A Cross Sectional Study of the Systems Immunology and Viral Diversity of SARS-CoV2 Infection, COVID-19 Disease and Multisystem Inflammatory Syndrome in Children

Scientific Background:

COVID-19 is a global health crisis. The clinical characteristics, disease progression and outcome in children and young adults appear significantly milder compared to older individuals. Since first being reported in Wuhan, China in December 2019, COVID-19 has rapidly spread, affecting over 200 countries worldwide. Children account for 1-5% of diagnosed COVID-19 cases; although, many infected children may be asymptomatic and therefore not diagnosed without population screening. Most infected children are likely to be secondary cases and acquire the infection after exposure to a COVID-19 positive adult, although there are no longitudinal data to confirm this yet. Intra-family transmission may be important since, an unquantified proportion of children with COVID-19 areasymptomatic and may contribute to transmission. Multiple reports have demonstrated that children and young adults have a milder form of the disease compared to adults. Asymptomatic, mild and moderate infections comprise over 90% of all children who have tested positive for COVID-19 with fewer severe and critical cases (5.9%) compared to adults (18.5%). Given that severe COVID-19 appears very rare in children, an important part of this assessment is ascertaining whether a positive RT-PCR for SARS-CoV-2 is a clinically important factor in explaining the child's condition, or whether more occult pathology may be responsible.

When the COVID-19 pandemic was first reported in Asia and initially spread throughout the globe, pediatricians were grateful that children seemed to be only mildly symptomatic with the infection in most cases. Then, an alarming warning came from the National Health Service in England in April 2020 about cases of older school-aged children and adolescents presenting with fever, hypotension, severe abdominal pain and cardiac dysfunction who tested positive for SARS-CoV-2 infection either by nasopharyngeal RT-PCR assay or by antibody testing. These children had laboratory findings of cytokine storm, including high serum IL-6 levels, and generally required inotropic support to increase cardiac output with rare need for extracorporeal membrane oxygenation. Almost all of these children no longer required intensive care after only a few days and completely recovered, although rare deaths resulted from complications of extracorporeal membrane oxygenation. Case series of children presenting with this condition have now been reported from the UK, Italy, Spain, France and Switzerland, and the United States. The Centers for Disease Control and Prevention (CDC) has developed a case definition for use in the United States and has termed the condition multisystem inflammatory syndrome in children (MIS-C). If MIS-C is indeed related to infection with SARS-CoV-2, the pathophysiological mechanism of disease is unclear.

Very few studies have addressed the immune responses to SARS-CoV2 (either humoral or cell mediated immunity) in children. It is therefore necessary to study the immune responses in asymptomatic infections, prior infections and MIS-C to understand the pathogenesis of the disease.

Whole-genome sequencing of pathogens, especially viruses, is a powerful tool to generate rapid information on outbreaks, resulting in effective understanding of the introduction of the infection, dynamics of transmission, and impact of informed outbreak control decisions. In- deed, genomic data can be used to identify pathogen genes interacting with the host and allows characterisation of the more evolutionary constrained regions of a pathogen genome, which should be preferentially targeted to avoid rapid drug and vaccine escape mutants. (1). As the SARS-CoV-2 virus races around the world across the different population, there needs to be a consolidated effort to understand the divergence of demographically distributed strains. Since the transmission of SARS-CoV-2 is subject to the extent of human interaction, the insights from the correlation of genetic diversity would give vital information to tackle this transmission.