BACKGROUND: SARS-CoV-2 occurs in the majority of children as COVID-19, without 
symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion 
of children develop the systemic Multi Inflammatory Syndrome (MIS-C), 
characterized by persistent fever and systemic hyperinflammation, with some 
clinical features resembling Kawasaki Disease (KD).
OBJECTIVE: With this study we aimed to shed new light on the pathogenesis of 
these two SARS-CoV-2-related clinical manifestations.
METHODS: We investigated lymphocyte and dendritic cells subsets, 
chemokine/cytokine profiles and evaluated the neutrophil activity mediators, 
myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with 
COVID-19 and 9 with MIS-C at the time of hospital admission.
RESULTS: Patients with MIS-C showed higher plasma levels of C reactive protein 
(CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than 
COVID-19 children. In addition, they displayed higher levels of the chemokines 
CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in 
plasma of children with COVID-19, but not in patients with MIS-C. This 
observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells 
of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at 
levels comparable to healthy controls. Moreover, quantification of the number of 
plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, 
showed profound depletion of this subset in MIS-C, but not in COVID-19.
CONCLUSIONS: Our results show a pattern of immune response which is suggestive 
of type I interferon activation in COVID-19 children, probably related to a 
recent interaction with the virus, while in MIS-C the immune response is 
characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, 
and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active 
Th1 type immune response. We believe that these immunological events, together 
with neutrophil activation, might be crucial in inducing the multisystem and 
cardiovascular damage observed in MIS-C.