Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID‐19, inflammation level, severity, and death in patients with COVID‐19: A rapid systematic review and meta‐analysis

Abstract An association among the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin‐receptor blockers (ARBs) with the clinical outcomes of coronavirus disease 2019 (COVID‐19) is unclear. PubMed, EMBASE, MedRxiv, and BioRxiv were searched for relevant studies that assessed the association between application of ACEI/ARB and risk of COVID‐19, inflammation level, severity COVID‐19 infection, and death in patients with COVID‐19. Eleven studies were included with 33 483 patients. ACEI/ARB therapy might be associated with the reduced inflammatory factor (interleukin‐6) and elevated immune cells counts (CD3, CD8). Meta‐analysis showed no significant increase in the risk of COVID‐19 infection (odds ratio [OR]: 0.95, 95%CI: 0.89‐1.05) in patients receiving ACEI/ARB therapy, and ACEI/ARB therapy was associated with a decreased risk of severe COVID‐19 (OR: 0.75, 95%CI: 0.59‐0.96) and mortality (OR: 0.52, 95%CI: 0.35‐0.79). Subgroup analyses showed among the general population, ACEI/ARB therapy was associated with reduced severe COVID‐19 infection (OR: 0.79, 95%CI: 0.60‐1.05) and all‐cause mortality (OR: 0.31, 95%CI: 0.13‐0.75), and COVID‐19 infection (OR: 0.85, 95% CI: 0.66‐1.08) were not increased. Among patients with hypertension, the use of an ACEI/ARB was associated with a lower severity of COVID‐19 (OR: 0.73, 95%CI: 0.51‐1.03) and lower mortality (OR: 0.57, 95%CI: 0.37‐0.87), without evidence of an increased risk of COVID‐19 infection (OR: 1.00). On the basis of the available evidence, ACEI/ARB therapy should be continued in patients who are at risk for, or have COVID‐19, either in general population or hypertension patients. Our results need to be interpreted with caution considering the potential for residual confounders, and more well‐designed studies that control the clinical confounders are necessary to confirm our findings.


| INTRODUCTION
The coronavirus disease 2019  pandemic is becoming one of the most far-reaching public health crises in recorded history. At right time of writing this review, on 29 April 2020, the number of infected persons worldwide has exceeded 3.01 million, with more than 200 000 reported deaths (http://2019ncov.chinacdc.cn/2019-nCoV/global.html). At present, there is no specifically targeted, effective treatment for patients with COVID-19. There is an urgent need, therefore, to determine how to alleviate the severe clinical symptoms and reduce the morbidity and mortality due to this disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shares the same cell entry receptor as SARS-CoV, in which the viruses' spike proteins bind to the host cell surface. Angiotensin converting enzyme 2 (ACE2) receptors, which are an essential regulator of renin-angiotensin-aldosterone system (RAAS) activity. 1,2 The RAAS is a vital regulator of cardiovascular and renal function, including blood pressure, and which plays a vital role in regulating acute lung injury. 3,4 The ACE2 level is significantly reduced in patients following SARS-CoV infection, resulting in RAAS system imbalance, and eventually cause severe acute lung injury. Angiotensin I converting enzyme inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs) are ACE2 receptor antagonists that can reduce the activity of the RAAS system and which have been widely used in the past several decades to treat cardiovascular diseases, such as hypertension and hypertrophic cardiomyopathy. 3 However, some animal experiments and clinical trials have shown that ACEIs potentially result in an increase in ACE2 receptors. 5 Some concern has therefore been expressed that the use of ACEIs/ ARBs might increase the risk of COVID-19 infection after exposure to SARS-CoV-2 and result in a poor prognosis. 6 On 12 April 2020, the European Society of Hypertension COVID-19 Task Force issued the following statement: the current evidence does not support that RAAS inhibitors aggravate the condition of COVID-19 patients. 5 Accumulating evidence revealed that inflammatory cytokine storm and dysfunction of immune system largely contribute to the severe COVID-19, even cause death. 7 The latest evidence shows that peripheral blood interlekin-6 (IL-6) levels, a critical mediator of respiratory failure, shock, and multiorgan dysfunction, were significantly increased in COVID-19 patients who had used a RAAS inhibitor. 8,9 Moreover, CD3 and CD8 cell counts were significantly reduced, suggesting that the level of inflammation in patients treated with ACEIs is relatively low. 8 Several retrospective studies have shown that the use of ACEIs/ARBs prior to COVID-19 infection could reduce the severity of COVID-19 and was associated with a better prognosis, especially in patients with both hypertension and COVID-19. [10][11][12] However, other studies have shown that there is no significant correlation between the use of ACEIs/ARBs and the severity and mortality of patients with COVID-19. 10,13-17 Because the affection of RAAS inhibitors on the clinical prognosis of COVID-19 patients is unclear; in this article, we will review the current evidence and assess the clinical prognosis of COVID-19 patients with or without hypertension treated with ACEs/ARBs.

