From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations For Developing Precision Medicine in ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. In order to impact clinical care, identified subpopulations must do more than differentiate prognosis. They must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

Core sepsis-related competencies for medical students: an international consensus by Delphi technique.

BACKGROUND: Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. METHODS: Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13-18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. RESULTS: The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. CONCLUSION: Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development.

BACKGROUND: A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. MAIN TEXT: While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. CONCLUSIONS: A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.

Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises.

High-flow nasal cannula for acute hypoxemic respiratory failure in patients with COVID-19: systematic reviews of effectiveness and its risks of aerosolization, dispersion, and infection transmission.

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.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Lung function in woodsmoke-exposed Guatemalan children following a chimney stove intervention.

RATIONALE: Household air pollution (HAP) from solid fuel combustion is a major contributor to the global burden of disease, with considerable impact from respiratory infections in children. The impact of HAP on lung function is unknown. OBJECTIVES: The Childhood Exposure to Respirable Particulate Matter (CRECER) prospective cohort study followed Guatemalan children who participated in the Randomised Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) trial of a chimney stove intervention to determine the effect of early childhood HAP exposure on growth of lung function. METHODS: RESPIRE households with pregnant women or infant children were randomised to receive a chimney stove at the beginning or at the end of the 18-month trial. During CRECER, a subset of these children, as well as children from households with newly installed stoves, were followed with spirometry beginning at age 5. Biomass smoke exposure was measured using personal carbon monoxide tubes. Two-stage regression models were employed to analyse associations with lung function growth. MEASUREMENTS AND MAIN RESULTS: Longitudinal peak expiratory flow (PEF) and FEV1 data were available for 443 and 437 children, respectively, aged 5-8 (mean follow-up 1.3 years). Decreases in PEF growth of 173 mL/min/year (95% CI -341 to -7) and FEV1 of 44 mL/year (95% CI -91 to 4) were observed with stove installation at 18 months compared with stove installation at birth in analyses adjusted for multiple covariates. No statistically significant associations were observed between personal HAP exposure and lung function. CONCLUSIONS: A significant decrease in PEF growth and a large non-significant decrease in FEV1 growth were observed with later stove installation. Additional studies including longer follow-up and cleaner stoves or fuels are needed.

Severity and outcomes of Omicron variant of SARS-CoV-2 compared to Delta variant and severity of Omicron sublineages: a systematic review and metanalysis.

OBJECTIVES: To compare severity and clinical outcomes from Omicron as compared with the Delta variant and to compare outcomes between Omicron sublineages. METHODS: We searched the WHO COVID-19 Research database for studies that compared clinical outcomes for patients with Omicron variant and the Delta variant, and separately Omicron sublineages BA.1 and BA.2. A random-effects meta-analysis was used to pool estimates of relative risk (RR) between variants and sublineages. Heterogeneity between studies was assessed using the I2 index. Risk of bias was assessed using the tool developed by the Clinical Advances through Research and Information Translation team. RESULTS: Our search identified 1494 studies and 42 met the inclusion criteria. Eleven studies were published as preprints. Of the 42 studies, 29 adjusted for vaccination status; 12 had no adjustment; and for 1, the adjustment was unclear. Three of the included studies compared the sublineages of Omicron BA.1 versus BA.2. As compared with Delta, individuals infected with Omicron had 61% lower risk of death (RR 0.39, 95% CI 0.33 to 0.46) and 56% lower risk of hospitalisation (RR 0.44, 95% CI 0.34 to 0.56). Omicron was similarly associated with lower risk of intensive care unit (ICU) admission, oxygen therapy, and non-invasive and invasive ventilation. The pooled risk ratio for the outcome of hospitalisation when comparing sublineages BA.1 versus BA.2 was 0.55 (95% 0.23 to 1.30). DISCUSSION: Omicron variant was associated with lower risk of hospitalisation, ICU admission, oxygen therapy, ventilation and death as compared with Delta. There was no difference in the risk of hospitalisation between Omicron sublineages BA.1 and BA.2. PROSPERO REGISTRATION NUMBER: CRD42022310880.

WHO O2CoV2: oxygen requirements and respiratory support in patients with COVID-19 in low-and-middle income countries-protocol for a multicountry, prospective, observational cohort study.

INTRODUCTION: SARS-CoV-2 has been identified as the cause of the disease officially named COVID-19, primarily a respiratory illness. COVID-19 was characterised as a pandemic on 11 March 2020. It has been estimated that approximately 20% of people with COVID-19 require oxygen therapy. Oxygen has been listed on the WHO Model List of Essential Medicines List and Essential Medicines List for Children for almost two decades. The COVID-19 pandemic has highlighted, more than ever, the acute need for scale-up of oxygen therapy. Detailed data on the use of oxygen therapy in low-and-middle income countries at the patient and facility level are needed to target interventions better globally. METHODS AND ANALYSIS: We aim to describe the requirements and use of oxygen at the facility and patient level of approximately 4500 patients with COVID-19 in 30 countries. Our objectives are specifically to characterise type and duration of different modalities of oxygen therapy delivered to patients; describe demographics and outcomes of hospitalised patients with COVID-19; and describe facility-level oxygen production and support. Primary analyses will be descriptive in nature. Respiratory support transitions will be described in Sankey plots, and Kaplan-Meier models will be used to estimate probability of each transition. A multistate model will be used to study the course of hospital stay of the study population, evaluating transitions of escalating respiratory support transitions to the absorbing states. ETHICS AND DISSEMINATION: WHO Ad Hoc COVID-19 Research Ethics Review Committee (ERC) has approved this global protocol. When this protocol is adopted at specific country sites, national ERCs may make require adjustments in accordance with their respective national research ethics guidelines. Dissemination of this protocol and global findings will be open access through peer-reviewed scientific journals, study website, press and online media. TRIAL REGISTRATION NUMBER: NCT04918875.

