ArticleInfectious diseases and therapy2026
Impact of Risk Factor Combinations on Severe COVID-19 Outcomes Among Outpatients.
Article in Infectious diseases and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionSeveral risk factors for progression to severe COVID-19 have been identified, but whether multiple concomitant risk factors (risk stacking) further increase risk remains unknown. We sought to identify outpatient populations at the highest risk for severe COVID-19 using risk factor stacking.
methodsWe conducted a retrospective cohort study of Veterans Affairs (VA) outpatient adults (≥ 18 years) at high risk for severe COVID-19 with a positive SARS-CoV-2 test or COVID-19 diagnosis between April 1, 2022 and August 21, 2024. Severe COVID-19 was defined as COVID-19-related hospitalization or all-cause mortality within 30 days. Logistic regression models were used to quantify the impact of combinations of multiple risk factors (stacked risks) on severe COVID-19. Risk factors, selected based on prevalence and CDC criteria, included age ≥ 50 years, chronic lung disease, cancer, neurological conditions/cerebrovascular disease, chronic kidney disease, chronic liver disease, diabetes mellitus, heart conditions, mental health conditions, obesity, smoking, immunosuppression, hypertension, and not being up to date on COVID-19 vaccination.
resultsAmong 379,144 VA outpatients with COVID-19, 1.5% (5801) had severe outcomes within 30 days. Risk increased with each additional factor from two (adjusted odds ratio [aOR] 2.10, 95% confidence interval [CI] 1.37-3.23) to 14 risk factors (aOR 43.49, 95% CI 4.94-382.66) compared to one. Overall, 239 significant risk factor combinations were identified. Hypertension appeared in 196 combinations (82.0%), not up-to-date on COVID-19 vaccination in 173 combinations (72.4%), smoking in 168 combinations (70.3%), and heart conditions in 154 combinations (64.4%). The combination with the highest risk (aOR 35.25, 95% CI 16.06-77.37) included age ≥ 50 years, chronic lung disease, neurological conditions/cerebrovascular disease, diabetes mellitus, heart conditions, smoking, hypertension, and not being up-to-date on COVID-19 vaccination.
conclusionsIn this large national cohort, severe COVID-19 risk increased with the number of risk factors present. Patients with multiple overlapping risk factors who were not vaccinated were at the highest risk for severe COVID-19. As recommendations have shifted toward risk-based clinical decision-making, identifying patients with particularly high-risk combinations of conditions is increasingly important to support targeted vaccination and timely antiviral treatment.
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