key: cord-0896526-mvcy2gl5
authors: Naveed, Hiba; Elshafeey, Abdallah; Al‐Ali, Dana; Janjua, Emmad; Nauman, Areej; Kawas, Hussam; Kaul, Ridhima; Aldien, Arwa Saed; Elshazly, Mohamed B.; Zakaria, Dalia
title: The Interplay between the Immune System, the Renin Angiotensin Aldosterone System (RAAS) and RAAS Inhibitors May Modulate the Outcome of COVID‐19: A Systematic Review
date: 2021-02-26
journal: J Clin Pharmacol
DOI: 10.1002/jcph.1852
sha: 2fd56bdeead5ad85c6ba4e9b524b9666e49ff179
doc_id: 896526
cord_uid: mvcy2gl5

Since the discovery of the severe acute respiratory syndrome coronarvirus 2 (SARS‐CoV‐2) numerous research was undertaken to delineate the various effects of the virus which manifests in many ways all over the body. The association between the SARS‐CoV‐2 invasion mechanism and the RAAS receptors, created many debates about the possible consequences of using RAAS modulating drugs including the ACE inhibitors (ACEi) and the Angiotensin II Receptor Blockers (ARBs) during the pandemic. Many clinical studies were conducted to assess the outcomes of COVID‐19 in patients who use ACEi/ARBs following the arguments claiming to discontinue these drugs as a precautionary measure. While several studies mainly analyzed the outcomes of the disease, this review aimed at comparing specific blood markers in both groups of COVID‐19 patients in order to gain a better insight into the interaction of ACEi/ARBs with the different body functions during the infection. Several databases were searched using a combination of keywords followed by screening and data extraction. Only 28 studies met our inclusion criteria, the majority of which showed no significant difference between the inflammation markers of COVID‐19 patients who used or did not use ACEi/ARBs. Interestingly, six studies reported lower inflammatory markers in COVID‐19 patients who used ACEi/ARBs and ten studies reported better outcomes among the same group. We therefore conclude that the use of ACEi/ARBs may not lead to worse prognosis of COVID‐19 and may even play a protective role against the hyperinflammatory response associated with COVID‐19. This article is protected by copyright. All rights reserved

The first cases of a novel coronavirus causing a pneumonia like infection surfaced in December 2019 in Wuhan, China 1 . Now almost a year later, the world is still suffering from the effects of this virus. The virus, later named severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), is the implicated pathogen in Coronavirus Disease 2019 . To our present knowledge, there are three known coronaviruses capable of replicating in the lower respiratory tract causing pulmonary disease that can manifest in many ways and may be fatal in many cases. 1 They are called the Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronarvirus (SARS-CoV), and SARS-CoV-2, which is responsible for the current pandemic.

Early research showed a similar mechanism to that of SARS-CoV but with more aggressive inflammatory responses damaging the airways as well as other organ systems. The sister viruses share about 79% of the same genome sequence. 2 The virus SARS-CoV-2, said to have zoonotic origins, has since dispersed quickly across the world and by the twenty-fourth of March 2020, had infected over 381,000 people and taken the lives of 16,000. By 23 rd January 2021, COVID-19 cases had gone up to more than 98 million worldwide with more than 2.1 million deaths. 3 The scale of this pandemic calls for relevant research urgently, as professionals continue to develop efficient vaccines and communities attempt to maintain the proper protocols.

