Angiotensin-Converting Enzyme inhibitors (ACE inhibitors) and Angiotensin II Receptor Blockers (ARBs) role in SARS-CoV-2 infection: A Rapid Systematic Review CURRENT STATUS: POSTED

No medications specific treatments are known to be effective for COVID-19 until now. Several drug therapies are being used to optimize supportive care to relieve symptoms. Some observational and essentially theoretical studies have shared opposite opinions regarding the use of ACE inhibitors and ARBs in SARS-CoV-2 infected patients. Therefore, the aim of this review is to evaluate the relationship between ACE inhibitors and ARBs use and clinical effects in COVID-19 patients to guide clinicians for their medical early decision. Electronic searches were conducted on Embase, Medline via PubMed and ClinicalTrials.gov. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was followed and adapted the research as a rapid review. Due to the emergency of the COVID-19 pandemic, any research in English, Portuguese or Spanish that discuss the mechanism of action, in vitro studies and those that draw conclusions based on observational or experimental studies were included. No studies were excluded based on the participant’s clinical or demographical characteristics. The risk of bias was assessed by one reviewer and checked by a second reviewer, using the Joanna Briggs Institute Checklist for Case Series. Any other mechanistic, theoretical or in vitro studies were evaluated as high risk of bias for clinical. Out of 64 studies retrieved, 17 were included in the review. Three studies suggest that both medications may increase the risk of worsening COVID-19, while three suggest they could be beneficial. Currently, there are seven ongoing trials on ARBs and ACE inhibitors. The available evidence does not allow us to draw definite conclusions on either harm or benefit of these medications in the presence of COVID-19. Discontinuing the therapy may be hasty and more robust evidence-based research is needed. High-throughput sequencing from lower respiratory tract samples indicated a novel coronavirus, named 2019 novel coronavirus (2019-nCoV) or, more recently, SARS-CoV-2, which had previously not been detected in humans or animals. Coronavirus Disease 2019 (COVID-19) common symptoms include fever, fatigue, and dry cough, followed by anorexia, myalgia and dyspnea. 10,12–14 Chest imaging frequently shows bilateral infiltration. 15 A case study with 1,099 COVID-19 patients in China found that the most common abnormalities found on computerized tomography (CT) scans were ground-glass opacity and bilateral patchy shadowing. 13


