BACKGROUND. Pediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail. METHODS.We retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS). RESULTS.Twenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort. CONCLUSION. MIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.

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Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children; yet, the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk and single-cell RNA sequencing, DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4 + , CD8 + , and gd T cells expressed Th1-related markers, while Th17 cells were not enriched. Th1 skewing was prominent in CD4 + T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4 + T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. While synovial fluid CD4 + T cells displayed an overall Th1 phenotype, scRNA-seq uncovered heterogeneous effector and regulatory sub-populations, including interferoninduced Tregs, peripheral helper T cells, and cytotoxic CD4 + T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

CONCLUSIONS AND RELEVANCE Kawasaki disease is a hybrid condition at the junction of infectious diseases, immunology, rheumatology, and cardiology. Rather than being left an orphan disease, KD is bringing disciplines together to identify its genetic, pathophysiological, and hemodynamic features. In turn, this work promises to shed light on many other inflammatory conditions as well.

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