Characteristics of out-of-hospital cardiac arrest patients in Riyadh province, Saudi Arabia: a cross-sectional study.

Introduction: Little work has been done on out-of-hospital cardiac arrest (OHCA) in Saudi Arabia. Our goal is to report the characteristics of OHCA patients and predictors of bystander cardiopulmonary resuscitation (CPR). Materials and methods: This cross-sectional study utilized data from the Saudi Red Crescent Authority (SRCA), a governmental emergency medical service (EMS). A standardized data collection form based on the "Utstein-style" guidelines was developed. Data were retrieved from the electronic patient care reports that SRCA providers fill out for every case. OHCA cases that were attended by SRCA in Riyadh province between June 1st, 2020 and May 31st, 2021 were included. Multivariate regression analysis was performed to assess independent predictors of bystander CPR. Results: A total of 1,023 OHCA cases were included. The mean age was 57.2 (±22.6). 95.7% (979/1,023) of cases were adults and 65.2% (667/1,023) were males. Home was the most common location of OHCA [784/1,011 (77.5%)]. The initial recorded rhythm was shockable in 131/742 (17.7%). The EMS mean response time was 15.9 min (±11.1). Bystander CPR was performed in 130/1,023 (12.7%) and was more commonly performed in children as compared to adults [12/44 (27.3%) vs. 118/979 (12.1%), p = 0.003]. Independent predictors of bystander CPR were being a child (OR = 3.26, 95% CI [1.21-8.82], p = 0.02) and having OHCA in a healthcare institution (OR = 6.35, 95% CI [2.15-18.72], p = 0.001). Conclusion: Our study reported the characteristics of OHCA cases in Saudi Arabia using EMS data. We observed young age at presentation, low rates of bystander CPR, and long response time. These characteristics are distinctly different from other countries and call for urgent attention to OHCA care in Saudi Arabia. Lastly, being a child and having OHCA in a healthcare institution were found to be independent predictors of bystander CPR.

Characteristics and predictors of out-of-hospital cardiac arrest in young adults hospitalized with acute coronary syndrome: A retrospective cohort study of 30,000 patients in the Gulf region.

INTRODUCTION: The characteristics of young adults with out-of-hospital cardiac arrest (OHCA) due to acute coronary syndrome (ACS) has not been well described. The mean age of gulf citizens in ACS registries is 10-15 years younger than their western counterparts, which provided us with a unique opportunity to investigate the characteristics and predictors of OHCA in young adults presenting with ACS. METHODOLOGY: This was a retrospective cohort study using data from 7 prospective ACS registries in the Gulf region. In brief, all registries included consecutive adults who were admitted with ACS. OHCA was defined as cardiac arrest upon presentation (i.e., before admission to the hospital). We described the characteristics of young adults (< 50 years) who had OHCA and performed multivariate logistic regression analysis to assess independent predictors of OHCA. RESULTS: A total of 31,620 ACS patients were included in the study. There were 611 (1.93%) OHCA cases in the whole cohort [188/10,848 (1.73%) in young adults vs 423/20,772 (2.04%) in older adults, p = 0.06]. Young adults were predominantly males presenting with ST-elevation myocardial infarction (STEMI) [182/188 (96.8%) and 172/188 (91.49%), respectively]. OHCA was the sentinel event of coronary artery disease (CAD) in 70% of young adults. STEMI, male sex, and non-smoking status were found to be independent predictors of OHCA [OR = 5.862 (95% CI 2.623-13.096), OR: 4.515 (95% CI 1.085-18.786), and OR = 2.27 (95% CI 1.335-3.86), respectively]. CONCLUSION: We observed a lower prevalence of OHCA in ACS patients in our region as compared to previous literature from other regions. Moreover, OHCA was the sentinel event of CAD in the majority of young adults, who were predominantly males with STEMIs. These findings should help risk-stratify patients with ACS and inform further research into the characteristics of OHCA in young adults.

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 2 = 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 2 = 0%) and 0.97, 95% CI (0.73-1.30) (I 2 = 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.

