Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis.

OBJECTIVES: Clinical studies of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 disease reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin on outcomes of COVID-19 patients. METHODS: We searched multiple databases, preprints and grey literature up to 17 July 2020. We pooled only adjusted-effect estimates of mortality using a random-effect model. We summarized the effect of CQ or HCQ on viral clearance, ICU admission/mechanical ventilation and hospitalization. RESULTS: Seven randomized clinical trials (RCTs) and 14 cohort studies were included (20 979 patients). Thirteen studies (1 RCT and 12 cohort studies) with 15 938 hospitalized patients examined the effect of HCQ on short-term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2 = 0%). Six cohort studies examined the effect of the HCQ+azithromycin combination with a pooled adjusted OR of 1.32 (95% CI 1.00-1.75, I2 = 68.1%). Two cohort studies and four RCTs found no effect of HCQ on viral clearance. One small RCT demonstrated improved viral clearance with CQ and HCQ. Three cohort studies found that HCQ had no significant effect on mechanical ventilation/ICU admission. Two RCTs found no effect for HCQ on hospitalization risk in outpatients with COVID-19. CONCLUSIONS: Moderate certainty evidence suggests that HCQ, with or without azithromycin, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or risk of hospitalization in outpatients with 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.

Acute viral respiratory infections among children in MERS-endemic Riyadh, Saudi Arabia, 2012-2013.

The emergence of the Middle East Respiratory Syndrome (MERS) in Saudi Arabia has intensified focus on Acute Respiratory Infections [ARIs]. This study sought to identify respiratory viruses (RVs) associated with ARIs in children presenting at a tertiary hospital. Children (aged ≤13) presenting with ARI between January 2012 and December 2013 tested for 15 RVs using the SeeplexR RV15 kit were retrospectively included. Epidemiological data was retrieved from patient records. Of the 2235 children tested, 61.5% were ≤1 year with a male: female ratio of 3:2. Viruses were detected in 1364 (61.02%) children, 233 (10.4%) having dual infections: these viruses include respiratory syncytial virus (RSV) (24%), human rhinovirus (hRV) (19.7%), adenovirus (5.7%), influenza virus (5.3%), and parainfluenzavirus-3 (4.6%). Children, aged 9-11 months, were most infected (60.9%). Lower respiratory tract infections (55.4%) were significantly more than upper respiratory tract infection (45.3%) (P < 0.001). Seasonal variation of RV was directly and inversely proportional to relative humidity and temperature, respectively, for non MERS coronaviruses (NL63, 229E, and OC43). The study confirms community-acquired RV associated with ARI in children and suggests modulating roles for abiotic factors in RV epidemiology. However, community-based studies are needed to elucidate how these factors locally influence RV epidemiology. J. Med. Virol. 89:195-201, 2017. © 2016 Wiley Periodicals, Inc.

Sex disparities in outcomes among adults on long-term antiretroviral treatment in northern Nigeria.

BACKGROUND: There are conflicting reports of sex differences in HIV treatment outcomes in Africa. We investigated sex disparities in treatment outcomes for adults on first line antiretroviral treatment (ART) in Nigeria. METHODS: We compared clinical and immunologic responses to ART between HIV-infected men (n=205) and women (n=140) enrolled in an ART program between June 2004 and December 2007, with follow-up through June 2014. We employed Kaplan-Meier estimates to examine differences in time to immunologic failure and loss to follow-up (LTFU), and generalized estimating equations to assess changes in CD4+ count by sex. RESULTS: Men had lower baseline mean CD4+ count compared to women (327.6 cells/µL vs 413.4, respectively, p<0.01). Women had significantly higher rates of increase in CD4+ count than men, even after adjusting for confounders, p<0.0001. There was no significant difference in LTFU by sex: LTFU rate was 2.47/1000 person-months (95% CI 1.6-3.9) in the first five years for men vs 1.98/1000 person-months (95% CI (1.3-3.0) for women. There was no difference in time to LTFU by sex over the study period. CONCLUSIONS: Women achieved better long-term immune response to ART at baseline and during treatment, but had similar rates of long-term retention in care to men. Targeted efforts are needed to improve immune outcomes in men in our setting.

