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

Abstract

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.

Figure 1.. Cohorts and Subcohorts Included in the Study, With Results for Total Breakthrough Infections, Severe Breakthrough Infections, and Deaths 2 to 28 Days After Diagnosis of Infection

The Methods section and eMethods in the Supplement include the definition of immunocompromised (IC) status, time periods for Delta and Omicron periods, and time periods for US Food and Drug Administration approval of vaccination for the general adult population. ^aIn addition to no booster (B), started initial vaccination on or after recommendation for all US adults (March 29, 2021).

Figure 2.. Risk of Severe vs Nonsevere Breakthrough Infection

All variables that met significance criteria (P < .05 after adjustment for multiple comparisons, and adjusted odds ratio [aOR] ≥1.50 or ≤0.67) and selected additional variables (eg, diabetes and HIV infection) chosen a priori for comparison.

Figure 3.. Risk of Severe vs Nonsevere Breakthrough Infection as a Function of Time Since Vaccination in Subcohorts Defined by Age, Vaccine Eligibility, and Immunocompromise

The focus of the plots is on time since initial vaccination, but results are derived from multivariable logistic regression. aOR indicates adjusted odds ratio.