Lam et al. 27 included patients who used ACEi/ARBs before admission. They conducted a separate analysis to assess the outcome of patients who continued or discontinued taking the medications during hospitalization. However, the blood marker results were not available for this type of analysis. Similarly, Chaudhri et al. 48 compared patients who used ACEi/ARBs before hospitalization, regardless whether they continued or discontinued the medications during hospitalization with those who did not use ACEi/ARBs before hospitalization (part I). Then they compared the blood markers and outcomes of patients who continued ACEi/ARBs after admission with those who discontinued (part II). Some studies did not specify whether ACEi/ARBs were used before or after hospitalization or both. The total number of COVID-19 patients in all of the studies was 7574 patients out of which 2723 were identified in each study as the ACEi/ARBs group. The ages of the patients were expressed as ranges or as mean values. The reported age ranges/means ranged from 32 to 86 and from 48 to 86.9 years in the ACEi/ARBs and control groups respectively. Moreover, Table 1 summarizes the reported underlying comorbidities and the p-values reported by each study to determine any significant differences between the two groups of COVID-19 patients who used or did not use ACEi/ARBs. Only two studies reported significantly higher proportions of the control patients with underlying chronic kidney disease (CKD, p = 0.001) 27 or dementia (p = 0.003) 41 . However, both of these studies as well as 15 other studies reported that the ACEi/ARBs groups had significantly higher proportions of patients with different comorbidities. The underlying comorbidities are summarized at the end of the results section in relation to any significantly different blood marker levels/outcomes between the two groups. No significantly different underlying comorbidities were reported in 11 studies. [32] [33] [34] [35] 37, [42] [43] [44] [45] [46] [47] 51 This article is protected by copyright. All rights reserved. 13 Table 2 summarizes the different treatments and interventions used for the two patient populations in the different studies. It also summarizes the blood test results for the various physiological markers being looked at in this review. This included inflammation markers such as IL-6, CRP, PCT, ferritin, D-dimer, cardiac markers such as BNP/NT-proBNP, troponin, CK-MB liver markers such as ALT, AST, bilirubin, renal markers such as creatinine and tissue damage markers like LDH. Table 3 shows the normal values for the different blood marker for reference. 52 -54 The outcomes of each family of blood markers in COVID-19 patients who used or did not use ACEi/ARBs in the included studies are detailed below.

Out of the 28 studies that reported the levels of blood markers, 22 studies showed no by Chaudhri et al. 48 , the CRP level was lower (p=0.03) in the ACEi/ARBs group, as compared with the This article is protected by copyright. All rights reserved. 14 control group. CRP was higher (p=0.02) in the ACEi/ARBs group as compared with the control group in part I. However, an inflammatory score was created for each patient in both parts of the study by dividing the peak value of each inflammation marker by the admission value to produce what is called a fold change (FC) score. Quartiles were calculated and scored for the peak and FC values of each inflammation marker and the sum of these scores was calculated across the different inflammation markers. No significant differences were observed in the FC scores between the ACEi/ARBs and the control groups in either parts of the study.

Only three out of the 18 studies that reported the D-dimer values showed significantly different levels between the two groups. The D-dimer was found to be higher (p = 0.002) in the ACEi/ARBs group compared with the control by Selçuk et al. 31 . Lam et al. 27 

Fifteen out of 28 included studies reported the results of at least one cardiac blood marker in the ACEi/ARBs and control groups. Thirteen of such studies showed no significant difference between the two groups. Huang et al. 26 reported that both troponin and NT-proBNP levels were lower (p = 0.03, 0.04 respectively) in the ACEi/ARBs group as compared to the control group.

Similarly, lower troponin (p = 0.005) and BNP (p = 0.01) levels were detected by Lam et al. 27 , in the ACEi/ARBs group as compared to the control group. This article is protected by copyright. All rights reserved.

Nineteen studies reported the laboratory results of at least one blood liver marker in the ACEi/ARBs and the control groups. None of these studies reported any significant difference between the levels of bilirubin, ALT or AST between the ACEi/ARBs and the control groups.

Creatinine levels were reported in 22 studies out of which 18 studies did not report any significant difference between the ACEi/ARBs and the control groups. López-Otero et al. 29 , Lim et al. 49 , and Soleimani et al. 50 found that the ACEi/ARBs group had higher creatinine (p = 0.019, 0.01, 0.037 respectively) levels than the control group. Conversely, Wang et al., found that the control group had higher level of creatinine (p=0.047) as compared to the ACEi/ARBs group.

In 16 out of the 19 studies that reported the LDH blood test results, no significant difference was observed in the LDH levels between the ACEi/ARBs and the control groups. Rossi et al. 44 found that the ACEi/ARBs had a higher level of LDH in the ACEi/ARBs group (p=0.009). Meng et al. 30 and Chaudhri et al. 48 (part II) reported lower LDH in the ACEi/ARBs group (p < 0.001, p=0.04).

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The outcome of COVID-19 was assessed in most of the studies based on the mortality or the disease severity expressed as percentages of patients in each category. Out of the 26 studies that reported the outcome, 18 studies reported no significant difference in the outcome of the disease between the ACEi/ARBs and the control group. Selçuk et al. 31 In many studies, multivariate regression analysis was conducted to adjust for cofounding only to assess certain clinical outcomes. These outcomes included mortality, length of hospitalization, admission to ICU or need of mechanical ventilation. These data were reported in the additional information part of table 2 if available. However, most of the studies did not match the blood marker data to eliminate confounding. Therefore, comorbidities were taken into account to discuss the effect of using RAAS inhibitors on the levels of the different blood markers using the unmatched data. For all studies, the unmatched data were reported in table 2 for consistency while the matched data were summarized whenever available in the conclusion part of the table.

