Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and the Risk of SARS-CoV-2 Infection or Hospitalization With COVID-19 Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: SARS-CoV-2 infects its target cells via angiotensin converting enzyme 2 receptor, a membrane-bound protein found on the surface of many human cells. Treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptors blockers (ARB) has been shown to increase angiotensin converting enzyme 2 expression by up to 5-fold. AREAS OF UNCERTAINTY: These findings coupled with observations of the high prevalence and mortality among SARS-CoV-2-infected patients with underlying cardiovascular disease have led to a speculation that ACEIs/ARBs may predispose to higher risk of being infected with SARS-CoV-2. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and the risk of SARS-CoV-2 infection or hospitalization due to COVID-19 disease. DATA SOURCES: We searched Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Medrxiv.org preprint server until June 18, 2020. THERAPEUTIC ADVANCES: Ten studies (6 cohorts and 4 case control) that enrolled a total of 23,892 patients and 853,369 controls were eligible for inclusion in our meta-analysis. One study was excluded from the analysis because of high risk of bias. Prior use of ACEIs was not associated with an increased risk of acquiring SARS-CoV-2 or hospitalization due to COVID-19 disease, odds ratio 0.98, 95% confidence interval (0.91-1.05), I2 = 15%. Similarly, prior use of ARBs was not associated with an increased risk of acquiring SARS-CoV-2, odds ratio 1.04, 95% confidence interval (0.98-1.10), I2 = 0%. CONCLUSION: Cumulative evidence suggests that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19 or hospitalization due to COVID-19 disease. Our results provide a reassurance to the public not to discontinue prescribed ACEIs/ARBs because of fear of COVID-19.

A Multi-centric Evaluation of Deep Learning Models for Segmentation of COVID-19 Lung Lesions on Chest CT Scans

Background: Chest computed tomography (CT) scan is one of the most common tools used for the diagnosis of patients with coronavirus disease 2019 (COVID-19). While segmentation of COVID-19 lung lesions by radiologists can be time-consuming, the application of advanced deep learning techniques for automated segmentation can be a promising step toward the management of this infection and similar diseases in the future. Objective(s): This study aimed to evaluate the performance and generalizability of deep learning-based models for the automated segmentation of COVID-19 lung lesions. Patients and Methods: Four datasets (2 private and 2 public) were used in this study. The first and second private datasets included 297 (147 healthy and 150 COVID-19 cases) and 82 COVID-19 subjects. The public datasets included the COVID19-P20 (20 COVID-19 cases from 2 centers) and the MosMedData datasets (50 COVID-19 patients from a single center). Model comparisons were made based on the Dice similarity coefficient (DSC), receiver operating characteristic (ROC) curve, and area under the curve (AUC). The predicted CT severity scores by the model were compared with those of radiologists by measuring the Pearson's correlation coefficients (PCC). Also, DSC was used to compare the inter-rater agreement of the model and expert against that of 2 experts on an unseen dataset. Finally, the generalizability of the model was evaluated, and a simple calibration strategy was proposed. Result(s): The VGG16-UNet model showed the best performance across both private datasets, with a DSC of 84.23% +/- 1.73% on the first private dataset and 56.61% +/- 1.48% on the second private dataset. Similar results were obtained on public datasets, with a DSC of 60.10% +/- 2.34% on the COVID19-P20 dataset and 66.28% +/- 2.80% on a combined dataset of COVID19-P20 and MosMedData. The predicted CT severity scores of the model were compared against those of radiologists and were found to be 0.89 and 0.85 on the first private dataset and 0.77 and 0.74 on the second private dataset for the right and left lungs, respectively. Moreover, the model trained on the first private dataset was examined on the second private dataset and compared against the radiologist, which revealed a performance gap of 5.74% based on DSCs. A calibration strategy was employed to reduce this gap to 0.53%. Conclusion(s): The results demonstrated the potential of the proposed model in localizing COVID-19 lesions on CT scans across multi-ple datasets;its accuracy competed with the radiologists and could assist them in diagnostic and treatment procedures. The effect of model calibration on the performance of an unseen dataset was also reported, increasing the DSC by more than 5%. Copyright © 2022, Author(s).

