Cellular, Antibody and Cytokine Pathways in Children with Acute SARS-CoV-2 Infection and MIS-C—Can We Match the Puzzle?

Abstract

The newly identified strain of the Coronaviridae family called severe acute respiratory syndrome (SARS-CoV-2) recently became the most significant health threat for adults and children. Some main predictors of severe clinical course in patients with SARS-CoV-2 infection are age and concomitant health conditions. Therefore, the proper evaluation of SARS-CoV-2-specific immunity is urgently required to understand and predict the spectrum of possible clinical phenotypes and recommend vaccination options and regimens in children. Furthermore, it is critical to characterize the nature of SARS-CoV-2-specific immune responses in children following asymptomatic infection and COVID-19 and other related conditions such as multisystem inflammatory syndrome (MIS-C), para-infectious and late postinfectious consequences. Recent studies involving children revealed a variety of cytokines, T cells and antibody responses in the pathogenesis of the disease. Moreover, different clinical scenarios in children were observed-asymptomatic seroprevalence, acute SARS-CoV-2 infection, and rarely severe COVID-19 with typical cytokine storm, MIS-C, long COVID-19, etc. Therefore, to gain a better clinical view, adequate diagnostic criteria and treatment algorithms, it is essential to create a realistic picture of the immunological puzzle of SARS-CoV-2 infection in different age groups. Finally, it was demonstrated that children may exert a potent and prolonged adaptive anti-SARS-CoV-2 immune response, with significant cross-reactions against other human Corona Viruses, that might contribute to disease sparing effect in this age range. However, the immunopathology of the virus has to be elucidated first.

Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)

“…Distinct from MAS, MIS-C induces acute gastrointestinal symptoms and more prominent myocardial dysfunction. Together, these data suggest MIS-C is similar but distinct from KD and MAS (Carter et al, 2020; Filippatos et al, 2023; Lazova et al, 2022; Lee et al, 2020; Sacco et al, 2022).…”

IFIH1loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases

“…Additionally, children were observed to have higher expression of RIG-I, MDA5 and LGP2 63 which can be translated to a pre-activated innate immune response leading to an early onset of interferon production in children’s infected airways 63,64 . This allows a faster viral clearance and lower viral load compared to adults, which might explain the severity of SARS-CoV-2 infection in the MIS-C patient possessing a potential truncated form of MDA5, as these patients are vulnerable to viral infections.…”

Update on the treatment of multisystem inflammatory syndrome in children associated with COVID-19

“…It may be a delayed immune phenomenon associated with inflammation [ 25 ]. Normally, SARS-CoV-2 invades the body via nasopharyngeal cells, where the S protein of the virus interacts with host ACE2 receptors, and host cells and innate immune cells exert intrinsic immunity through pattern recognition receptors [ 26 ]. Moreover, MIS-C can be mediated by both humoral and cellular immunity [ 27 ].…”

“…Germinal center-matured antibody secreting cells develop into long-lived plasma cells and memory B cells, providing higher and more persistent titers of virus-specific antibodies [ 29 ]. In addition, more naive T cells are present in young children, and, more importantly, the presence of lectin-like receptors on cytotoxic T cells maintains specific CD8 + T cells expressing high levels of cytotoxic mediators [ 26 ]. The SARS-CoV-2 infection triggers the release of large amounts of cytokines including interleukin-1 β (IL-1β), IL-6, IL-8, IL-10, IL-17, TNF-α and IFN-γ [ 30 ], which mediate a hyperinflammatory state which causes fever and systemic multisystem dysfunction in critically ill children ( Figure 1 ) [ 27 ].…”