Furthermore, the conclusions made by the authors of each study have been summarized in table 2.

The blood marker and outcome results are summarized in Figure 2 . In general, the use of RAAS inhibitors did not increase the levels of inflammatory, cardiac or liver markers in any of the studies. CRP was higher in the ACEi/ARBs group in part I of the study conducted by Chaudhri et al 48 , however it is not shown in Figure 2 as their calculated total inflammatory scores showed no significant difference between the two groups. Additionally, significantly higher proportions of the ACEi/ARBs group in this part of study had HTN, CAD, CKD and COPD. 48 This article is protected by copyright. All rights reserved.

This systematic review included 28 articles that reported the demographic and clinical data of 7628 COVID-19 patients who either used or did not use RAAS inhibitors. There is an accumulating evidence suggests that mortality and the severe outcomes of COVID-19 are associated with elevated levels of inflammatory mediators. This hyperinflammatory results from a dysregulated host innate immune response leading to what is called the cytokine storm. 55-57 For this reason, it was essential to compare the level of some blood inflammation markers in the ACEi/ARBs and the control groups as an important indicator of prognosis.

Previous studies have shown inflammatory markers such as CRP, IL-6, and ferritin to be significantly elevated in COVID-19 patients. 58 Elevated CRP levels were strongly linked to poor prognosis of COVID-19 and was reported to be a tool to predict the outcome of the diseases. 59 One study found that ferritin levels are related to the severity of COVID-19 which is directly related to the hyperinflammation response as a result of the infection. 60 PCT which is commonly used to differentiate bacterial from viral infections was also found to be associated with severe cases of COVID-19 and could be used as a useful tool for predicting the prognosis. 61 In this review, only Chaudhri et al. 48 (part I) reported a significantly higher levels of CRP in the ACEi/ARBs as compared to the control group. This could be attributed to the observed significantly higher proportions of patients in the ACEi/ARBs group who had comorbid diabetes, HTN, HF, CKD and COPD. This was confirmed by the multivariate analysis which revealed that using ACEi/ARBs during hospitalization was associated with a reduction in the inflammatory burden. Furthermore, when multiple inflammation markers were considered, comparable peak inflammation and FC scores were This article is protected by copyright. All rights reserved. The role of the RAAS in the immune system has long been studied and established. ACEi were reported to reduce the Th1/Th2 cytokines ratio and consequently modulate inflammation. 62 ATII has been found to mediate inflammatory responses through upregulation of many proinflammatory receptors such as E-selectin and P-selectin. 63 Furthermore, ATII has been implicated in the increase in production of reactive oxygen species (ROS) through the activation of NADPH oxidase. 63 ATII has been also found to trigger the expression of toll like receptors by many cells as well as induce dendritic cell maturation. 63 All of these proinflammatory effects of ATII lead to the hypothesis that the upregulation of ACE2 can modulate the immune response through its main action of degrading ATII. 64 This may play a significant role during infection with SARS-CoV-2 which is known to cause a hyperactive immune response that can get out of check and proceed to harm many organs in the body causing the many systemic effects observed in the COVID-19 era. It was found that mice deficient in the ACE2 gene had significantly more severe ARDS when infected with SARS-CoV-2 as compared with the wild type. Loss of ACE2 expression in SARS-CoV-2, caused higher vascular permeability and lung edema. Interestingly, treatment with catalytically active recombinant ACE2 protein led to improving the symptoms. 65,66 Several studies from the SARS-CoV era as well as This article is protected by copyright. All rights reserved. 21 some during this pandemic have shown that these viruses can cause downregulation of the ACE2 receptor. 67 This downregulation of ACE2 disturbs the balance in the RAAS favoring increased levels of ATII and therefore a heightened inflammatory response. 12 It would be interesting to be able to quantify the exact levels of the different RAAS components during a COVID-19 infection to further test this hypothesis. This distortion in the balance of the RAAS towards the proinflammatory side could very well be what causes such severe disease in patients. Thus, it would seem that anything that can upregulate ACE2 and block ATII might have the potential to tip the balance back to normal and modulate the immune response. Interestingly enough, RAAS inhibitors have been shown to cause upregulation of ACE2 in many studies. 14 The D-dimer is produced during the cleavage of fibrin by plasmin to break down clots. Ddimer has been identified as a biomarker for disease severity and mortality in COVID-19 patients. It is still unclear whether this association is attributed to the direct effect of SARS-CoV-2 or to the consequences of systemic inflammatory response. 68 Interestingly, Human and mouse platelets were found to express ACE2. Zhang et al. 69 , reported that SARS-CoV-2 binds platelets ACE2 and enhances thrombosis in COVID-19 patients. SARS-CoV-2 was found to promote ACE2 internalization and degradation which was also observed as a gradual reduction in the expression of ACE2 in platelets in COVID-19. Furthermore, SARS-CoV-2 directly activates the ACE2/mitogen-activated protein kinase pathway to potentiate platelet activation and aggregation. This was found to be reversed by using This article is protected by copyright. All rights reserved. 

