key: cord-0822454-ij1cgypg authors: Parigi, Tommaso Lorenzo; Vespa, Edoardo; Pugliese, Nicola title: COVID-19, ACEI/ARBs and gastrointestinal symptoms: the jury is still out on the association. date: 2020-07-16 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.06.095 sha: b2aa738afdb92dde17bc77580bd4ca5c2c126a78 doc_id: 822454 cord_uid: ij1cgypg nan We read with great interest the article by Tan and colleagues investigating the association between the use of Angiotensin Converting Enzyme Inhibitors (ACEIs) or Angiotensin Receptor II Blockers (ARBs), gastrointestinal (GI) involvement, and clinical outcome of COVID-19. 1 The authors concluded that ACEIs/ARBs treatment continuation was associated with a lower rate of GI manifestations (diarrhea, vomit, nausea, and abdominal pain) and increased mortality. We tried to replicate their analyses in a similar cohort from a single tertiary center in Milan, Italy. Our cohort included 325 consecutive, RT-PCR confirmed, COVID-19 patients that were hospitalized between February 22nd and March 30th, 2020; median age was 66 years (range 24-93, IQR 55-75); 68.6% were males. History of hypertension was reported in 51.3% (167/325) and coronary heart disease in 17.8% (58/325). At admission, a total of 114 patients (35.4%) were taking ACEIs/ARBs. We observed no difference in terms of severity of COVID-19 presentation between patients using ACEIs/ARBs or non-ACEIs/ARBs users: among the two groups, a similar percentage of patients were breathing in ambient air (34.2% vs 41.8%, p=0.18), were receiving supplemental oxygen (50% vs 43.27%, p=0.24) or needed mechanical ventilation (15.8% vs 14.9%, p=0.83). Despite our larger cohort, in univariable logistic regression analysis we could not find a statistically significant association between ACEIs/ARBs use and reduced GI involvement at admission (OR 0.63, 95% CI: 0.37-1.08; p=0.091). Considering diarrhea alone did not change the results appreciably (OR 0.63, 95% CI: 0.36-1.11; p = 0.107). Similarly, we found no negative association between use of ACEIs/ARBs and liver injury, using the same cutoffs: AST > 40 UI/L, ALT > 40 UI/L or total bilirubin >20 mmol/L (OR 0.94, 95% CI: 0.59-1.48; p=0.782). We noted that the prevalence of diarrhea at admission in our cohort was higher than reported by Tan et al. (23.4% vs 12%), while prevalence of other GI symptoms was lower (6.5% vs 15%). We chose to restrict our analysis to GI symptoms present ad admission only, in order to minimize the confounding effect of other hospitalization-related causes of diarrhea, such as antibiotics or antivirals use. Prognostic interpretation of these findings is not unequivocal and the interplay between SARS-CoV-2 digestive involvement and overall clinical outcome is still unclear. In a previously published analysis of this same cohort we found an association between GI symptoms and lower rate of clinical deterioration. 2 This finding is in contrast with a metaanalysis of Chinese studies, which concluded that patients with GI involvement tend to develop more severe COVID-19. 3 Further prospective studies are needed to investigate the implications of SARS-CoV-2 digestive involvement. In the secondary analysis, Tan and colleagues found a protective effect of ACEIs/ARBs use on overall clinical outcome. We could not confirm this result in our cohort. Although in univariable logistic regression analysis, the use of ACEIs or ARBs was associated with clinical deterioration, defined as death or ICU admission (OR 2.05, 95% CI: 1.28-3.28; p=0.003), in multivariable analysis, after adjustment for potential confounding factors such as age, coronary artery disease, hypertension and diabetes mellitus, use of ACEIs/ARBs did not remain significantly associated with the outcome (adjusted odds ratio [aOR] 0.99, 95% CI 0.49-1.55; p=0.975). Although a large retrospective Chinese study found a reduced risk of all-cause mortality among ACEI/ARBs users, 4 overall quality of evidence is still limited and often conflicting. 5 Finally, Tan et al. interpret their results according to the assumed protective effect of ACEIs/ARBs from endothelial damage, which could lead to reduced multi-organ involvement with milder gastrointestinal manifestations and overall more favorable outcome. This hypothesis lacks a strong biological background as the role of ACEIs/ARBs in the course of COVID-19 infection is still unclear. Moreover, it is in contrast with other studies reporting that multi-organ involvement such as GI or liver involvement is not associated with a more severe COVID-19 disease course. 6 7 Consequently, the gastrointestinal presentation of COVID-19 should not distract clinicians from giving patients the best level of medical care. In conclusion, our findings are in contrast with those presented by Tan et al and suggest caution when interpreting clinical associations between outcome ad concomitant medications. Since ACEIs/ARBs are commonly prescribed in elderly and comorbid patients, any analysis of related outcomes must account for the potential confounders often found in this subset of patients. Associations between Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality among Patients with COVID-19 Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 Renin-angiotensin-aldosterone system inhibitors in patients with covid-19 Liver tests abnormalities in COVID-19: trick or treat?