberian, R Bologna, MG Pérez, A Mangano, PhD, M Costa, MSc, S Calligaris, MA Morales, C Rugilo, E Ruiz-Burga, C Thorne

Published in: Sage Journals



There are gaps in understanding the causes and consequences of microcephaly. This paper describes the epidemiological characteristics, clinical presentations, and etiologies of children presenting microcephaly during the Zika outbreak in Argentina. This observational retrospective study conducted in the pediatric hospital of Juan P. Garrahan reviewed the medical records of 40 children presenting microcephaly between March 2017 and November 2019. The majority (60%) were males and born full-term. At first evaluation, microcephaly was defined as congenital (31/40, 77%) and associated with other features (68%) such as seizures, developmental delay, non-progressive chronic encephalopathy, and West Syndrome. It was found manifestations restricted to central nervous system (55%), ocular (8/40, 20%), and acoustic (9/40, 23%) defects, and abnormal neuroimaging findings (31/39, 79%). Non-infectious diseases were the primary cause of isolated microcephaly (21/37, 57%), largely related to genetic diseases (13/21, 62%). Only 3 were children were diagnosed with Congenital Zika infection (3/16, 7.5%).

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Aug, 2021

Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children


Authors: J. Loske, J. Röhmel, S. Lukassen, S. Stricker, V. G. Magalhães, J. Liebig, R. L. Chua, L. Thürmann, M. Messingschlager, A. Seegebarth, B. Timmermann, S. Klages, M. Ralser, B. Sawitzki, L. E. Sander, V. M. Corman, C. Conrad, S. Laudi, M. Binder, S. Trump, R. Eils, M. A. Mall and I. Lehmann

Published in: Nature Biotechnology



Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

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Aug, 2021

Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents


Authors: K Ali, GBerman, H Zhou, W Deng, V Faughnan, M Coronado-Voges, B Ding, J Dooley, B Girard, W Hillebrand, R Pajon, JM. Miller, B Leav, and R McPhee

Published in: New England Journal of Medicine



Background The incidence of coronavirus disease 2019 (Covid-19) among adolescents between 12 and 17 years of age was approximately 900 per 100,000 population from April 1 through June 11, 2021. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in adolescents are unknown.

Methods In this ongoing phase 2–3, placebo-controlled trial, we randomly assigned healthy adolescents (12 to 17 years of age) in a 2:1 ratio to receive two injections of the mRNA-1273 vaccine (100 μg in each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of mRNA-1273 in adolescents and the noninferiority of the immune response in adolescents as compared with that in young adults (18 to 25 years of age) in a phase 3 trial. Secondary objectives included the efficacy of mRNA-1273 in preventing Covid-19 or asymptomatic severe acute respiratory syndrome coronavirus 2 infection.

Results A total of 3732 participants were randomly assigned to receive mRNA-1273 (2489 participants) or placebo (1243 participants). In the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted. The geometric mean titer ratio of pseudovirus neutralizing antibody titers in adolescents relative to young adults was 1.08 (95% confidence interval [CI], 0.94 to 1.24), and the absolute difference in serologic response was 0.2 percentage points (95% CI, −1.8 to 2.4), which met the noninferiority criterion. No cases of Covid-19 with an onset of 14 days after the second injection were reported in the mRNA-1273 group, and four cases occurred in the placebo group.

Conclusions The mRNA-1273 vaccine had an acceptable safety profile in adolescents. The immune response was similar to that in young adults, and the vaccine was efficacious in preventing Covid-19. (Funded by Moderna and the Biomedical Advanced Research and Development Authority; Teen COVE number, NCT04649151. opens in new tab.)


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Aug, 2021

Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2


Authors: E Molteni, CH Sudre, LS Canas, SS Bhopal, RC Hughes, M Antonelli, B Murray, K Kläser, E Kerfoot, L Chen, J Deng, C Hu, Somesh Selvachandran, Kenneth Read, Joan Capdevila Pujol, Prof Alexander Hammers, Prof Tim D Spector, Prof Sebastien Ourselin, Claire J Steves, Marc Modat, Michael Absoud, Prof Emma L Duncan

Published in: The Lancet



Background In children, SARS-CoV-2 infection is usually asymptomatic or causes a mild illness of short duration. Persistent illness has been reported; however, its prevalence and characteristics are unclear. We aimed to determine illness duration and characteristics in symptomatic UK school-aged children tested for SARS-CoV-2 using data from the COVID Symptom Study, one of the largest UK citizen participatory epidemiological studies to date.

Methods In this prospective cohort study, data from UK school-aged children (age 5–17 years) were reported by an adult proxy. Participants were voluntary, and used a mobile application (app) launched jointly by Zoe Limited and King’s College London. Illness duration and symptom prevalence, duration, and burden were analysed for children testing positive for SARS-CoV-2 for whom illness duration could be determined, and were assessed overall and for younger (age 5–11 years) and older (age 12–17 years) groups. Children with longer than 1 week between symptomatic reports on the app were excluded from analysis. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed.

