Values and preferences in COVID-19 public health guidelines: A systematic review (preprint)

Abstract Background: Internationally accepted standards for trustworthy guidelines include the necessity to ground recommendations in values and preferences. Considering values and preferences respects the rights of citizens to participate in health decision-making and ensures that guidelines align with the needs and priorities of the communities they are intended to serve. Early anecdotal reports suggest that COVID-19 public health guidelines did not consider values and preferences. Objective: To capture and characterize whether and how COVID-19 public health guidelines considered values and preferences. Methods: We performed a systematic review of COVID-19 public health guidelines. We searched the eCOVID19 RecMap platform-a comprehensive international catalog of COVID-19 guidelines-up to July 2023. We included guidelines that made recommendations addressing vaccination, masking, isolation, lockdowns, travel restrictions, contact tracing, infection surveillance, and school closures. Reviewers worked independently and in duplicate to review guidelines for consideration of values and preferences. Results: Our search yielded 129 eligible guidelines, of which 43 (33.3%) were published by national organizations, 73 (56.6%) by international organizations, and 14 (10.9%) by professional societies and associations. Twenty-six (20.2%) guidelines considered values and preferences. Among guidelines that considered values and preferences, most did so to assess the acceptability of recommendations (23; 88.5%) and by referencing published research (24; 92.3%). Guidelines only occasionally engaged laypersons as part of the guideline development group (6; 23.1%). None of the guidelines performed systematic reviews of the literature addressing values and preferences. Conclusion: Most COVID-19 public health guidelines did not consider values and preferences. When values and preferences were considered, it was suboptimal. Disregard for values and preferences in guidelines might have partly contributed to divisive and unpopular COVID-19 policies. Given the possibility of future health emergencies, we recommend guideline developers identify efficient methods for considering values and preferences in crisis situations.

Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis (preprint)

Background: Up to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia, and impaired cognitive function, termed post COVID-19 condition or long COVID. Several trials that study the benefits and harms of various interventions to manage long COVID have been published and hundreds more are planned or are ongoing. Trustworthy systematic reviews that clarify the benefits and harms of interventions are critical to promote evidence-based practice. Objective To create and maintain a living systematic review and network meta-analysis addressing the benefits and harms of pharmacologic and non-pharmacologic interventions for the treatment and management of long COVID. Methods Eligible trials will randomize adults with long COVID, to pharmacologic or non-pharmacologic interventions, placebo, sham, or usual care. We will identify eligible studies by searches of MEDLINE, EMBASE, CINAHL, PsycInfo, AMED, and CENTRAL, from inception, without language restrictions. Reviewers will work independently and in duplicate to screen search records, collect data from eligible trials, including trial and patient characteristics and outcomes of interest, and assess risk of bias. Our outcomes of interest will include fatigue, pain, post-exertional malaise, changes in education or employment status, cognitive function, mental health, dyspnea, quality of life, patient-reported physical function, recovery, and serious adverse events. For each outcome, when possible, we will perform a frequentist random-effects network meta-analysis. When there are compelling reasons to suspect that certain interventions are only applicable or effective for a subtype of long COVID, we will perform separate network meta-analyses. The GRADE approach will guide our assessment of the certainty of evidence. We will update our living review biannually, upon the publication of a seminal trial, or when new evidence emerges that may change clinical practice. Conclusion This living systematic review and network meta-analysis will provide comprehensive, trustworthy, and up-to-date summaries of the evidence addressing the benefits and harms of interventions for the treatment and management of long COVID. We will make our findings available publicly and work with guideline producing organizations to inform their recommendations.

Effects of allocation concealment and blinding in trials addressing treatments for COVID-19: A methods study (preprint)

Objective: Assess the impact of allocation concealment and blinding on the results of trials addressing COVID-19 therapeutics. Data sources: World Health Organization (WHO) COVID-19 database and the Living Overview of the Evidence (L-OVE) COVID-19 platform by the Epistemonikos Foundation (up to February 4th 2022) Methods: We included trials that compared drug treatments, antiviral antibodies and cellular therapies with placebo or standard care. For the five most commonly reported outcomes, if sufficient data were available, we performed random-effects meta-regression comparing the results of trials with and without allocation concealment and trials in which both healthcare providers and patients were blinded with trials in which healthcare providers and/or patients were aware of the intervention. A ratio of odds ratios (ROR) > 1 or a difference in mean difference (DMD) > 0 indicates that trials without allocation concealment or open-label trials produced larger effects than trials with allocation concealment or blinded trials. Results: As of February 4th 2022, we have identified 488 trials addressing COVID-19 drug treatments and antiviral antibodies and cellular therapies. Of these, 436 trials reported on one or more of our outcomes of interest and were included in our analyses. We found that trials without allocation concealment probably overestimate mortality (ROR 1.14 [95% CI 0.92 to 1.41]), need for mechanical ventilation (ROR 1.26 [95% CI 0.97 to 1.64]), admission to hospital (ROR 1.93 [95% CI 0.83 to 4.48]), duration of hospitalization (DMD 1.94 [95% CI 0.86 to 3.02]), and duration of mechanical ventilation (DMD 2.64 [95% CI -0.90 to 6.18]), but results were imprecise. We did not find compelling evidence that double-blind and open-label trials produce consistently different results for mortality (ROR 1.00 [95% CI 0.87 to 1.15]), need for mechanical ventilation (ROR 1.03 [95% CI 0.84 to 1.26]), and duration of hospitalization (DMD 0.47 days [95% CI -0.38 to 1.32]). We found that open-label trials may overestimate the beneficial effects of interventions for hospitalizations (ROR 1.87 [95% CI 0.95 to 3.67] and duration of mechanical ventilation (DMD 1.02 days [95% CI -1.30 to 3.35]), but results were imprecise. Conclusion: We found compelling evidence that, compared to trials with allocation concealment, trials without allocation concealment may overestimate the beneficial effects of treatments. We did not find evidence that trials without blinding addressing COVID-19 interventions produce consistently different results from trials with blinding. Our results suggest that consideration of blinding status may not be sufficient to judge risk of bias due to imbalances in co-interventions. Evidence users may consider evidence of differences in co-interventions between trial arms when judging the trustworthiness of open-label trials. We suggest, however, evidence users to remain skeptical of trials without allocation concealment.