Prevalence and characteristics of family history of sudden unexplained death and predictors of negative attitude of family members toward medical autopsy and family screening in Saudi Arabia: A cross-sectional study.

INTRODUCTION: Little is known about sudden unexplained death (SUD) in Saudi Arabia. Moreover, family screening and medical autopsy are not routinely performed due to perceived religious and cultural resistance. However, this has never been systematically examined. We sought to describe the prevalence and characteristics of family history of SUD and the attitude of family members toward medical autopsy and family screening. METHODS: This was a cross-sectional study utilizing an online survey distributed though social media platforms from August 15 to September 15, 2021. Participants' characteristics, details about SUD cases, and the attitude toward medical autopsy and family screening were collected. Multivariable logistic regression was used to identify independent predictors of negative attitude toward medical autopsy. RESULTS: A total of 11374 were included in the final analysis after excluding children. The prevalence of FHx of at least one first degree relative (FDR) with SUD was found to be 9.4% [95% CI (8.9% - 10%)]. Among participants with any FHx of SUD, 1346/3489 (38.6%) had ≥ 2 family members affected. Only 183 participants with a FHx of SUD visited a physician for the purpose of family screening (183/3489, 5.3%). The total number of SUD cases reported was 5474. Of those, 22% were 35-year-old or younger. Only 22% of participants (2458/11374) had a negative attitude towards medical autopsy, and the most common reason was the perceived lack of benefit. Older age (> 35 years), family history of SUD, female gender, and lack of knowledge about the yield of medical autopsy were associated with negative attitude in the adjusted analysis. CONCLUSION: SUD occurred at young age and affected multiple family members in a significant proportion of families. Despite that, family screening was seldom performed. There is an urgent need to improve the care of SUD by incorporating medical autopsy and developing clinical pathways to screen family members.

Medical Autopsy for Sudden Unexplained Death in Saudi Arabia: A Call to Action.

Sudden unexplained death (SUD) is a sudden, unexpected, and unexplained death in an individual older than 1 year. It is one of the most devastating and tragic events to families and the community at large, particularly when it happens at a young age. Finding the cause of SUD is extremely important in order to prevent its recurrence in the family, and to help understand the epidemiology of SUD in the community. It has been well-established that the most effective way of finding the cause of SUD is by performing a medical autopsy. In many countries, medical autopsy is mandated in SUD cases. In others, however, medical autopsy is rarely performed for the purpose of identifying the cause of SUD, which is the case in Saudi Arabia. In this review, we discussed the importance of finding the cause of death in SUD cases, the role of different types of medical autopsies, and the state of medical autopsy in Saudi Arabia. Moreover, we proposed a clinical pathway to incorporate medical autopsy in the care of SUD cases, and to connect family members to the health care system in order to perform cascade screening.

Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome.

Galloway-Mowat syndrome is a rare autosomal recessive disease characterized by a unique combination of renal and neurological manifestations, including early-onset steroid-resistant nephrotic syndrome, microcephaly, psychomotor delay, and gyral abnormalities of the brain. Most patients die during early childhood. Here, we identified a novel homozygous O-sialoglycoprotein endopeptidase (OSGEP) variant, NM_017807.3:c.973C>G (p.Arg325Gly), in four affected individuals in an extended consanguineous family from Saudi Arabia. We have described the detailed clinical characterization, brain imaging results, and muscle biopsy findings. The described phenotype varied from embryonic lethality to early pregnancy loss or death at the age of 9. Renal disease is often the cause of death. Protein modeling of this OSGEP variant confirmed its pathogenicity. In addition, proteomic analysis of the affected patients proposed a link between the KEOPS complex function and human pathology and suggested potential pathogenic mechanisms.

