BACKGROUND: Recently, cases of multisystem inflammatory syndrome in children 
(MIS-C) associated with coronavirus disease 2019 (COVID-19) have been reported 
worldwide. Negative polymerase chain reaction (RT-PCR) testing associated with 
positive serology in most of the cases suggests a postinfectious syndrome. 
Because the pathophysiology of this syndrome is still poorly understood, 
extensive virological and immunological investigations are needed.
METHODS: We report a series of 4 pediatric patients admitted to Geneva 
University Hospitals with persistent fever and laboratory evidence of 
inflammation meeting the 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-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin 
A (IgA) and immunoglobulin G (IgG) were strongly positive by enzyme-linked 
immunosorbent assay and immunofluorescence. Both pseudoneutralization and full 
virus neutralization assays showed the presence of neutralizing antibodies in 
all children, confirming a recent infection with SARS-CoV-2. The 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 hemophagocytic lymphohistiocytosis (HLH). 
In contrast to patients with primary HLH, our patients showed normal perforin 
expression and natural killer (NK) cell degranulation. The levels of soluble 
interleukin (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 
postinfectious inflammatory syndrome associated with an elevation in all 
cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a 
strong and specific humoral response to SARS-CoV-2. Further functional and 
genetic analyses are essential to better understand the mechanisms of 
host-pathogen interactions.