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1.
Intern Emerg Med ; 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1797521

ABSTRACT

The global pandemic caused by SARS-CoV-2 (COVID-19) has led to significant morbidity and mortality, and unprecedented economic and health system disruption. Non-pharmacologic interventions (NPIs) such as masking and physical distancing have formed the underpinnings of COVID-19 infection control strategies. Concomitantly, numerous jurisdictions have seen a decrease in hospitalizations for non-COVID-19 respiratory illnesses (NCRIs) such as asthma, community-acquired pneumonia, influenza, and chronic obstructive pulmonary disease relative to pre-pandemic levels. These associations give rise to a number of testable hypotheses regarding the efficacy of NPIs in reducing the substantial burden of NCRIs. Here, we review emerging perspectives on the role of NPIs in NCRI prevention with the ultimate goal of informing future research and public policy development as we move into what may be the endemic phase of the COVID-19 pandemic.

2.
JMIR Res Protoc ; 11(1): e33989, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1573631

ABSTRACT

BACKGROUND: Severe infections are characterized by inflammation and oxidative damage. Ascorbic acid (vitamin C) administration may attenuate oxidative damage and, in turn, reduce vascular endothelial injury in pulmonary and systemic vasculature. OBJECTIVE: We aim to describe a protocol for a living systematic review that will evaluate the effectiveness and safety of parenteral vitamin C administration in adults with severe infections, including those with COVID-19. METHODS: We searched Ovid MEDLINE, Embase, CINAHL, the Centers for Disease Control and Prevention COVID-19 database, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to March 30, 2021, for randomized controlled trials evaluating parenteral vitamin C versus no parenteral vitamin C in hospitalized adults with severe infection. Eligible studies will include at least 1 arm involving any dose of parenteral vitamin C alone or in combination with other cointerventions and at least 1 arm not involving parenteral vitamin C. The primary outcomes of interest will include in-hospital, 30-day, and 90-day mortality. Title and abstract screening, full-text screening, data extraction, and risk of bias evaluation via a modified Risk of Bias 2.0 tool will be conducted independently and in pairs. We will perform random effects modeling for meta-analyses, in which study weights will be generated by using the inverse variance method. We will assess certainty in effect estimates by using the Grading of Recommendations Assessment, Development and Evaluation methodology. Meta-analyses will be updated iteratively as new trial evidence becomes available. RESULTS: Among the 1386 citations identified as of March 30, 2021, a total of 17 eligible randomized controlled trials have been identified as of September 2021. We are in the process of updating the search strategy and associated data analyses. CONCLUSIONS: The results will be of importance to critical care physicians and hospitalists who manage severe infection and COVID-19 in daily practice, and they may directly inform international clinical guidance. Although our systematic review will incorporate the most recent trial evidence, ongoing trials may change our confidence in the estimates of effects, thereby necessitating iterative updates in the form of a living review. TRIAL REGISTRATION: PROSPERO CRD42020209187; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209187. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/33989.

3.
JAMA Netw Open ; 4(12): e2136263, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1565151

ABSTRACT

Importance: The COVID-19 pandemic created the need for rapid and urgent guidance for clinicians to manage COVID-19 among patients and prevent transmission. Objective: To appraise the quality of clinical practice guidelines (CPGs) using the National Academy of Medicine (NAM) criteria. Evidence Review: A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials to December 14, 2020, and a search of related articles to February 28, 2021, that included CPGs developed by societies or by government or nongovernment organizations that reported pharmacologic treatments of hospitalized patients with COVID-19. Teams of 2 reviewers independently abstracted data and assessed CPG quality using the 15-item National Guideline Clearinghouse Extent of Adherence to Trustworthy Standards (NEATS) instrument. Findings: Thirty-two CPGs were included in the review. Of these, 25 (78.1%) were developed by professional societies and emanated from a single World Health Organization (WHO) region. Overall, the CPGs were of low quality. Only 7 CPGs (21.9%) reported funding sources, and 12 (37.5%) reported conflicts of interest. Only 5 CPGs (15.6%) included a methodologist, described a search strategy or study selection process, or synthesized the evidence. Although 14 CPGs (43.8%) made recommendations or suggestions for or against treatments, they infrequently rated confidence in the quality of the evidence (6 of 32 [18.8%]), described potential benefits and harms (6 of 32 [18.8%]), or graded the strength of the recommendations (5 of 32 [15.6%]). External review, patient or public perspectives, or a process for updating were rare. High-quality CPGs included a methodologist and multidisciplinary collaborations involving investigators from 2 or more WHO regions. Conclusions and Relevance: In this review, few COVID-19 CPGs met NAM standards for trustworthy guidelines. Approaches that prioritize engagement of a methodologist and multidisciplinary collaborators from at least 2 WHO regions may lead to the production of fewer, high-quality CPGs that are poised for updates as new evidence emerges. Trial Registration: PROSPERO Identifier: CRD42021245239.


