A living WHO guideline on drugs for covid-19

UPDATES: This is the twelfth version (eleventh 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 randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19. NEW OR UPDATED RECOMMENDATIONS: • Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use. UNDERSTANDING THE NEW RECOMMENDATIONS: When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted. PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19­strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation­a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation­a conditional recommendation against nirmatrelvir/ritonavir. • 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 the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendations against hydroxychloroquine and 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 evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the 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. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline.

Challenges and health-care priorities for reducing the burden of paediatric sepsis in Latin America: a call to action.

Sepsis is a worldwide public health problem due to its high incidence and accompanying mortality, morbidity, and financial burden. It is a major cause of admission to paediatric intensive care units; despite advances in the diagnosis and treatment, both incidence and mortality are high in low-income and middle-income countries. There are several barriers in addressing the enormous burden of paediatric sepsis in these countries, which include: lack of data of incidence and mortality; unfamiliarity of sepsis by the lay public, leading to failure to seek care early, and by health professionals, leading to failure to treat emergently; and insufficient government funding for sepsis care programmes leading to inadequate staffing, material, and financial resources, and therefore, poor health systems. Socioeconomic inequalities, such as inequity and marked variation in income and education, high rates of malnutrition, high percentage of young population, and health systems that do not meet the population's demands also represent barriers in the care of children with sepsis in Latin America. In this Viewpoint, we draw attention to the problem of paediatric sepsis in Latin America and call for action to reduce the disease burden by proposing some solutions.

Diagnosis and Acute Management of COVID-19 and Multisystem Inflammatory Syndrome in Children.

ABSTRACT: Most children with coronavirus disease 2019 (COVID-19) infection are asymptomatic or have mild disease. About 5% of infected children will develop severe or critical disease. Rapid identification and treatment are essential for children who are critically ill with signs and symptoms of respiratory failure, septic shock, and multisystem inflammatory syndrome in children. This article is intended for pediatricians, pediatric emergency physicians, and individuals involved in the emergency care of children. It reviews the current epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children, summarizes key aspects of clinical assessment including identification of high-risk patients and manifestations of severe disease, and provides an overview of COVID-19 management in the emergency department based on clinical severity.

Repurposing a PICU for Adult Care in a State Mandated COVID-19 Only Hospital: Outcome Comparison to the MICU Cohort to Determine Safety and Effectiveness.

Objective: The ongoing coronavirus 2019 (COVID-19) pandemic is disproportionally impacting the adult population. This study describes the experiences after repurposing a PICU and its staff for adult critical care within a state mandated COVID-19 hospital and compares the outcomes to adult patients admitted to the institution's MICU during the same period. Design: A retrospective chart review was performed to analyze outcomes for the adults admitted to the PICU and MICU during the 27-day period the PICU was incorporated into the institution's adult critical care surge plan. Setting: Tertiary care state University hospital. Patients: Critically ill adult patients with proven or suspected COVID-19. Interventions: To select the most ideal adult patients for PICU admission a tiered approach that incorporated older patients with more comorbidities at each stage was implemented. Measurements and Main Results: There were 140 patients admitted to the MICU and 9 patients admitted to the PICU during this period. The mean age of the adult patients admitted to the PICU was lower (49.1 vs. 63.2 p = 0.017). There was no statistically significant difference in the number of comorbidities, intubation rates, days of ventilation, dialysis or LOS. Patients selected for PICU care did not have coronary artery disease, CHF, cerebrovascular disease or COPD. Mean admission Sequential Organ Failure Assessment (SOFA) score was lower in patients admitted to the PICU (4 vs. 6.4, p = 0.017) with similar rates of survival to discharge (66.7 vs. 44.4%, p = 0.64). Conclusion: Outcomes for the adult patients who received care in the PICU did not appear to be worse than those who were admitted to the MICU during this time. While limited by a small sample size, this single center cohort study revealed that careful assessment of critical illness considering age and type of co-morbidities may be a safe and effective approach in determining which critically ill adult patients with known or suspected COVID-19 are the most appropriate for PICU admission in general hospitals with primary management by its physicians and nurses.