It was reported that COVID-19 may cause cardiac injury even to those who do not have any underlying CVDs. An early study coming out of Wuhan, China found that some of the causes of death in COVID-19 patients included fatal arrythmias, acute coronary syndrome (ACS), and cardiac arrest. 70 Both troponins and BNP have been found to be elevated in patients with COVID-19. 71 It has since been extensively argued whether the reported cardiac injury is due to COVID-19 or due to the underlying comorbidities that affect many of the COVID-19 patients in the reported studies. 72 A This article is protected by copyright. All rights reserved.

23 study looking at biopsy specimens from COVID-19 patients with myocarditis suggests that the degree of cardiac inflammation and macrophage infiltration was too high to be accounted for simply by viral invasion and theorizes that the pathological process taking place in the heart is a mixture of the ramped up immune response associated with COVID-19 and underlying heart disease. 73 In our review, two studies (Huang et al. 26 and Lam et al. 27 ) revealed that the ACEi/ARBs group had a significantly lower levels of cardiac markers (Troponin, BNP or NT-pro-BNP). In the study conducted by Huang et al., the ACEi/ARBs and the control groups had different proportions of patients with different comorbidities, but the differences did not reach the level of statistical significance.

However, they reported that a significantly higher proportion of patients in the control group were over the age of 65. Therefore, Huang et al. 26 , concluded that the level of cardiac markers was not significantly different in the two groups after excluding the age factor. Lam et al. 27 reported comparable proportions of patients in both groups with CHD/HF. However, the ACEi/ARBs group had a higher proportion of patients with comorbid diabetes which does not justify the significantly lower levels of cardiac markers. Conversely, it was reported that elevated serum concentrations of cardiac biomarkers were detected in patients with type 2 diabetes due to the higher risk of developing CVD. 74-76 Furthermore, after correction for multiple comparisons, Lam et al. 27 , found that troponin level remained significantly different between the ACEi/ARBs and the control groups.

It is also important to note that patients taking RAAS inhibitors are more likely to have underlying heart disease which would predispose this population to worse cardiac outcomes with a COVID-19 infection. However, none of the included studies reported that the ACEi/ARBs group had significantly higher levels of cardiac markers than the control group. This can be attributed to the immunomodulatory effect of RAAS inhibitors during infection. 47 As it is now established that inflammation plays an important role in the progression and outcome of COVID-19, it may also lead This article is protected by copyright. All rights reserved.

to different types of cardiac dysfunctions including myocardial infarction and heart failure. 77 Troponins are enzymes released from cardiac myocytes when they are injured. It could be then hypothesized that since RAAS inhibitors have been shown to modulate the immune response, their use can decrease systemic inflammation which would protect the cardiac myocytes from inflammatory injury. BNP is a peptide released from cardiac myocytes when they experience excessive stretch such as during states of volume overload and is generally used as a surrogate for cardiac function. The more the heart loses its contractile function, the more stretched it becomes and thus releases more BNP which functions as part of the body's main mechanism to counteract RAAS by promoting natriuresis and preventing excessive volume overload. RAAS inhibitors have long been established to have a cardioprotective effect in patients with CVD. 78 This mechanism may explain the lower levels of cardiac markers reported by Lam et al. 27 in the ACEi/ARBs group.

