Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)

Characteristics, treatment and in-hospital outcomes of patients with STEMI in a metropolitan area of a developing country: an initial report of the extended Jakarta Acute Coronary Syndrome registry

Objective: We studied the characteristics of patients with ST segment elevation myocardial infarction (STEMI) after expansion of a STEMI registry as part of the STEMI network programme in a metropolitan city and the surrounding area covering ∼26 million inhabitants. Design: Retrospective cohort study. Setting: Emergency department of 56 health centres. Participants: 3015 patients with acute coronary syndrome, of which 1024 patients had STEMI. Main outcome measure: Characteristics of reperfusion therapy. Results: The majority of patients with STEMI (81%; N=826) were admitted to six academic percutaneous coronary intervention (PCI) centres. PCI centres received patients predominantly (56%; N=514) from a transfer process. The proportion of patients receiving acute reperfusion therapy was higher than nonreperfused patients (54% vs 46%, p<0.001), and primary PCI was the most common method of reperfusion (86%). The mean door-to-device (DTD) time was 102±68 min. In-hospital mortality of nonreperfused patients was higher than patients receiving primary PCI or fibrinolytic therapy (9.1% vs 3.2% vs 3.8%, p<0.001). Compared with non-academic PCI centres, patients with STEMI admitted to academic PCI centres who underwent primary PCI had shorter mean DTD time (96±44 min vs 140±151 min, p<0.001), higher use of manual thrombectomy (60.2% vs13.8%, p<0.001) and drug-eluting stent implantation (87% vs 69%, p=0.001), but had similar use of radial approach and intraaortic balloon pump (55.7% vs 67.2%, and 2.2% vs 3.4%, respectively). In patients transferred for primary PCI, TIMI risk score ≥4 on presentation was associated with a prolonged door-in to doorout (DI-DO) time (adjusted OR 2.08; 95% CI 1.09 to 3.95, p=0.02). Conclusions: In the expanded JAC registry, a higher proportion of patients with STEMI received reperfusion therapy, but 46% still did not. In developing countries, focusing the prehospital care in the network should be a major focus of care to improve the DI-DO time along with improvement of DTD time at PCI centres. Trial registration number: NCT02319473

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Tocilizumab as a Treatment for ‘Cytokine Storm Syndrome’ in COVID-19: A Case Report

Coronavirus disease 19 (COVID-19) which is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has been a problem worldwide, particularly due to the high rate of transmission and wide range of clinical manifestations. Acute respiratory distress syndrome (ARDS) and multiorgan failure are the most common events observed in severe cases and can be fatal. Cytokine storm syndrome emerges as one of the possibilities for the development of ARDS and multiorgan failure in severe cases of COVID-19. This case report describes a case of a 53-year-old male patient who has been diagnosed with COVID-19. Further evaluation in this patient showed that there was a marked increase in IL-6 level in blood accompanied with hyperferritinemia, which was in accordance with the characteristic of cytokine storm syndrome. Patient was treated with tocilizumab, a monoclonal antibody and is an antagonist to IL-6 receptor. The binding between tocilizumab and IL-6 receptors effectively inhibit and manage cytokine storm syndrome. Although this case report reported the efficacy of tocilizumab in managing cytokine storm syndrome, tocilizumab has several adverse effects requiring close monitoring. Further clinical randomized control trial is required to evaluate the efficacy and safety of tocilizumab administration in participants with various clinical characteristics and greater number of subjects.

Characteristics, treatment and in-hospital outcomes of patients with STEMI in a metropolitan area of a developing country: an initial report of the extended Jakarta Acute Coronary Syndrome registry

