Is long-term disruption of the renin-angiotensin-aldosterone system associated with long COVID? A retrospective cohort study among healthcare workers

Background: Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin aldosterone system (RAAS), is the main receptor for SARS-CoV-2 entry into human cells. The occurrence of long-term symptoms post-COVID 19 infection (Long COVID, LC) is an important public health issue with an unclear etiological mechanism. We aimed to determine whether LC was associated with long-term RAAS disruption. Methods: We recruited a cohort of healthcare workers (HCWs) from Ziv Medical Center in Safed, Israel, who were uninfected and unvaccinated at baseline, and who later became infected with SARS-CoV-2. We measured serum circulating levels of four RAAS components (ACE, ACE2, Ang1-7 and AngII) using commercially available ELISA assays at three time points, using serum samples regularly collected from consenting hospital workers during the COVID-19 pandemic: pre-infection, 3–6 months post-infection, and a year post-infection. Post-serum collection we determined LC status using an online survey based on self-reported, LC-compatible symptoms not explained by alternative diagnoses. We excluded participants with conditions or medications interfering with the RAAS (e.g. hypertension, chronic kidney disease, antihypertensives, antidiuretics). At each time point we compared the levels of each of the four RAAS components between those infected and reporting LC and those infected not reporting LC using Mann Whitney U tests and Wilcoxon signed-rank tests, corrected for multiple testing. Results: We included 38 LC positive and 38 LC negative participants. Age/gender distribution was similar in both groups. No statistically significant differences in any of the four RAAS markers were observed between LC cases and controls at either 3–6 months or 12 months post-infection in our study sample. Conclusion: No evidence was detected within the limits of the study design and sample size to conclude that long-term disruption of RAAS is a significant contributor to LC pathophysiology. Clinical trial: Not applicable.