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Factors Associated With Severe COVID-19 Among Vaccinated Adults Treated in US Veterans Affairs Hospitals

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What are risk factors for severe breakthrough SARS-CoV-2 infections among vaccinated individuals?

Findings  In this cohort study of 110 760 vaccinated US veterans, increasing age was most strongly associated with severe disease, with risk increasing steadily among patients older than 50 years. Immunocompromising conditions and comorbidities indicating chronic heart, lung, kidney, or neurologic damage also increased risk, with a magnitude similar to or less than a 10-year age increase.

Meaning  Identification of the risk factors for severe breakthrough COVID-19 could be used to guide policies and decision-making about preventive measures for those who remain at risk of disease progression despite vaccination.


Importance  With a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination.

Objective  To characterize risk factors for severe COVID-19 disease in a vaccinated population.

Design, Setting, and Participants  This nationwide, retrospective cohort study included US veterans who received a SARS-CoV-2 vaccination series and later developed laboratory-confirmed SARS-CoV-2 infection and were treated at US Department of Veterans Affairs (VA) hospitals. Data were collected from December 15, 2020, through February 28, 2022.

Exposures  Demographic characteristics, comorbidities, immunocompromised status, and vaccination-related variables.

Main Outcomes and Measures  Development of severe vs nonsevere SARS-CoV-2 infection. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days. Association between severe disease and exposures was estimated using logistic regression models.

Results  Among 110 760 patients with infections following vaccination (97 614 [88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%] Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had severe COVID-19. The strongest association with risk of severe disease after vaccination was age, which increased among patients aged 50 years or older with an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age, such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37) relative to patients aged 45 to 50 years. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (eg, leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy (aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia (aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI, 1.49-1.69), were also associated with increased risk. Receipt of an additional (ie, booster) dose of vaccine was associated with reduced odds of severe disease (aOR, 0.50; CI, 0.44-0.57).

Conclusions and Relevance  In this nationwide, retrospective cohort of predominantly male US Veterans, we identified risk factors associated with severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision-making about patients most likely to benefit from preexposure prophylaxis and antiviral therapy.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 19, 2022.

Published: October 20, 2022. doi:10.1001/jamanetworkopen.2022.40037

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Vo AD et al. JAMA Network Open.

Corresponding Author: Westyn Branch-Elliman, MD, MMSc, Department of Medicine, VA Boston Healthcare System, Section of Infectious Diseases, 1400 VFW Pkwy, West Roxbury, MA 02132 (Westyn.Branch-Elliman@va.gov).

Author Contributions: Drs Fillmore and Monach had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Mr Vo and Dr La equally contributed as first authors. Drs Branch-Elliman, Fillmore, and Monach equally contributed as senior authors.

Concept and design: Wu, Strymish, Ronan, Brophy, Do, Branch-Elliman, Fillmore, Monach.

Acquisition, analysis, or interpretation of data: Vo, La, Wu, Strymish, Branch-Elliman, Fillmore, Monach.

Drafting of the manuscript: Branch-Elliman, Fillmore, Monach.

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

Statistical analysis: Vo, La, Fillmore, Monach.

Obtained funding: Brophy.

Administrative, technical, or material support: Vo, Brophy, Do, Fillmore.

Supervision: Brophy, Do, Branch-Elliman, Fillmore, Monach.

Conflict of Interest Disclosures: Dr Branch-Elliman reported receiving grants from Gilead Sciences and funds to their institution during the conduct of the study. Dr Fillmore reported receiving grants from American Heart Association and grants from Veterans Affairs (VA) Cooperative Studies Program during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by the VA Cooperative Studies Program.

Role of the Funder/Sponsor: The funder had no role in the 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: Views represented are those of the authors and do not necessarily represent those of the VA or the US Federal Government.

Additional Information: Patient-level data cannot be shared due to privacy laws. Code underlying the data will be made available upon request to the authors.

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