Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) causes coronavirus disease , a potentially fatal disease that is of immense global public health concern. The initial cases were reported in December 2019 in Wuhan, China [1] . Since then, there have been 3,041,764 confirmed COVID-19 patients in the world as of April 27th ,2020 with a total of 211,167 deaths. The United States has the maximum number (988,189) of confirmed cases with a total of 56,259 deaths. Most cases were diagnosed in New York (291,996) with a total of 22,668 deaths [2] .
Several studies, including a recent meta-analysis have reported that coexisting conditions, including hypertension, cardiac diseases, cerebrovascular diseases and diabetes were common among patients with Covid-19 who had severe illness, got admitted to the intensive care unit (ICU), received mechanical ventilation, or died than among patients who had mild illness [3, 4] .
Notably, the most frequent comorbidities reported in these studies of patients with COVID-19, especially hypertension is often treated with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) [5] . This could theoretically result in an upregulation of ACE2 in the epithelial cells of the lung, intestine, kidney, and blood vessels, which is an active binding target for SARS-CoV-2 virus [6] .
Although this raised concerns regarding the use of these drugs in COVID-19 patients, several animal studies presented conflicting findings regarding increased ACE2 expression due to ACEI and ARB in animal studies and the previous human studies suggested that administration of ACEI/ARBs does not increase ACE2 expression [7] . In light of these findings and a paucity of clinical outcome studies, many professional cardiovascular and hypertension societies including the Italian Society of Pharmacology, International Society of Hypertension (ISH), European Society of Hypertension, Joint American Heart Association/American College of Cardiology/American Heart Failure Association and others recommended the continued use of ACEI/ARBs in COVID-19 patients [8] [9] [10] [11] .
However, since the conception of these recommendations, several clinical studies have been conducted which evaluated the association of ACEI and ARB with clinical severity and mortality outcomes in COVID-19 patients. Therefore, the medical literature was systematically reviewed for the current clinical evidence evaluating the safety and efficacy of ACE inhibitors and ARB in COVID-19 patients.
Literature search was conducted on the PubMed/MEDLINE database using key words, viz., "ACE inhibitors AND coronavirus." and "ARB AND coronavirus." We applied search filters to include humans and English language published till April 26 th , 2020. Additional papers of possible interest were identified by examining references of pertinent review articles and searching Google Scholar and preprint servers like MedRxiv and Biorxiv. We included studies which evaluated clinical severity and mortality outcomes for patients with COVID-19 on ACEinhibitors or ARB or both.
We excluded those studies which dealt with in-vitro or animal studies as well as those which only evaluated only ACE expression levels. (Figure 1 The information on the demographics, comorbidities, pharmacotherapy with ACE-I, ARBs and other drugs, clinical severity outcomes and mortality was extracted.
Articles from preliminary search of PubMed, Google Scholar and preprint servers (n=79) Articles included for further review after screening the titles and abstracts (n=56) Articles whose full text was reviewed (n=35) Articles included after review and addition of pertinent crossreferences (n=8)
A total of 79 articles were found in the search. Based on titles of the articles, 23 were excluded as they did not meet the inclusion criteria. Further, abstracts of 56 articles were read and subsequently, the full text of 35 articles were reviewed. Of these, six articles were shortlisted which compared the clinical and/or mortality outcomes of COVID-19 patients on ACEI or ARB with non-users [12] [13] [14] [15] [16] [17] . Additionally, a couple of studies from the United Kingdom and China published on a preprint server was also included [18, 19] . Finally, eight studies were included for review. (Table 1) All the included studies compared clinical severity related outcomes in COVID-19 patients on ACEI or ARB with non-users. However, there was non-uniformity in the definition of the severe outcomes amongst the studies. Table 2) Richardson S. et al and Zhang P. et al compared the rates of invasive ventilation and found that they were slightly higher or equivalent in patients on ACEI/ARB as compared to non-users, respectively. In addition, Richardson S. et al also reported slightly higher rates of ICU admissions in patients on ACEI (21.4%) and ARB (20.8%) as compared to non-users (14.8%). Zhang P. et al reported that the patients on ACEI/ARB had lower rates of septic shock (HR = 0.32, p value = 0.01) and acute respiratory distress syndrome (ARDS) (HR = 0.65, p value = 0.07) as compared to non-users [15, 16] . On the other hand, Guo J. et al found that patients on ACEI/ARB had higher rates of cardiovascular disease and elevated troponin T (TnT) levels as compared to non-users (21.1% vs 5.9%) [17] . (Table 2 
Despite the worldwide implementation of public health measures like social distancing, contact tracing and mass testing to aid in the control of COVID-19, the global cases have risen to more than 3 million and over 200.000 patients lost their lives by April 27 th , 2020 [2, 21] , which further requires attention. Several studies have reported increased rates of COVID-19 associated mortality in patients with significant comorbidities viz hypertension, cardiovascular disease, chronic kidney disease, heart failure etc. [3, 4] Although ACEI and ARB are commonly prescribed to treat some of these comorbidities, the fact that ACE2 receptor is the main binding site for entry of SARS-CoV-2, caused concerns regarding the use of ACEI and ARB in such patients [5, 22] .
Several evidence-based consensus and position statements were formulated by various cardiovascular and hypertension societies which recommended continued use of ACE inhibitors and ARB in COVID-19 patients citing the lack of any contrary clinical evidence [8] [9] [10] [11] . Since then, however, several clinical studies have evaluated the association of ACE inhibitors and ARB in COVID-19 patients and comorbidities.
It is imperative to accurately predict clinical outcomes of COVID-19 patients especially those with comorbidities and taking ACEI or ARB to decide whether to continue or switch to another medication. However, there were conflicting findings reported in several studies as Meng J. et al, Liu Y. et al and Feng Y. reported that patients on ACE inhibitors/ARB had lower rates of severe outcomes whereas Richardson S. et al reported higher rates of invasive ventilation and ICU admissions in patients on ACE inhibitors/ARB as compared to non-users and Guo J. et al found that patients on ACE inhibitors/ARB had higher rates of cardiovascular disease and elevated troponin T (TnT) levels. It is pertinent to note that all above studies did not perform adjustment for covariates or matching for analysis, undermining the statistical strength of their results to a certain extent [12, 14, 15, 17, 18] . However, Zhang P. et al did perform matching and an adjusted analysis of 348 patients in which he found slightly higher rates of ICU admissions in patients on ACE inhibitors (21.4%) and ARB (20.8%) as compared to non-users (14.8%) [16] . Zhang P. et al again performed matching and adjustment in assessing the mortality outcomes strengthening their conclusions regarding safety of ACEI/ARB, however a large sample size study conducted in New York in over 1000 COVID-19 patients by Richardson S. et al raised concerns of worse mortality outcomes with ACEI/ ARB and cannot be overlooked [15, 16] .
Several hypotheses have been put forward explaining the positive and negative aspects of ACEI/ARB administration in COVID-19 patients. Positive effects include ACE2 receptor blockade, disabling viral entry into the heart and lungs, and an overall decrease in inflammation secondary to ACEI/ARB, suggesting the use of ACEI might be protective against respiratory complications. Negative effects include a possible retrograde feedback mechanism, by which . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 5, 2020. . ACE2 receptors are upregulated, which may lead to severe pneumonia increasing risk of severe outcomes and mortality [23] . Individuals with ACE2 polymorphisms have an increased genetic predisposition for an increased risk of SARS-CoV-2 infection and may have harmful effects of ACEI/ARB [24] . This aspect is worth considering and needs to be evaluated in future studies .
To best of our knowledge, this systematic review is a comprehensive exploration and analysis of existing literature in this topic till date. Our review has limitations in its rigor due to the scarce existing data and diverse study types available. The rapidly emerging knowledge base of COVID-19 poses the possibility that few studies (particularly unpublished/under peer review) remain un-captured. However, we have tried our best to mitigate this by allowing broadest search terms and by including many databases and repositories. We have also tried to comprehensively review and analyze the existing data.
Considering the inconsistent clinical studies and conflicting hypothesis, it is essential to evaluate the clinical outcomes in COVID-19 patients on ACEI/ARB in future large studies, particularly randomized controlled trials and additionally evaluate the association of clinical outcomes with ACE2 polymorphisms. Based on this, there are ongoing trials studying the effect of Losartan (an ARB) in patients with COVID-19 in outpatient and inpatient settings (NCT04311177, NCT04312009) [25, 26] .
It is concluded that ACEI and ARB should be continued in COVID-19 patients, albeit while exercising caution until larger clinical studies and RCT confirm their safety. Additionally, the individual patient factors like ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.
. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 5, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 5, 2020. . https://doi.org/10.1101/2020.04.29.20085787 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted May 5, 2020. . https://doi.org/10.1101/2020.04.29.20085787 doi: medRxiv preprint * The severity of COVID-19 was identified during the hospitalization according to the guidelines established by the National Health Commission of the People's Republic of China ***The severity of COVID-19 pneumonia was classified according to the diagnosis and treatment scheme for COVID-19 of Chinese(5thedition). 1 Severe illness was defined as blood oxygen saturation levels of 93% or less, respiratory frequency of 30/min or greater, a partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, lung infiltrates more than 50% within 24 to 48 hours, septic shock, respiratory failure, and/or multiple organ dysfunction or failure. Non severe illness was defined as the absence of the previously described characteristics. ** Mortality rates for patients with hypertension # Among the 78 patients, 40 were classified as having mild disease (COVID-19-M), and 38 were classified as severe condition (COVID-19-S) according to New Coronavirus Pneumonia Prevention and Control Program published by the National Health Commission of China + Other regimens $ Primary endpoint primary endpoint being death or transfer to a critical care unit for organ support within 7-days of symptom onset. @ Before matching; ! After matching . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted May 5, 2020. . https://doi.org/10.1101/2020.04.29.20085787 doi: medRxiv preprint