Functional outcomes of COVID-19 patients with acute ischemic stroke: A prospective, observational, single-center study in North Jordan.

We assessed whether stroke severity, functional outcome, and mortality in patients with ischemic stroke differed between patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and those without. We conducted a prospective, single-center cohort study in Irbid, North Jordan. All patients diagnosed with ischemic stroke and SARS-CoV-2 infection were consecutively recruited from October 15, 2020, to October 16, 2021. We recorded demographic data, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score, stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment Criteria (TOAST), treatments at admission, and laboratory variables for all patients. The primary endpoint was the functional outcome at 3 months assessed using the modified Rankin Score. Secondary outcomes involved in-hospital mortality and mortality at 3 months. We included 178 patients with a mean (standard deviation) age of 67.3 (12), and more than half of the cases were males (96/178; 53.9%). Thirty-six cases were coronavirus disease 2019 (COVID-19) related and had a mean (standard deviation) age of 70 (11.5). When compared with COVID-19-negative patients, COVID-19-positive patients were more likely to have a higher median NIHSS score at baseline (6 vs 11; P = .043), after 72 hours (6 vs 12; P = .006), and at discharge (4 vs 16; P < .001). They were also more likely to have a higher median modified Rankin Score after 3 months of follow-up (P < .001). NIHSS score at admission (odds ratio = 1.387, 95% confidence interval = 1.238-1.553]; P < .001) predicted having an unfavorable outcome after 3 months. On the other hand, having a concomitant SARS-CoV-2 infection did not significantly impact the likelihood of unfavorable outcomes (odds ratio = 1.098, 95% confidence interval = 0.270-4.473; P = .896). The finding conclude that SARS-CoV-2 infection led to an increase in both stroke severity and in-hospital mortality but had no significant impact on the likelihood of developing unfavorable outcomes.

Reply to Zandi, M.; Soltani, S. Comment on "Alfassam et al. Development of a Colorimetric Tool for SARS-CoV-2 and Other Respiratory Viruses Detection Using Sialic Acid Fabricated Gold Nanoparticles. Pharmaceutics 2021, 13, 502".

When COVID-19 was first announced back in 2019, there were vast number of attempts to halt the progression of the SARS-CoV-2 virus once and for all [...].

Trends of Prevalence Estimates and Risk Factors of Depressive Symptoms among Healthcare Workers Over one Year of the COVID-19 Pandemic.

Background: COVID-19 pandemic has an overwhelming psychologic burden on healthcare workers (HCWs). This study aims to investigate the changes in the prevalence, estimates, severity, and risk factors of depressive symptoms among HCWs within the first year of the COVID-19 pandemic. Methods: An observational e-survey collected data on HCWs' socio-demographic characteristics, occupational situation, and depressive symptoms as measured by Patient Health Questionnaire-9 (PHQ-9). The e-survey was distributed one month after the onset of the COVID-19 pandemic (onset group) and again after one year (one-year group). Results: A total of 422 HCWs were included (Mean (SD) age, 35.3 (9.9) years; 71.3% males), with 211 (50%) participants in each group. In the total cohort, the mean PHQ-9 score was 8.5, and 36.7% reported clinically significant levels of depressive symptoms with a PHQ-9 score of ≥10. Compared to the onset group, the one-year group reported a higher risk of major depressive disorder (41.7% vs. 31.8%; OR 1.538; 95%CI 1.032-2.291; p=0.034), a higher mean PHQ-9 score (9.5 (6.8) vs. 7.4 (5.3), p<0.001), and more severe depressive symptoms (p<0.005). Participants who were younger, unmarried, underwent testing for COVID-19, reported lower monthly income, did not receive special COVID-19 education, or had lower satisfaction with institutional preparedness had significantly higher depression scores and symptoms in both onset and one-year groups (p<0.05 for each category). Female gender and direct contact with COVID-19 patients or samples were significant risk factors within the onset group. Occupation as a physician, history of COVID-19 testing or infection, and perception of significant changes in work schedule or intensity were significantly associated with higher depression scores and symptoms among the one-year group. Conclusion: This study sheds light on an unspoken but significant rise in prevalence estimates and severity of depressive symptoms among HCWs over a year of the COVID-19 pandemic and shows the vulnerable subgroups for whom a psychological intervention might be warranted.