Subject(s)
COVID-19/drug therapy , Delivery of Health Care/standards , Hospitalization , Pandemics , Practice Guidelines as Topic/standards , Academies and Institutes , Humans , SARS-CoV-2 , Societies, Medical , Trust
4.
Can J Anaesth ; 67(9): 1217-1248, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-1536371

ABSTRACT

PURPOSE: We conducted two World Health Organization-commissioned reviews to inform use of high-flow nasal cannula (HFNC) in patients with coronavirus disease (COVID-19). We synthesized the evidence regarding efficacy and safety (review 1), as well as risks of droplet dispersion, aerosol generation, and associated transmission (review 2) of viral products. SOURCE: Literature searches were performed in Ovid MEDLINE, Embase, Web of Science, Chinese databases, and medRxiv. Review 1: we synthesized results from randomized-controlled trials (RCTs) comparing HFNC to conventional oxygen therapy (COT) in critically ill patients with acute hypoxemic respiratory failure. Review 2: we narratively summarized findings from studies evaluating droplet dispersion, aerosol generation, or infection transmission associated with HFNC. For both reviews, paired reviewers independently conducted screening, data extraction, and risk of bias assessment. We evaluated certainty of evidence using GRADE methodology. PRINCIPAL FINDINGS: No eligible studies included COVID-19 patients. Review 1: 12 RCTs (n = 1,989 patients) provided low-certainty evidence that HFNC may reduce invasive ventilation (relative risk [RR], 0.85; 95% confidence interval [CI], 0.74 to 0.99) and escalation of oxygen therapy (RR, 0.71; 95% CI, 0.51 to 0.98) in patients with respiratory failure. Results provided no support for differences in mortality (moderate certainty), or in-hospital or intensive care length of stay (moderate and low certainty, respectively). Review 2: four studies evaluating droplet dispersion and three evaluating aerosol generation and dispersion provided very low certainty evidence. Two simulation studies and a crossover study showed mixed findings regarding the effect of HFNC on droplet dispersion. Although two simulation studies reported no associated increase in aerosol dispersion, one reported that higher flow rates were associated with increased regions of aerosol density. CONCLUSIONS: High-flow nasal cannula may reduce the need for invasive ventilation and escalation of therapy compared with COT in COVID-19 patients with acute hypoxemic respiratory failure. This benefit must be balanced against the unknown risk of airborne transmission.


