2 0 2 6 C O M P E N D I U M O F F E D E R A L M E D I C I N E 9 5 To do that, they conducted a retrospective cohort study of VA outpatient adults at high risk for severe COVID-19 with a positive SARS-CoV-2 test or COVID- 19 diag-nosis between April 1, 2022, and Aug. 21, 2024. The study defined severe COVID-19 as COVID-19- related hospitalization or all-cause mortality within 30 days. The focus was on risk factors, selected based on prevalence and CDC criteria. Those included: • 50 years old or older, • 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 indicated that, among 379,144 VA outpatients with COVID-19, 1.5% (5,801) had severe outcomes within 30 days. The researchers determined that 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 combina- tions (70.3%), and heart conditions in 154 combinations (64.4%). The researchers reported that the combination with the highest risk (aOR 35.25, 95% CI 16.06-77.37) included age ≥ 50 years, chronic lung disease, neurologi- cal conditions/cerebrovascular disease, diabetes mellitus, heart conditions, smoking, hypertension and not being up-to-date on COVID-19 vaccination. “In this large national cohort, severe COVID-19 risk increased with the number of risk factors present,” the authors advised. “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, identify- ing patients with particularly high-risk combinations of conditions is increasingly important to sup-port targeted vaccination and timely antiviral treatment.” Complicating the efforts to measure the effects of co-morbidities is that COVID-19, caused by the SARS- CoV-2 virus, can cause a wide spectrum of disease from asymp-tomatic infection and mild respiratory tract infec- tion to severe pneumonia with acute respiratory illness and multiorgan dysfunction. “While a single comorbidity may increase the risk of severe outcomes, combinations of comorbidities often interact in ways that significantly amplify the over- all risk (risk stack-ing),” the study authors explained. “Understanding this combined impact is essential to fully understanding the heightened vulnerability of cer- tain patients with COVID-19 and underscores the need for further research to better define how specific comor- bidity combinations influence clinical outcomes. We sought to quantify how combinations of 14 CDC-defined risk factors influence the probability of 30-day severe COVID-19 among high-risk outpatients and to identify specific high-risk multimorbidity profiles.” The findings confirmed prior research which showed that severe COVID-19 risk increases with additional underlying conditions. It was more comprehensive, how- ever, because “those earlier studies assessed only a lim- ited number of risk factors. By ana-lyzing combinations of 14 unique risk factors, our study provides one of the most comprehensive evaluations of multimorbidity and risk stacking for severe COVID-19 to date. Our find- ings extend earlier work by identifying the highest-risk patient populations defined by their combinations of risk factors, including older adults with heart disease, smoking history, hypertension, and lacking up-to-date COVID-19 vaccination, who may benefit most from tar- geted prevention efforts. Moreover, our findings are con- sistent with current CDC vaccine guidance, which iden- tifies these 14 risk factors as individually associated with an increased risk of severe COVID-19 and highlights the importance of updated COVID-19 vaccination for these populations.” A previous study from the national Centers for Disease Control & Prevention, which looked at adults across 800 US hospitals from March 2020 to March 2021, advised that the number of underlying conditions increased the risk of death by 1.53 times for one condition (95% CI 1.41-1.67) up to 3.82 times for ten conditions (95% CI 3.45-4.23) compared to those with no underlying medi- cation conditions, with hypertension being the most common condition (50.4%).2 Although hypertension was the most common
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