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To The Editor: In early 2020, multisystemic inflammatory syndrome in children (MIS-C) was recognized as an emerging life-threatening disease occurring 2 to 6 weeks after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with symptoms resembling those of Kawasaki’s disease or toxic shock syndrome.1 Unlike typical Kawasaki’s disease, MIS-C has been frequently associated with gastrointestinal symptoms and circulatory failure necessitating treatment with vasoactive drugs. We and others have identified a specific immune MIS-C signature, namely a superantigen-like polyclonal expansion of T-cell receptor (TCR) Vβ21.3+ CD4+ and CD8+ T cells.2-4 This skewing of the TCR repertoire was not observed in Kawasaki’s disease, toxic shock syndrome, or mild-to-severe coronavirus disease 2019 (Covid-19).3 The SARS-CoV-2 spike protein contains a putative superantigenic motif that is absent in other coronaviruses, a factor that has been speculated to be a reason for the absence of MIS-C cases before the onset of the Covid-19 pandemic.

s disease, toxic shock syndrome, or mild-to-severe coronavirus disease 2019 (Covid-19).3 The SARS-CoV-2 spike protein contains a putative superantigenic motif that is absent in other coronaviruses, a factor that has been speculated to be a reason for the absence of MIS-C cases before the onset of the Covid-19 pandemic. We conducted a retrospective analysis involving 74 children who had been admitted to our hospital pediatric intensive care unit from 2006 through 2018 and in whom TCR repertoire analyses had been performed (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Surprisingly, three patients had the Vβ21.3+ T-cell expansion, with no definitive diagnosis but rather an MIS-C phenotype (Figure 1A, 1B, and 1C and Fig. S1 in the Supplementary Appendix), reported here as non–SARS-CoV-2 MIS-C Patients 1, 2, and 3 (nsMIS-C1, nsMIS-C2, and nsMIS-C3). An available serum sample that had been obtained from nsMIS-C1 was tested with VirScan, a high-throughput method of screening for IgG against pathogens, which detected enrichment for antibodies against 18 human pathogens, including coronaviruses (Fig. S2A and S2B).

tients 1, 2, and 3 (nsMIS-C1, nsMIS-C2, and nsMIS-C3). An available serum sample that had been obtained from nsMIS-C1 was tested with VirScan, a high-throughput method of screening for IgG against pathogens, which detected enrichment for antibodies against 18 human pathogens, including coronaviruses (Fig. S2A and S2B). We also found a fourth patient (nsMIS-C4) during the Covid-19 pandemic who had an MIS-C phenotype with the specific Vβ21.3+ T-cell expansion, but this patient tested negative for SARS-CoV-2 (serologic specimens were tested by enzyme-linked immunosorbent spot assay, and nasal swabs were tested by polymerase-chain-reaction [PCR] assay). However, nsMIS-C4 tested positive for seasonal human coronavirus (HCoV) 229E by nasal PCR (Fig. S2C). Owing to the resemblance of MIS-C to Kawasaki’s disease shock syndrome, we then explored the peripheral-blood mononuclear cells in an independent Dutch cohort of four children in whom Kawasaki’s disease shock syndrome had been diagnosed. We observed a Vβ21.3+ T-cell expansion in CD4+ and CD8+ T cells in one patient (nsMIS-C5) and CD8+ T cells in another (nsMIS-C6); both of these patients also presented with an up-regulation of activation (CD38) and exhaustion (TIM3 and programmed death 1) markers within Vβ21.3+ CD4+ and CD8+ T cells, as had been previously reported in MIS-C (Figure 1D and Fig. S3).4

nd CD8+ T cells in one patient (nsMIS-C5) and CD8+ T cells in another (nsMIS-C6); both of these patients also presented with an up-regulation of activation (CD38) and exhaustion (TIM3 and programmed death 1) markers within Vβ21.3+ CD4+ and CD8+ T cells, as had been previously reported in MIS-C (Figure 1D and Fig. S3).4 The clinical, biologic, and immunologic features that we observed in these prepandemic and SARS-CoV-2–negative patients are indistinguishable from those seen in patients with MIS-C. Rarely seen before the Covid-19 pandemic, this syndrome was not individualized and was reported as atypical Kawasaki’s disease, a syndrome resembling toxic shock syndrome, or Kawasaki’s disease shock syndrome (Tables S1 and S2). Therefore, MIS-C characterized by Vβ21.3+ T-cell expansion would appear to represent a severe pediatric condition that may be triggered by other pathogens, including seasonal HCoV. The presence of a SARS-CoV-2 spike is dispensable for Vβ21.3+ T-cell expansion and MIS-C. Although the management of MIS-C has improved,5 further research is needed to elucidate the underlying mechanisms of T-cell activation and to develop targeted interventions for this critical pediatric condition.