Immunology of severe febrile illness in children in the COVID-19 era

Abstract

Abstract Severe febrile illnesses in children, such as multi-system inflammatory syndrome in children (MIS-C), severe bacterial infection (SBI), severe viral infection (SVI), and Kawasaki disease (KD), have shared clinical features. We used immunophenotyping with mass cytometry and cell stimulation experiments to illustrate shared and distinct mechanisms of immune dysfunction in 74 children with MIS-C, 30 with SBI, 16 with SVI, 8 with KD, and 42 controls. We then used targeted gene expression analysis to explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. Immunophenotyping and clustering analysis revealed neutrophil activation and apoptosis and T cell activation to be prominent in MIS-C and SBI. Cell stimulation experiments showed T cells from patients with acute MIS-C were exhausted. SVI was characterized by phosphorylated STAT signaling but lower gene expression for interferon receptors. Improved understanding of immune dysfunction may improve immunomodulator therapy in severe childhood febrile illnesses.