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Pathologic Analysis of Twenty-one Appendices From Children With Multisystem Inflammatory Syndrome Compared to
Magdalena Okarska-Napierała1, Weronika Woźniak1, Joanna Mańdziuk1
1From the Department of Pediatrics with Clinical Assessment Unit, Medical University of Warsaw, Warsaw, Poland.
Insights
Appendectomy specimens from children with Multisystem Inflammatory Syndrome (MIS-C) show no SARS-CoV-2 antigens or lymphocyte exhaustion. These findings suggest gut viral persistence is not a primary MIS-C trigger.
Area of Science:
- Pediatric Gastroenterology
- Infectious Diseases
- Immunology
Background:
- Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe COVID-19 complication affecting the GI tract.
- Some MIS-C patients undergo appendectomy before diagnosis.
- Hypotheses suggest viral antigen persistence and lymphocyte exhaustion in the gut contribute to MIS-C.
Purpose of the Study:
- To investigate appendectomy specimens from MIS-C patients.
- To assess pathologic features and SARS-CoV-2 antigen presence.
- To evaluate lymphocyte subpopulations and exhaustion markers.
Main Methods:
- Cross-sectional study of 21 MIS-C patients who had appendectomy.
- Control group of 21 children with acute appendicitis (AA).
- Histologic and immunohistochemical analysis of appendiceal specimens for immune cells, PD-1, and SARS-CoV-2 antigens.
Main Results:
- MIS-C appendices lacked neutrophilic infiltrate and edema typical of AA.
- Higher CD20+ to CD5+ and CD4+ to CD8+ cell ratios were observed in MIS-C patients.
- No evidence of SARS-CoV-2 antigens or lymphocyte exhaustion was found in MIS-C appendices.
Conclusions:
- Appendiceal pathology in MIS-C differs significantly from acute appendicitis.
- Absence of SARS-CoV-2 antigens and PD-1 in MIS-C appendices challenges gut viral persistence theories.
- These findings suggest SARS-CoV-2 gut persistence and lymphocyte exhaustion are unlikely primary MIS-C triggers.
Background:
Multisystem inflammatory syndrome in children (MIS-C) is a rare, 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 the pathomechanism of MIS-C, including the central role of the viral antigen persistence in the gut, associated with lymphocyte exhaustion. We aimed to examine appendectomy specimens from MIS-C patients and assess their pathologic features, as well as the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens.
Methods:
In this cross-sectional study we included 21 children with MIS-C who underwent appendectomy. The control group included 21 sex- and age-matched children with acute appendicitis (AA) unrelated to SARS-CoV-2 infection. Histologic evaluation of appendiceal specimens included hematoxylin and eosin staining and immunohistochemical identification of lymphocyte subpopulations, programmed cell death protein-1 (PD-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 was 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:
The appendiceal muscularis of patients with MIS-C lack edema and neutrophilic infiltration typical for AA. SARS-CoV-2 antigens and PD-1 are absent in the appendices of children with MIS-C. These findings argue against the central role of SARS-CoV-2 persistence in the gut and lymphocyte exhaustion as the major triggers of MIS-C.
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