Comparative Analysis of Severe Clinical Outcomes in Hospitalized Patients with RSV, Influenza, and COVID-19 Across Early and Late COVID-19 Pandemic Phases (2021-2024).

COVID-19, influenza, and respiratory syncytial virus (RSV) are major respiratory infections with overlapping clinical presentations. Comparative data on the severity of these infections in hospitalized adults are limited, particularly across phases of the COVID-19 pandemic. The objectives of this study are to compare the risk of severe outcomes among hospitalized patients with COVID-19, influenza, or RSV and to evaluate the role of vaccination and demographic subgroups using recent, real-world data. This is a retrospective cohort study. Setting: Eight hospitals within the Corewell Health system in Michigan, USA, were studied. The participants included adults aged ≥ 18 years hospitalized between 1 January 2021 and 20 July 2024 with a principal diagnosis of COVID-19, influenza, or RSV. The primary outcome was a composite of ICU admission, mechanical ventilation, or in-hospital death. Multivariable Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs), with subgroup analyses in terms of vaccination status, age group, and time period. Among 27,885 hospitalized patients (90.5% COVID-19, 7.2% influenza, 2.3% RSV), COVID-19 was associated with a higher risk of severe outcomes compared to influenza (aHR 1.30, 95% CI: 1.11-1.54). RSV showed no significant difference from influenza. Across all infection groups, older age (≥65 years), high comorbidity burden, and immunocompromised status were associated with an increased risk of severe outcomes. Recent COVID-19 vaccination was protective, particularly among older adults. Differences in severity were more pronounced in the pre-March 2022 period. Using one of the most recent large-scale datasets, this study is among the first to directly compare the severity of COVID-19, influenza, and RSV in hospitalized adults. COVID-19 continues to pose a higher risk of severe illness compared to the other viral infections. The findings underscore the importance of up-to-date vaccination and focused clinical strategies for older and high-risk individuals. This study offers timely evidence to guide future respiratory virus response strategies across hospital settings.