COVID-19 and RAS Inhibition

Viruses need receptors to enter human cells. Receptors are protein structures on the cell wall which pass through the cell wall and have an external component. In the case of the coronavirus, its proven entry receptor is the "Angiotensin Converting Enzyme 2" (ACE2). ACE2 is a very special protein that fulfills many positive tasks in the human body, including the regulation of blood pressure. An important group of medications for hypertension are ACE inhibitors, the overarching term for this is RAS blockers. "ACE" is the abbreviation for angiotensin converting enzyme and "RAS" is the abbreviation for "renin -angiotensin aldosterone system". The entry receptor for the coronavirus, the above -mentioned ACE2, is a central part of this RAS (system). From the beginning of the COVID-19 crisis, there was an accumulation of severe courses in elderly patients with high blood pressure and diabetes, who are very often treated with ACE inhibitors and another class of drugs, called angiotensin receptor blockers (ARBs). T he first hypothesis now was: The ("rated as good") ACE2 is up-regulated in elderly patients with high blood pressure, diabetes (and heart failure), which is the reason why there are more difficult courses in these patients because the coronavirus finds a particularly large number of entry points. The other hypothesis was: The ONLY REASON why ACE2 is upregulated in elderly patients with high blood pressure, diabetes (and heart failure) is BECAUSE these patients usually take ACE inhibitors and other medications (e.g. ARBs). Doctors from various specialist societies (first and foremost cardiologists) have, however, warned against stopping these important drugs without yet having a clear plan of what may really be going on. There is also another hypothesis: COVID-19 could even take a milder course if patients take RAS blockers because the RAS and possibly the course of the disease are positively influenced by RAS blockers. In the present study, the study arm B of the Austrian Coronavirus Adaptive Clinical Trial (ACOVACT), we therefore plan to randomly control the administration of RAS blockers in patients with pre-existing RAS-blocking therapy and, in parallel, to randomly administer an ARB (candesartan) to patients who are not yet taking an ARB. In addition to the collection of standardized clinical endpoints, the "RAS fingerprint" developed in Vienna is also being tested as a new biomarker for SARS-CoV-2 infections. The "RAS fingerprint" can us help to demonstrate a basic "dysregulation" of the RAS, which is currently of great scientific interest. However, this RAS fingerprint could not only win us intellectual, scientific fame, but more importantly result in personalized treatment options, which may differ from case to case. Or we could also prove at the molecular level that it makes no difference whether SARS-CoV-2 infected patients use RAS blockers or not. Our patients are also interviewed as part of this FWF-funded study. The qualitative coding of personal experiences resulting from quarantine and potentially life-threatening illness will thus provide relevant insights into patient care on a social level and with regard to their treatment preferences.

Our project was based around the finding that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses an entry receptor which connects to an important hormonal system for blood pressure and blood volume control, entitled renin angiotensin system (RAS). This entry receptor is angiotensin converting enzyme 2 (ACE2) and can be found in various human tissues such as the lungs. In our research proposal, we conducted a randomized controlled trial, asking the questions: (1) if SARS-CoV-2 dysregulates the RAS in the human body (2) if blood pressure medications that interfere with the RAS should be discontinued when people become infected with SARS-CoV-2 (3) what patients reported about their disease and the experience of being included in a research study. We analyzed 532 blood samples from 126 patients with SARS-CoV-2 infection and found that ACE2 increases in patients with severe COVID-19 from early to late time periods during their disease course. Our data were among the first, disproving the view that ACE2 might be down-regulated during the course of the disease (based on an earlier study where infection of mice with SARS-CoV-1, the coronavirus causing the 2002-2004 SARS outbreak, resulted in lung injury, which appeared to be mediated by ACE2 downregulation). We also found that ACE2 levels were unaltered by RASi discontinuation in our randomized controlled trial and were mainly influenced by disease severity. Clinical outcomes did not seem to be affected by RASi continuation versus discontinuation, which was consistent with larger trials. From the clinical and metabolic perspectives, our findings clearly supported continuation of ACEi and ARB therapy in patients with COVID-19. When we asked patients about their experiences and challenges upon being hospitalized and participating in a randomized controlled trial, using a semi-structured interview guide, we identified several themes, in accordance with the grounded theory process: Theme 1, "A Severe Disease", characterized by sub-themes "symptom burden", "unpredictability of the disease's course", "fear of death", and "long-term aftermaths with lifestyle consequences" Theme 2, "Saved and Burdened by Hospitalization", with sub-themes "hospital = safe haven versus place of fear", and "influence of isolation" Theme 3, "Managing One's Own Health", with sub-themes "self-management" and "coping" Theme 4, "Belief in Medical Research", with sub-themes "motivation for study participation", "information gaps" and "situational helplessness" in response to study inclusion. We concluded that several of the identified themes (2, 3, 4) were modifiable and open for interventions to improve care of patients with COVID-19, that disease self-management should be actively encouraged and information during clinical trial participation, especially in the recent COVID-19 crisis.