Immunity interrupted: Links between SARS-CoV-2 and the tripledemic of 2022

The post-pandemic resurgence of respiratory viral infections, commonly referred to as the "tripledemic," raised concerns that prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may increase susceptibility to subsequent respiratory illnesses. However, the relationship between SARS-CoV-2 infection and future respiratory viral infections in children remains poorly understood.

To determine whether pediatric patients with SARS-CoV-2 infection were at increased risk of subsequent respiratory viral infections within 120 days compared with children diagnosed with other respiratory viral infections and to evaluate coinfection frequency and clinical outcomes.

We conducted a retrospective cohort study of pediatric patients aged 6 months to < 18 years presenting to emergency departments within a large healthcare system between January 1, 2021, and December 31, 2023. Patients were categorized as SARS-CoV-2 only (n = 4004), SARS-CoV-2 with respiratory viral coinfection (n = 1678), or other respiratory viral infection only (n = 31,434). Patients were followed for 120 days after the index encounter. Primary outcomes included subsequent respiratory viral infections and laboratory-confirmed reinfections. Secondary outcomes included coinfection rates, oxygen supplementation, mechanical ventilation, and hospital length of stay.

A total of 37,116 pediatric patients met inclusion criteria. Subsequent respiratory viral infections occurred less frequently among patients with SARS-CoV-2-only infection (4.4%) compared with patients with SARS-CoV-2 coinfection (6.0%; OR 1.39, 95% CI 1.08-1.79) and those with other respiratory viral infections (6.1%; OR 1.43, 95% CI 1.22-1.68). The mean time to subsequent infection was longest in the SARS-CoV-2-only group (68.4 days) compared with the SARS-CoV-2 coinfection (60.8 days) and other viral infection groups (58.8 days). Laboratory-confirmed reinfections occurred in 2.0% of patients with SARS-CoV-2-only infection and 2.8% of patients in both comparison groups. Coinfections were less common among patients with SARS-CoV-2 infection than among those with other respiratory viral infections. Severe clinical outcomes were uncommon across all groups. Although patients with SARS-CoV-2-only infection had slightly longer hospital stays and higher rates of mechanical ventilation, absolute event rates remained low.

Prior SARS-CoV-2 infection was not associated with an increased risk of subsequent respiratory viral infections in children. Instead, SARS-CoV-2 infection was associated with fewer subsequent infections, lower coinfection rates, and a longer interval before reinfection compared with other respiratory viral illnesses. These findings support the possibility of viral interference or transient immune-mediated protection following SARS-CoV-2 infection and suggest that factors other than prior SARS-CoV-2 infection were more likely responsible for the increased burden of respiratory viral illnesses observed during the post-pandemic period.