Introduction
Coronavirus infections are generally mild, however, the epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) 1-3 and Middle East respiratory syndrome coronavirus (MERS-CoV) 4,5 have caused more than 10,000 cumulative cases in the past two decades. 6 Both prominent coronaviruses, 2002 SARS-CoV and 2012 MERS-CoV, have markedly affected humans, causing 8,422 and 1,600 infections, as well as 916 and 574 deaths, respectively. [7][8][9] These viruses are categorized within the same genus of the subfamily Orthocoronavirinae within the family Coronaviridae. 10 In December 2019, a group of patients with pneumonia of unknown cause was identified in Wuhan, in the Hubei province, China. 10 High-throughput sequencing from lower respiratory tract samples indicated a novel coronavirus, named 2019 novel coronavirus (2019-nCoV) or, more recently, SARS-CoV-2, which had previously not been detected in humans or animals. 6,[9][10][11] Coronavirus Disease 2019 (COVID-19) common symptoms include fever, fatigue, and dry cough, followed by anorexia, myalgia and dyspnea. 10,[12][13][14] Chest imaging frequently shows bilateral infiltration. 15 A case study with 1,099 COVID-19 patients in China found that the most common abnormalities found on computerized tomography (CT) scans were ground-glass opacity and bilateral patchy shadowing. 13 As of March 30 th , The World Health Organization (WHO) had been notified of 693,282 confirmed cases, from which 58,469 were notified in the last 24 hours. Furthermore, until the same date 33 106 deaths were registered, and 3,215 occurred in the last 24 hours. Among these confirmed new cases, 987 (23 deaths) were in the Western Pacific Region, 31,784 (2,535 deaths) in Europe, 375 (19 deaths) in South-East Asia Region, 3,552 (145 deaths) in Eastern Mediterranean Region, 21,289 (484 deaths) in the Americas, and 482 (nine deaths) in Africa. According to WHO, these situations are classified as very high risk at a global level. 16 16 Case series and other observational data regarding aggravation and risk of Acute Respiratory Distress Syndrome (ARDS) and death related to SARS-CoV-2 infection have been published. 6,9,23,24,[12][13][14][15][19][20][21][22] Some of these studies investigated factors specifically related to Intensive Care Unit (ICU) admission. 6,9,12 According to recent publications, some clinical characteristics and comorbidities as age, presence of diabetes, hypertension, cardiovascular disease, elevated Sequential Organ Failure Assessment (SOFA) score, and serum D-dimer, lead to an increased risk of aggravation and death. 15,19 Therefore, there is raising concern regarding COVID-19 patients with such comorbidities. Patients with diabetes have higher expression of Angiotensin-Converting Enzyme 2 (ACE-2) receptor as well as hypertensive patients treated with ACE inhibitors or Angiotensin II Receptor Blockers (ARBs). 25 According to a Chinese case series, the plasma levels of Angiotensin II in 2019-nCoV infected patients were significantly higher than those of healthy individuals. 26 In addition, the level of angiotensin II in patients with nCoV-2019 was strongly associated with viral load and lung injury, suggesting that the imbalance of the renin-angiotensin system (RAS) in patients is related to 2019-nCoV. The mechanism of infection by SARS-CoV-2 appears to be related to a glycoprotein, called Spike, which is responsible for the entry of viruses into host cells. The receptor binding domain (RBD) in the Spike molecule directly binds the receptors on the surface of host cells. In the case of SARS-CoV and bat-type-CoV, the receptor is ACE-2. As a result, it has been speculated that ACE-2 plays an important role in the pathogenesis of SARS-CoV-2. 27 Some observational and essentially theoretical studies have shared opposite opinions on this issue, mainly regarding the use of ACE inhibitors and ARBs. 25-28 Some of them postulate that the increase in ACE-2 receptors caused by ACE inhibitors and ARBs could increase the viral load. 25,27 On the other hand, some authors believe that due to the increase in angiotensin II in 2019-nCoV infected subjects and the augmented lung permeability, the use of ACE inhibitors and ARBs could be an adjuvant for recovering of pneumonia. 26,28 Our aim is to evaluate the relationship between ACE inhibitors and ARBs use and clinical effects in nCoV-2019 infected patients, by means of a systematic rapid review, which could guide clinicians for their medical early decision, since clear and reliable evidence is not yet available.

Study design
We conducted a systematic rapid review to evaluate the risks and benefits of using ACE inhibitors and ARBs in SARS-CoV-2 infected patients. The current analysis was a response to the need for scientific evidence to support the compilation of a COVID-19 guideline for the German Hospital Oswaldo Cruz in São Paulo, Brazil, one of the Brazilian Excellence hospitals and, consequently, one of the hospitals with many confirmed cases of COVID-19.
We did not register any protocol at PROSPERO database due to the urgency of this issue and to the warning of PROSPERO regarding a delay in reviews for protocol approval. However, the research question that guides this study was formulated before conducting any review. We also followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement 29 and adapted the research as a rapid review according to Tricco et al., 2017. 30

Eligibility Criteria
Due to the emergency of the COVID-19 pandemic and the low certainty of evidence, we considered eligible any research that discuss the mechanism of action, in vitro studies and those that draw conclusions based on observational or experimental studies regarding the use of ACE inhibitors or ARBs in COVID-19 patients. We considered studies published in English, Portuguese or Spanish.
In vitro studies, pharmacodynamic studies, and state-of-the-art reviews about COVID-19, without necessarily being linked to the disclosure of relevant clinical information were excluded. No studies were excluded based on the participant's clinical or demographical characteristics.
Data selection, extraction and methodological assessment quality were performed by one reviewer and checked by a second reviewer. Any disagreement was solved by consensus.

Research question
As there is a lack of evidence on comparative effectiveness, it was not suitable to format our question following PICO acronym. In this way, and to run a sensitive search, we adopted only "P" and "I". Thus, our aim is to approach all the evidence of ACE inhibitors and ARBs use in patients with COVID-19, independently if the use was for primary disease (i.e. cardiovascular disease, hypertension, etc.) or as a treatment for COVID-19.