Trends in Insomnia, Burnout, and Functional Impairment among Health Care Providers over the First Year of the COVID-19 Pandemic.

Background: COVID-19 pandemic has negatively impacted the psychological well-being and quality of life of health care providers (HCPs). Objectives: This study assessed the trends in prevalence and predictors of insomnia, burnout, and functional impairment among HCPs over the first year of the pandemic. Methods: An online survey was conducted one month after the pandemic's onset (onset group) and a year later (one-year group). The demographic features of participants were collected. Insomnia, burnout, and functional impairment were assessed using Insomnia Severity Index (ISI), Mini-Z survey, and Sheehan Disability Scale (SDS), respectively. Results: The onset group included 211 HCPs (mean (SD) age 34.7 (9.3) years and 73% men), while 212 HCPs participated in the one-year survey (mean (SD) age 35.9 (10.5) years and 69% men). High prevalence estimates were found in both onset and one-year groups of symptoms of insomnia (52% vs. 49%), of diagnosis of clinical insomnia (15% vs. 18%), with a high mean ISI score (8.4 vs. 8.7), but with no significant difference between the onset and one-year groups. Risk factors for clinical insomnia included age in both groups, lower income and contact level with COVID-19 patients/samples in the onset group, and lower Mini-Z scores and higher SDS scores in the one-year group. Approximately one-third of respondents reported at least one or more burnout symptoms, with a higher percentage in the one-year group (35.4%) than in the onset group (24.2%) (p=0.012). Younger age, lower monthly income, and higher ISI and SDS scores were risk factors for burnout in both groups. Greater perceived changes in social life were associated with burnout in the onset group. In contrast, higher weekly working hours, worse participants' evaluation of their institution's preparation, and more changes in workload were risk factors for burnout in the one-year group. The SDS score and its subscales scores were higher in the one-year group than in the onset group. Changes in workload and social life predicted higher SDS scores among both groups. Living with older people predicted higher SDS scores among the onset group, while contact level and estimated number of COVID-19 patients that participants engaged in during caring predicted higher SDS scores among the one-year group. ISI scores were significantly correlated with the Mini-Z scores and SDS scores in both groups, while the Mini-Z and SDS scores were significantly correlated only in the one-year group. Conclusion: This study demonstrated high rates of insomnia, burnout, and functional impairment among HCPs during the pandemic. It reveals a significant rise in job burnout and functional impairment of HCPs overtime during the pandemic. Furthermore, high-risk subgroups are also highlighted for whom comprehensive psychosocial and occupational interventions might be warranted.

Prevalence Estimates and Risk Factors of Anxiety among Healthcare Workers in Jordan over One Year of the COVID-19 Pandemic: A Cross-Sectional Study.

This study investigates the changes in prevalence estimates, severity, and risk factors of anxiety among healthcare workers (HCWs) over the first year of the COVID-19 pandemic. A survey was distributed among HCWs using snowball sampling, collecting their socio-demographics, occupation, and anxiety symptoms as measured by the Generalized Anxiety Disorder-7 (GAD-7) scale. It was distributed one month after the pandemic's onset in Jordan between 15 and 30 April 2020 (onset group) and after one year between 15 and 30 March 2021 (one-year group). A total of 422 HCWs were included (211 in each group). The one-year group reported a higher risk of GAD (30.8% vs. 16.6%; p = 0.001), a higher mean (SD) GAD-7 score (7.94 (5.29) vs. 6.15 (4.15); p < 0.001), and more severe symptoms (p = 0.003). Univariate analyses showed that participants who were younger, women, unmarried, had lower monthly incomes, underwent testing for COVID-19, had higher contact with COVID-19 patients, did not receive special education, and were unsatisfied with the institutional COVID-19 preparedness scored higher on the GAD-7 scale and had more severe symptoms than their counterparts in both groups. Unlike the onset group, occupation as a physician, COVID-19 infection history, and perception of remarkable changes in work were associated with higher anxiety scores and severity among the one-year group. The COVID-19 vaccine was a relative protective action. Logistic regression analyses showed that the female gender was a risk factor for developing GAD at the pandemic onset, while poor satisfaction with institutional preparedness was a significant GAD risk factor in the one-year group. Low monthly income and lack of special education were the shared risk factors for GAD in both groups. This study reveals a significant rise in anxiety among HCWs over a year of the COVID-19 pandemic and shows the vulnerable sub-groups who likely need psychological interventions.

A Performance Measurement Framework for Socially Sustainable and Resilient Supply Chains using Environmental Goods Valuation Methods

Socially sustainable and resilient supply chains are critical for organizations to succeed during both normal and uncertain times. Informed by supply chain disruption events, this study uses the resource-based view to conceptualize a performance framework for firms to strategically measure supply chain social sustainability and resilience capabilities. The performance framework integrates (a) the environmental goods valuation to evaluate social sustainability and (b) digitalization using blockchain technology to enhance supply chain process sustainability and resilience. Using secondary COVID-19 supply chain disruption data, the performance framework illustrates various social sustainability implications, market-based valuation methods, and supporting blockchain capabilities for supply chains. The study identifies potential future research to further evaluate the effectiveness of the proposed performance measurement framework and to advance it theoretically. The study also suggests practitioners utilize the performance measurement framework to manage supply chain social sustainability issues and resilience such that it can contribute to their competitive advantages.

Review of Current Diagnostics Developed for COVID-19

COVID-19 emerged in 2019 as a pandemic that affected the world in many aspects and it has been the biggest challenge for many countries in the past year. Due to the lack of approved treatment methods for the disease, and more importantly, to inhibit its spread, the critical task is to detect it fast and reliable. Many research groups and companies have been developing different methods and products for the diagnosis of COVID-19. Each method has advantages and disadvantages, while rapid, inexpensive, and high-throughput detection methods are needed. In this regard, significant progress has been achieved so far. In this article, we reviewed in-vitro Diagnostics (IVD) and Commercial Kits in three main categories including real-time reverse transcription-polymerase chain reaction kits, serology-based tests, and point-of-care diagnostic tests. In addition, familiarizing with coronavirus and its detection methods, genome study, Cell entrance and antigenicity, and Specimen, Lab Biosafety, and Authorization of Medical Devices for COVID-19 were discussed.

Elevated Expression Levels of Lung Complement Anaphylatoxin, Neutrophil Chemoattractant Chemokine IL-8, and RANTES in MERS-CoV-Infected Patients: Predictive Biomarkers for Disease Severity and Mortality.

The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein-protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.

Elevated Expression Levels of Lung Complement Anaphylatoxin, Neutrophil Chemoattractant Chemokine IL-8, and RANTES in MERS-CoV-Infected Patients: Predictive Biomarkers for Disease Severity and Mortality (preprint)

The complement system represents an innate immune response consisting of a protein network. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement‐modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including Seven complement proteins including complement regulatory factors during MERS-CoV infection. We also measured the expression of lung neutrophil chemoattractant chemokine IL-8 (CXCL8) and RANTES (CCL5). Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a and C3a, was positively correlated with IL-8, RANTES and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P (properdin), suggesting positive regulation of the complement during MERS-CoV infection. In addition, we also demonstrated that a high viral load in all patients with MERS-CoV correlated with C5a and C3a levels. Pulmonary complement mediators, disease severity, and an increased fatality rate may be linked to the degree of complement activation against MERS-CoV. High levels of lung C5a, C3a, factor P, IL-8 and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8 and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the functional partners (protiens) prediction of highly expressed proteins (C5a, C3a, factor P, IL-8 and RANTES), the computational protein–protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.  

