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

In the wake of COVID-19 pandemic, Multisystem Inflammatory Syndrome in Children (MIS-C) has evolved as anew threat to children exposed to SARS-CoV-2. The emergence of MIS-C is so new and so rapidly evolvingthat there are currently no diagnostic tests to identify these patients nor are there tools to predict diseaseprogression. Through established, funded, multi-center consortia in the U.S. (CHARMS: Characterization ofMIS-C and its Relationship to Kawasaki Disease funded by PCORI) and the UK (DIAMONDS), we will collectclinical data and samples to support the proposed studies. First, we will generate transcript, protein andantibody datasets from children with COVID-19, MIS-C, and with other febrile illnesses. Next, we will use thesedata to devise tests to distinguish children at risk of progression to severe COVID-19 or MIS-C and diagnostictests to distinguish these conditions from other causes of fever in children. Continuing our establishedcollaboration with Columbia University, we will define the antibody repertoire against all known humancoronaviruses and determine how pre-existing antibody to other coronaviruses may shape the immuneresponse in acute SARS-CoV-2 infection and MIS-C. The first two years (R61) will build on the expertise of theassembled 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 onpeptide arrays. This work will leverage already banked plasma, serum, and RNA samples from children withCOVID-19, MIS-C, Kawasaki disease and other inflammatory conditions. Rigorous Go/NoGo criteria havebeen established and will determine progression to the R33 phase. The final two years (R33) will focus onplatform development and multicenter and bi-national test validation to diagnose and predict severity inchildren 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 datawill be deposited in the RADx-rad hub to facilitate data sharing. Many potential hurdles in this type of researchhave already been overcome: a) IRB-approved patient recruitment for data and samples is on-going, b) clinicalsamples 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 andproductivity. The synergistic expertise of these investigative teams in this multi-center proposal provides aunique opportunity to create diagnostic and prognostic tools for children suffering from the spectrum of SARS-CoV-2 illnesses.1