RéSUMé: OBJECTIF: Nous avons réalisé deux comptes rendus sur commande de l'Organisation mondiale de la santé pour guider l'utilisation de canules nasales à haut débit (CNHD) chez les patients ayant contracté le coronavirus (COVID-19). Nous avons synthétisé les données probantes concernant leur efficacité et leur innocuité (compte rendu 1), ainsi que les risques de dispersion des gouttelettes, de génération d'aérosols, et de transmission associée d'éléments viraux (compte rendu 2). SOURCE: Des recherches de littérature ont été réalisées dans les bases de données Ovid MEDLINE, Embase, Web of Science, ainsi que dans les bases de données chinoises et medRxiv. Compte rendu 1 : nous avons synthétisé les résultats d'études randomisées contrôlées (ERC) comparant les CNHD à une oxygénothérapie conventionnelle chez des patients en état critique atteints d'insuffisance respiratoire hypoxémique aiguë. Compte rendu 2 : nous avons résumé sous forme narrative les constatations d'études évaluant la dispersion de gouttelettes, la génération d'aérosols ou la transmission infectieuse associées aux CNHD. Pour les deux comptes rendus, des réviseurs appariés ont réalisé la sélection des études, l'extraction des données et l'évaluation du risque de biais de manière indépendante. Nous avons évalué la certitude des données probantes en nous fondant sur la méthodologie GRADE. CONSTATATIONS PRINCIPALES: Aucune étude éligible n'incluait de patients atteints de COVID-19. Compte rendu 1 : 12 ERC (n = 1989 patients) ont fourni des données probantes de certitude faible selon lesquelles les CNHD réduiraient la ventilation invasive (risque relatif [RR], 0,85; intervalle de confiance [IC] 95 %, 0,74 à 0,99) et l'intensification de l'oxygénothérapie (RR, 0,71; IC 95 %, 0,51 à 0,98) chez les patients atteints d'insuffisance respiratoire. Les résultats n'ont pas démontré de différences en matière de mortalité (certitude modérée), ni de durée du séjour hospitalier ou à l'unité des soins intensifs (certitude modérée et faible, respectivement). Compte rendu 2 : quatre études évaluant la dispersion de gouttelettes et trois évaluant la génération et la dispersion d'aérosols ont fourni des données probantes de très faible certitude. Deux études de simulation et une étude croisée ont donné des résultats mitigés quant à l'effet des CNHD sur la dispersion des gouttelettes. Bien que deux études de simulation n'aient rapporté aucune augmentation associée concernant la dispersion d'aérosols, l'une a rapporté que des taux de débit plus élevés étaient associés à des régions à densité d'aérosols élevée plus grandes. CONCLUSION: Les canules nasales à haut débit pourraient réduire la nécessité de recourir à la ventilation invasive et l'escalade des traitements par rapport à l'oxygénothérapie conventionnelle chez les patients atteints de COVID-19 souffrant d'insuffisance respiratoire hypoxémique aiguë. Cet avantage doit être soupesé contre le risque inconnu de transmission atmosphérique.


Subject(s)
Coronavirus Infections/therapy , Oxygen Inhalation Therapy/methods , Pneumonia, Viral/therapy , Respiratory Insufficiency/therapy , Aerosols , COVID-19 , Cannula , Coronavirus Infections/complications , Coronavirus Infections/mortality , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Randomized Controlled Trials as Topic , Respiratory Insufficiency/physiopathology , Respiratory Insufficiency/virology
5.
J Clin Epidemiol ; 139: 68-79, 2021 11.
Article in English | MEDLINE | ID: covidwho-1466592

ABSTRACT

OBJECTIVE: To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. STUDY DESIGN: We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. RESULTS: We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. CONCLUSIONS: There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. REGISTRATION: CRD42020192095.


Subject(s)
COVID-19/prevention & control , Randomized Controlled Trials as Topic/methods , Research Design/standards , COVID-19/epidemiology , Epidemiologic Studies , Humans
6.
Ann Intern Med ; 174(8): JC95, 2021 08.
Article in English | MEDLINE | ID: covidwho-1405521

ABSTRACT

SOURCE CITATION: Chua F, Vancheeswaran R, Draper A, et al. Early prognostication of COVID-19 to guide hospitalisation versus outpatient monitoring using a point-of-test risk prediction score. Thorax. 2021;76:696-703. 33692174.


Subject(s)
COVID-19 , Adult , Hospital Mortality , Hospitalization , Humans , Risk Factors , SARS-CoV-2
7.
Ann Intern Med ; 174(6): W58-W59, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1278693
8.
BMJ ; 373: n949, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1203960

ABSTRACT

OBJECTIVE: To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021. STUDY SELECTION: Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS: The first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. CONCLUSIONS: Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.