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Mortality Among COVID-19 Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known to increase the expression of angiotensin converting enzyme 2 receptor, which has been shown to be the receptor for the acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). AREAS OF UNCERTAINTY: Based on these observations, speculations raised the concerns that ACEIs/ARBs users would be more susceptible to SARS-CoV-2 infection and would be at higher risk for severe COVID-19 disease and death. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and mortality due to COVID-19 disease. DATA SOURCES: A comprehensive search of several databases from November 2019 to June 18, 2020 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Medrxiv.org was also searched for unpublished data. THERAPEUTIC ADVANCES: Nine studies with a total of 18,833 patients infected with SARS-CoV-2 met our eligibility criteria. Prior use of ACEIs and/or ARBs was associated with reduced mortality among SARS-CoV-2-infected patients, with a pooled adjusted relative risk (aRR) from 6 studies of 0.63, 95% confidence interval (CI) (0.42-0.94) (I = 65%). Three studies reported separately on ACEIs or ARBs and their association with survival among SARS-CoV-2-infected patients, with a pooled adjusted relative risk of 0.78, 95% CI (0.58-1.04) (I = 0%) and 0.97, 95% CI (0.73-1.30) (I = 0%) respectively. The results of sensitivity analyses were consistent with the main analysis. CONCLUSION: Our meta-analysis suggests that use of ACEIs/ARBs is associated with a decreased risk of death among SARS-CoV-2-infected patients. This finding provides a reassurance to the public not to stop prescribed ACEIs/ARBs because of fear of severe COVID-19.

Cardiac Toxicity of Chloroquine or Hydroxychloroquine in Patients With COVID-19: A Systematic Review and Meta-regression Analysis.

OBJECTIVE: To systematically review the literature and to estimate the risk of chloroquine (CQ) and hydroxychloroquine (HCQ) cardiac toxicity in patients with coronavirus disease 2019 (COVID-19). METHODS: We searched multiple data sources including PubMed/MEDLINE, Ovid Embase, Ovid EBM Reviews, Scopus, and Web of Science and medrxiv.org from November 2019 through May 27, 2020. We included studies that enrolled patients with COVID-19 treated with CQ or HCQ, with or without azithromycin, and reported on cardiac toxic effects. We performed a meta-analysis using the arcsine transformation of the different incidences. RESULTS: A total of 19 studies with a total of 5652 patients were included. The pooled incidence of torsades de pointes arrhythmia, ventricular tachycardia, or cardiac arrest was 3 per 1000 (95% CI, 0-21; I 2 =96%) in 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5% (95% CI, 1-11; I 2 =98%). The pooled incidence of change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more was 9% (95% CI, 3-17; I 2 =97%). Mean or median age, coronary artery disease, hypertension, diabetes, concomitant QT-prolonging medications, intensive care unit admission, and severity of illness in the study populations explained between-studies heterogeneity. CONCLUSION: Treatment of patients with COVID-19 with CQ or HCQ is associated with an important risk of drug-induced QT prolongation and relatively higher incidence of torsades de pointes, ventricular tachycardia, or cardiac arrest. Therefore, these agents should not be used routinely in the management of COVID-19 disease. Patients with COVID-19 who are treated with antimalarials for other indications should be adequately monitored.

Covid-19 global spread analyzer: An ML-based attempt

The novel Coronavirus 2019 (COVID-19) has caused a pandemic disease over 200 countries, influencing billions of humans. In this consequence, it is very much essential to the identify factors that correlate with the spread of this virus. The detection of coronavirus spread factors open up new challenges to the research community. Artificial Intelligence (AI) driven methods can be useful to predict the parameters, risks and effects of such an epidemic. Such predictions can be helpful to control and prevent the spread of such diseases. In this study, we introduce two datasets, each of which consists of 25 country-level factors and covers 137 countries summarizing different domains. COVID-19STC aims to detect the increase of the total cases, whereas COVID-19STD aimed for total death detection. For each data set, we applied three feature selection algorithms (vis. correlation coefficient, information gain and gain ratio). We also apply feature selection by the Wrapper methods using four classifiers, namely, NaiveBayes, SMO, J48 and Random Forest. The GDP, GDP Per Capital, E-Government Index and Smoking Habit factors found to be the main factors for the total cases detection with accuracy of 73% using the J48 classifier. The GDP and E-Government Index are found to be the main factors for total deaths detection with accuracy of 71% using J48 classifier. © 2020 Rana Husni Al Mahmoud, Eman Omar, Khaled Taha, Mahmoud Al-Sharif and Abdullah Aref.

