Emerging Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome Associated With COVID-19 in Children

Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare delayed hyperinflammatory response to SARS-CoV-2 infection and causes severe morbidity in the pediatric age group. Although MIS-C shares many clinical similarities to Kawasaki disease (KD), impor-tant differences in epidemiologic, clinical, immunologic, and poten-tially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemio-logic features include male predominance, peak age of 6 to12 years, and specific racial or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous mani-festations, respiratory symptoms, and neurologic complaints, and pa-tients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnor-malities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein-as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens -are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that un-derlie the pathogenesis of MIS-C vs both acute SARS-CoV-2 infection and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine-associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac com-plications, provide insights into the underlying immunologic patho-physiology, and define similarities and differences with KD.

Automated summary

Multisystem inflammatory syndrome in children (MIS-C) is a rare delayed hyperinflammatory response to SARS-CoV-2 infection that causes severe morbidity in pediatric patients. Although sharing similarities with Kawasaki disease (KD), there are important differences in epidemiological, clinical, immunological, and potentially genetic factors, indicating potential differences in pathophysiology.