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

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, : 0.04) and showed a trend toward higher values in African Americans than Whites (OR: 1.57, 95% CI: 0.98-2.50, : 0.057). The frequency of MIS-C was considerably higher in African Americans than Whites (18.1% versus 9%, : 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.IMPORTANCEThe 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.