The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis (preprint)

ImportanceThe antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as a potential treatment for COVID-19 due their effect on several cellular processes that impact viral replication. Although more than 100 ongoing trials are testing their efficacy, CQ and HCQ are being used widely in clinical practice, exposing COVID-19 patients to potentially significant cardiac adverse effects. ObjectiveTo systematically review the literature and estimate the risk of cardiac toxicity in patients receiving CQ or HCQ for COVID-19. Data SourcesA systematic search was conducted on May 27, 2020 of Ovid EBM Reviews, Ovid Embase (1974+), Ovid Medline (1946+ including epub ahead of print, in-process & other non-indexed citations), Scopus (1970+) and Web of Science (1975+) and preprint servers (Medrvix and ResearchSquare) and manual search of references lists. Study SelectionStudies that included COVID-19 patients treated with CQ or HCQ, with or without azithromycin, were included as follows: (1) COVID-19 patient population, (2) the study included more than 10 patients receiving either one of the medications, (3) reported electrocardiographic changes and/or cardiac arrhythmias. Data Extraction and SynthesisStudy characteristics and endpoints incidence were extracted. Due to the very low incidence of torsades de pointes (TdP) and other endpoints (rare events), the arcsine transformation was used to obtain a pooled estimate of the different incidences using a random-effects meta-analysis. Meta-regression analyses were used to assess whether the incidence of different endpoints significantly varied by multiple study-level variables specified a priori. Main Outcomes and MeasuresPooled Incidence of: (1) change in QTc value from baseline [≥] 60 ms, (2) QTc [≥] 500 ms, (3) the composite of endpoint 1 and 2, (4) TdP arrhythmia or ventricular tachycardia (VT) or cardiac arrest, (5) discontinuation of treatment due to drug-induced QT prolongation or arrhythmias. ResultsA total of 19 studies with a total of 5652 patients were included. All included studies were of high methodological quality in terms of exposure ascertainment or outcome assessment. Among 2719 patients treated with CQ or HCQ, only two episodes of TdP were reported; the pooled incidence of TdP arrhythmia or VT or cardiac arrest was 3 per 1000, 95% CI (0-21), I2=96%, 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5%, 95% CI (1-11), I2=98%. The pooled incidence of change in QTc from baseline of [≥] 60 ms was 7%, 95% CI (3-14), I2=94% (12 studies of 2008 patients). The pooled incidence of QTc [≥] 500 ms was 6%, 95% CI (2-12), I2=95% (16 studies of 2317 patients). Among 11 studies of 3127 patients, the pooled incidence of change in QTc from baseline of [≥] 60 ms or QTc [≥] 500 ms was 9%, 95% CI (3-17), I2=97%. Mean/median age, coronary artery disease, hypertension, diabetes, concomitant QT prolonging medications, ICU care, and severity of illness in the study populations explained between-studies heterogeneity. Conclusions and RelevanceTreatment of COVID-19 patients with CQ or HCQ is associated with a significant risk of drug-induced QT prolongation, which is a harbinger for drug-induced TdP/VT or cardiac arrest. CQ/HCQ use resulted in a relatively higher incidence of TdP as compared to drugs withdrawn from the market for this particular adverse effect. Therefore, these agents should be used only in the context of randomized clinical trials, in patients at low risk for drug-induced QT prolongation, with adequate safety monitoring. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the risks of different cardiac toxicities in patients receiving chloroquine (CQ) or hydroxychloroquine (HCQ) for COVID-19. FindingsIn this systematic review, treatment of COVID-19 patients with CQ or HCQ is associated with a clinically significant risk of drug-induced QT prolongation, and torsades de pointes (TdP) arrhythmia/ventricular tachycardia/cardiac arrest in a relatively higher incidence compared to drugs withdrawn from the market for such adverse effects. MeaningThese agents should be used only in the context of clinical trials, in patients at low risk for drug-induced QT prolongation, with adequate safety monitoring.

