The Spectrum of Postacute Sequelae of COVID-19 in Children: From MIS-C to Long COVID

Abstract

The effects of SARS-CoV-2 infection on children continue to evolve following the onset of the COVID-19 pandemic. Although life-threatening multisystem inflammatory syndrome in children (MIS-C) has become rare, long-standing symptoms stemming from persistent immune activation beyond the resolution of acute SARS-CoV-2 infection contribute to major health sequelae and continue to pose an economic burden. Shared pathophysiologic mechanisms place MIS-C and long COVID within a vast spectrum of postinfectious conditions characterized by intestinal dysbiosis, increased gut permeability, and varying degrees of immune dysregulation. Insights obtained from MIS-C will help shape our understanding of the more indolent and prevalent postacute sequelae of COVID and ultimately guide efforts to improve diagnosis and management of postinfectious complications of SARS-CoV-2 infection in children.

Keywords: COVID-19; MIS-C; PASC; long COVID; spike.

Figure 1

Mechanism driving PASC, including MIS-C and long COVID. Abbreviations: MIS-C, multisystem inflammatory syndrome in children; PASC, postacute sequelae of COVID-19. Figure adapted from images created with BioRender.com.

Figure 2

A SAg-like motif in SARS-CoV-2 spike protein. (a) SARS-CoV-2 spike (blue) proteins expressed at the surface of SARS-CoV-2 are composed of two subunits, S1 and S2. Spike proteins interact with the host cell ACE2 receptor (green) and transmembrane protease TMPRSS2 (red). After binding to ACE2, spike proteins are cleaved by proteases (furin and TMPRSS2) at the S1/S2 junction, leading to S2 membrane fusion and the shedding of S1. (b) SARS-CoV-2 S1 has a unique insertion of four amino acids, PRRA, adjacent to the S1/S2 cleavage site (R₆₈₅-S₆₈₆). This polybasic PRRA insert is part of a motif (bolded) whose sequence and structure highly resemble a segment of a bacterial SAg, Staphylococcal enterotoxin B (17). (c) Studies have reported a unique TCR repertoire in MIS-C patients, consistent with a TCR skewing typical of the reaction to SAgs, which for MIS-C patients is characterized by the expansion of TRBV11–2 cells (18, 20, 21, 23). This TRBV11–2 cell T cell expansion also correlates with disease severity and hyperinflammation in MIS-C patients (18, 21). Abbreviations: ACE2, angiotensin-converting enzyme 2; APC, antigen-presenting cell; MIS-C, multisystem inflammatory syndrome in children; PRRA, P₆₈₁RRA₆₈₄; SAg, superantigen; TCR, T cell receptor; TMPRSS2, transmembrane serine protease 2; TRBV11–2, T lymphocytes containing Vβ gene 11–2. Figure adapted from An In-depth Look into the Structure of the SARS-CoV2 Spike Glycoprotein by BioRender.com (2024), retrieved from https://app.biorender.com/biorender-templates.

Figure 3

Gaps in knowledge regarding MIS-C and long COVID. Abbreviations: MIS-C, multisystem inflammatory syndrome in children; PASC, postacute sequelae of COVID-19; SAg, superantigen. Figure adapted from images created with BioRender.com.