OBJECTIVE: We studied the characteristics of patients with ST segment elevation myocardial infarction (STEMI) after expansion of a STEMI registry as part of the STEMI network programme in a metropolitan city and the surrounding area covering ∼26 million inhabitants. DESIGN: Retrospective cohort study. SETTING: Emergency department of 56 health centres. PARTICIPANTS: 3015 patients with acute coronary syndrome, of which 1024 patients had STEMI. MAIN OUTCOME MEASURE: Characteristics of reperfusion therapy. RESULTS: The majority of patients with STEMI (81%; N=826) were admitted to six academic percutaneous coronary intervention (PCI) centres. PCI centres received patients predominantly (56%; N=514) from a transfer process. The proportion of patients receiving acute reperfusion therapy was higher than non-reperfused patients (54% vs 46%, p<0.001), and primary PCI was the most common method of reperfusion (86%). The mean door-to-device (DTD) time was 102±68 min. In-hospital mortality of non-reperfused patients was higher than patients receiving primary PCI or fibrinolytic therapy (9.1% vs 3.2% vs 3.8%, p<0.001). Compared with non-academic PCI centres, patients with STEMI admitted to academic PCI centres who underwent primary PCI had shorter mean DTD time (96±44 min vs 140±151 min, p<0.001), higher use of manual thrombectomy (60.2% vs13.8%, p<0.001) and drug-eluting stent implantation (87% vs 69%, p=0.001), but had similar use of radial approach and intra-aortic balloon pump (55.7% vs 67.2%, and 2.2% vs 3.4%, respectively). In patients transferred for primary PCI, TIMI risk score ≥4 on presentation was associated with a prolonged door-in to door-out (DI-DO) time (adjusted OR 2.08; 95% CI 1.09 to 3.95, p=0.02). CONCLUSIONS: In the expanded JAC registry, a higher proportion of patients with STEMI received reperfusion therapy, but 46% still did not. In developing countries, focusing the prehospital care in the network should be a major focus of care to improve the DI-DO time along with improvement of DTD time at PCI centres. TRIAL REGISTRATION NUMBER: NCT02319473

Stroke in critically ill patients with respiratory failure due to COVID-19: Disparities between low-middle and high-income countries

Purpose: We aimed to compare the incidence of stroke in low-and middle-income countries (LMICs) versus high-income countries (HICs) in critically ill patients with COVID-19 and its impact on in-hospital mortality. Methods: International observational study conducted in 43 countries. Stroke and mortality incidence rates and rate ratios (IRR) were calculated per admitted days using Poisson regression. Inverse probability weighting (IPW) was used to address the HICs vs. LMICs imbalance for confounders. Results: 23,738 patients [20,511(86.4 %) HICs vs. 3,227(13.6 %) LMICs] were included. The incidence stroke/1000 admitted-days was 35.7 (95 %CI = 28.4–44.9) LMICs and 17.6 (95 %CI = 15.8–19.7) HICs; ischemic 9.47 (95 %CI = 6.57–13.7) LMICs, 1.97 (95 %CI = 1.53, 2.55) HICs; hemorrhagic, 7.18 (95 %CI = 4.73–10.9) LMICs, and 2.52 (95 %CI = 2.00–3.16) HICs; unspecified stroke type 11.6 (95 %CI = 7.75–17.3) LMICs, 8.99 (95 %CI = 7.70–10.5) HICs. In regression with IPW, LMICs vs. HICs had IRR = 1.78 (95 %CI = 1.31–2.42, p &lt; 0.001). Patients from LMICs were more likely to die than those from HICs [43.6% vs 29.2 %; Relative Risk (RR) = 2.59 (95 %CI = 2.29–2.93), p &lt; 0.001)]. Patients with stroke were more likely to die than those without stroke [RR = 1.43 (95 %CI = 1.19–1.72), p &lt; 0.001)]. Conclusions: Stroke incidence was low in HICs and LMICs although the stroke risk was higher in LMICs. Both LMIC status and stroke increased the risk of death. Improving early diagnosis of stroke and redistribution of healthcare resources should be a priority. Trial registration: ACTRN12620000421932 registered on 30/03/2020

Correction: Epidemiology and outcomes of early-onset AKI in COVID-19-related ARDS in comparison with non-COVID-19-related ARDS: insights from two prospective global cohort studies (Critical Care, (2023), 27, 1, (3), 10.1186/s13054-022-04294-5)

Following publication of the original article [1], the authors identified that the collaborating authors part of the collaborating author group CCCC Consortium was missing. The collaborating author group is available and included as Additional file 1 in this article

Repurposed Antiviral Drugs for Covid-19 : Interim WHO Solidarity Trial Results

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)Medicine, Faculty ofNon UBCPediatrics, Department ofReviewedFacultyResearche

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18&nbsp;years: 69, 48, 23; 85%), older adults (≥ 70&nbsp;years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60&nbsp;years of age were nausea and vomiting and abdominal pain, and over 60&nbsp;years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30&nbsp;years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60&nbsp;years. Women are less likely to experience typical symptoms than men

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis

Background: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. Methods: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2&nbsp;days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48&nbsp;h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Results: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2&nbsp;years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90&nbsp;days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28&nbsp;days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). Conclusions: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting