Multisystem inflammatory syndrome in children is a SARS-CoV-2 triggered Kawasaki disease

Background: Multisystem Inflammatory Syndrome in Children (MIS-C) encompasses a spectrum of phenotypes: shock, Kawasaki disease (KD), and fever with hyperinflammation. Whether MIS-C is a new syndrome or SARS-CoV-2-triggered KD remains debated. To explore this, we investigated the relationship between clinical phenotypes and viral variants, and the contribution of pre-pandemic KD incidence to MIS-C reporting. Methods: Single center, prospective, observational study of 384 patients with MIS-C, from March 2020 to September 2023. Clinical and laboratory features, complications, and outcomes were evaluated across the MIS-C waves. Results: Three clinical phenotypes were identified: shock, KD, and fever with hyperinflammation. KD was most common across all variants, particularly during Omicron, while shock predominated in Delta cohort. Stratifying by phenotype outperformed the WHO MIS-C and RCPCH PIMS definitions in distinguishing subgroups. Countries with low pre-pandemic KD incidence identified MIS-C as a new syndrome, while countries with high KD incidence did not. Conclusions: MIS-C phenotypes vary accordingly to SARS-CoV-2 variants, with KD being most common. Stratification by clinical phenotypes out-performed MIS-C case definitions for patient identification, highlighting the value of clinical features in managing infection-triggered hyperinflammation. These findings, coupled with the inverse relationship between pre-pandemic KD incidence and MIS-C reporting, support the hypothesis that MIS-C is SARS-CoV-2-triggered KD. Impact: KD and MIS-C are not separate entities but different ends of the immune response spectrum. Among the hyperinflammation spectrum, each viral variant induces a distinct MIS-C phenotype, with the Omicron wave resembling KD. Clinical phenotype stratification outperformed MIS-C definitions in identifying patient subgroups, confirming the value of clinical features in managing infection-triggered hyperinflammation. The inverse relationship between pre-pandemic KD incidence and MIS-C reporting supports MIS-C being a SARS-CoV-2–triggered KD, underscoring critical equity and diversity considerations. A pathogen-agnostic approach to post-infectious hyperinflammation would recognize the full spectrum of phenotypes and complications and avoid confusion due to new naming conventions.