Immunological assessment of pediatric multisystem inflammatory syndrome related to COVID-19

Grazioli, Serge; Tavaglione, Fedora; Torriani, Giulia; Wagner, Noemie; Rohr, Marie; L’Huillier, Arnaud G; Leclercq, Charlotte; Perrin, Anne; Bordessoule, Alice; Beghetti, Maurice; Pachlopnik, Jana; Vavassori, Stefano; Perreau, Matthieu; Eberhardt, Christiane; Didierlaurent, Arnaud; Kaiser, Laurent; Eckerle, Isabella; Roux-Lombard, Pascale; Blanchard-Rohner, Geraldine

BACKGROUND: Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been reported worldwide. Negative RT-PCR testing associated with positive serology in most cases suggests a post-infectious syndrome. Because the pathophysiology of this syndrome is still poorly understood, extensive virological and immunological investigations are needed. METHODS: We report a series of four pediatric patients admitted to Geneva University Hospitals with persistent fever and laboratory evidence of inflammation meeting published definition of MIS-C related to COVID-19, to whom an extensive virological and immunological workup was performed. RESULTS: RT-PCRs on multiple anatomical compartments were negative whereas anti-SARS-CoV-2 IgA and IgG were strongly positive by ELISA and immunofluorescence. Both pseudo- and full virus neutralization assays showed the presence of neutralizing antibodies in all children, confirming a recent infection with SARS-CoV-2. Analyses of cytokine profiles revealed an elevation in all cytokines, as reported in adults with severe COVID-19. Although differing in clinical presentation, some features of MIS-C show phenotypic overlap with haemophagocytic lymphohistiocytosis (HLH). In contrast to patients with primary HLH, our patients showed normal perforin expression and NK cell degranulation. The levels of soluble IL-2 receptor (sIL-2R) correlated with the severity of disease, reflecting recent T-cell activation. CONCLUSION: Our findings suggest that MIS-C related to COVID-19 is caused by a post-infectious inflammatory syndrome associated with elevation in all cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a strong and specific humoral response to SARS-CoV2. Further functional and genetic analyses are essential to better understand the mechanisms of host-pathogen interactions.