Impact of Risk Factor Combinations on Severe COVID-19 Outcomes Among Outpatients

Abstract Introduction Several 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. Methods We 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. Results Among 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. Conclusions In 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.