A Comparative Study of Clinical Presentation and Risk Factors for Adverse Outcome in Patients Hospitalised with Acute Respiratory Disease Due to MERS Coronavirus or Other Causes.

Middle East Respiratory syndrome (MERS) first emerged in Saudi Arabia in 2012 and remains a global health concern. The objective of this study was to compare the clinical features and risk factors for adverse outcome in patients with RT-PCR confirmed MERS and in those with acute respiratory disease who were MERS-CoV negative, presenting to the King Fahad Medical City (KFMC) in Riyadh between October 2012 and May 2014. The demographics, clinical and laboratory characteristics and clinical outcomes of patients with RT-PCR confirmed MERS-CoV infection was compared with those testing negative MERS-CoV PCR. Health care workers (HCW) with MERS were compared with MERS patients who were not health care workers. One hundred and fifty nine patients were eligible for inclusion. Forty eight tested positive for MERS CoV, 44 (92%) being hospital acquired infections and 23 were HCW. There were 111 MERS-CoV negative patients with acute respiratory illnesses included in this study as "negative controls". Patient with confirmed MERS-CoV infection were not clinically distinguishable from those with negative MERS-CoV RT-PCR results although diarrhoea was commoner in MERS patients. A high level of suspicion in initiating laboratory tests for MERS-CoV is therefore indicated. Variables associated with adverse outcome were older age and diabetes as a co-morbid illness. Interestingly, co-morbid illnesses other than diabetes were not significantly associated with poor outcome. Health care workers with MERS had a markedly better clinical outcome compared to non HCW MERS patients.

Molecular Epidemiology of Hospital Outbreak of Middle East Respiratory Syndrome, Riyadh, Saudi Arabia, 2014.

We investigated an outbreak of Middle East respiratory syndrome (MERS) at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia, during March 29-May 21, 2014. This outbreak involved 45 patients: 8 infected outside KFMC, 13 long-term patients at KFMC, 23 health care workers, and 1 who had an indeterminate source of infection. Sequences of full-length MERS coronavirus (MERS-CoV) from 10 patients and a partial sequence of MERS-CoV from another patient, when compared with other MERS-CoV sequences, demonstrated that this outbreak was part of a larger outbreak that affected multiple health care facilities in Riyadh and possibly arose from a single zoonotic transmission event that occurred in December 2013 (95% highest posterior density interval November 8, 2013-February 10, 2014). This finding suggested continued health care-associated transmission for 5 months. Molecular epidemiology documented multiple external introductions in a seemingly contiguous outbreak and helped support or refute transmission pathways suspected through epidemiologic investigation.

Azithromycin and Risk of Cardiovascular Death: A Meta-Analytic Review of Observational Studies.

Recent evidence, though conflicting, suggests an association between azithromycin use and cardiovascular death. We conducted a systematic review and meta-analysis to evaluate the effect of azithromycin on risk of death. Multiple databases were searched. Authors independently screened and extracted the data from studies. Primary outcome of interest was risk of death (cardiovascular and/or noncardiovascular). Subgroup analyses were conducted to explore the source of a possible heterogeneity. Random effects model meta-analysis and hazards ratio (HR) were used to pool the data and calculate the overall effect estimate, respectively. Eight hundred twenty-eight citations, identified with 5 cohort studies that involved 2,246,178 episodes of azithromycin use, met our inclusion criteria. Azithromycin use was not associated with higher risk of death from any cause, HR = 0.99 [confidence interval (CI), 0.82-1.19], I = 54%, or cardiovascular cause, HR = 1.15 (CI, 0.66-2.00), I = 64%, but there was a moderate degree of heterogeneity. Subgroup analyses have shown no increased risk of death with azithromycin use in younger population with zero degree of heterogeneity, HR = 0.85 (CI, 0.66-1.09), I = 0%. However, current use of azithromycin (within 1-5 days of therapy) was associated with a higher risk of death among older population with mild degree of heterogeneity, HR = 1.64 (CI, 1.23-2.19), I = 4%. In summary, azithromycin use was not associated with higher risk of death particularly in younger population. Nevertheless, older population might be at higher risk of death with current use of azithromycin, and an alternative therapy should probably be considered.

Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis.

AIMS: To examine the safety (defined as bleeding risk) and efficacy (defined as prevention of thromboembolic events) of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation (CA) of atrial fibrillation (AF) in comparison with warfarin. METHODS AND RESULTS: Reviewers independently searched literature databases from January 2010 through April 2013 for studies comparing the safety and efficacy of dabigatran and warfarin in CA of AF and extracted pre-defined data. The Mantel-Haenszel method was used to pool data of bleeding and thromboembolism outcomes into random and fixed effect model meta-analyses, respectively. Odds ratios (ORs), and risk difference (RD) analysis when studies reported no events in either arm, were used to generate an overall effect estimate of both outcomes. Publication bias and heterogeneity were assessed by contour funnel plot and the I(2) test, respectively. Nine citations, including 3036 patients (1073 dabigatran), met the inclusion criteria. There was no significant difference between interrupted dabigatran and warfarin therapy in CA of AF in occurrence of bleeding [dabigatran 58 (5.4%), warfarin 103 (5.2%); OR 0.92 (95% confidence interval (CI) 0.55-1.45); χ(2) = 13.03-P = 0.11; I(2) = 39%] or thromboembolism [dabigatran 5 (0.4%), warfarin 2 (0.1%); OR 2.15 (95% CI-0.58-7.98); χ(2) = 2.14, P = 0.54; I(2) = 0%; RD 0.00 (95% CI-0.00 to 0.01); χ(2) = 3.37, P = 0.81; I(2) = 0%]. Analysis of pre-defined subgroups (published articles vs. abstracts), sensitivity analyses (interrupted warfarin, USA studies, and Japanese studies) and fixed effect model analyses showed similar results. Heterogeneity was mild in the bleeding outcome analysis and zero in thromboembolism. There was no evidence of publication bias in either meta-analysis. CONCLUSION: Meta-analysis of currently available studies showed no significant difference in bleeding and thromboembolism between interrupted dabigatran and warfarin therapy in CA of AF. Dabigatran appears to be safe and effective for peri-procedural anticoagulation in CA of AF.

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

BACKGROUND: Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. PURPOSE: We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. DATA SOURCE: We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. STUDY SELECTION: Two authors independently reviewed the studies for eligibility. DATA EXTRACTION: Data about studies characteristics, adjusted effect estimates and quality were extracted. DATA SYNTHESIS: Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22-1.7), I(2) = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15-1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). CONCLUSION: In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics.

The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis.

BACKGROUND: Emerging epidemiological evidence suggests that statins may reduce the risk of community-acquired pneumonia (CAP) and its complications. PURPOSE: Performed a systematic review to address the role of statins in the prevention or treatment of CAP. DATA SOURCE: Ovid MEDLINE, Cochrane, EMBASE, ISI Web of Science, and Scopus from inception through December 2011 were searched for randomized clinical trials, cohort and case-control studies. STUDY SELECTION: Two authors independently reviewed studies that examined the role of statins in CAP. DATA EXTRACTION: Data about study characteristics, adjusted effect-estimates and quality characteristics was extracted. DATA SYNTHESIS: Eighteen studies corresponding to 21 effect-estimates (eight and 13 of which addressed the preventive and therapeutic roles of statins, respectively) were included. All studies were of good methodological quality. Random-effects meta-analyses of adjusted effect-estimates were used. Statins were associated with a lower risk of CAP, 0.84 (95% CI, 0.74-0.95), I(2) = 90.5% and a lower short-term mortality in patients with CAP, 0.68 (95% CI, 0.59-0.78), I(2) = 75.7%. Meta-regression did not identify sources of heterogeneity. A funnel plot suggested publication bias in the treatment group, which was adjusted by a novel regression method with a resultant effect-estimate of 0.85 (95% CI, 0.77-0.93). Sensitivity analyses using the rule-out approach showed that it is unlikely that the results were due to an unmeasured confounder. CONCLUSIONS: Our meta-analysis reveals a beneficial role of statins for the risk of development and mortality associated with CAP. However, the results constitute very low quality evidence as per the GRADE framework due to observational study design, heterogeneity and publication bias.

