Bias as a source of inconsistency in ivermectin trials for COVID-19: A systematic review (preprint)

Background and purposeThe objective of this systematic review is to summarize the effects of ivermectin for the prevention and treatment of patients with COVID-19 and to assess inconsistencies in results from individual studies with focus on risk of bias due to methodological limitations. Evidence reviewWe searched the L.OVE platform through July 6, 2021 and included randomized trials (RCTs) comparing ivermectin to standard or other active treatments. We conducted random-effects pairwise meta-analysis, assessed the certainty of evidence using the GRADE approach and performed sensitivity analysis excluding trials with risk of bias. ResultsWe included 29 RCTs which enrolled 5592 cases. Overall, the certainty of the evidence was very low to low. Compared to standard of care, ivermectin may reduce mortality, may increase symptom resolution or improvement, may increase viral clearance, may reduce infections in exposed individuals and may decrease hospitalizations (Risk difference (RD) 21 fewer per 1000, 95%CI: 35 fewer to 4 more). However, after excluding trials classified as "high risk" or "some concerns" in the risk of bias assessment, most estimates of effect changed substantially: Compared to standard of care, low certainty evidence suggests that ivermectin may not significantly reduce mortality (RD 7 fewer per 1000, 95%CI: 77 fewer to 108 more) nor mechanical ventilation (RD 6 more per 1000, 95%CI: 43 fewer to 86 more), and moderate certainty evidence shows that it probably does not significantly increase symptom resolution or improvement (RD 14 more per 1000, 95%CI: 29 fewer to 71 more) nor viral clearance (RD 12 fewer per 1000, 95%CI: 84 fewer to 76 more). It is uncertain if ivermectin increases or decreases severe adverse events and symptomatic infections in exposed individuals. Conclusions and RelevanceIvermectin may not improve clinically important outcomes in patients with COVID-19 and its effects as a prophylactic intervention in exposed individuals are uncertain. Previous reports concluding significant benefits associated with ivermectin are based on potentially biased results reported by studies with substantial methodological limitations. Further research is needed.

Prognostic Factors for Severity and Mortality in Patients Infected with COVID-19: A Systematic Review (preprint)

Background: The objective of our systematic review is to identify prognostic factors that may be used in decision-making related to the care of patients infected with COVID-19. Methods: We conducted highly sensitive searches in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase. The searches covered the period from the inception date of each database until April 28, 2020. No study design, publication status or language restriction were applied. We included studies that assessed patients with confirmed or suspected SARS-CoV-2 infection and examined one or more prognostic factors for mortality or disease severity. Reviewers working in pairs independently screened studies for eligibility, extracted data and assessed the risk of bias. We performed meta-analyses and used GRADE to assess the certainty of the evidence for each prognostic factor and outcome. Findings: We included 207 studies and found high or moderate certainty that the following 49 variables provide valuable prognostic information on mortality and/or severe disease in patients with COVID-19 infection: Demographic factors (age, male sex, smoking), patient history factors (comorbidities, cerebrovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cardiac arrhythmia, arterial hypertension, diabetes, dementia, cancer and dyslipidemia), physical examination factors (respiratory failure, low blood pressure, hypoxemia, tachycardia, dyspnea, anorexia, tachypnea, haemoptysis, abdominal pain, fatigue, fever and myalgia or arthralgia), laboratory factors (high blood procalcitonin, myocardial injury markers, high blood White Blood Cell count (WBC), high blood lactate, low blood platelet count, plasma creatinine increase, high blood D-dimer, high blood lactate dehydrogenase (LDH), high blood C-reactive protein (CRP), decrease in lymphocyte count, high blood aspartate aminotransferase (AST), decrease in blood albumin, high blood interleukin-6 (IL-6), high blood neutrophil count, high blood B-type natriuretic peptide (BNP), high blood urea nitrogen (BUN), high blood creatine kinase (CK), high blood bilirubin and high erythrocyte sedimentation rate (ESR)), radiological factors (consolidative infiltrate and pleural effusion) and high SOFA score. Interpretation: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infection while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes. Funding Statement: NoneDeclaration of Interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Prognostic factors for severity and mortality in patients infected with COVID-19: A living systematic review protocol (preprint)

Objective The objective of our systematic review is to identify prognostic factors that can potentially be used in decision-making related to the care of patients infected with COVID-19. Design This is the protocol of a living systematic review. Data sources We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L-OVE (Living OVerview of Evidence). L-OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L-OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. Eligibility criteria for selecting studies and methods We will follow a common protocol for multiple parallel systematic reviews, already published and submitted to PROSPERO (awaiting ID allocation). We will include studies that assess patients with confirmed or suspected infection with SARS-CoV-2 and inform the relation of potential prognostic factors with death or disease severity. Two groups of two reviewers will independently screen studies for eligibility, extract data, and assess the risk of bias. We will perform meta-analyses and use GRADE to assess the certainty of evidence for each prognostic factor and outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it if the conclusions change or there are substantial updates. Ethics and dissemination No ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.