Source of evidence and Search Strategy
Medline (via PubMed) and Embase were searched on March 20 th and ClinicalTrials.gov on March 23 rd .
Posteriorly, a search updating was conducted on March 31 st . No validated or unvalidated filters were applied. We combined MeSH, entry terms, and word variations for "ACE inhibitors", "ARBs", and "COVID-19/SARS-CoV-2", by means of the appropriate Boolean operator. In the clinical trials protocol registry database (ClinicalTrials.gov) we only selected evidence directly related to ACE inhibitors and ARBs as a therapeutic option for COVID-19. Any other health technology different from those were excluded, unless it was described as a comparator. The fully reproducible search strategies are described in Table 1.

Risk of bias Assessment
We planned to evaluate any epidemiological study and, since we did not insert any filter that could restrict data gathering, we could accomplish that. However, due to the scarcity of data in this particular period we could only find observational non-comparative data. Therefore, for case series we applied the Joanna Briggs Institute Checklist for Case Series. 31 Nevertheless, following hierarchy of evidence, we consider case series a very weak and biased source of evidence. Any other mechanistic, theoretical or in vitro studies were evaluated as high risk of bias for clinical conclusions.

Ethics Compliance
This study did not recruit patients or involve any personal data that required consent or Ethic's Board approval.

Search results
Through search strategies on Medline (via PubMed) and Embase, 58 references were retrieved.
Additionally, in a validation search in Google Scholar, 32,33 two references were inserted through manual search. 25,34 Seven clinical trial records specifically related to ACE inhibitors or ARBs were found on ClinicalTrials.gov. After removing duplicates, 64 references were evaluated by their titles and abstracts. Of these, 42 references were excluded, and 22 were evaluated by full text reading.
Five reports were excluded after complete reading: four because they were opinion reports that mentioned therapeutic options in general, not specifying discussions about mechanisms of action or addressing any outcomes data or other results. 35-38 One case report was also excluded 39 , because it presented a specific result for an end-stage renal disease patient (Table 2). Thus, 17 studies were included in the current review: two case series, 26,40 seven opinion/commentary reports, 25,28,34, [41][42][43][44] one in vitro study, 27 and seven ClinicalTrials.gov registries. The ClinicalTrials.gov results will be discussed in detail below. The complete screening procedure is exhibited in Figure 1.