The growing resistance of Klebsiella pneumoniae; the need to expand our antibiogram: case report and review of the literature.

Carbapenemases are being increasingly reported in Enterobacteriaceae including Klebsiella pneumoniae causing considerable increases in morbidity and mortality with limited therapeutic options. Issues related to difficulties associated with pathogen identification and infection control have been identified as major obstacles to the control of these multi-drug resistant organisms. Identification of this enzyme in organisms not previously found to harbor them has added to the already existing challenge in the control of this growing problem. The case of a 60 year-old Saudi lady with diabetes, hypertension, pituitary adenoma, hypothyroidism, and obstructive sleep apnea who was admitted in our intensive care unit following a cardiac arrest is hereby presented. During the course of her treatment she acquired various infections that led to her exposure to antimicrobials from almost all classes at various times; including bacteremia due to a pan-drug resistant Klebsiella pneumoniae and multi-drug resistant Acinetobacter baumannii. She was successfully treated with a combination of colistin and amikacin. This case highlights the resurgence of colistin in clinical practice and also calls for the need to expand our antibiogram to include antibiotics not conventionally reported, especially in areas where drug resistance is a growing problem. Improving susceptibility detection methods for Klebsiella pneumoniae and hand hygiene could prove effective in reducing nosocomial infections. Involvement of clinical pharmacists in antimicrobial stewardship could reduce the development of antimicrobial drug resistance.

Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

INTRODUCTION: Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). METHODS: Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. RESULTS: We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I(2) = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26-1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. CONCLUSIONS: In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship.

Association between preoperative statin therapy and postoperative infectious complications in patients undergoing cardiac surgery: a systematic review and meta-analysis.

Infectious complications of cardiac surgery are often severe and life threatening. Statins having both immunomodulatory and anti-inflammatory effects were intuitively thought to influence the development of postsurgical infections. We sought to systematically examine whether any association exists between statin use and risk of infectious complications in patients undergoing cardiac surgery. We searched Ovid MEDLINE, Ovid EMBASE, Thomson Scientific Web of Science, and Elsevier Scopus from inception through February 2011 for comparative studies examining the association between statin use and risk of postoperative infections in patients undergoing cardiac surgery. We contacted a study's author for missing information. We conducted a random-effects meta-analysis of individual studies' odds ratios (adjusted for potential confounders). We identified 6 cohort studies for inclusion, 3 of which were conducted in Canada and 3 of which were conducted in the United States. Four were single-center studies, and 2 were population based. Exposure ascertainment was based on a review of admission medication list or prescription databases. Infectious outcomes were heterogeneous and included surgical site infections within 30 days, serious infections (sepsis), or any other postoperative infection. Statin use in the preoperative period was associated with a trend toward reduction in the incidence of postoperative infections in patients who underwent cardiac surgery (odds ratio, 0.81 [95% confidence interval, 0.64-1.01]; [Formula: see text]; [Formula: see text]). Heterogeneity was explained by country effect. Studies performed in Canada showed weaker associations than studies performed in the United States. This difference could not be attributed to study quality alone. We did not find good evidence to support an association between statin use and postoperative infectious complications. However, the trend toward statistical significance for this association indicates that further investigation is warranted.

Lemierre's syndrome due to Klebsiella pneumoniae in a 63-year-old man with diabetes: a case report.

