Risk of Death in Patients Hospitalized for COVID-19 vs Seasonal Influenza in Fall-Winter 2022-2023

In the first year of the COVID-19 pandemic, 2 US studies suggested that people hospitalized for COVID-19 had nearly 5 times the risk of 30-day mortality compared with those hospitalized for seasonal influenza.^1,2 Since then, much has changed, including SARS-CoV-2 itself, clinical care, and population-level immunity; mortality from influenza may have also changed. This study assessed whether COVID-19 remains associated with higher risk of death compared with seasonal influenza in fall-winter 2022-2023.

We used the electronic health databases of the US Department of Veterans Affairs (VA). Between October 1, 2022, and January 31, 2023, we enrolled all individuals with at least 1 hospital admission record between 2 days before and 10 days after a positive test result for SARS-CoV-2 or influenza and an admission diagnosis for COVID-19 or seasonal influenza. We removed 143 participants hospitalized with both infections. The cohort was followed up until the first occurrence of death, 30 days after hospital admission, or March 2, 2023. Differences in baseline characteristics between the groups were evaluated through absolute standardized differences (<0.1 indicating good balance).

We evaluated the risk of death in people hospitalized for COVID-19 vs influenza through inverse probability-weighted Cox survival models. Logistic regression was used to generate a propensity score, which was then applied in inverse probability weighting to balance the 2 groups; covariates were defined based on prior knowledge and ascertained in the 3 years preceding admission (eMethods in Supplement 1). We also estimated the absolute risk as the percentage of excess deaths (difference in death rates between COVID-19 and influenza groups at 30 days). Risk was also examined in prespecified subgroups (age ≤65 years vs >65 years; COVID-19 vaccination; SARS-CoV-2 infection status; and use of outpatient COVID-19 antiviral treatment before admission) (eMethods in Supplement 1). Interaction analyses were undertaken to assess statistically significant risk differences between subgroups.

Analyses were performed with SAS Enterprise Guide version 8.2 (SAS Institute Inc). Statistical significance was defined as a 95% CI that did not cross 1.0 on a relative scale. The study was approved with a waiver of informed consent by the VA St Louis Health Care System institutional review board.

There were 8996 hospitalizations (538 deaths [5.98%] within 30 days) for COVID-19 and 2403 hospitalizations (76 deaths [3.16%]) for seasonal influenza (Table). After propensity score weighting, the 2 groups were well balanced (mean age, 73 years; 95% male).

The death rate at 30 days was 5.97% for COVID-19 and 3.75% for influenza, with an excess death rate of 2.23% (95% CI, 1.32%-3.13%) (Figure). Compared with hospitalization for influenza, hospitalization for COVID-19 was associated with a higher risk of death (hazard ratio, 1.61 [95% CI, 1.29-2.02]).

The risk of death decreased with the number of COVID-19 vaccinations (P = .009 for interaction between unvaccinated and vaccinated; P < .001 for interaction between unvaccinated and boosted). No statistically significant interactions were observed across other subgroups (Figure).

This study found that, in a VA population in fall-winter 2022-2023, being hospitalized for COVID-19 vs seasonal influenza was associated with an increased risk of death. This finding should be interpreted in the context of a 2 to 3 times greater number of people being hospitalized for COVID-19 vs influenza in the US in this period.^3,4 However, the difference in mortality rates between COVID-19 and influenza appears to have decreased since early in the pandemic; death rates among people hospitalized for COVID-19 were 17% to 21% in 2020 vs 6% in this study, while death rates for those hospitalized for influenza were 3.8% in 2020 vs 3.7% in this study.^1,2 The decline in death rates among people hospitalized for COVID-19 may be due to changes in SARS-CoV-2 variants, increased immunity levels (from vaccination and prior infection), and improved clinical care.⁵

The increased risk of death was greater among unvaccinated individuals compared with those vaccinated or boosted—findings that highlight the importance of vaccination in reducing risk of COVID-19 death.

Study limitations include that the older and predominantly male VA population may limit generalizability to broader populations. The results may not reflect risk in nonhospitalized individuals. The analyses did not examine causes of death, and residual confounding cannot be ruled out.

Accepted for Publication: March 19, 2023.

Published Online: April 6, 2023. doi:10.1001/jama.2023.5348

Corresponding Author: Ziyad Al-Aly, MD, VA Saint Louis Health Care System, 915 N Grand Blvd, 151-JC, St Louis, MO 63106 (zalaly@gmail.com).

Author Contributions: Dr Al-Aly had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Xie, Al-Aly.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Xie, Al-Aly.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: Al-Aly.

Administrative, technical, or material support: Al-Aly.

Supervision: Al-Aly.

Conflict of Interest Disclosures: Dr Xie reported serving as a consultant (uncompensated) for Pfizer. Dr Al-Aly reported receiving consulting fees from Gilead Sciences and Tonix Pharmaceuticals and serving as a consultant (uncompensated) for Pfizer. No other disclosures were reported.

Funding/Support: This research was funded by the US Department of Veterans Affairs (Dr Al-Aly).

Role of Funder/Sponsor: The US Department of Veterans Affairs had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The contents do not represent the views of the US Department of Veterans Affairs or the US government.

Data Sharing Statement: See Supplement 2.