Persistent COVID-19 symptoms at least one month after diagnosis: A national survey.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) is an important healthcare burden. We examined persistent symptoms in COVID-19 patients at least four weeks after the onset of infection, participants' return to pre-COVID-19 health status and associated risk factors. METHODS: Cross-sectional study was conducted (December 2020 to January 2021). A validated online questionnaire was sent to randomly selected individuals aged more than 14 years from a total of 1397,386 people confirmed to have COVID-19 at least 4 weeks prior to the start of this survey. This sample was drawn from the Saudi ministry of health COVID-19 testing registry system. RESULTS: Out of the 9507 COVID-19 patients who responded to the survey, 5946 (62.5%) of them adequately completed it. 2895 patients (48.7%) were aged 35-44 years, 64.4% were males, and 91.5% were Middle Eastern or North African. 79.4% experienced unresolved symptoms for at least 4 weeks after the disease onset. 9.3% were hospitalized with 42.7% visiting healthcare facility after discharge and 14.3% requiring readmission. The rates of main reported persistent symptoms in descending order were fatigue 53.5%, muscle and body ache 38.2%, loss of smell 35.0%, joint pain 30.5%, and loss of taste 29.1%. There was moderate correlation between the number of symptoms at the onset and post-four weeks of COVID-19 infection. Female sex, pre-existing comorbidities, increased number of baseline symptoms, longer hospital-stay, and hospital readmission were predictors of delayed return to baseline health state (p < 0.05). CONCLUSION: The symptoms of PACS are prevalent after contracting COVID-19 disease. Several risk factors could predict delayed return to baseline health state.

COVID-19-Associated cardiac pathology at the postmortem evaluation: a collaborative systematic review.

BACKGROUND: Many postmortem studies address the cardiovascular effects of COVID-19 and provide valuable information, but are limited by their small sample size. OBJECTIVES: The aim of this systematic review is to better understand the various aspects of the cardiovascular complications of COVID-19 by pooling data from a large number of autopsy studies. DATA SOURCES: We searched the online databases Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science for concepts of autopsy or histopathology combined with COVID-19, published between database inception and February 2021. We also searched for unpublished manuscripts using the medRxiv services operated by Cold Spring Harbor Laboratory. STUDY ELIGIBILITY CRITERIA: Articles were considered eligible for inclusion if they reported human postmortem cardiovascular findings among individuals with a confirmed SARS coronavirus type 2 (CoV-2) infection. PARTICIPANTS: Confirmed COVID-19 patients with post-mortem cardiovascular findings. INTERVENTIONS: None. METHODS: Studies were individually assessed for risk of selection, detection, and reporting biases. The median prevalence of different autopsy findings with associated interquartile ranges (IQRs). RESULTS: This review cohort contained 50 studies including 548 hearts. The median age of the deceased was 69 years. The most prevalent acute cardiovascular findings were myocardial necrosis (median: 100.0%; IQR, 20%-100%; number of studies = 9; number of patients = 64) and myocardial oedema (median: 55.5%; IQR, 19.5%-92.5%; number of studies = 4; number of patients = 46). The median reported prevalence of extensive, focal active, and multifocal myocarditis were all 0.0%. The most prevalent chronic changes were myocyte hypertrophy (median: 69.0%; IQR, 46.8%-92.1%) and fibrosis (median: 35.0%; IQR, 35.0%-90.5%). SARS-CoV-2 was detected in the myocardium with median prevalence of 60.8% (IQR 40.4-95.6%). CONCLUSIONS: Our systematic review confirmed the high prevalence of acute and chronic cardiac pathologies in COVID-19 and SARS-CoV-2 cardiac tropism, as well as the low prevalence of myocarditis in COVID-19.

Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis.

