Since the beginning of COVID-19 pandemic, a new post-infectious inflammatory manifestation of SARS-CoV-2 affecting children has been described. It was defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS/PIMS-TS) by the Royal College of Pediatrics and Child Health, or as Multisystem Inflammatory Syndrome in Children (MIS-C) by the World Health Organization and the Center for Disease Control and Prevention. MIS-C represents a late manifestation of SARS-CoV-2 infection affecting predominantly previously healthy school-age children presenting with moderate to severe multi-organ dysfunction associated with an exaggerated proinflammatory response and presence of elevated SARS-CoV-2 immunoglobulin G antibodies. Although MIS-C shares similarities with Kawasaki Disease (KD), children with MIS-C tend to be older and present with a more severe proinflammatory response and myocardial injury than children with KD.

The pathophysiology of MIS-C remains largely unknown, and the current management of MIS-C is extrapolated from KD and focuses on restoring immune homeostasis with intravenous immunoglobulin, corticosteroids, and biologics as well as on the prevention of vascular complications with antiplatelet therapy and anticoagulation. Recent immunoprofile studies on MIS-C patients discovered the presence of a superantigenic-like motif on SARS-CoV-2 spike glycoprotein and an autoimmune signature targeting the various organs involved in MIS-C.

This review provides an extensive update on the state of knowledge of this new post-infectious hyperinflammatory syndrome affecting children. This topic is important for two reasons. Firstly, SARS-CoV-2 continues to infect children worldwide who may therefore still be at risk of developing MIS-C. The additional knowledge brought by this review to the clinicians may help them in the care of MIS-C patients. Secondly, a better understanding of the immunopathogenesis of MIS-C and how its immunopathological signature is distinct from acute SARS-CoV-2 infection or KD will not only be useful to guide optimal treatment in MIS-C but may also help in the management of similar hyperinflammatory conditions affecting children such as KD or haemophagocytic lymphohistiocytosis.