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. 2025 Mar 1;185(3):324-334.
doi: 10.1001/jamainternmed.2024.7452.

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

Kristina L Bajema  1   2 , David P Bui  1 , Lei Yan  3   4 , Yuli Li  3   5 , Nallakkandi Rajeevan  3   5 , Robert Vergun  1 , Kristin Berry  6 , Yuan Huang  3   4 , Hung-Mo Lin  3   4 , Mihaela Aslan  3   7 , George N Ioannou  6   8
Affiliations

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

Kristina L Bajema et al. JAMA Intern Med. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ioannou reported grants from the US Department of Veterans Affairs during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Eligible Veterans With a First Positive SARS-CoV-2, Influenza, or Respiratory Syncytial Virus (RSV) Test Result Each Season
This figure shows how eligible veterans with a first positive SARS-CoV-2, influenza, or RSV test results for both (A) the 2022 to 2023 season and (B) the 2023 to 2024 season were identified. eFigure 1 in Supplement 1 outlines the identification of eligible tests. The 2022 to 2023 season included testing from August 1, 2022, through March 31, 2023, and the 2023 to 2024 season included testing from August 1, 2023, through March 31, 2024. VHA indicates Veterans Health Administration. aDoes not include non-VHA long-term care facilities.
Figure 2.
Figure 2.. Risk of Hospitalization, Intensive Care Unit (ICU) Admission, or Death Comparing COVID-19, Influenza, and Respiratory Syncytial Virus (RSV)
The 2022 to 2023 season included testing from August 1, 2022, through March 31, 2023, and the 2023 to 2024 season included testing from August 1, 2023, through March 31, 2024. Error bars indicate 95% CIs. A 180-day follow-up during the 2023 to 2024 season was available for 2812 persons with RSV (29%), 2809 with influenza (15%), and 21 092 with COVID-19 (48%). RD indicates risk difference.
Figure 3.
Figure 3.. Weighted Cumulative Incidence of Death Following Diagnosis of COVID-19, Influenza, and Respiratory Syncytial Virus (RSV)
Analysis was performed after weighting. Cumulative incidence of death is shown for RSV, influenza, and COVID-19 for the 2022 to 2023 season (A) and the 2023 to 2024 season (B). The 2022 to 2023 season included testing from August 1, 2022, through March 31, 2023, and the 2023 to 2024 season included testing from August 1, 2023, through March 31, 2024. The shaded areas indicate 95% CIs.
Figure 4.
Figure 4.. Risk of Hospitalization, Intensive Care Unit (ICU) Admission, or Death Comparing COVID-19 and Influenza Among Persons With and Without Updated Vaccination
Influenza vaccination was defined among persons diagnosed with influenza as receipt of any same-season influenza vaccine, and persons unvaccinated for influenza did not receive a same-season influenza vaccine. Updated COVID-19 vaccination was defined among persons diagnosed with COVID-19 as receipt of the bivalent vaccine (2022-2023 season) or monovalent XBB.1.5 vaccine (2023-2024 season), and persons unvaccinated for COVID-19 did not receive any COVID-19 vaccination within the previous year, beginning August 1, 2021 (2022-2023 season), or August 1, 2022 (2023-2024 season), through 7 days prior to the index date. The 2022 to 2023 season included testing from August 1, 2022, through March 31, 2023, and the 2023 to 2024 season included testing from August 1, 2023, through March 31, 2024. Error bars indicate 95% CIs. The arrows on 95% CIs indicate that the value extends past the scale on the pictured plot. RD indicates risk difference.
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