Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections

Associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a pooled individual patient data analysis : Mechanical ventilation during ECMO

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate associations between ventilatory settings during ECMO for refractory hypoxemia and outcome in ARDS patients. In this individual patient data meta-analysis of observational studies in adult ARDS patients receiving ECMO for refractory hypoxemia, a time-dependent frailty model was used to determine which ventilator settings in the first 3 days of ECMO had an independent association with in-hospital mortality. Nine studies including 545 patients were included. Initiation of ECMO was accompanied by significant decreases in tidal volume size, positive end-expiratory pressure (PEEP), plateau pressure, and driving pressure (plateau pressure - PEEP) levels, and respiratory rate and minute ventilation, and resulted in higher PaO2/FiO2, higher arterial pH and lower PaCO2 levels. Higher age, male gender and lower body mass index were independently associated with mortality. Driving pressure was the only ventilatory parameter during ECMO that showed an independent association with in-hospital mortality [adjusted HR, 1.06 (95 % CI, 1.03-1.10)]. In this series of ARDS patients receiving ECMO for refractory hypoxemia, driving pressure during ECMO was the only ventilator setting that showed an independent association with in-hospital mortalit

Drotrecogin alfa (Activated) in adults with septic shock

There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.)