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and The Risk of SARS-CoV-2 Infection: A Systematic Review and Meta-analysis (preprint)

Importance:SARS-CoV-2 virus gains access and infects target cells via angiotensin converting enzyme 2 (ACE2) receptor. Because angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) could increase the expression of ACE2, there are growing concerns that their use could increase the risk of SARS-CoV-2 infection. Cardiac societies have called for epidemiological research about this emerging controversy. Objective:We sought to systematically review the literature and perform a meta-analysis about prior use of ACEI/ARBs and risk of SARS-CoV-2 infection.Data source:We searched multiple data sources including PubMed , ClinicalTrial.org , and medrxiv.org from November 2019 through May 16, 2020. Study selection:Any study that reported on the adjusted association of prior use of ACEIs / ARBs and risk of acquiring SARS-CoV-2 infection was eligible. Two authors independently reviewed eligible studies and extracted data into a prespecified data collection form. Data synthesis:An inverse variance meta-analytic approach was used to pool adjusted odds ratios using a random effect model meta-analysis. I2 test was used to assess in-between studies heterogeneity. The Newcastle–Ottawa quality assessment scale (NOS) was used to assess the quality of included studies. Main outcome and Measures:The association between the prior use of ACEIs or ARBs and risk of SARS-CoV-2 infection was assessed using pooled OR and 95% confidence interval. Results:Six case control studies that enrolled a total of 5657 patients (2536 patients in ACEIs arm and 3121 patients  in ARBs arm ) and 721,859 controls were included in our meta-analysis.  Two of the included studies were from the USA, one from Italy, one from China, one from Spain, and one from South Korea. All included studies scored high based on NOS scale. Prior use of ACEIs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.93, CI (0.85,1.02), I2=20%. Similarly, prior use of ARBs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.86, CI (0.67,1.10), I2=93%. Sensitivity analysis was performed by removing a study that could have been affected by residual confounding; OR for ARB 1.04, CI (0.96,1.12), I2=32%.Conclusion:Findings from this systematic review and meta-analysis suggest that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19. Our results are in support of the recent recommendations of cardiac societies and provide a reassurance to the public not to discontinue prescribed ACEIs/ARBs due to fear of COVID-19. 

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Outcome of COVID-19 : A Systematic Review and Meta-analysis (preprint)

Importace: There is conflicting evidence about the role of angiotensin converting enzymes inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) in the pathogenesis and outcome of patients infected with acute severe respiratory syndrome coronavirus 2 (SASR-CoV-2) virus and growing public concern. Methods: We systematically reviewed the literature and performed a meta-analysis using inverse variance random effect models including all studies that evaluate the role of ACEIs/ARBs and reported adjusted odds ratio. Results: Nine studies met our eligibility criteria that enrolled a population of 58615 patients infected with SASR-CoV-2. Prior use of ACEIs/ARBs were associated with significant reduction of inpatient mortality among infected patients with SASR-CoV-2, adjusted odds ratio from 4 studies 0.33, 95% confidence interval ( 0.22,0.49) with zero in between studies heterogeneity and with significant reduction of critical or fatal outcome , pooled adjusted odds ratio from 5 studies 0.32,95% confidence interval ( 0.22,0.46) with no in between studies heterogeneity. Conclusion: Our findings suggest that prior use ACEIs /ARBs is associated with a decreased risk of death or critical outcome among SASR-CoV-2 infected patients.This findings is limited by the observational nature of included studies.However, it provides a reassurance to the public not to stop prescribed ACEIs /ARBs due to fear of severe COVID-19. It also calls upon investigators and ethics committee to reconsider the ongoing randomized trials of discontinuation of these drugs.