Differential associations of pathogen-specific co-infections with disease severity in pediatric RSV hospitalizations: a 3-year multicenter analysis

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory tract infections (ARTI) in infants and young children. Co-infection with other respiratory pathogens is common in RSV infection. However, the associations of co-infection with disease severity and their potential interactions remain poorly understood, especially in light of evolving epidemiological patterns of respiratory pathogens following the COVID-19 pandemic. This multicenter, retrospective study included 2,862 children under 5 years of age and hospitalized with RSV at three pediatric centers in Wuhan, China, between June 2020 and May 2023. We evaluated the associations of co-infecting pathogens, including bacteria, viruses, fungi, and atypical bacteria, with disease severity, length of hospital stay, and inpatient medical expenses. We found that nearly 44% of children with RSV were co-infected with at least one additional pathogen. Co-infection rates fluctuated in correlation with the implementation and relaxation of COVID-19 non-pharmaceutical interventions. While viral and atypical bacterial co-infections did not significantly alter outcomes, bacterial (OR = 2.00, 95% CI: 1.48, 2.70) and fungal (OR = 2.57, 95% CI: 1.23, 5.35) co-infections were strongly associated with increased disease severity. Both types were also linked to longer hospital stays (days, β = 0.63, 95% CI: 0.38, 0.88 for bacterial; β = 2.68, 95% CI: 1.94, 3.43 for fungal) and higher inpatient medical expenses (Chinese Yuan [CNY], β = 2,317.16, 95% CI: 1,534.43, 3,099.88 for bacterial; β = 6,636.55, 95% CI: 4,366, 8,907.10 for fungal). No significant additive interactions were found between bacterial and fungal co-infections. These findings highlight the importance of distinguishing co-infection types in the clinical management of RSV. IMPORTANCE: This study clarifies the clinical significance of pathogen co-infections in children hospitalized with respiratory syncytial virus (RSV). We demonstrate a critical distinction that co-infections with bacteria or fungi are associated with more severe disease, longer hospitalizations, and higher costs, whereas viral or atypical bacterial co-infections are not. In the context of evolving RSV epidemiology and pathogen co-infections in the post-pandemic era, this finding may help risk-based clinical management when co-infection exists.