Findings 258 790 children aged 5–17 years were reported by an adult proxy between March 24, 2020, and Feb 22, 2021, of whom 75 529 had valid test results for SARS-CoV-2. 1734 children (588 younger and 1146 older children) had a positive SARS-CoV-2 test result and calculable illness duration within the study timeframe (illness onset between Sept 1, 2021, and Jan 24, 2021). The most common symptoms were headache (1079 [62·2%] of 1734 children), and fatigue (954 [55·0%] of 1734 children). Median illness duration was 6 days (IQR 3–11) versus 3 days (2–7) in children testing negative, and was positively associated with age (Spearman’s rank-order rs 0·19, p<0·0001). Median illness duration was longer for older children (7 days, IQR 3–12) than younger children (5 days, 2–9). 77 (4·4%) of 1734 children had illness duration of at least 28 days, more commonly in older than younger children (59 [5·1%] of 1146 older children vs 18 [3·1%] of 588 younger children; p=0·046). The commonest symptoms experienced by these children during the first 4 weeks of illness were fatigue (65 [84·4%] of 77), headache (60 [77·9%] of 77), and anosmia (60 [77·9%] of 77); however, after day 28 the symptom burden was low (median 2 symptoms, IQR 1–4) compared with the first week of illness (median 6 symptoms, 4–8). Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2.

Interpretation Although COVID-19 in children is usually of short duration with low symptom burden, some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.


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Aug, 2021

Risk of infection and transmission of SARSCoV-2 among children and adolescents in households, communities and educational settings: A systematic review and meta-analysis


Authors: O Irfan, J Li, K Tang, Z Wang, ZA Bhuta

Published in: Journal of global health



Background There is uncertainty with respect to SARS-CoV-2 transmission in children (0-19 years) with controversy on effectiveness of school-closures in controlling the pandemic. It is of equal importance to evaluate the risk of transmission in children who are often asymptomatic or mildly symptomatic carriers that may incidentally transmit SARS-CoV-2 in different settings. We conducted this review to assess transmission and risks for SARS-CoV-2 in children (by age groups or grades) in community and educational-settings compared to adults.

Methods Data for the review were retrieved from PubMed, EMBASE, Cochrane Library, WHO COVID-19 Database, China National Knowledge Infrastructure (CNKI) Database, WanFang Database, Latin American and Caribbean Health Sciences Literature (LILACS), Google Scholar, and preprints from medRixv and bioRixv) covering a timeline from December 1, 2019 to April 1, 2021. Population-screening, contact-tracing and cohort studies reporting prevalence and transmission of SARS-CoV-2 in children were included. Data were extracted according to PRISMA guidelines. Meta-analyses were performed using Review Manager 5.3.

Results Ninety studies were included. Compared to adults, children showed comparable national (risk ratio (RR)=0.87, 95% confidence interval (CI)=0.71-1.060 and subnational (RR=0.81, 95% CI=0.66-1.01) prevalence in population-screening studies, and lower odds of infection in community/household contact-tracing studies (odds ratio (OR) =0.62, 95% CI=0.46-0.84). On disaggregation, adolescents observed comparable risk (OR=1.22, 95% CI=0.74-2.04) with adults. In educational-settings, children attending daycare/preschools (OR=0.53, 95% CI=0.38-0.72) were observed to be at lower-risk when compared to adults, with odds of infection among primary (OR=0.85, 95% CI=0.55-1.31) and high-schoolers (OR=1.30, 95% CI=0.71-2.38) comparable to adults. Overall, children and adolescents had lower odds of infection in educational-settings compared to community and household clusters.

Conclusions Children (<10 years) showed lower susceptibility to COVID-19 compared to adults, whereas adolescents in communities and high-schoolers had comparable risk. Risks of infection among children in educational-settings was lower than in communities. Evidence from school-based studies demonstrate it is largely safe for children (<10 years) to be at schools, however older children (10-19 years) might facilitate transmission. Despite this evidence, studies focusing on the effectiveness of mitigation measures in educational settings are urgently needed to support both public health and educational policy-making for school reopening.