INTRODUCTION: Lemierre's syndrome was originally documented to be caused by Fusobacterium necrophorum. It is a very rare condition with a prevalence of one to 14.4 instances per million. Its presentation is varied, not only in composition but also in the infecting organism. Treatment with anticoagulants has been controversial and applied only on a case-by-case basis. CASE PRESENTATION: A 63-year-old Saudi man who had had uncontrolled diabetes mellitus for 47 years presented to our facility with a five-day history of swelling on the right side of his neck and fever. The swelling progressively increased in size and was associated with pain, dysphagia, odynophagia, change of voice ('hot potato voice'), and reduced appetite. Abscess content culture and sensitivity testing revealed Klebsiella pneumoniae. However, blood culture results were repeatedly negative. The abscess was incised and drained without any complication. Our patient was treated with clindamycin and cefuroxime. Warfarin was also administered concurrently for six weeks, for an isolated internal jugular vein thrombosis (IJV), with complete resolution of the thrombus. Normoglycemia was achieved and our patient was discharged after complete wound healing and the return of his biochemical parameters to normal. CONCLUSIONS: Only two cases of Lemierre's syndrome in patients with diabetes due to K. pneumoniae have been reported previously. A review of the literature suggested that an association exists between deep neck infections due to K. pneumoniae and diabetes mellitus. The reasons for this association are still not clear. This poses a question as to whether diabetes mellitus specifically predisposes these patients to infection with this organism. It is suggested that clinicians should consider infectious agents other than F. necrophorum in the causation of Lemierre's syndrome, especially in patients with diabetes.

The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review.

BACKGROUND: Because treatment outcomes of invasive aspergillosis (IA) remain suboptimal, clinicians have resorted to the use of combination antifungal therapy. We therefore sought to systematically review the evidence that addresses the role of combination antifungal therapy in the treatment of invasive aspergillosis. METHODS: We retrieved the literature from MEDLINE, EMBASE, Web of Science, Cochrane Controlled Trials Register, and Scopus from inception up to March 2011 for cohort and randomized controlled trial (RCT) studies that assessed the efficacy of combination antifungal therapy for IA and reported on clinical outcomes. RESULTS: Eight studies (one RCT and seven cohort studies) that enrolled a total of 1071 patients met our inclusion criteria. Six cohort studies examined the role of combination therapy for the primary treatment of IA and two for salvage therapy. Various antifungal combinations were used, mainly azoles with either an echinocandin or a polyene. Of the seven cohort studies, four reported adjusted effect estimates, one of which showed a better outcome with combination antifungal therapy and one a trend towards a better outcome, while the remaining two revealed that there was no added advantage of combination antifungal therapy over monotherapy or a better response with monotherapy, respectively. The randomized controlled trial revealed that the use of combination therapy was associated with a better outcome. CONCLUSION: Cumulative evidence supporting the use of combination antifungal therapy in IA is conflicting and of moderate strength. Well-designed RCTs are required to adequately address the issue of the usefulness of this approach.

Complicated community-acquired Staphylococcus endocarditis and multiple lung abscesses: case report and review of literature.

Background. Isolated tricuspid valve endocarditis in the absence of risk factors in the community setting is very rare and can be easily missed in patients with hitherto normal valves. Case Presentation. We present a case of a 49 year old gentleman who presented with generalized body aches, fever, and jaundice and was initial diagnosed as hepatitis. He subsequently developed recurrent episodes of panic attacks and shortness of breath and later multiple skin abscesses. Further investigations excluded pulmonary embolism but revealed multiple abscesses in the body including the lungs. Blood cultures and culture from abscesses grew S. aureus. An initial transthoracic echocardiogram was normal. A transesophageal echocardiogram subsequently confirmed endocarditis on a normal natural tricuspid valve and multiple lung abscesses. He was successfully treated with appropriate antibiotics. Conclusion. We discuss the pathogenesis of this patient's presentation highlight the need for assessment and proper evaluation of patients with unexplained bacteremia.