Associated factors for mortality in a COVID-19 colombian cohort: is the third wave relevant when Mu variant was predominant epidemiologically?

OBJECTIVES: To evaluate the association between Colombia's third wave when the Mu variant was predominant epidemiologically (until 75%) in Colombia and COVID-19 all-cause in-hospital mortality. METHODS: In this retrospective cohort, we included hospitalized patients ≥18 years with SARS-CoV-2 infection between March 2020 to September 2021 in ten hospitals from three cities in Colombia. Description analysis, survival, and multivariate Cox regression analyses were performed to evaluate the association between the third epidemic wave and in-hospital mortality. RESULTS: A total of 25,371 patients were included. The age-stratified time-to-mortality curves showed differences according to epidemic waves in patients ≥75 years (log-rank test p = 0.012). In the multivariate Cox analysis, the third wave was not associated with increased mortality relative to the first wave (aHR 0.95; 95%CI 0.84-1.08), but there was an interaction between age ≥75 years and the third wave finding a lower HR for mortality (aHR 0.56, 95%CI 0.36-0.86). CONCLUSIONS: We did not find an increase in in-hospital mortality during the third epidemic wave in which the Mu variant was predominant in Colombia. The reduced hazard in mortality in patients ≥75 years hospitalized in the third wave could be explained by the high coverage of SARS-CoV-2 vaccination in this population and patients with underlying conditions.

A clinical case definition of post-COVID-19 condition by a Delphi consensus.

People with COVID-19 might have sustained postinfection sequelae. Known by a variety of names, including long COVID or long-haul COVID, and listed in the ICD-10 classification as post-COVID-19 condition since September, 2020, this occurrence is variable in its expression and its impact. The absence of a globally standardised and agreed-upon definition hampers progress in characterisation of its epidemiology and the development of candidate treatments. In a WHO-led Delphi process, we engaged with an international panel of 265 patients, clinicians, researchers, and WHO staff to develop a consensus definition for this condition. 14 domains and 45 items were evaluated in two rounds of the Delphi process to create a final consensus definition for adults: post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on everyday functioning. Symptoms might be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms might also fluctuate or relapse over time. A separate definition might be applicable for children. Although the consensus definition is likely to change as knowledge increases, this common framework provides a foundation for ongoing and future studies of epidemiology, risk factors, clinical characteristics, and therapy.

Clinical features of, and risk factors for, severe or fatal COVID-19 among people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-19.

BACKGROUND: WHO has established a Global Clinical Platform for the clinical characterisation of COVID-19 among hospitalised individuals. We assessed whether people living with HIV hospitalised with COVID-19 had increased odds of severe presentation and of in-hospital mortality compared with individuals who were HIV-negative and associated risk factors. METHODS: Between Jan 1, 2020, and July 1, 2021, anonymised individual-level data from 338 566 patients in 38 countries were reported to WHO. Using the Platform pooled dataset, we performed descriptive statistics and regression analyses to compare outcomes in the two populations and identify risk factors. FINDINGS: Of 197 479 patients reporting HIV status, 16 955 (8·6%) were people living with HIV. 16 283 (96.0%) of the 16 955 people living with HIV were from Africa; 10 603 (62·9%) were female and 6271 (37·1%) were male; the mean age was 45·5 years (SD 13·7); 6339 (38·3%) were admitted to hospital with severe illness; and 3913 (24·3%) died in hospital. Of the 10 166 people living with HIV with known antiretroviral therapy (ART) status, 9302 (91·5%) were on ART. Compared with individuals without HIV, people living with HIV had 15% increased odds of severe presentation with COVID-19 (aOR 1·15, 95% CI 1·10-1·20) and were 38% more likely to die in hospital (aHR 1·38, 1·34-1·41). Among people living with HIV, male sex, age 45-75 years, and having chronic cardiac disease or hypertension increased the odds of severe COVID-19; male sex, age older than 18 years, having diabetes, hypertension, malignancy, tuberculosis, or chronic kidney disease increased the risk of in-hospital mortality. The use of ART or viral load suppression were associated with a reduced risk of poor outcomes; however, HIV infection remained a risk factor for severity and mortality regardless of ART and viral load suppression status. INTERPRETATION: In this sample of hospitalised people contributing data to the WHO Global Clinical Platform for COVID-19, HIV was an independent risk factor for both severe COVID-19 at admission and in-hospital mortality. These findings have informed WHO immunisation policy that prioritises vaccination for people living with HIV. As the results mostly reflect the data contribution from Africa, this analysis will be updated as more data from other regions become available. FUNDING: None. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.