Clinical, immunological and genetic characteristics of multisystemic inflammatory syndrome associated with COVID-19 in children and adolescents

Multisystemic inflammatory syndrome in children (MIS-C) is a newly identified immune-mediated syndrome that is characteristically observed in the pediatric population. Patients with MIS-C usually present 2-6 weeks after the initial SARS-CoV-2 infection with high fever, intense inflammation and signs of multiple organ dysfunction. There are few data on the clinical course of the disease and very limited information on prognosis and outcome. Moreover, the underlying pathophysiology of MIS-C is not fully understood. In this project, we plan to analyze clinical and laboratory data and use patient biosamples from patients with MIS-C diagnosed at the University Children’s Hospital, University Medical Center Ljubljana in order to better define the clinical course and immunopathogenesis of MIS-C. For early clinical recognition of MIS-C we plan to evaluate distinctions between the MIS-C patients and patients with febrile conditions admitted as suspected MIS-C, but with a different final diagnosis. Cardiac and neurological involvement are one of the most concerning clinical features of MIS-C and we plan to systematically evaluate both acute manifestations and long-term cardiac and neuropsychological outcomes associated with MIS-C. To better characterize and understand the immunologic basis of MIS-C, we will specifically explore the roles of the innate and adaptive immune systems as well as interactions with the endothelial cells. We plan to analyze a detailed immunoserological response to SARS-CoV-2 in patients with MIS-C and assess the SARS-CoV-2 genotypes in patients with MIS-C in comparison to the general population. Genetic studies in patients with MIS-C will include Whole Genome Sequencing (WGS), transcriptome sequencing as well as single cell sequencing. WGS will be performed to explore rare genetic variants as well as structural genetic variations in MIS-C patient’s. Gene expressions analyses will be performed in MIS-C patients at acute phase and after remission in order to identify up or down-regulated genes, and single cell analysis will be used to identify cell subsets and activation pathways in the pathogenesis of MIS-C. The results of this project are expected to support our clinical impression for particular dynamics of clinical and laboratory features in MIS-C patients which could help in establishing early diagnosis and improve long-term outcome including prevention of myocardial and neuropsychological impairment. Moreover, we expect to provide a new insights into the role of innate and adaptive immunity in the pathogenesis of MIS-C, identify possible high-risk SARS-CoV-2 genotypes and generate and analyze genetic data that could be further explored in larger multicenter international studies.