Individual study results
Study characteristics, such as study design, population, brief results and methodological quality are exhibited in Table 3. Due to the essential descriptive characteristics of the included studies, results are presented in a narrative form. Diaz, 2020 postulates that ACE-2 receptors serve as binding sites for SARS-CoV-2 virions in the lungs. Therefore, patients taking ACE inhibitors and ARBs may be at increased risk for severe disease outcomes due to SARS-CoV-2 infections. The author exemplifies his point of view based on Chinese studies, which showed that patients with nCoV-2019 who had more severe conditions also had hypertension, cardiovascular diseases, diabetes, among other diseases, for which ACE inhibitors and ARBs are frequently prescribed. 44 A commentary discusses the idea of considering angiotensin receptor 1 (AT1R) blockers as a provisional treatment for SARS-CoV-2 infections and proposes a research direction based on modeling data from patient clinical records to assess its feasibility. The author postulates that the use of ARBs causes an increase in the concentration of circulating ACE based on examples in mice and humans. In this sense, the author adds that, being aware that ACE is the main link between SARS-CoV-2 and the cell, the suggestion to treat patients with SARS with AT1R antagonists, to increase their expression of ACE-2, seems counterintuitive. 28 Danser et al., 2020 presented a narrative review that indicates that there is there is no evidence to abandon renin-angiotensin system blockers. 42 They discussed that, as previously shown in previous studies, ACE-2 is the receptor responsible for SARS coronavirus entry and that binding to the ACE-2 receptor requires the surface unit of a viral spike protein. Additionally, it was discussed that because of this incipient assumption, much confusion started, with controversial opinions and great fear about the influence of cardiovascular comorbidities and their respective treatments on the pathogenicity of COVID-19. 42 Sparks et al., 2020 expose the mechanistic and biochemical perspectives on the interaction between SARS-CoV-2 and ACE-2. The authors analyze the molecular aspects that may explain the benefits and harms of using ACE inhibitors and ARBs in the treatment of patients with cardiovascular diseases and COVID-19. Because of the lack of adjustment by confounders, the authors conclude that a clear relationship between hypertension and increased COVID-19 morbidity is premature. The authors recommend that those patients who use antihypertensive drugs for cardiovascular diseases do not interrupt the use, as there is still no evidence to support it. 41 One viewpoint paper discusses that, despite the increased mortality and morbity in COVID-19 hypertensive patients, no study have checked this assumption when controlling for confounding. 43 Thus, it remains unclear if this association is related to the pathogenesis of hypertension or another associated comorbidity or treatment. The authors postulate that there has been a growing concern that this association with hypertension is confounded by ACEI inhibitors and ARBs use. The link with these medications is because of the known association between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2. 43 In a Chinese case series, respiratory samples from patients, including throat smears and bronchoalveolar fluid (BALF), were collected and real-time PCR was used to confirm the 2019-nCoV infection. The authors assessed potential biomarkers of disease severity. They found an elevated level of serum angiotensin II in patients with nCoV 2019 and this was strongly associated with viral load and lung injury, suggesting that the imbalance of the renin-angiotensin system (RAS) in patients was caused by 2019-nCoV and that enzyme-inhibiting drugs such as ACE inhibitors and ARBs, that balance RAS, can be used to treat patients infected with 2019-nCoV. 26 Fang et al., 2020 explain that patients with diabetes have a higher expression of ACE-2 as well as hypertensive patients treated with ACE inhibitors or ARBs. According to the authors, as the virus uses ACE-2 to replicate, having the aforementioned comorbidities and using ACE inhibitors and ARBs may contribute to the pathogenicity of SARS-CoV2. 25 Guo et al., 2020 conducted a case series of 187 patients with COVID-19, 77% of whom were discharged and another 23% died. 40 These patients were evaluated at the Seventh Hospital of Wuhan City, China and 63 (35.3%) had some cardiovascular disease such as hypertension, coronary heart disease, cardiomyopathy, and 52 (27.8%) had myocardial damage indicated by high levels of troponin T (TnT). This study showed that patients with high levels of TnT were elderly, had more comorbidities, higher proportion of SARS, higher mortality, higher white blood cell count, neutrophilia, high level of D-dimer and higher concentration of inflammatory markers than individuals with normal TnT level.
Despite reporting that there is a greater proportion of patients using ACE inhibitors and ARBs among those with high TnT, the authors states that there was no difference in mortality between these groups. 40 Vaduganathan et al., 2020 is a narrative review that discusses potential benefits and harms of Renin-Angiotensin-Aldosterone System Inhibitors (RAAS) in Patients with Covid-19. 34 These paper gathers in vitro, animal models, other respiratory viruses and recent COVID-19 research data. The authors highlight that the data in humans are too limited to support or refute the hypotheses of harm (raise of viral load) or benefit (downregulation of angiotensin II) of the RAAS. They discuss the lack of clinical tests of RAAS blockers on ACE-2 levels and activity in humans, stating that ACE-2 may be beneficial rather than harmful in patients with lung injury patients, not only COVID-patients. Finally, they discuss that withdrawal of RAAS inhibitors may be harmful in certain high-risk patients with known or suspected Covid-19. 34

Methodological quality
The majority of the studies were comments, opinions and in vitro studies. Regarding the usefulness of data in the context of clinical decision, these reports should be interpreted with caution. Furthermore, only two study in humans were found. 26,40 These case series, according to JBI Critical Appraisal Tool for case series, were classified as having moderate 26 and good 40 methodological quality, respectively.
We emphasize that this classification does not put the evidence from case series close to that of comparative observational or randomized studies and that the confidence in this evidence is low (Table 4).

Clinical trials protocols
Seven records of clinical trials involving ACE inhibitors, ARBs and recombinant ACE-2 therapy were found in the ClinicalTrials.gov database (

