In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

A 6-month-old girl born to a primigravid mother presented with a lump attached on the posterior side of the right auricle. Pregnancy and spontaneous vaginal delivery were uncomplicated.The lesion was first noticed at the age of 3 months as a small nodule with subsequent rapid growth, plateauing after 1 month, and was initially considered as a hemangioma. She was referred to us because of ulceration of the lesion since 1 week.On physical examination, the lump was 3.5 cm 9 1.5 cm and the overlying skin had a reddish-blue discoloration. On palpation, the posterior part was firm to gritty and the anterior side was ulcerated, tender, and inflamed ( Fig. 1). Haemophilus influenzae was cultured from the ulcerated part.Ultrasound examination showed an ovoid complex mass with calcification at the junction of the dermis and subcutaneous fat and focal thinning of the overlying dermis. She was treated with ampicillin for 5 days and then the lump was excised.

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