# Serology supportive of recent coxsackievirus B infection is correlated with multisystem inflammatory syndrome in children (MIS-C)

## TL;DR

The study finds a link between recent coxsackievirus B infection and a rare inflammatory condition in children called MIS-C, suggesting a possible role in its development.

## Contribution

The study identifies a correlation between elevated coxsackievirus B serology and MIS-C cases, supporting a potential two-hit hypothesis involving prior viral infections.

## Key findings

- Elevated coxsackievirus B titers are significantly more common in MIS-C patients compared to those unlikely to have acute coxsackievirus infection.
- A significant drop in coxsackievirus B seropositivity was observed during the peak of social distancing in 2020.
- MIS-C occurs at a higher frequency in African American children compared to White children.

## Abstract

Rarely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will lead to myocarditis associated with multisystem inflammatory syndrome in children (MIS-C). It remains unclear why MIS-C only targets specific children. To explore an association between coxsackievirus infections with MIS-C, we investigated the sero-epidemiology of CV in admitted pediatric patients in relation to the pandemic. This retrospective case–control study was performed by chart review of children (age ≤21 years) admitted to a tertiary care hospital with CV serological testing from January 2017 to August 2023. Clinical, laboratory, and imaging findings were used to classify patients as MIS-C and CV-unlikely or CV-possible for non-MIS-C patients. Out of 182 admissions (179 patients, median age, 6), CVB complement fixation (CF) assay on serotypes B1–B6 and CVA immunofluorescence assay IgG on serotypes A7, A9, A16, and A24 were positive in at least one serotype in 59.2% and 80.7% of cases, respectively. We observed a significant drop in CVB CF seropositivity during the peak of social distancing in 2020. The likelihood of elevated CVB CF titers was significantly higher in MIS-C than the CV-unlikely group (OR: 1.92, 95% CI: 1.02–3.63, P: 0.04) and showed a trend toward higher values in African Americans than Whites (OR: 1.57, 95% CI: 0.98–2.50, P: 0.057). The frequency of MIS-C was considerably higher in African Americans than Whites (18.1% versus 9%, P: 0.1). A higher likelihood of elevated CVB CF titers in patients with MIS-C compared with those unlikely to have acute CV infection along with a relatively higher frequency of MIS-C in African Americans warrants further investigation into the role of CVB infection in MIS-C development.

The emergence of multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic raised major concerns in providers caring for children. This condition presents a hyper-inflammation state that can lead to severe complications, including myocarditis and cardiogenic shock. The pathogenesis of MIS-C has not been fully understood. Understanding the pathogenesis of this condition is not only important for developing effective treatments but also for applying preventive strategies. A two-hit hypothesis leading to MIS-C has been proposed. Coxsackievirus infections are prevalent during childhood and can also cause myocarditis, and coxsackievirus B specifically has been shown to cause persistent RNA presence in host cells, leading to continued inflammation. Herein, we show that elevated coxsackievirus B titers are associated with MIS-C cases, implying a role of successive infections with these viruses contributing to such a hyperinflammatory state. This study supports the need for larger investigations into this association.