Subject(s)
COVID-19 , Carrageenan/pharmacology , Global Health/statistics & numerical data , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Anti-Infective Agents/pharmacology , COVID-19/prevention & control , Chemoprevention/methods , Chemoprevention/statistics & numerical data , Humans , SARS-CoV-2 , Treatment Outcome , Uncertainty
9.
BMJ Open ; 11(3): e040616, 2021 03 17.
Article in English | MEDLINE | ID: covidwho-1140331

ABSTRACT

OBJECTIVES: SARS-CoV-2-related disease, referred to as COVID-19, has emerged as a global pandemic since December 2019. While there is growing recognition regarding possible airborne transmission, particularly in the setting of aerosol-generating procedures and treatments, whether nasopharyngeal and oropharyngeal swabs for SARS-CoV-2 generate aerosols remains unclear. DESIGN: Systematic review. DATA SOURCES: We searched Ovid MEDLINE and EMBASE up to 3 November 2020. We also searched the China National Knowledge Infrastructure, Chinese Medical Journal Network, medRxiv and ClinicalTrials.gov up to 29 March 2020. ELIGIBILITY CRITERIA: All comparative and non-comparative studies that evaluated dispersion or aerosolisation of viable airborne organisms, or transmission of infection associated with nasopharyngeal or oropharyngeal swab testing. RESULTS: Of 7702 citations, only one study was deemed eligible. Using a dedicated sampling room with negative pressure isolation room, personal protective equipment including N95 or higher masks, strict sterilisation protocols, structured training with standardised collection methods and a structured collection and delivery system, a tertiary care hospital proved a 0% healthcare worker infection rate among eight nurses conducting over 11 000 nasopharyngeal swabs. No studies examining transmissibility with other safety protocols, nor any studies quantifying the risk of aerosol generation with nasopharyngeal or oropharyngeal swabs for detection of SARS-CoV-2, were identified. CONCLUSIONS: There is limited to no published data regarding aerosol generation and risk of transmission with nasopharyngeal and oropharyngeal swabs for the detection of SARS-CoV-2. Field experiments to quantify this risk are warranted. Vigilance in adhering to current standards for infection control is suggested.


Subject(s)
Aerosols , COVID-19 Testing/instrumentation , COVID-19/diagnosis , COVID-19/transmission , Humans , Infection Control , Nasopharynx/virology , Oropharynx/virology , Pandemics
10.
J Clin Epidemiol ; 129: 1-11, 2021 01.
Article in English | MEDLINE | ID: covidwho-1012425

ABSTRACT

OBJECTIVES: The aim of this study is to propose an approach for developing trustworthy recommendations as part of urgent responses (1-2 week) in the clinical, public health, and health systems fields. STUDY DESIGN AND SETTING: We conducted a review of the literature, outlined a draft approach, refined the concept through iterative discussions, a workshop by the Grading of Recommendations Assessment, Development and Evaluation Rapid Guidelines project group, and obtained feedback from the larger Grading of Recommendations Assessment, Development and Evaluation working group. RESULTS: A request for developing recommendations within 2 week is the usual trigger for an urgent response. Although the approach builds on the general principles of trustworthy guideline development, we highlight the following steps: (1) assess the level of urgency; (2) assess feasibility; (3) set up the organizational logistics; (4) specify the question(s); (5) collect the information needed; (6) assess the adequacy of identified information; (7) develop the recommendations using one of the 4 potential approaches: adopt existing recommendations, adapt existing recommendations, develop new recommendations using existing adequate systematic review, or develop new recommendations using expert panel input; and (8) consider an updating plan. CONCLUSION: An urgent response for developing recommendations requires building a cohesive, skilled, and highly motivated multidisciplinary team with the necessary clinical, scientific, and methodological expertise; adapting to shifting needs; complying with the principles of transparency; and properly managing conflicts of interest.


Subject(s)
Information Management , Practice Guidelines as Topic/standards , Consensus , Evidence-Based Medicine/standards , Evidence-Based Medicine/trends , Humans , Information Management/methods , Information Management/organization & administration , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/organization & administration , Systematic Reviews as Topic
11.
PLoS One ; 15(11): e0241955, 2020.
Article in English | MEDLINE | ID: covidwho-930640