Furthermore, it suggests that RAAS inhibitors may play a cardioprotective role against the COVID-19 associated cardiac injury which has been widely reported. 79

In addition to cardiac injury, it was reported that COVID-19 may lead to multiple organ failure, which could be mainly attributed to the severe inflammatory response associated with the virus which attacks many organs in the body and leads to dysfunction. 80 inhibitors as compared to the control group. However, the comorbidities data in the RAAS inhibitor group had a significantly higher number of patients with kidney disease, CVD, diabetes, obesity and/or stroke. In general, RAAS inhibitors were found to be associated with increased levels of serum creatinine. 81 RAAS inhibitors impair the effect of ATII by either preventing its formation (ACEi) or blocking its receptor (ARBs). Angiotensin II is known to constrict the afferent and efferent arterioles with a preference to increase the resistance of the efferent arteriole. Therefore, RAAS inhibitors decrease the resistance at the post glomerular arteriole which lowers the intra glomerular pressure and reduces the glomerular filtration rate (GFR). This can be caused by volume depletion due to the over aggressive diuresis in the CKD and HF patients. 82 However, as RAAS inhibitors are antihypertensive drugs, they can slow the rate of progression of nephropathy in both diabetic and nondiabetic CKD. RAAS inhibitors may reduce the intraglomerular pressure and hyperfiltration and reduce proteinuria which impairs the progression of CKD. 83 Several studies revealed that RAAS inhibitors offer beneficial therapeutic strategies to treat and prevent chronic liver disease and portal hypertension. ATII was found to induce various profibrotic pathways by binding to its receptors expressed in different types of organs such as heart, kidney and liver. Activation of these receptors may enhance the transformation of the quiescent hepatic stellate cell (HSC) into the myofibroblast like activated HSC and the production of profibrotic cytokines. RAAS inhibitors were reported to reduce the proliferation of HSC to reduce the profibrotic molecules which may improve liver fibrosis. 84 None of the included studies reported that using RAAS inhibitors significantly increased any of the liver markers in the ACEi/ARBs group as compared with the control group. This article is protected by copyright. All rights reserved. found that the ACEi/ARBs had a significantly higher level of LDH in the ACEi/ARBs group. This can be attributed to the underlying COPD which was reported in a significantly higher proportion of the ACEi/ARBs group. The LDH level was reported to be elevated in patients with COPD due to the oxidative metabolic response of the muscles to compensate for the ventilation abnormalities. 86 No other significant differences were observed in the LDH levels between the ACEi/ARBs and control groups in the included studies.

Although ACEi and ARBs affect RAAS through two different mechanisms, however, it was reported that their impact on the outcomes of COVID-19 is not significantly different. A large observational study conducted by the Cleveland Clinic 87 which compared patients on ACEi to those on ARBs found no significant difference in the rates of hospitalization, ICU admission, or need for a ventilator. This aligns with what was mentioned before about ATII being the main effector driving an out-of-control immune response. Both ACEi and ARBs reduce the effects of ATII by either inhibiting This article is protected by copyright. All rights reserved. 27 the conversion of ATI to ATII or by blocking the ATII receptors respectively. 88 Multivariable analysis conducted by Selçuk et al. 31 revealed that the use of RAAS inhibitors was an independent predictor of in-hospital mortality as a significantly higher proportion of the ACEi/ARBs group died in hospital.

They also reported a higher rate of ICU admission within the same group. No significant difference was observed in the blood inflammatory and physiology markers except for the D-dimer which was significantly higher in the ACEi/ARBs group. Accordingly, Selçuk et al. 31 ACEi/ARBs group and patients who stopped using the ACEi/ARBs. Furthermore, no significant difference was observed between the two groups in the common adverse events such as respiratory failure requiring IMV, shock requiring vasopressors, acute myocardial infarction or worsening heart failure and acute kidney failure requiring hemodialysis. Therefore, suspending ACEi/ARBs was not beneficial and it did not improve the days alive and out of the hospital. 89, 90, 91 In summary, the use of RAAS inhibitors did not increase the levels of inflammatory, cardiac or liver markers in any of the studies. CRP was higher in the ACEi/ARBs group in part I of the study This article is protected by copyright. All rights reserved. 29 conducted by Chaudhri et al. 48 , however, their calculated total inflammatory scores showed no significant difference between the two groups. Additionally, significantly higher proportions of the ACEi/ARBs group in this part of study had HTN, CAD, CKD and COPD. 48 Lower inflammation markers in the ACEi/ARBs group were reported in six studies 32, 39, 35, 42, 43, 48(partII) . Five of these studies did not report any significantly different comorbidities between the two groups. Furthermore, the ACEi/ARBs group had a higher proportion of patients with comorbid CHD 39 in one study. These 100% and 84% did not show any significant difference between the ACEi/ARBs and the control groups. Morever, 69% of the studies that reported the disease outcome (severity/mortality) observed no significant difference between the two groups.

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It was challenging to link the timing of using the medications with the reported results.

