Characterization of Multisystem Inflammatory Syndrome in Children and Its Relationship to Kawasaki Disease

In the wake of COVID-19 pandemic, Multisystem Inflammatory Syndrome in Children (MIS-C) has evolved as a new threat to children exposed to SARS-CoV-2. The emergence of MIS-C is so new and so rapidly evolving that there are currently no diagnostic tests to identify these patients nor are there tools to predict disease progression. Through established, funded, multi-center consortia in the U.S. (CHARMS: Characterization of MIS-C and its Relationship to Kawasaki Disease funded by PCORI) and the UK (DIAMONDS), clinical data and samples were collected to support the proposed studies. First, transcript, protein and antibody datasets from children with COVID-19, MIS-C, and with other febrile illnesses were generated. These data were used to devise tests to distinguish children at risk of progression to severe COVID-19 or MIS-C and diagnostic tests to distinguish these conditions from other causes of fever in children. Continuing the established collaboration with Columbia University, the antibody repertoire against all known human coronaviruses was defined and how pre-existing antibody to other coronaviruses may shape the immune response in acute SARS-CoV-2 infection and MIS-C was determined. The first two years (R61) built on the expertise of the assembled teams to discover unique proteomic and transcriptomic patterns in MIS-C and SARS-CoV-2-infected patients and relate clinical parameters to the antibody response to coronaviral antigens profiled on peptide arrays. This work leveraged already banked plasma, serum, and RNA samples from children with COVID-19, MIS-C, Kawasaki disease and other inflammatory conditions. Rigorous Go/No-Go criteria were established and used to determine progression to the R33 phase. The final two years (R33) focused on platform development and multicenter and bi-national test validation to diagnose and predict severity in children with SARS-CoV-2 infection or MIS-C based on aptamer technology, lateral-flow protein detection, point-of-service RNA or antibody profiling with commercial partners. De-identified clinical and molecular data were deposited in the RADx-rad hub to facilitate data sharing. Many potential hurdles in this type of research have already been overcome: a) IRB-approved patient recruitment for data and samples is on-going, b) clinical samples have been banked, c) strong preliminary data has been generated on RNAseq, aptamer proteomics, and coronaviral antibody responses, and d) the teams have a strong track record of previous collaboration and productivity. The synergistic expertise of these investigative teams in this multi-center proposal provided a unique opportunity to create diagnostic and prognostic tools for children suffering from the spectrum of SARS- CoV-2 illnesses. Public Health Relevance: As the COVID-19 pandemic evolved in early 2020, case reports appeared describing children with unusual febrile illnesses with elevated inflammatory markers and multi-system involvement that is now termed Multisystem Inflammatory Syndrome in Children (MIS-C). The illness occurs weeks following exposure to SARS-CoV-2 and these children have a wide spectrum of disease severity ranging from cardiogenic shock to milder illness that can be self-limited. To address an urgent, unmet clinical need, investigative teams across three countries joined forces to discover and validate a diagnostic test to identify children with MIS-C and predict progression of disease.