ABSTRACT

BACKGROUND AND PURPOSE: 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. DATA SOURCES: 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. STUDY SELECTION AND DATA EXTRACTION: We included studies that assessed patients with confirmed or suspected SARS-CoV-2 infectious disease 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. RESULTS: 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 infectious disease: 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 (sequential organ failure assessment score). CONCLUSION: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infectious disease while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes. SYSTEMATIC REVIEW REGISTRATION: Prospero registration number: CRD42020178802. Protocol available at: https://www.medrxiv.org/content/10.1101/2020.04.08.20056598v1.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Aged , Aging , Betacoronavirus , COVID-19 , Comorbidity , Data Management , Female , Humans , Male , Middle Aged , Pandemics , Prognosis , Risk Factors , SARS-CoV-2 , Socioeconomic Factors
13.
BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-744846

ABSTRACT

UPDATES: This is the tenth version (ninth update) of the living guideline, replacing earlier versions, available as data supplements. New recommendations will be published as updates to this guideline. CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19? CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous recently completed randomised controlled trials (RCTs). In this update the Guideline Development Group (GDG) developed new recommendations for patients with non-severe covid-19, concerning the use of nirmatrelvir/ritonavir (2 RCTs, 3100 participants) and remdesivir (5 RCTs, 2710 participants). We have also revised the structure of the guideline to accommodate for an increasing number of effective treatment options to choose between. NEW RECOMMENDATION: • Nirmatrelvir/ritonavir: a strong recommendation for its use in patients at highest risk of hospitalisation; and a conditional recommendation against its use in patients at low risk of hospitalisation. In the absence of trial data, no recommendation on nirmatrelvir/ritonavir was made in patients with severe or critical illness. • Remdesivir: a conditional recommendation for its use in patients at highest risk of hospitalisation. UNDERSTANDING THE NEW RECOMMENDATIONS: In patients with non-severe illness at highest risk of hospitalisation, the recommendations for treatment with nirmatrelvir/ritonavir and remdesivir reflect what the GDG considered to be important reductions in admission to hospital (moderate certainty) with little or no impact on mortality, mechanical ventilation, time to symptom resolution (low to very low certainty), and adverse effects leading to drug discontinuation (high certainty for nirmatrelvir/ritonavir, moderate certainty for remdesivir), though diarrhoea and altered taste were noted more often with nirmatrelvir/ritonavir. Several treatment alternatives are now available for patients with non-severe covid-19 at highest risk of hospitalisation. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis have been used to inform the use of one drug over another with a related mechanism of action. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir), duration of treatment, and time from onset of symptoms to starting treatment in the trials. The strong recommendation for nirmatrelvir/ritonavir reflects what the GDG considered to represent a superior choice over other treatment options for those with non-severe illness at highest risk; it may prevent more hospitalisations than the alternatives, has fewer harms than molnupiravir, and is easier to administer than intravenous options such as remdesivir and the monoclonal antibodies. For monoclonal antibodies, efficacy may depend on the given SARS-CoV-2 variant, with a less certain benefit seen with the omicron BA1-2 variant which is dominating in many regions. There are no clinical data on combination treatment, and currently the GDG advises against combining antivirals in the absence of supporting evidence. UPDATES TO PRIOR RECOMMENDATIONS: The conditional (weak) recommendation for remdesivir in patients with non-severe illness at highest risk of hospitalisation replaces a previous conditional recommendation against treatment with remdesivir in all patients with covid-19 regardless of disease severity. The recommendation for patients with severe or critical illness is being updated using new evidence. PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19­a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab), in combination with corticosteroids; a strong recommendation for baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids; and a conditional recommendation for casirivimab-imdevimab, for those with seronegative status, (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Recommended for patients with non-severe covid-19­conditional recommendations for those at highest risk of hospitalisation for molnupiravir; sotrovimab; and for casirivimab-imdevimab (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma. • Not recommended for patients with severe or critical covid-19­a recommendation against convalescent plasma, except in the context of a clinical trial; and a conditional recommendation against ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial. ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new recommendations on two drugs for covid-19 and updates existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Humans , Pandemics , SARS-CoV-2 , World Health Organization
14.
BMJ ; 370: m2980, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-691120

ABSTRACT

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. CONCLUSION: Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiration, Artificial/statistics & numerical data , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Betacoronavirus/pathogenicity , COVID-19 , Centers for Disease Control and Prevention, U.S./statistics & numerical data , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Databases, Factual/statistics & numerical data , Drug Combinations , Evidence-Based Medicine/methods , Evidence-Based Medicine/statistics & numerical data , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Network Meta-Analysis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Standard of Care , Treatment Outcome , United States/epidemiology
15.
BMJ ; 370: m2924, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-691027

