Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome.

Robert Eriksson,Andreas Ronit,Ulrik W Iepsen,Casper Roed,Ronni R Plovsing,Merete Storgaard,Ann-Brit E Hansen,Sofie E Jørgensen,Finn Gustafsson,Trine H Mogensen

doi:10.3389/fimmu.2021.718744

Abstract

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.

Highlights

Coronavirus disease 2019 (COVID-19) in its severe forms may present as a systemic disease with multi-organ dysfunction, but the most common presentation of critical disease constitutes pneumonia with mono-organ respiratory failure
To provide a further understanding of the host immune response associated with multisystem inflammatory syndrome (MIS)-C/A we studied inflammatory mediators in response to SARS-CoV-2 infection of patient peripheral blood mononuclear cells (PBMCs) in vitro and used whole exome sequencing (WES) to identify possible disease-causing genetic variants
Four weeks after a mild polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection (Figure 1), he presented with severe headache and fever accompanied by a sore throat, vomiting and loose stools

Summary

Introduction

Coronavirus disease 2019 (COVID-19) in its severe forms may present as a systemic disease with multi-organ dysfunction, but the most common presentation of critical disease constitutes pneumonia with mono-organ respiratory failure. A minority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals develop an inflammatory syndrome with multiorgan affection, which initially was referred to as a Kawasaki-like disease and was first reported in children and adolescents [8]. The syndrome is typically seen 2-6 weeks after infection with SARS-CoV-2 and involve several organ systems with fever and elevated markers of inflammation as hallmarks of the condition [9]. Differing names and definitions have been used to describe this syndrome, including multisystem inflammatory syndrome in children (MIS-C) with case definitions published by both the Centers for Disease Control and Prevention [10] and the World Health Organization [11]. A similar, yet seemingly more severe, syndrome has been reported in adults and named multisystem inflammatory syndrome in adults (MIS-A). Several thousand MIS-C cases have been reported globally [9, 12], whereas the number of MIS-A cases is much lower counting a limited number of case reports [13]

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