| Literature search
Two authors (L. X. and L. C-Y.) independently searched the PubMed and Embase databases for published articles and the preprint platforms medRxiv (https://www.medrxiv.org/) and bioRxiv (https:// www.biorxiv.org/) (since many studies are available on these websites prior to publication, which allows for collection of the latest data) without language restrictions. Furthermore, the research references were traced and cross-checked. In the case of any discrepancy, it was resolved by consensus with the third author (H.

| Study selection
Studies were considered eligible for inclusion if they (a) were designed as a randomized controlled trial, case-control study, or cohort study; and (b) assessed the relationship between ACEI/ARB use and the level of inflammation, disease severity, and mortality in patients with COVID-19. If multiple studies used the same population, we selected the most recent publication. Certain publication types (eg, reviews, editorials, letters, conference abstracts, and animal studies) or studies with insufficient data were excluded from this analysis.

| Data extraction and quality assessment
Two authors (L. X. and L. C-Y.) independently extracted the study information and the basic characteristics of the articles using a standardized form, including the first author, year of publication, country, sample size, sex ratio, age, sample size, RAAS type, length of follow-up, adjustments for confounders and adjusted odds ratio (OR) with 95% confidence intervals (CIs). Two authors independently used modified Jadad scores and Newcastle-Ottawa Scale (NOS) scores to evaluate the quality of the randomized controlled trials (RCTs) and observational studies, respectively. A Jadad score >5 and an NOS score >7 were considered high quality scores. 19 Collaboration) software was used for statistical data processing, and the OR and 95% CIs were used to estimate the effect. Heterogeneity among the studies was analyzed using the I 2 test with the following interpretation: low heterogeneity, defined as I 2 < 50%; moderate heterogeneity, defined as I 2 = 50% to 75%; and high heterogeneity, defined as I 2 > 75%. 21 The meta-analysis was performed using the random effects model when the heterogeneity was more than 25%, otherwise, the fixed effects model was applied. If there were ACEI and ARB subgroups in the study, the combined OR and the 95% CIs were pooled using the RevMan5.3 software. If the study did not report the OR directly, count data for outcomes were used to generate unadjusted ORs and 95% CIs. We also excluded reports with unadjusted ORs in the sensitivity analysis to assess the robustness of our results. A funnel plot was used to test for the presence of publication bias, and P value <.05 was considered statistically significant.

| Inflammation level
There were four articles that evaluated the relationship between ACEI/ARB and level of inflammation in patients with COVID- 19,8,13,17,22 but since the data were not reported in the same unit across studies, they were not pooled; therefore, we conducted a systematic review instead (

| Risk of severe COVID-19
Eight studies assessed the relationship between the use of ACEI/ARB therapy and severe COVID-19, 8,11,[13][14][15][16][17]22 with two reports in the general population, 11,15 and six reports in patients with hypertension. 8,13,14,16,17,22 Compared with the non-ACEI/ARB group, the risk of  Lot of studies have shown that RAAS system is an important target for the treatment of acute lung injury. 31 For example, a retrospective analysis showed that ACEIs and AT1R inhibitors can also reduce the incidence of radiation pneumonitis. 32 In patients with severe COVID-19, the levels of many pro-inflammatory factors (eg, IL-6, IL-2, and tumor necrosis factor-alpha) were significantly elevated, and levels of regulatory T cells decreased significantly. 7 A nonrandomized controlled clinical trial showed that the IL-6 inhibitor tocilizumab could significantly reduce oxygen consumption, imaging abnormalities, and clinical prognosis in patients with COVID-19. 33 Moreover, in patients receiving ACEI/ARB therapy, IL-6 and CRP levels were significantly decreased, and the level of CD3 andCD8 increased significantly. 8 Overall, this evidence suggests that ACEI/ARB therapy might reduce lung injury and infection severity by downregulating inflammation levels in patients with COVID-19.

| Publication bias
Although we found use of ACEI/ARB was associated with the  we were unable to perform subgroup analyses of ACEIs and ARBs.
Fourth, some characteristic clinical values (eg, drug variables) were missing. For example, the specific details of RAAS inhibitors were lacking in all studies, which might have impact on our results. Fifth, considering that all of the included studies were retrospective, the introduction of recall bias was inevitable and may affect the reliability of the conclusions. Sixth, although we did not register the protocol of this meta-analysis in the PROSPERO database, no relevant protocols of this topic were found in this database at the writing of this review.

| CONCLUSIONS
On the basis of the available evidence, we found that the use of ACEI/ ARB therapy was not associated with an increased risk of COVID-19 and that there was a decreased trend between ACEI/ARB use and