The trustworthiness and impact of trial preprints for COVID-19 decision-making: A methodological study (preprint)

Purpose: To assess the trustworthiness and impact of preprint trial reports during the COVID-19 pandemic. Data sources: WHO COVID-19 database and the L-OVE COVID-19 platform by the Epistemonikos Foundation (up to August 3rd, 2021) Design: We compare the characteristics of COVID-19 trials with and without preprints, estimate time to publication of COVID-19 preprint reports, describe discrepancies in key methods and results between preprint and published trial reports, report the number of retracted preprints and publications, and assess whether including versus excluding preprint reports affects meta-analytic estimates and the certainty of evidence. For the effects of eight therapies on mortality and mechanical ventilation, we performed meta-analyses including preprints and excluding preprints at 1 month, 3 months, and 6 months after the first trial addressing the therapy became available either as a preprint or publication (120 meta-analyses in total). Results: We included 356 trials, 101 of which are only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. Half of all preprints remain unpublished at six months and a third at one year. There were few important differences in key methods and results between trial preprints and their subsequent published reports. We identified four retracted trials, three of which were published in peer-reviewed journals. With two exceptions (2/60; 3.3%), point estimates were consistent between meta-analyses including versus excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. There were nine comparisons (9/60; 15%) for which the rating of the certainty of evidence differed when preprints were included versus excluded, for four of these comparisons the certainty of evidence including preprints was higher and for five of these comparisons the certainty of evidence including preprints was lower. Limitations: The generalizability of our results is limited to COVID-19. Preprints that are subsequently published in journals may be the most rigorous and may not represent all trial preprints. Conclusion: We found no compelling evidence that preprints provide less trustworthy results than published papers. We show that preprints remain the only source of findings of many trials for several months, for a length of time that is unacceptable in a health emergency. We show that including preprints may affect the results of meta-analyses and the certainty of evidence. We encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed.

Higher versus lower dose corticosteroids for severe to critical COVID-19: A systematic review and dose-response meta-analysis (preprint)

Rationale Corticosteroids are standard of care for patients with severe COVID-19. However, the optimal dose is uncertain. Objective To compare higher doses of corticosteroids with lower doses in patients with COVID-19. Methods We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to August 1st, 2022, for trials that randomized patients with severe-to-critical COVID-19 to corticosteroids, standard care, or placebo. Reviewers, working in duplicate, screened references, extracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. We performed a dose-response meta-analysis and used the GRADE framework to assess the certainty of evidence. We present our results both in relative risk and  absolute risk difference (RD) per 1000 with 95% confidence intervals (CI). Results We included 20 trials, with 10,155 patients. We show that, compared to lower-dose corticosteroids, higher-dose corticosteroids probably reduce mortality (RD 14 fewer deaths per 1000 [95% CI 26 to 2 fewer]; moderate certainty), may reduce the need for mechanical ventilation (RD 11.6 fewer per 1000 [95% CI 23.2 fewer to 6.9 more]; low certainty) and may or may not reduce risk of nosocomial infections (16.7 fewer infections per 1000 [95% CI 5.4 to 25.0 fewer]; very low certainty). Conclusions Relatively higher doses of corticosteroids may be beneficial in patients with severe-to-critical COVID-19 and may not increase the risk of nosocomial infections.

External Validation of the 4C Mortality Score among COVID-19 Patients Visiting the Emergency Department or admitted to Hospital in Ontario, Canada (preprint)

Objectives: Risk prediction scores are important tools to support clinical decision-making for patients with coronavirus disease (COVID-19). The objective of this paper was to validate the 4C mortality score, originally developed in the United Kingdom, for a Canadian population. Methods: We conducted an external validation study within a registry of COVID-19 positive emergency department visits and hospital admissions in the Kitchener-Waterloo and Hamilton regions of southern Ontario between March 4 and January 9, 2020.  We examined the validity of the 4C score to prognosticate in-hospital mortality using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals calculated via bootstrapping. Results: The study included 560 individuals, of whom 115 (20.5%) died in-hospital. Median age was 69 years and 281 individuals (51%) were male. The AUC of the 4C score was 0.83, 95% confidence interval 0.79-0.87. Mortality rates across the pre-defined risk groups were 0% (Low), 3.2% (Intermediate), 25.9% (High), and 59.5% (Very High). The AUC was 0.80 (0.76-0.85) among hospital inpatients.  Interpretation: The 4C score is a valid tool to prognosticate mortality from COVID-19 in Canadian emergency departments and hospitals.