BACKGROUND: Post-acute coronavirus 2019 (COVID-19) syndrome is now recognized as a complex systemic disease that is associated with substantial morbidity. OBJECTIVES: To estimate the prevalence of persistent symptoms and signs at least 12 weeks after acute COVID-19 at different follow-up periods. DATA SOURCES: Searches were conducted up to October 2021 in Ovid Embase, Ovid Medline, and PubMed. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Articles in English that reported the prevalence of persistent symptoms among individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection and included at least 50 patients with a follow-up of at least 12 weeks after acute illness. METHODS: Random-effect meta-analysis was performed to produce a pooled prevalence for each symptom at four different follow-up time intervals. Between-study heterogeneity was evaluated using the I2 statistic and was explored via meta-regression, considering several a priori study-level variables. Risk of bias was assessed using the Joanna Briggs Institute tool and the Newcastle-Ottawa Scale for prevalence studies and comparative studies, respectively. RESULTS: After screening 3209 studies, a total of 63 studies were eligible, with a total COVID-19 population of 257 348. The most commonly reported symptoms were fatigue, dyspnea, sleep disorder, and difficulty concentrating (32%, 25%, 24%, and 22%, respectively, at 3- to <6-month follow-up); effort intolerance, fatigue, sleep disorder, and dyspnea (45%, 36%, 29%, and 25%, respectively, at 6- to <9-month follow-up); fatigue (37%) and dyspnea (21%) at 9 to <12 months; and fatigue, dyspnea, sleep disorder, and myalgia (41%, 31%, 30%, and 22%, respectively, at >12-month follow-up). There was substantial between-study heterogeneity for all reported symptom prevalences. Meta-regressions identified statistically significant effect modifiers: world region, male sex, diabetes mellitus, disease severity, and overall study quality score. Five of six studies including a comparator group consisting of COVID-19-negative cases observed significant adjusted associations between COVID-19 and several long-term symptoms. CONCLUSIONS: This systematic review found that a large proportion of patients experience post-acute COVID-19 syndrome 3 to 12 months after recovery from the acute phase of COVID-19. However, available studies of post-acute COVID-19 syndrome are highly heterogeneous. Future studies need to have appropriate comparator groups, standardized symptom definitions and measurements, and longer follow-up.

Anti-Diabetic Drugs GLP-1 Agonists and DPP-4 Inhibitors may Represent Potential Therapeutic Approaches for COVID-19.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Therapeutic effect of statins on airway remodeling during asthma.

INTRODUCTION: Asthma is a chronic inflammatory disease of the airways, which is usually characterized by remodeling, hyperresponsiveness and episodic obstruction of the airways. The underlying chronic airway inflammation leads to pathological restructuring of both the large and small airways. Since the effects of current asthma medications on airway remodeling have been met with contradictions, many therapeutic agents have been redirected from their primary use for the treatment of asthma. Such treatments, which could target several signaling molecules implicated in the inflammatory and airway remodeling processes of asthma, would be an ideal choice. AREAS COVERED: Statins are effective serum cholesterol-lowering agents that were found to have potential anti-inflammatory and anti-remodeling properties. Literature search was done for the past 10 years to include research and review articles in the field of statins and asthma complications. In this review, we discuss the role of statins in airway tissue remodeling and their potential therapeutic modalities in asthma. EXPERT OPINION: With improved understanding of the role of statins in airway remodeling and inflammation, statins represent a potential therapeutic option for various asthma phenotypes. Further research is warranted to optimize statins for asthma therapy through inhalation as a possible route of administration.

Interrupted versus uninterrupted anticoagulation therapy for catheter ablation in adults with arrhythmias.