Discussion
After the publication of Fang et al., 2020, 25 in which the authors discussed the potential harms in the use of ACE inhibitors, ARBs and some anti-inflammatory drugs, as ibuprofen in COVID-19 patients, much has been said about the care for the diabetic, hypertensive and cardiovascular population, as there is a potential risk in the use of these drugs for these comorbidities.
The primary WHO recommendation was to avoid the use of ibuprofen was based on concerns raised by French officials, who cited the above-mentioned study. Currently, some institutions like Health Canada, European Medicines Agency and The UK government published that there is no scientific evidence establishing a link between ibuprofen and worsening of COVID-19. Therefore, they recommend that subjects who currently use any NSAIDs to treat their chronic diseases should not stop their treatment and seek for specialized information. [46][47][48] These events drew our attention to the need to assess the role of ACE inhibitors and ARBs in COVID-19 pathogenesis.
Fang et al., 2020 point out that, in different reports, patients who presented with severe forms of disease, had comorbidities frequently treated with ACE inhibitors or ARBs. 25 However, none of them assessed the use of those medications in their cohorts or verified their association with disease severity or other outcomes. 13,49,50 Additionally, their assumption that those medications pose significant harm to COVID-19 pneumonia patients is based on the hypothesis of an upregulation of ACE-2, to which SARS-CoV-2 binds. However, the response of an individual does not depend solely on the exposure to ACE inhibitors or ARBs 25 .
The available evidence is conflicting, given the weak methodological quality of the scientific evidence and the heterogeneous assumptions presented by the studies. Among evaluated studies, three 25,27,44 highlight the fact that SARS-CoV-2 binds to ACE-2 receptors, increases its capacity for dissemination and, consequently, increases its pathogenicity. Thus, they emphasized that patients with cardiovascular comorbidities and/or using ACE inhibitors and ARBs may have a higher risk of worsening with COVID-19.
On the other hand, some studies 26,28,34 suggest that infected patients present an increase in the concentration of angiotensin II, increasing pulmonary permeability and, consequently, the pathogenicity of COVID-19. These authors suggest that ACE inhibitors and ARBs may be therapeutic options for SARS-CoV2, as they lead to decreased angiotensin II concentration and reduced pulmonary permeability.
Indeed, there are some research pointing that there is no evidence to interrupt or withhold treatment with ACE inhibitors or ARBs in COVID-19 patients who also present cardiovascular comorbidities. 34, [41][42][43] These studies jointly analyze the pathways that suggest benefits and harms of ACE inhibitors and ARBs and conclude that no strong adjustments by confounders have been made, and that comorbidities themselves or other factors strongly associated with the COVID-19 condition, such as age, need to be better assessed.
Two studies showed results from tests on humans, 26,40 both are case series one with 12 26 and the other with 187 40 Chinese patients with COVID-19. Liu et al., 2020 found an increased level of angiotensin II in those patients, which was associated with viral load and lung injury. According to the authors, considering this RAS imbalance, those patients, potentially, could benefit from drugs that regulate this system, like ACE inhibitors and ARBs. 26 Guo et al., 2020 found that patients with higher levels of troponin T presented more comorbidities, were aged, were using more frequently ACE inhibitors and ARBs and showed an increase in biochemical inflammatory biomarkers. However, there was no difference in mortality between those treated and not treated with ACE inhibitors or ARBs. 40 . Therefore, it is possible to infer that there are still some doubts about how much the severity of COVID-19 may be related to the use of ACE inhibitors or ARB or to the very complications of the age group or comorbidities. Additionally, the American, European and Brazilian cardiology societies, 51-53 the latter endorsed by the Brazilian Ministry of Health, 54 published statements in which they highlighted the weak evidence available so far, and that any decision of avoiding ACE inhibitors and ARBs therapies is hasty. These Medical Societies also recommended that best care practices being observed to ensure the effectiveness of treatments, until more robust data can prove the true effect of SARS-CoV-2 on the ACE-2 receptor mechanism, as well as the role of ACE inhibitors and ARBs in pathogenesis of SARS-CoV-2.
Much of the available evidence on the use of ACE inhibitors and ARBs still lie in theoretical grounds, based on molecular assays, animal studies and the previous experience with other coronaviruses infections.
To date, there are no studies with ARBs and ACE inhibitors in patients with COVID-19 in terms of comparative efficacy, comparing both active treatments, one active treatment vs. placebo or supportive measures, or no treatment. Furthermore, answers to these medicines' effectiveness is not about to be published. According to our search in ClinicalTrials.gov, there are only two registered RCT protocols with losartan versus placebo, both with preliminary results planned to 2021 (NCT04312009 and NCT04311177). There are also retrospective case-control studies registered that aims to evaluate outcomes of hypertensive patients with confirmed diagnosis of COVID-19 on ACE inhibitors or ARBs versus control. Their estimated completion date is March/April, 2020 (NCT04318301 e NCT04318418).
More recently, a new RCT have been registered, and it aims to compare the efficacy of different medication (lopinavir/ ritonavir or hydroxychloroquine or losartan compared to placebo on disease severity. This study is expected to be completed in April, 2021 (NCT04328012).
Our review has some important limitations, most of them related to the weak quality of the evidence found. The whole evidence is observational and most of it purely theoretical and descriptive, and no study has ever evaluated the ACE inhibitors and ARBs effectiveness in the context of clinical research or comparative randomized or non-randomized studies.
We conducted a systematic rapid review, as proposed by Tricco et al., 2017, 30 due to the urgency of response. We had to save time and, therefore, instead of conducting the steps by independent reviewers, one author performed the steps and a second reviewer checked the data and the assessments. Nevertheless, we believe that the most relevant evidence published had been included in this research and that the omission of some systematic steps has not invalidated the results. We did not include evidence published in Chinese due to the language barrier, but we checked their abstracts in English and found that only one study which would be eligible. 26 Finally, results should be interpreted cautiously, taking into account the presence of bias associated with the outcomes.
To our knowledge, this is the first systematic rapid review to compile the available evidence on the Authorship HAOJ is the main author and paper organizer. He was the main reviewer and worked with evidence screening, data analysis and paper writing and formatting. This author worked in the tables content and in the methodological quality judgement. JYM was the second reviewer responsible for checking and updating all the evidence, paper writing and formatting, including the tables and figure. PP, LPM, FM and GVB contributed to the study concept and design, participated in the final review of the manuscript. AAJ is the Hospital's Research Manager and the responsible for planning the study and research question. He also supervised the whole review process.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures
The authors have no conflicts to declare.

