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Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19–infected older adults residing in nursing homes. We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction). A total of 154 COVID-19–positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks. Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates. We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27–6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13–6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24–1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59–25.1) or serious clinical outcome (OR 0.48; CI 0.10–1.97). Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials. [ABSTRACT FROM AUTHOR]