Severity and Long-Term Mortality of COVID-19, Influenza, and Respiratory Syncytial Virus.

Importance: SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) contribute to many hospitalizations and deaths each year. Understanding relative disease severity can help to inform vaccination guidance.

Objective: To compare disease severity of COVID-19, influenza, and RSV among US veterans.

Design, Setting, And Participants: This retrospective cohort study analyzed national US Veterans Health Administration electronic health record data of nonhospitalized veterans who underwent same-day testing for SARS-CoV-2, influenza, and RSV, and were diagnosed with a single infection between August 1, 2022, and March 31, 2023, or between August 1, 2023, and March 31, 2024.

Exposures: Infection with SARS-CoV-2, influenza, or RSV.

Main Outcomes And Measures: Following inverse probability weighting, the cumulative incidence and risk differences (RDs) were calculated for the primary outcomes of 30-day hospitalization, intensive care unit admission, and death, as well as the secondary outcome of long-term death extending through 180 days.

Results: Among 68 581 patients included in the 2022 to 2023 cohort (6239 [9.1%] with RSV, 16 947 [24.7%] with influenza, and 45 395 [66.2%] with COVID-19) and 72 939 in the 2023 to 2024 cohort (9748 [13.4%] with RSV, 19 242 [26.4%] with influenza, and 43 949 [60.3%] with COVID-19), the median (IQR) age was 66 (53-75) years, and 123 090 (87.0%) were male. During the 2023 to 2024 season, the 30-day risk of hospitalization was similar for COVID-19 (16.2%) and influenza (16.3%) but lower for RSV at 14.3% (RD for COVID-19 vs RSV, 1.9% [95% CI, 0.9%-2.9%]; RD for influenza vs RSV, 2.0% [95% CI, 0.8%-3.3%]). The 30-day risk of death during the 2022 to 2023 season was slightly higher for COVID-19 (1.0%) compared with influenza (0.7%) (RD, 0.4% [95% CI, 0.1%-0.6%]) or RSV (0.7%) (RD, 0.4% [95% CI, 0.1%-0.6%]) but similar during the 2023 to 2024 season. Mortality risk at 180 days was higher for COVID-19 during both seasons (2023-2024 RD for COVID-19 vs influenza, 0.8% [95% CI, 0.3%-1.2%]; RD for COVID-19 vs RSV, 0.6% [95% CI, 0.1%-1.1%]). Higher mortality in both seasons was observed for veterans without COVID-19 vaccination in the previous year compared to veterans without seasonal influenza vaccination. In contrast, among groups vaccinated against their respective infections, there were no mortality differences at any time point between COVID-19 and influenza.

Conclusions And Relevance: This cohort study showed that, during the 2022 to 2023 season, infection with SARS-CoV-2 was associated with more severe disease outcomes than influenza or RSV, whereas differences were less pronounced during the 2023 to 2024 season. During both seasons, RSV remained a milder illness, whereas COVID-19 was associated with higher long-term mortality. Vaccination attenuated differences in disease severity and long-term mortality.