A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

The Surviving Sepsis Campaign: Research Priorities for Coronavirus Disease 2019 in Critical Illness.

OBJECTIVES: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. DESIGN: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. METHODS: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. RESULTS: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? CONCLUSIONS: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019.

Coronavirus Disease 2019 in Critically Ill Children: A Narrative Review of the Literature.

Coronavirus disease 2019 has spread around the world. In the 3 months since its emergence, we have learned a great deal about its clinical management and its relevance to the pediatric critical care provider. In this article, we review the available literature and provide valuable insight into the clinical management of this disease, as well as information on preparedness activities that every PICU should perform.

The US Strategic National Stockpile Ventilators in Coronavirus Disease 2019: A Comparison of Functionality and Analysis Regarding the Emergency Purchase of 200,000 Devices.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was serious concern that the United States would encounter a shortfall of mechanical ventilators. In response, the US government, using the Defense Production Act, ordered the development of 200,000 ventilators from 11 different manufacturers. These ventilators have different capabilities, and whether all are able to support COVID-19 patients is not evident. RESEARCH QUESTION: Evaluate ventilator requirements for affected COVID-19 patients, assess the clinical performance of current US Strategic National Stockpile (SNS) ventilators employed during the pandemic, and finally, compare ordered ventilators' functionality based on COVID-19 patient needs. STUDY DESIGN AND METHODS: Current published literature, publicly available documents, and lay press articles were reviewed by a diverse team of disaster experts. Data were assembled into tabular format, which formed the basis for analysis and future recommendations. RESULTS: COVID-19 patients often develop severe hypoxemic acute respiratory failure and adult respiratory defense syndrome (ARDS), requiring high levels of ventilator support. Current SNS ventilators were unable to fully support all COVID-19 patients, and only approximately half of newly ordered ventilators have the capacity to support the most severely affected patients; ventilators with less capacity for providing high-level support are still of significant value in caring for many patients. INTERPRETATION: Current SNS ventilators and those on order are capable of supporting most but not all COVID-19 patients. Technologic, logistic, and educational challenges encountered from current SNS ventilators are summarized, with potential next-generation SNS ventilator updates offered.

Perspective of the Surviving Sepsis Campaign on the Management of Pediatric Sepsis in the Era of Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 is a novel cause of organ dysfunction in children, presenting as either coronavirus disease 2019 with sepsis and/or respiratory failure or a hyperinflammatory shock syndrome. Clinicians must now consider these diagnoses when evaluating children for septic shock and sepsis-associated organ dysfunction. The Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children provide an appropriate framework for the early recognition and initial resuscitation of children with sepsis or septic shock caused by all pathogens, including severe acute respiratory syndrome coronavirus 2. However, the potential benefits of select adjunctive therapies may differ from non-coronavirus disease 2019 sepsis.

Triage of Scarce Critical Care Resources in COVID-19 An Implementation Guide for Regional Allocation: An Expert Panel Report of the Task Force for Mass Critical Care and the American College of Chest Physicians.

Public health emergencies have the potential to place enormous strain on health systems. The current pandemic of the novel 2019 coronavirus disease has required hospitals in numerous countries to expand their surge capacity to meet the needs of patients with critical illness. When even surge capacity is exceeded, however, principles of critical care triage may be needed as a means to allocate scarce resources, such as mechanical ventilators or key medications. The goal of a triage system is to direct limited resources towards patients most likely to benefit from them. Implementing a triage system requires careful coordination between clinicians, health systems, local and regional governments, and the public, with a goal of transparency to maintain trust. We discuss the principles of tertiary triage and methods for implementing such a system, emphasizing that these systems should serve only as a last resort. Even under triage, we must uphold our obligation to care for all patients as best possible under difficult circumstances.