ABSTRACT

CLINICAL QUESTION: What is the role of remdesivir in the treatment of severe covid-19? This guideline was triggered by the ACTT-1 trial published in the New England Journal of Medicine on 22 May 2020. CURRENT PRACTICE: Remdesivir has received worldwide attention as a potentially effective treatment for severe covid-19. After rapid market approval in the US, remdesivir is already being used in clinical practice. RECOMMENDATIONS: The guideline panel makes a weak recommendation for the use of remdesivir in severe covid-19 while recommending continuation of active enrolment of patients into ongoing randomised controlled trials examining remdesivir. HOW THIS GUIDELINE WAS CREATED: An international panel of patients, clinicians, and methodologists produced these recommendations in adherence with standards for trustworthy guidelines using the GRADE approach. The recommendations are based on a linked systematic review and network meta-analysis. The panel considered an individual patient perspective and allowed contextual factors (such as resources) to be taken into account for countries and healthcare systems. THE EVIDENCE: The linked systematic review (published 31 Jul 2020) identified two randomised trials with 1300 participants, showing low certainty evidence that remdesivir may be effective in reducing time to clinical improvement and may decrease mortality in patients with severe covid-19. Remdesivir probably has no important effect on need for invasive mechanical ventilation. Remdesivir may have little or no effect on hospital length of stay. UNDERSTANDING THE RECOMMENDATION: Most patients with severe covid-19 would likely choose treatment with remdesivir given the potential reduction in time to clinical improvement. However, given the low certainty evidence for critical outcomes and the fact that different perspectives, values, and preferences may alter decisions regarding remdesivir, the panel issued a weak recommendation with strong support for continued recruitment in randomised trials.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Guideline Adherence , Humans , Length of Stay/statistics & numerical data , Network Meta-Analysis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2 , Severity of Illness Index , Time Factors , Treatment Outcome
16.
Canadian Journal of Anaesthesia ; 2020.
Article | WHO COVID | ID: covidwho-608089

ABSTRACT

PURPOSE: We conducted two World Health Organization-commissioned reviews to inform use of high-flow nasal cannula (HFNC) in patients with coronavirus disease (COVID-19). We synthesized the evidence regarding efficacy and safety (review 1), as well as risks of droplet dispersion, aerosol generation, and associated transmission (review 2) of viral products. SOURCE: Literature searches were performed in Ovid MEDLINE, Embase, Web of Science, Chinese databases, and medRxiv. Review 1: we synthesized results from randomized-controlled trials (RCTs) comparing HFNC to conventional oxygen therapy (COT) in critically ill patients with acute hypoxemic respiratory failure. Review 2: we narratively summarized findings from studies evaluating droplet dispersion, aerosol generation, or infection transmission associated with HFNC. For both reviews, paired reviewers independently conducted screening, data extraction, and risk of bias assessment. We evaluated certainty of evidence using GRADE methodology. PRINCIPAL FINDINGS: No eligible studies included COVID-19 patients. Review 1: 12 RCTs (n = 1,989 patients) provided low-certainty evidence that HFNC may reduce invasive ventilation (relative risk [RR], 0.85;95% confidence interval [CI], 0.74 to 0.99) and escalation of oxygen therapy (RR, 0.71;95% CI, 0.51 to 0.98) in patients with respiratory failure. Results provided no support for differences in mortality (moderate certainty), or in-hospital or intensive care length of stay (moderate and low certainty, respectively). Review 2: four studies evaluating droplet dispersion and three evaluating aerosol generation and dispersion provided very low certainty evidence. Two simulation studies and a crossover study showed mixed findings regarding the effect of HFNC on droplet dispersion. Although two simulation studies reported no associated increase in aerosol dispersion, one reported that higher flow rates were associated with increased regions of aerosol density. CONCLUSIONS: High-flow nasal cannula may reduce the need for invasive ventilation and escalation of therapy compared with COT in COVID-19 patients with acute hypoxemic respiratory failure. This benefit must be balanced against the unknown risk of airborne transmission.

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