Although some papers stated clearly that ACEi/ARBs were used before hospitalization, but nothing was mentioned about the in-hospital use. It is possible that among those who were classified as ACEi/ARBs groups based on their chronic use of the medications, some may have continued or discontinued using the medications during hospitalization. Similarly, some studies stated clearly that ACEi/ARBs were used during hospitalization without specifying the history of usage. It is also possible that some patients were using the medications before admission. This may create an overlap between all the three groups of studies that classified their ACEi/ARBs groups based on using the medications before, during or before and during hospitalization. Furthermore, 24% of the studies did not clearly explain the timing of ACEi/ARBs usage.

There are some limitations in this review. Some studies clearly defined the ACEi/ARBs group.

However, it was not clear in many others whether the ACEi/ARBs groups used the RAAS inhibitors before or during hospitalization or both. Another limitation was the large difference in the number of patients in the ACEi/ARBs and the control groups where the former usually had lower number of COVID-19 patients. Furthermore, some studies compared the clinical outcomes in hypertensive patients who take ACEi/ARBs with those who take other types of drugs. However, in many studies, patients in the control group did not always have HTN. Multivariate regression analysis was conducted in some studies to adjust for cofounding only to assess certain clinical outcomes. These outcomes included mortality, length of hospitalization, admission to ICU or need of mechanical This article is protected by copyright. All rights reserved. 31 ventilation. However, most of the studies did not match the blood marker results to eliminate confounding.

There is an accumulating evidence that RAAS inhibitors do not have any harmful effect on COVID-19 patients. This is also evident from the data collected in this review which indicate no significantly higher inflammation markers which were found to be linked to a worse disease prognosis. Moreover, using RAAS inhibitors was not found to be linked to any significantly higher physiological blood markers or bad prognosis of COVID-19 or even mortality in most of the studies. This is in agreement with several other studies including the BRACE CORONA trial 89-95 , which reported that the suspension of ACEi/ARBs was not associated with better outcomes and/or using the medications was not associated with worse outcomes.

In summary, the use of RAAS inhibitors may not lead to higher disease markers or worse prognosis or mortality. Furthermore, several results suggested an added benefit and a protective effect of RAAS inhibitors. Therefore, it is our recommendation is to not discontinue RAAS inhibitors out of unfounded fear of increased susceptibility for infection. This is the same recommendation adopted by the major professional societies such as the American College of Cardiology. Suspension of these drugs can lead to significant harm to patients with comorbid conditions where an ACEi/ARBs is a primary indication and, in some diseases, can improve mortality. We also see an importance in further testing RAAS inhibitors in patients without comorbid conditions who are not already using these medications in order to utilize their possible added protective effect through immune modulation during COVID-19 infection that warrants further trials and investigation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

44 Figure 2 . Summary of the blood marker and outcome results in the 28 included studies. Each pie chart illustrates the percentage and number of studies that reported no sginificant difference, significantly higher or significantly lower blood marker/outcome in the ACEi/ARBs as compared to the control group. The significantly different proportions in patients with underlying comorbidtires between the two groups in the studies that reported significantly different levels of markers/outcomes are reported next to each sector. Matched data did not show any significant difference between the 2 groups in the ICU admission.

Conclu sion by Bae et al.

In the unmatched cohort, there was no significant difference in cardiac or inflammatory biomarkers between the ACEi/ARBs and non-ACEI/ARB groups. After propensity matching, those in the ACEI/ARB group were found to have significantly lower median peak inflammatory markers as compared to the non-ACEi/ARBs group with no significant difference in baseline demographics and comorbidities between the 2 groups. 

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Intensive Care Unit; IL-6: Interleukin 6; IMV: Intermittent Mandatory Ventilation; I: Indirect; LDH: Lactate Dehydrogenase; MODS: Multiple Organ Dysfunction Syndrome, NC: Nasal Canula; NIV: Non-invasive Ventilation

Not reported; ns: not significant; NT-proBNP: N-terminal pro Brain Natriuretic Peptide; OR: Odd Ratio; PCT: Procalcitonin; PPI: Proton Pump Inhibitor; T: Total; * significant. §, †, ‡: There is a significant difference between §: control group and the ACEi/ARBs group

In part I, ACEi/ARBs were used before hospitalization while in part II, ACEi/ARBs were used before and after hospitalization (the control group discontinued the medications during hospitalization).Only peak markers are reported here while levels at admission were also reported in the study and did not show any significant difference between the 2 groups.