Diagnosing and predicting risk in children with SARS-CoV-2- related illness

Multisystem Inflammatory Syndrome in Children (MIS-C) caused significant morbidity and mortality in children during the COVID-19 pandemic, but we know little about the molecular pathogenesis or response to treatments for children with MIS-C. The goal of this administrative supplement is to harness the strength of collaboration and expertise from PreVAIL and evaluate the molecular signature of MIS-C pre- and post- treatment to better understand the response to different treatments. Therefore, this application is responsive to NOSI NOT-HD-22-003. Children with MIS-C presented with fever and some had rash, conjunctival injection, erythema of the lips, and even coronary artery dilation, all signs associated with Kawasaki disease (KD). For this reason, when the first patients presented to intensive care units in Italy, England and then the East Coast of the United States, physicians reached for many of the therapeutics used to treat KD. While some patients improved with intravenous immunoglobulin (IVIG) alone, more than 70% required treatment with steroids, anakinra (IL-1 blockade) and/or infliximab (TNFα blockade). As there was clinical equipoise as to which of these therapies was best for treating MIS-C, our PreVAIL kIds (Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence Initiative) team at UC San Diego designed and launched a two-site randomized, clinical trial (Multisystem Inflammatory Syndrome Therapies in Children (MISTIC) Comparative Effectiveness Study). The goal was to determine which combination of therapies (IVIG with steroids, infliximab and/or anakinra) was most effective in reducing morbidity and mortality in children with MIS-C (NCT04898231). This study enrolled 74 subjects and is now closed for enrollment and under analysis using a novel Bayesian joint stage model applied to the snSMART design. As part of MISTIC, serum, plasma and whole blood RNA were collected pre-IVIG and 12 hours after IVIG or the first-randomized therapy. In this administrative supplement, we will evaluate the molecular signature of MIS-C pre- and post-treatment through whole blood (wb) RNAseq, plasma cell free (cf) RNA, and plasma proteomics to better understand the response to different treatments administered to children with MIS-C. We propose three specific aims to achieve this goal. Specific Aim 1 will analyze the wbRNA profiles using RNAseq of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra, and steroid treatment. Specific Aim 2 will analyze the cfRNA tissue of origin profile of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra and steroid treatment. Specific Aim 3 will analyze the plasma proteome of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra and steroid treatment. The synergistic expertise of these two PreVAIL teams in this multi-center proposal provides a unique opportunity to understand the pathophysiology and response to treatment of MIS- C, as well as potentially develop biomarkers for this acute, inflammatory condition.