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Aug, 2021

Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection


Authors: D Buonsenso, DD Giuda, L Sigfrid, DA Pizzuto, GD Sante, CD Rose, I Lazzareschi, M Sali, F Baldi, DPR Chieffo, D Munblit, P Valentini

Published in: The Lancet



Although more patients are surviving COVID-19, there are emerging data on a substantial proportion of patients with persisting, and often debilitating, symptoms and sequelae for months following acute COVID-19. This scenario is commonly referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or long COVID. Some of the most commonly reported symptoms are fatigue, weakness, breathlessness, chest pain, and concentration impairment. Several independent studies have shown the existence of PASC, with chronic inflammation and chronic endothelial disease suggested among the possible pathophysiological mechanisms of this multifaceted condition. Although the course of acute SARS-CoV-2 infection in children is normally milder and can present with less typical symptoms compared with adults, emerging evidence from Sweden, Italy, the UK, and Russia suggests that children can also have persisting symptoms more than 3 months after acute COVID-19, with a similar pattern of symptoms as reported by adults. In light of an increasing number of parents and clinicians asking for guidance and support for children with PASC in our centre, we have set up a post-COVID Paediatric Unit. Children with a microbiologically confirmed diagnosis of COVID-19 are assessed in our post-COVID Paediatric Unit at least 5 weeks after the onset of acute infection (see the appendix for our post-COVID paediatric follow-up protocol).


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Aug, 2021

COVID-19 vaccines for children in LMICs: another equity issue


Authors: B Kampmann U Okomo

Published in: The Lancet



Given the success of COVID-19 vaccines in preventing death and severe disease in adults  and their impact on community transmission, use in children and young people (CYP) inevitably requires consideration. Although severe COVID-19 is rare in CYP, they are affected by SARS-CoV-2 infection and the impacts of the COVID-19 pandemic, including education, mental health, and general wellbeing.
As of late July, 2021, no COVID-19 vaccine is recommended for children younger than 12 years and safety and efficacy data from phase 3 clinical trials are so far limited: 1131 CYP aged 12–15 years received the Pfizer–BioNTech mRNA vaccine and safety data are available from phase 1 and 2 trials of Sinovac’s inactivated CoronaVac vaccine in 438 children aged 3–17 years.
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Aug, 2021

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe—results from the PED-MERMAIDS multicentre case–control study


Authors: MK Vasconcelos, K Loens, L Sigfrid, E Iosifidis, C Epalza, D Donà, V Matheeussen, S Papachristou, E Roilides, M Gijon, P Rojo, C Minotti, L Da Dalt, S Islam, J Jarvis, A Syggelou, M Tsolia, MN Nyang’wa, S Keers, H Renk, AL Gemmel, C D’Amore, MC degli Atti, CRT Sánchez, F Martinón-Torres, S Burokienė, T Goetghebuer, V Spoulou, A Riordan, C Calvo, D Gkentzi, M Hufnagel, PJ Openshaw, MD de Jong, M Koopmans, H Goossens, M Ieven, PLA Fraaij, CGiaquinto, JA Bielicki, P Horby, M Sharland

Published in: BMJ Journals



Background Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation.

Methods 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets.

Results RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses.

Conclusion RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.

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Jul, 2021

No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial


Authors: T.G Jacobs, A. Colbers, H. Waalewijn, P. Amuge, D. Bbuye, E. Kaudha, A. Nanduudu, S. Makumbi, L. Atwine, S. Mudzingwa, K. Nathoo, J. Hakim, A. Liberty, A.J. Van Rensburg, M. Archary, D.M Gibb, D. Ford, A. Turkova, D.M Burger, ODYSSEY trial team

Published in: IAS 2021



Background: ODYSSEY and IMPAACT-P1093 found lower and more variable dolutegravir (DTG) exposure in children compared to adults based on mg/kg dose. Investigating the main metabolic pathway (UGT1A1) for DTG could help to explain these findings. Estimates of DTG glucuronide/DTG molar metabolic ratio (DTG-MR) are 0.05-0.08 in adults but this has not been studied in children.

Methods: A subset of children was selected from PK substudies within the ODYSSEY trial, including all children aged <2 years and a random sample of older children receiving DTG film-coated tablets (FCT; >=20kg) or dispersible tablets (DT; 3-<25kg). DTG and DTG-glucuronide concentrations were measured with a validated UPLC-MS/MS assay and geometric mean (GM) DTG-MR was determined using 3 plasma samples per PK curve (t=2, 6 and 24h).   We assessed correlation between DTG-MR and DTG clearance in children, as clearance adjusted for formulation is independent of DTG dose, and it is associated with DTG exposure. Pearson’s correlation coefficient was used on log-transformed data to assess the relationships between DTG-MR and DTG clearance/kg (corrected for higher bioavailability of DT), and DTG-MR and age (not logtransformed).

Results: In total, 37 children (age 3 months – 18 years) were included in this study. There was positive relationship between DTG-MR and DTG clearance/kg in children (r(37)=0.64, p<.001) (Figure). No association was found between DTG-MR and age (r(37)=-0.12, p=0.50). GM(CV%) DTG-MR in children was 0.051(66%), in line with adult values.

Conclusions: Intersubject variability in DTG-MR was high in children and as the ratio correlates with clearance, this may explain high variability of DTG exposure between children. DTG-MR was similar to adult values and did not change with age, hence increased glucuronidation does not appear to explain the relatively low DTG exposure observed in children aged >3 months. Further studies are needed to assess the role other factors contributing to differences in DTG exposure in children.

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