ABSTRACT
RATIONALE: There are limited therapeutic options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. OBJECTIVES: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-induced respiratory failure. METHODS: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to standard of care. We hypothesized that cell therapy would be superior to sham-control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. MEASUREMENTS AND MAIN RESULTS: At the third interim analysis, the Data and Safety Monitoring Board recommended that the trial halt enrollment as the pre-specified mortality reduction from 40% to 23% was unlikely to be achieved (n=222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (RR 0.88;95% CI 0.64,1.21;p=0.43). There were no significant differences in days alive off ventilation within 60 days (median rank 117.3 [IQR:60.0,169.5] in cell patients and 102.0 [IQR:54.0,162.5] in controls; higher is better). Resolution or improvement of ARDS at 30-days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) of control patients (OR 1.36;95% CI 0.57, 3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. CONCLUSIONS: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate/severe COVID-related acute respiratory distress syndrome. Clinical trial registration available at www. CLINICALTRIALS: gov, ID:NCT04371393. 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/).
ABSTRACT
OBJECTIVES: To examine whether increasing time between admission and intubation was associated with mortality in patients with coronavirus disease 2019 who underwent mechanical ventilation. DESIGN: Retrospective cohort study of patients with severe acute respiratory syndrome coronavirus 2 infection who were admitted between January 30, 2020, and April 30, 2020, and underwent intubation and mechanical ventilation prior to May 1, 2020. Patients were followed up through August 15, 2020. SETTING: Five hospitals within the Mount Sinai Health System in New York City, NY. PATIENTS: Adult patients with severe acute respiratory syndrome coronavirus 2 infection who underwent intubation and mechanical ventilation. INTERVENTIONS: Tracheal intubation and mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. A hospital-stratified time-varying Cox model was used to evaluate the effect of time from admission to intubation on in-hospital death. A total of 755 adult patients out of 5,843 admitted with confirmed severe acute respiratory syndrome coronavirus 2 infection underwent tracheal intubation and mechanical ventilation during the study period. The median age of patients was 65 years (interquartile range, 56-72 yr) and 64% were male. As of the time of follow-up, 121 patients (16%) who were intubated and mechanically ventilated had been discharged home, 512 (68%) had died, 113 (15%) had been discharged to a skilled nursing facility, and 9 (1%) remained in the hospital. The median time from admission to intubation was 2.3 days (interquartile range, 0.6-6.3 d). Each additional day between hospital admission and intubation was significantly associated with higher in-hospital death (adjusted hazard ratio, 1.03; 95% CI, 1.01-1.05). CONCLUSIONS: Among patients with coronavirus disease 2019 who were intubated and mechanically ventilated, intubation earlier in the course of hospital admission may be associated with improved survival.
ABSTRACT
BACKGROUND: Thromboembolic disease is common in coronavirus disease-2019 (COVID-19). There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postmortem findings. OBJECTIVES: The purpose of this study was to examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies. METHODS: This retrospective analysis examined the association of AC with mortality, intubation, and major bleeding. Subanalyses were also conducted on the association of therapeutic versus prophylactic AC initiated ≤48 h from admission. Thromboembolic disease was contextualized by premortem AC among consecutive autopsies. RESULTS: Among 4,389 patients, median age was 65 years with 44% women. Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53; 95% confidence interval [CI]: 0.45 to 0.62 and aHR: 0.50; 95% CI: 0.45 to 0.57, respectively), and intubation (aHR: 0.69; 95% CI: 0.51 to 0.94 and aHR: 0.72; 95% CI: 0.58 to 0.89, respectively). When initiated ≤48 h from admission, there was no statistically significant difference between therapeutic (n = 766) versus prophylactic AC (n = 1,860) (aHR: 0.86; 95% CI: 0.73 to 1.02; p = 0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC. CONCLUSIONS: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.