Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Early warning system of extreme clouds providing tailored alert products dedicated to ATM, transport modelling and observatory monitoring

info:eu-repo/semantics/nonPublishe

Early warning system of airborne hazards based on satellite and ground-based observations

info:eu-repo/semantics/publishe

EUNADICS-AV early warning system dedicated to supporting aviation in the case of a crisis from natural airborne hazards and radionuclide clouds

The purpose of the EUNADICS-AV (European Natural Airborne Disaster Information and Coordination System for Aviation) prototype early warning system (EWS) is to develop the combined use of harmonised data products from satellite, ground-based and in situ instruments to produce alerts of airborne hazards (volcanic, dust, smoke and radionuclide clouds), satisfying the requirement of aviation air traffic management (ATM) stakeholders (https://cordis.europa.eu/project/id/723986, last access: 5 November 2021). The alert products developed by the EUNADICS-AV EWS, i.e. near-real-time (NRT) observations, email notifications and netCDF (Network Common Data Form) alert data products (called NCAP files), have shown significant interest in using selective detection of natural airborne hazards from polar-orbiting satellites. The combination of several sensors inside a single global system demonstrates the advantage of using a triggered approach to obtain selective detection from observations, which cannot initially discriminate the different aerosol types. Satellite products from hyperspectral ultraviolet-visible (UV-vis) and infrared (IR) sensors (e.g. TROPOMI - TROPOspheric Monitoring Instrument - and IASI - Infrared Atmospheric Sounding Interferometer) and a broadband geostationary imager (Spinning Enhanced Visible and InfraRed Imager; SEVIRI) and retrievals from ground-based networks (e.g. EARLINET - European Aerosol Research Lidar Network, E-PROFILE and the regional network from volcano observatories) are combined by our system to create tailored alert products (e.g. selective ash detection, SO2 column and plume height, dust cloud, and smoke from wildfires). A total of 23 different alert products are implemented, using 1 geostationary and 13 polar-orbiting satellite platforms, 3 external existing service, and 2 EU and 2 regional ground-based networks. This allows for the identification and the tracking of extreme events. The EUNADICS-AV EWS has also shown the need to implement a future relay of radiological data (gamma dose rate and radionuclides concentrations in ground-level air) in the case of a nuclear accident. This highlights the interest of operating early warnings with the use of a homogenised dataset. For the four types of airborne hazard, the EUNADICS-AV EWS has demonstrated its capability to provide NRT alert data products to trigger data assimilation and dispersion modelling providing forecasts and inverse modelling for source term estimate. Not all of our alert data products (NCAP files) are publicly disseminated. Access to our alert products is currently restricted to key users (i.e. Volcanic Ash Advisory Centres, national meteorological services, the World Meteorological Organization, governments, volcano observatories and research collaborators), as these are considered pre-decisional products. On the other hand, thanks to the EUNADICS-AV-SACS (Support to Aviation Control Service) web interface (https://sacs.aeronomie.be, last access: 5 November 2021), the main part of the satellite observations used by the EUNADICS-AV EWS is shown in NRT, with public email notification of volcanic emission and delivery of tailored images and NCAP files. All of the ATM stakeholders (e.g. pilots, airlines and passengers) can access these alert products through this free channel

EUNADICS-AV early warning system dedicated to supporting aviation in the case of a crisis from natural airborne hazards and radionuclide clouds

Abstract. The purpose of the EUNADICS-AV (European Natural Airborne DisasterInformation and Coordination System for Aviation) prototype early warningsystem (EWS) is to develop the combined use of harmonised data products from satellite, ground-based and in situ instruments to produce alerts of airborne hazards (volcanic, dust, smoke and radionuclide clouds), satisfying the requirement of aviation air traffic management (ATM) stakeholders (https://cordis.europa.eu/project/id/723986, last access: 5 November 2021). The alert products developed by the EUNADICS-AV EWS, i.e. near-real-time (NRT) observations, email notifications and netCDF (Network Common Data Form) alert data products (called NCAP files), have shown significant interest in using selective detection of natural airborne hazards from polar-orbiting satellites. The combination of several sensors inside a single global system demonstrates the advantage of using a triggered approach to obtain selective detection from observations, which cannot initially discriminate the different aerosol types. Satellite products from hyperspectral ultraviolet–visible (UV–vis) and infrared (IR) sensors (e.g. TROPOMI – TROPOspheric Monitoring Instrument – and IASI – Infrared Atmospheric Sounding Interferometer) and a broadband geostationary imager (Spinning Enhanced Visible and InfraRed Imager; SEVIRI) and retrievals from ground-based networks (e.g. EARLINET – European Aerosol Research Lidar Network, E-PROFILE and the regional network from volcano observatories) are combined by our system to create tailored alert products (e.g. selective ash detection, SO2 column and plume height, dust cloud, and smoke from wildfires). A total of 23 different alert products are implemented, using 1 geostationary and 13 polar-orbiting satellite platforms, 3 external existing service, and 2 EU and 2 regional ground-based networks. This allows for the identification and the tracking of extreme events. The EUNADICS-AV EWS has also shown the need to implement a future relay of radiological data (gamma dose rate and radionuclides concentrations in ground-level air) in the case of a nuclear accident. This highlights the interest of operating early warnings with the use of a homogenised dataset. For the four types of airborne hazard, the EUNADICS-AV EWS has demonstrated its capability to provide NRT alert data products to trigger data assimilation and dispersion modelling providing forecasts and inverse modelling for source term estimate. Not all of our alert data products (NCAP files) are publicly disseminated. Access to our alert products is currently restricted to key users (i.e. Volcanic Ash Advisory Centres, national meteorological services, the World Meteorological Organization, governments, volcano observatories and research collaborators), as these are considered pre-decisional products. On the other hand, thanks to the EUNADICS-AV–SACS (Support to Aviation Control Service) web interface (https://sacs.aeronomie.be, last access: 5 November 2021), the main part of the satellite observations used by the EUNADICS-AV EWS is shown in NRT, with public email notification of volcanic emission and delivery of tailored images and NCAP files. All of the ATM stakeholders (e.g. pilots, airlines and passengers) can access these alert products through this free channel.info:eu-repo/semantics/publishe

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc