Background & Aims: Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019, commonly involving the gastrointestinal tract. Some children with MIS-C undergo appendectomy before the final diagnosis. There are several hypotheses explaining pathomechanism of MIS-C, with the central role of the viral antigen persistence in the gut, associated with lymphocyte exhaustion and immune system dysregulation. We aimed to examine appendectomy specimens obtained from MIS-C patients and analyze the pathological features of the disease and the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in the appendix. Methods: In this cross-sectional study we included 21 children with MIS-C who underwent appendectomy before the final diagnosis. MIS-C patients were recruited from the Polish national registry of inflammatory syndromes in children. The control group included 21 sex- and age-matched children with acute appendicitis (AA) unrelated to SARS-CoV-2 infection. Histological evaluation involved hematoxylin and eosin staining and immunohistochemical identification of lymphocyte subpopulations, programmed cell death protein 1, and SARS-CoV-2 nucleocapsid antigen. Results: Appendices of MIS-C patients lacked neutrophilic infiltrate of muscularis propria typical for AA (14 vs 95%, p<0.001). The proportion of CD20+ to CD5+ cells was higher in patients with MIS-C (p 0.04), as well as the proportion of CD4+ to CD8+ (p <0.001). We found no proof of SARS-CoV-2 antigen presence, nor lymphocyte exhaustion, in the appendices of MIS-C patients. Conclusions: Our findings describe pathomorphological features of the appendix in MIS-C and argue against the central role of SARS-CoV-2 persistence in the gut and concomitant lymphocyte exhaustion as the major triggers of MIS-C.

The authors have declared no competing interest.

Sources of funding: The Polish National Agency for Academic Exchange (NAWA) grant BPN/GIN/2021/1/00031 Medical University of Warsaw, Department of Pediatrics with Clinical Assessment Unit Medical University of Warsaw, Department of Pathology

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The study was approved by the Bioethical Committee of Medical University of Warsaw (Approval No: KB/135/2021).

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