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Juanita Pang, BSc, Florencia A.T. Boshier, PhD, Nele Alders, MD,
Garth Dixon, PhD, Judith Breuer, MD
DOI: 10.1542/peds.2020-019844
Journal: Pediatrics
Article Type: Research Brief
This is a prepublication version of an article that has undergone peer review and been accepted
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described in this version.
Juanita Panga*, BSc, Florencia A.T. Boshiera*, PhD, Nele Aldersb, MD,
Garth Dixonc, PhD, Judith Breuera, MD
Affiliations: aDepartment of Infection, Immunity and Inflammation, UCL Great Ormond Street
Institute of Child Health, University College London, London, United Kingdom.
b
Department of Infectious Disease, Great Ormond Street Hospital for Children NHS Foundation
Trust, London, United Kingdom.
c
Department of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for
Children NHS Foundation Trust, London, United Kingdom.
Address correspondence to: Judith Breuer, Research Department of Infection UCL, Infection
and Immunity, The Cruciform Building, Gower street , WC1E 6BT, +44-203 108 2030
Conflict of Interest Disclosures (includes financial disclosures): The authors have no example
conflicts of interest to disclose.
Funding/Support: No funding was secured for this study.
Role of Funder/Sponsor: The funders had no role in the design and conduct of the study.
Juanita Pang and Florencia A.T. Boshier: completed the data analysis, literature search, drafted
the initial manuscript, reviewed and revised the manuscript, approved the final manuscript as
submitted and agree to be accountable for all aspects of the work.
Nele Alders and Garth Dixon: collected the data, reviewed the manuscript, approved the final
manuscript as submitted and agree to be accountable for all aspects of the work.
Judith Breuer: conceived the study, completed the data interpretation and literature search,
approved the final manuscript as submitted and agrees to be accountable for all aspects of the
work.
Introduction
Disease 2019 (COVID-19), was first identified in Wuhan, China in December 2019. It rapidly
spread across the world and on 11th March 2020, the WHO declared COVID-19 as a global
pandemic1.
with approximately 3-5% of infections requiring admission to critical care2,3. In contrast, severe
illness and death due to SARS-CoV-2 infection in children is rare4. However recently, a small
number of cases of shock and multisystem inflammation have been reported in children who
have either been tested positive for SARS-CoV-2 (by PCR or serology) or had epidemiological
links to it. This new syndrome, which has overlapping features of Kawasaki disease, is called the
The exact pathogenesis of MIS-C is as yet unknown. However, it has been suggested that part of
the SARS-CoV-2 viral spike (S) protein may resemble a superantigen which could drive the
development of MIS-C and trigger cytokine storms in adults6. Specifically, polymorphic residues
in S including A831V and D839Y/N/E which are predicted to enhance binding affinity to the
TCR have been observed in lineages circulating in Europe and North America, where most MIS-
C cases have been described. In addition, the 614G Spike protein polymorphism may be
comparisons of SARS-CoV-2 viral sequences from MIS-C patients and non MIS-C cases is
To this end, we compare SARS-CoV-2 viral sequences found in 5 children diagnosed with MIS-
C to sequences from 8 non-MIS-C children and 130 community cases in North London.
Methods
We sequenced SARS-CoV-2 from children hospitalized for COVID-19 in London between late-
polymerase chain reaction (PCR) for SARS-CoV-2 RNA in nasopharyngeal aspirates, and/or by
binding assay), 36 were diagnosed with MIS-C based on the case definition of Royal College of
Pediatrics and Child Health8,9. Those classified as not having MIS-C were asymptomatically
MIS-C patients were positive for SARS-CoV-2 viral RNA, the remainder being positive for
All 25 non-MIS-C patients were positive for SARS-CoV-2 viral RNA. Full length SARS-CoV-2
genome sequences were obtained from 5 children classified as MIS-C and 8 non-MIS-C children
(Table 1) using SureSelectXT target enrichment and Illumina sequencing. Reads generated were
quality checked and mapped to the SARS-COV-2 reference genome (NC_045512) using BWA
Table 1.
Phylogenetics
We reconstructed a maximum likelihood phylogenetic tree of all sequences using RAxML v8.0.0
using model GTRGAMMA and 1000 bootstrap replicates10. In addition, single nucleotide
Statistical Analysis
(MIS-C, non MIS-C and community cases) was made by Chi-square (chi.test) in R11.
Results
The maximum likelihood phylogeny of 13 pediatric SARS-CoV-2 cases and 130 SARS-CoV-2
sequences generated from community cases across North London is shown in Figure 1A. We
found no clustering of viral sequences from MIS-C patients (red) or non MIS-C patients (blue)
We observed no SNPs unique to the MIS-C or to the other childhood cases and no difference in
the distribution of SNPs between MIS-C, non MIS-C and community cases as depicted in Figure
1 B. The proportion of non-synonymous SNPs did not differ in the MIS-C, non MIS-C and
All childhood cases were D839 and A831 as were all of the locally circulating samples. The
majority of PIMS-ST (3/5), non PIMS-ST (6/8) and community cases (118/130) were 614G
positive.
Discussion
treatment of the disease. This report compares viral sequences from children diagnosed with
MIS-C to viral sequences from children without MIS-C as well as the wider London community.
Overall, the data suggest that the viruses causing MIS-C in our patients are representative of
locally circulating SARS-CoV-2. We found no evidence for an association of MIS-C with the
presence of new or unusual sequence polymorphisms. This suggests that alternative factors, such
as host-genetics, may trigger MIS-C. Further studies are required to address this.
Study Approval
This study was approved by Great Ormond Street Hospital (Clinical Audit Number #2857) and
Acknowledgments
This work was supported by COG-UK, The James Black Charitable Foundation and the UCLH
and GOSH NIHR biomedical research centers. JP is supported by the Rosetrees Foundation and
FTB by a Wellcome Trust Collaborative Award to JB. We thank Richard Goldstein, Kathryn
Harris, Julianne Brown, Jack Lee, Rachel Williams, Helena Tutill and Sunando Roy for their
contribution to this work. We should also like to acknowledge the contribution of the UCL
Pathogen Genomics Unit, UCL Genomics, and the Great Ormond Street Hospital Departments of
References
Age 12y1m 5y8m 14y8m 15y0m 8y9m 5y11m 8y11m 1y8m 2y11m 10m 10y3m 1y4m 1m
A ●
PIMS-TS
MIS-C ●
No
NoPIMS-TS
MIS-C
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B
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3’ UTR
5’ UTR ORF1ab S ORF3a M ORF7 N ORF10
E ORF6 ORF8
1.00
0.75
Frequency
PIMS−TS
0.50 MIS-C
yes
No
no MIS-C
0.25
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