Compliance with Ethics guidelines
This study did not recruit patients or involve any personal data that required consent or Ethic's Board approval.

Data Availability
All the results and research methods are available in this publication. There is no additional scientific data to share.

References 1
Ksiazek   Case series reporting a patient with end-stage renal disease in whom losartan was withheld due to specific aggravation. No additional information is given. In vitro NA When performing the molecular simulation, the a that is almost fully superimposable with that of SA in a loop, which means the two cellular link struct Amino acid residues at the RBD/ ACE-2 binding in affinity. As a result, nCoV2019 has a stronger link compared with SARS-CoV.
The authors draw attention to the low expression pathogenicity of nCoV2019 in this organ may be d report which ones. They also draw attention to th kidneys, meaning SARS-CoV-2 can be present in t fluids transmission cannot be ruled out. This study aimed to evaluate the association of un outcomes in patients with COVID-19.
The authors discuss that, although there is a high patients with a high level of TnT relative to those mortality among groups. The authors did not prov is biased by the small sample. Patel et al., 2020 Viewpoint NA The study analyzes the mechanistic issues related out the lack of consistent evidence regarding the patients.
According to the authors, there is concern that th expression of ACE-2, resulting in increased patien propagation. On the other hand, animal modelling lung injury that was improved by treatment with A injury by decreasing ACE-2 that can be reversed b Finally, the authors postulate that despite the lac the use and cessation of ACE inhibitors and ARBs comorbidities. The authors highlight that the Euro stop those medicines and that physicians and pat anti-hypertensive therapy because there is no clin treatment with ACE inhibitors or ARBs should be d Sparks at al., 2020 Perspective NA The authors mentioned published data that suppo clear relationship between cardiovascular disease fact that none of the reports have adjusted this co the hypertension and mortality association to und They postulate that the complex relationship betw binding to ACE-2, RAS components, and viral path is not fully understood. Thus, they emphasize tha inhibitors and ARBs harms or benefits.
The authors also suggested that stopping ACE inh with heart failure, kidney disease, or hypertension will disrupt clinical care, resulting in utilization, thus disrupting attempts at social dista Vaduganathan et al., 2020 Opinion/narrative review NA The authors discuss that there is some concern a report an increased risk of COVID-19 aggravation comorbidities, such as hypertension. However, ba state that advanced age emerges as the most im However, no study has yet carried out analyses c allow a risk to be established.
The authors point out that only 25 to 30% of treat and that studies designed to assess the influence Because ACE inhibitors and ARBs have different e ACE-2, the effects of these agents on ACE-2 levels been highlighted, based on animal and human mo been no increase in angiotensin (1-7) production, activity was not different between individuals rec controls.
The authors discuss that there is insufficient data humans and that there is still no evidence of the It is argued that there is a potential increase in an is related to lung damage. Based on in vitro studi continued viral infection, there is a reduction in A 2 activity in the lungs may facilitate the initial neu using ACE inbitors and ARBs.
Finally, the authors conclude that stopping chroni and not recommended. They also report that the