BACKGROUND: The management of anticoagulation therapy around the time of catheter ablation (CA) procedure for adults with arrhythmia is critical and yet is variable in clinical practice. The ideal approach for safe and effective perioperative management should balance the risk of bleeding during uninterrupted anticoagulation while minimising the risk of thromboembolic events with interrupted therapy. OBJECTIVES: To compare the efficacy and harms of interrupted versus uninterrupted anticoagulation therapy for catheter ablation (CA) in adults with arrhythmias. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and SCI-Expanded on the Web of Science for randomised controlled trials on 5 January 2021. We also searched three registers on 29 May 2021 to identify ongoing or unpublished trials. We performed backward and forward searches on reference lists of included trials and other systematic reviews and contacted experts in the field. We applied no restrictions on language or publication status. SELECTION CRITERIA: We included randomised controlled trials comparing uninterrupted anticoagulation with any modality of interruption with or without heparin bridging for CA in adults aged 18 years or older with arrhythmia. DATA COLLECTION AND ANALYSIS: Two review authors conducted independent screening, data extraction, and assessment of risk of bias. A third review author resolved disagreements. We extracted data on study population, interruption strategy, ablation procedure, thromboembolic events (stroke or systemic embolism), major and minor bleeding, asymptomatic thromboembolic events, cardiovascular and all-cause mortality, quality of life (QoL), length of hospital stay, cost, and source of funding. We used GRADE to assess the certainty of the evidence.  MAIN RESULTS: We identified 12 studies (4714 participants) that compared uninterrupted periprocedural anticoagulation with interrupted anticoagulation. Studies performed an interruption strategy by either a complete interruption (one study) or by a minimal interruption (11 studies), of which a single-dose skipped strategy was used (nine studies) or two-dose skipped strategy (two studies), with or without heparin bridging. Studies included participants with a mean age of 65 years or greater, with only two studies conducted in relatively younger individuals (mean age less than 60 years). Paroxysmal atrial fibrillation (AF) was the primary type of AF in all studies, and seven studies included other types of AF (persistent and long-standing persistent). Most participants had CHADS2 or CHADS2-VASc demonstrating a low-moderate risk of stroke, with almost all participants having normal or mildly reduced renal function. Ablation source using radiofrequency energy was the most common (seven studies). Ten studies (2835 participants) were conducted in East Asian countries (Japan, China, and South Korea), while the remaining two studies were conducted in the USA. Eight studies were conducted in a single centre. Postablation follow-up was variable among studies at less than 30 days (three studies), 30 days (six studies), and more than 30 days postablation (three studies). Overall, the meta-analysis showed high uncertainty of the effect between the interrupted strategy compared to uninterrupted strategy on the primary outcomes of thromboembolic events (risk ratio (RR) 1.76, 95% confidence interval (CI) 0.33 to 9.46; I2 = 59%; 6 studies, 3468 participants; very low-certainty evidence). However, subgroup analysis showed that uninterrupted vitamin A antagonist (VKA) is associated with a lower risk of thromboembolic events without increasing the risk of bleeding. There is also uncertainty on the outcome of major bleeding events (RR 1.10, 95% CI 0.59 to 2.05; I2 = 6%; 10 studies, 4584 participants; low-certainty evidence). The uncertainty was also evident for the secondary outcomes of minor bleeding (RR 1.01, 95% CI 0.46 to 2.22; I2 = 87%; 9 studies, 3843 participants; very low-certainty evidence), all-cause mortality (RR 0.34, 95% CI 0.01 to 8.21; 442 participants; low-certainty evidence) and asymptomatic thromboembolic events (RR 1.45, 95% CI 0.85 to 2.47; I2 = 56%; 6 studies, 1268 participants; very low-certainty evidence). There was a lower risk of the composite endpoint of thromboembolic events (stroke, systemic embolism, major bleeding, and all-cause mortality) in the interrupted compared to uninterrupted arm (RR 0.23, 95% CI 0.07 to 0.81; 1 study, 442 participants; low-certainty evidence). In general, the low event rates, different comparator anticoagulants, and use of different ablation procedures may be the cause of imprecision and heterogeneity observed. AUTHORS' CONCLUSIONS: This meta-analysis showed that the evidence is uncertain to inform the decision to either interrupt or continue anticoagulation therapy around CA procedure in adults with arrhythmia on outcomes of thromboembolic events, major and minor bleeding, all-cause mortality, asymptomatic thromboembolic events, and a composite endpoint of thromboembolic events (stroke, systemic embolism, major bleeding, and all-cause mortality).  Most studies in the review adopted a minimal interruption strategy which has the advantage of reducing the risk of bleeding while maintaining a lower level of anticoagulation to prevent periprocedural thromboembolism, hence low event rates on the primary outcomes of thromboembolism and bleeding. The one study that adopted a complete interruption of VKA showed that uninterrupted VKA reduces the risk of thromboembolism without increasing the risk of bleeding. Hence, future trials with larger samples, tailored to a more generalisable population and using homogeneous periprocedural anticoagulant therapy and ablation source are required to address the safety and efficacy of the optimal management of anticoagulant therapy prior to ablation.

