Clinical impact of coinfection with SARS-CoV-2, influenza virus, and respiratory syncytial virus among adults: a multicenter retrospective cohort study [2021-2025].

Background: Coinfections involving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza virus, and respiratory syncytial virus (RSV) may contribute to increased healthcare utilization and disease severity, particularly during periods of viral co-circulation. However, data on their combined impact in adult populations remain limited. This study aimed to evaluate the association between monoinfection and coinfection with SARS-CoV-2, influenza virus, and/or RSV and the risk of hospital admission and severe clinical outcomes among adults presenting to the emergency department (ED). Methods: This was a retrospective cohort study conducted across eight hospitals in southeastern Michigan. We included all adults (≥18 years) with an ED encounter between January 1, 2021 and May 31, 2025, who received a principal diagnosis of coronavirus disease 2019 (COVID-19), influenza, or RSV. The primary outcome was hospital admission following the ED visit. The secondary outcome was a composite severe outcome, defined as intensive care unit (ICU) admission, mechanical ventilation, or in-hospital death. Multivariable logistic regression and Cox proportional hazards models were used to assess associations, with adjustment for age, sex, race, comorbidities, vaccination status, and respiratory virus season of encounter. Sensitivity and subgroup analyses were performed, including a six-group infection classification and a prespecified subgroup of adults aged ≥65 years. Results: Among 68,697 adult ED encounters, 52,922 (77.0%) involved COVID-19 only, 13,996 (20.4%) influenza only, 1,356 (2.0%) RSV only, and 423 (0.6%) coinfections. In adjusted analyses, coinfection was associated with higher odds of admission compared to influenza only [adjusted odds ratio (aOR), 0.55; 95% confidence interval (CI): 0.54-0.57] and COVID-19 only (aOR, 0.86; 95% CI: 0.84-0.89). Severe outcomes occurred in 3.5% of cases and were most frequent among RSV-only and coinfected patients, coinfection had a significantly higher hazard compared to influenza only [adjusted hazard ratio (aHR) 0.48; 95% CI: 0.25-0.90] and RSV only (aHR 0.45; 95% CI: 0.21-0.95). Sensitivity and subgroup analyses confirmed the robustness of findings. Conclusions: Coinfection with SARS-CoV-2, influenza virus, and/or RSV was associated with increased odds of hospital admission, particularly in older adults and when RSV was involved. Although severe outcomes were relatively uncommon, coinfected patients had a significantly higher hazard of severe outcomes compared with those infected with influenza or RSV alone. These findings support the need for ongoing viral surveillance, multiplex diagnostics, and preventive strategies during periods of respiratory virus co-circulation.