Role of Drugs used for chronic disease management on Susceptibility and Severity of COVID-19: A Large Case-Control Study

Yan, Huadong; Valdes, Ana M.; Vijay, Amrita; Wang, Shanbo; Liang, Lili; Yang, Shiqing; Wang, Hongxia; Tan, Xiaoyan; Du, Jingyuan; Jin, Susu; Huang, Kecheng; Jiang, Fanrong; Zhang, Shun; Zheng, Naihang; Hu, Yaoren; Cai, Ting; Aithal, Guruprasad P.

doi:10.1101/2020.04.24.20077875

Cited by 27 publications

(36 citation statements)

References 40 publications

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“…In a separate, larger study of 610 cases and 48,667 high-coverage population-based controls, individuals with hypertension using ARBs were reported to have a 76% lower likelihood of developing COVID-19. However, a similar effect was not reported for ACE inhibitors (Yan et al, 2020).…”

Section: Ace2-mediated Viral Entry and Priming Of Inflammatory Responsementioning

confidence: 56%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

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Section: Ace2-mediated Viral Entry and Priming Of Inflammatory Responsementioning

confidence: 56%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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“…Nine studies were conducted in Europe (UK, Italy, France, Spain, Belgium) [18][19][20][21][22][23][24][25][26], 7 studies took place in North America (the USA) [27][28][29][30][31][32][33], while 9 studies were conducted in Asia, mainly in China [31,[34][35][36][37][38][39][40][41]. Finally, we initially included in our quantitative synthesis a study utilizing data from an observational database from 169 hospitals in Asia, Europe, and North America, which was recently retracted and thus excluded from our analysis [42].…”

Section: Resultsmentioning

confidence: 99%

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities

et al. 2020

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Purpose of Review While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection. For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis. Recent Findings In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16-0.89, I 2 = 83%, and OR = 0.62, 95% CI 0.39-0.99, I 2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37-2.23, I 2 = 0%, and OR = 1.68, 95% CI 1.05-2.70, I 2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74-1.00, I 2 = 0%). Summary Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.

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“…Further, abstracts of 98 articles were read and subsequently, the full text of 41 articles were reviewed. Of these, sixteen 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][18][19][20][21][22][23][24][25][26][27]. Finally, these sixteen studies were included for review and out of these, nine and five studies were included in the meta-analysis of mortality and severity outcomes in COVID-19 patients on ACEI/ARB, respectively.…”

Section: Resultsmentioning

confidence: 99%

A systematic review and meta-analysis to evaluate the clinical outcomes in COVID -19 patients on angiotensin converting enzyme inhibitors or angiotensin receptor blockers

Grover

Oberoi

2020

Preprint

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Introduction: Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor upregulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence but there is need for an updated systematic review of latest clinical studies. Methods:A search was conducted on PubMed, Google Scholar, EMBASE and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEI and/or ARB and a meta-analysis was performed. Results: A total of sixteen studies were included for review and meta-analysis. There were conflicting findings reported in several studies as Meng J. et al, Liu Y. et al, Feng Y. et al, Zhang P. et al, Mancia G. et al and Reynolds H.R. et al 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 intensive care unit (ICU) admissions in patients on ACE inhibitors/ARB as compared to non-users. Similarly, there were conflicting results in the rate of mortality reported in the various studies. Meng J. et al, Li J. et al, Zhang P. et al, Yang G. et al, Zeng Z. et al and Andrew Ip et al reported lower rates of mortality in ACE inhibitors/ARB users versus non-users whereas Richardson S. et al and Guo T. et al reported higher rates of mortality.In a pooled analysis of 9 studies, there was a statistically significant reduction (OR = 0.86, 95% CI = 0.75-0.99, I 2 = 53.25, p value = 0.03) in the odds of death in those on ACEI/ARB as compared to patients not on ACEI/ARB. In a pooled analysis of five studies, there was a statistically nonsignificant reduction (OR = 0.90, 95% CI: 0.63-1.23, I 2 =70.36) in the odds of developing severe disease in patients on ACEI/ARB versus non-users.

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Role of Drugs used for chronic disease management on Susceptibility and Severity of COVID-19: A Large Case-Control Study

Cited by 27 publications

References 40 publications

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities

A systematic review and meta-analysis to evaluate the clinical outcomes in COVID -19 patients on angiotensin converting enzyme inhibitors or angiotensin receptor blockers

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