Overlooked Shortcomings of Observational Studies of Interventions in Coronavirus Disease 2019: An Illustrated Review for the Clinician.

The rapid spread of severe acute respiratory syndrome coronavirus 2 infection across the globe triggered an unprecedented increase in research activities that resulted in an astronomical publication output of observational studies. However, most studies failed to apply fully the necessary methodological techniques that systematically deal with different biases and confounding, which not only limits their scientific merit but may result in harm through misleading information. In this article, we address a few important biases that can seriously threaten the validity of observational studies of coronavirus disease 2019 (COVID-19). We focus on treatment selection bias due to patients' preference on goals of care, medical futility and disability bias, survivor bias, competing risks, and the misuse of propensity score analysis. We attempt to raise awareness and to help readers assess shortcomings of observational studies of interventions in COVID-19.

Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19.

More than one year since its emergence, corona virus disease 2019 (COVID-19) is still looming large with a paucity of treatment options. To add to this burden, a sizeable subset of patients who have recovered from acute COVID-19 infection have reported lingering symptoms, leading to significant disability and impairment of their daily life activities. These patients are considered to suffer from what has been termed as "chronic" or "long" COVID-19 or a form of post-acute sequelae of COVID-19, and patients experiencing this syndrome have been termed COVID-19 long-haulers. Despite recovery from infection, the persistence of atypical chronic symptoms, including extreme fatigue, shortness of breath, joint pains, brain fogs, anxiety and depression, that could last for months implies an underlying disease pathology that persist beyond the acute presentation of the disease. As opposed to the direct effects of the virus itself, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process. In this review, we hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19.

Prior Statin Use and Risk of Mortality and Severe Disease From Coronavirus Disease 2019: A Systematic Review and Meta-analysis.

BACKGROUND: Statins up-regulate angiotensin-converting enzyme 2, the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while also exhibiting pleiotropic antiviral, antithrombotic, and anti-inflammatory properties. Uncertainties exist about their effect on the course of SARS-CoV-2 infection. We sought to systematically review the literature and perform a meta-analysis to examine the association between prior statin use and outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: We searched Ovid Medline, Web of Science, Scopus, and the preprint server medRxiv from inception to December 2020. We assessed the quality of eligible studies with the Newcastle-Ottawa quality scale. We pooled adjusted relative risk (aRRs) of the association between prior statin use and outcomes of patients with COVID-19 using the DerSimonian-Laird random-effects model and assessed heterogeneity using the I 2 index. RESULTS: Overall, 19 (16 cohorts and 3 case-control) studies were eligible, with a total of 395 513 patients. Sixteen of 19 studies had low or moderate risk of bias. Among 109 080 patients enrolled in 13 separate studies, prior statin use was associated with a lower risk of mortality (pooled aRR, 0.65 [95% confidence interval {CI}, .56-.77], I 2 = 84.1%) and a reduced risk of severe COVID-19 was also observed in 48 110 patients enrolled in 9 studies (pooled aRR, 0.73 [95% CI, .57-.94], I 2 = 82.8%), with no evidence of publication bias. CONCLUSIONS: Cumulative evidence suggests that prior statin use is associated with lower risks of mortality or severe disease in patients with COVID-19. These data support the continued use of statins medications in patients with an indication for lipid-lowering therapy during the COVID-19 pandemic.

Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis, first update.

OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to update the data in a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. METHODS: Data sources were 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 up, preprint servers and Google from 8th October 2020 till 24th February 2021. Eligible studies were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. The participants were hospitalized COVID-19 patients, and intervention was tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs with a random effects model and evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1600 citations, eight RCTs and 28 cohorts were eligible. The eight RCTs had low risk of bias, and with 6311 patients they examined the effect of tocilizumab on short-term mortality; pooled RR was 0.91 (95%CI 0.78-1.07, I2 25%). Only the REMAP-CAP and RECOVERY trials, with the majority of their patients on concomitant corticosteroids, showed lower 30-day mortality with tocilizumab use: RR 0.74 (95%CI 0.59-0.93) and 0.89 (95%CI 0.81-0.97), respectively. Seven RCTs, with 5391 patients, examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.84 (95%CI 0.76-0.93), I2 0%, with a corresponding number needed to treat of 20 (95%CI 14.3-33.3). Eight RCTs, with 5340 patients, examined the effect of tocilizumab on a composite of poor outcome; pooled RR was 0.82 (95%CI 0.76-0.90, I2 3%). Data from the RCTs showed a lower risk of infections and no higher risk of serious adverse events with tocilizumab: pooled RR 0.67 (95%CI 0.45-0.99, eight RCTs) and 0.85 (95%CI 0.63-1.16, seven RCTs), respectively. Among 28 cohorts with 15 484 patients, the pooled adjusted RR for mortality was 0.53 (95%CI 0.43-0.67, I2 76%). CONCLUSIONS: Cumulative high-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients with severe COVID-19. Moderate-certainty evidence shows that tocilizumab reduces the risk of poor outcome and the risk of secondary infections in hospitalized COVID-19 patients. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.

Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

Many meta-analyses have been published about the efficacy of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19). Most of them included observational studies, and few have assessed HCQ as a prophylaxis or evaluated its safety profile. We searched multiple databases and preprint servers for randomized controlled trials (RCTs) that assessed HCQ for the treatment or prevention of COVID-19. We summarized the effect of HCQ on mortality, viral clearance, and other clinical outcomes. Out of 768 papers screened, 21 RCTs with a total of 14,138 patients were included. A total of 9 inpatient and 3 outpatient RCTs assessed mortality in 8596 patients with a pooled risk difference of 0.01 (95% confidence interval [CI] 0.00-0.03, I2  = 1%, p = 0.07). Six studies assessed viral clearance at 7 days with a pooled risk ratio (RR) of 1.11 (95% CI 0.86-1.42, I2  = 61%, p = 0.44) and 5 studies at 14 days with a pooled RR of 0.96 (95% CI 0.89-1.04, I2  = 0%, p = 0.34). Several trials showed no significant effect of HCQ on other clinical outcomes and. Five prevention RCTs with 5012 patients found no effect of HCQ on the risk of acquiring COVID-19. Thirteen trials showed that HCQ was associated with increased risk of adverse events. We observed, with high level of certainty of evidence, that HCQ is not effective in reducing mortality in patients with COVID-19. Lower certainty evidence also suggests that HCQ neither improves viral clearance and other clinical outcomes, nor prevents COVID-19 infection in patients with high-risk exposure. HCQ is associated with an increased rate of adverse events.

Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has infected millions of individuals and has claimed hundreds of thousands of human lives worldwide. Patients with underlying cardiovascular conditions are at high risk for SARS-CoV-2 infection, and COVID-19 patients have high incidence of cardiovascular complications such as acute cardiac injury, arrhythmias, heart failure, and thromboembolism. The disease has no approved proven effective therapy and hence repurposing of existing approved drugs has been considered as the fastest treatment approach. Statins have been shown to exhibit lipid lowering dependent and independent cardiovascular protective effects as well as favorable effects in various other pathophysiological states. These beneficial properties of statins are a result of their multiple pleotropic effects that include, anti-inflammatory, immunomodulatory, antithrombotic and antimicrobial properties. In this review, we provide a comprehensive description of the mechanisms of the pleotropic effects of statins, the relevant pre-clinical and clinical data pertinent to their role in infections and acute lung injury, the possible cardiovascular benefits of statins in COVID-19, and the implications of the therapeutic potential of statins in COVID-19 disease. We conclude with the rationale for conducting randomized controlled trials of statins in COVID-19 disease.