Meta-analysis of Effect of Statins in Patients with COVID-19.

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-λ-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., FcγRIIA) and downstream signaling pathways (e.g., NF-κB 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-α/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, and DHA/EPA, pasireotide), as well as inhibitors targeted toward molecular mediators of the maladaptive COVID-19 immune response (e.g., IL-6, TNF-α, IL-17, JAK, and CDK9).

/pdf/cellular-and-molecular-pathways-of-covid-19-and-potential-127jrfoez8.pdf

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

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19 Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020 Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19 Severe AEs were defined as intensive care unit admission or the need for assisted ventilation For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19 Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101â¯949 total patients, of whom 26 545 (260%) were receiving ACEIs or ARBs When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 057; 95% CI, 043-076; P < 001) and severe AEs (aOR, 068; 95% CI, 053-088; P < 001) were found Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 066 [95% CI, 049-091]; P = 01; aOR, 051 [95% CI, 032-084]; P = 008) and severe AEs (unadjusted OR, 070 [95% CI, 054-091]; P = 007; aOR, 055 [95% CI, 036-085]; P = 007) Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension Future randomized clinical trials are warranted to establish causality

/pdf/association-between-renin-angiotensin-aldosterone-system-3i7qd7n576.pdf

Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

https://escholarship.org/content/qt6fw197ck/qt6fw197ck.pdf?t=qlp4zd

Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis.

While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensin-converting 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. 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, I2 = 83%, and OR = 0.62, 95% CI 0.39–0.99, I2 = 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, I2 = 0%, and OR = 1.68, 95% CI 1.05–2.70, I2 = 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, I2 = 0%). Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.

/pdf/renin-angiotensin-system-inhibitors-and-covid-19-a-shu5g602ld.pdf

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

Background. Medical editorials have suggested that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should not be given to people with arterial hypertension during the coronavirus disease 2019 (COVID-19) pandemic because of a potential increased risk of worse clinical outcomes and that calcium channel blockers (CCBs) should be used as an alternative. 
Methods Using a cohort of 610 COVID-19 cases and 48,667 population-based controls from Zheijang, China we have tested the role of usage of ACEIs, ARBs, CCBs and other medications on risk and severity of COVID 19. Analyses were adjusted for age, sex and BMI and for presence of relevant comorbidities.
Findings: Higher BMI, diabetes and cardio/ cerebrovascular disease as independent risk factors for the development of COVID-19. Individuals with hypertension taking CCBs had significantly increased risk [odds ratio (OR)= 1.67 (95% CI 1.2-2.9)) of manifesting symptoms of COVID-19 whereas those taking ARBs and diuretics had significantly lower disease risk (OR=0.24; 95%CI 0.17-0.34 and OR=0.32; 95%CI 0.19-0.57 respectively). Other antihypertensive drugs were not associated with increased risk of severe or critical form of the infection. Use of glucocorticoids was significantly associated with a severe/critical form of COVID-19 (OR= 7.56; 95%CI 1.17-48.93).
Interpretation: we found no evidence to alter ARBs or ACEIs therapy in the context of the pandemic. Patients on corticosteroids with COVID-19 are at higher risk of developing a severe form of COVID-19and therefore should be monitored closely.

https://www.medrxiv.org/content/medrxiv/early/2020/04/29/2020.04.24.20077875.full.pdf

Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China.

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Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China.