We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following E.coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MV) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. The current studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E.coli endotoxin-induced ALI in C57BL/6 mice. The intra-tracheal instillation of MVs improved several indices of ALI at 48 h. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49% respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC derived microvesicles were therapeutically effective following E.coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus.

Summary Background Patients with COVID-19 who develop severe acute respiratory distress syndrome (ARDS) can have symptoms that rapidly evolve to profound hypoxaemia and death. The efficacy of extracorporeal membrane oxygenation (ECMO) for patients with severe ARDS in the context of COVID-19 is unclear. We aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and COVID-19 treated with ECMO. Methods This retrospective cohort study was done in the Paris–Sorbonne University Hospital Network, comprising five intensive care units (ICUs) and included patients who received ECMO for COVID-19 associated ARDS. Patient demographics and daily pre-ECMO and on-ECMO data and outcomes were collected. Possible outcomes over time were categorised into four different states (states 1–4): on ECMO, in the ICU and weaned off ECMO, alive and out of ICU, or death. Daily probabilities of occupation in each state and of transitions between these states until day 90 post-ECMO onset were estimated with use of a multi-state Cox model stratified for each possible transition. Follow-up was right-censored on July 10, 2020. Findings From March 8 to May 2, 2020, 492 patients with COVID-19 were treated in our ICUs. Complete day-60 follow-up was available for 83 patients (median age 49 [IQR 41–56] years and 61 [73%] men) who received ECMO. Pre-ECMO, 78 (94%) patients had been prone-positioned; their median driving pressure was 18 (IQR 16–21) cm H 2 O and PaO 2 /FiO 2 was 60 (54–68) mm Hg. At 60 days post-ECMO initiation, the estimated probabilities of occupation in each state were 6% (95% CI 3–14) for state 1, 18% (11–28) for state 2, 45% (35–56) for state 3, and 31% (22–42) for state 4. 35 (42%) patients had major bleeding and four (5%) had a haemorrhagic stroke. 30 patients died. Interpretation The estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care. Funding None.

Rationale: Microvesicles (MVs) are anuclear fragments of cells released from the endosomal compartment or shed from surface membranes. We and other investigators demonstrated that MVs released by mesenchymal stem cells (MSCs) were as effective as the cells themselves in inflammatory injuries, such as after endotoxininduced acute lung injury. However, the therapeutic effects of MVs in an infectious model of acute lung injury remain unknown.Objectives: We investigated the effects of human MSC MVs on lung inflammation, protein permeability, bacterial clearance, and survival after severe bacterial pneumonia.Methods: We tested the effects of MVs derived from human MSCs on Escherichia coli pneumonia in mice. We also studied the interactions between MVs and human monocytes and human alveolar epithelial type 2 cells.Measurements and Main Results: Administration of MVs derived from human MSCs improved survival in part through keratinocyte growth factor secretion and decreased the influx of inflammatory cells, cytokines, protein, and bacteria in mice injured with bacterial pneumonia. In primary cultures of human monocytes or alveolar type 2 cells, the uptake of MVs was mediated by CD44 receptors, which were essential for the therapeutic effects. MVs enhanced monocyte phagocytosis of bacteria while decreasing inflammatory cytokine secretion and increased intracellular ATP levels in injured alveolar epithelial type 2 cells. Prestimulation of MSCs with a toll-like receptor 3 agonist further enhanced the therapeutic effects of the released MVs.Conclusions: MVs derived from human MSCs were as effective as the parent stem cells in severe bacterial pneumonia.

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Background In the Île-de-France region (henceforth termed Greater Paris), extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) was considered early in the COVID-19 pandemic. We report ECMO network organisation and outcomes during the first wave of the pandemic. Methods In this multicentre cohort study, we present an analysis of all adult patients with laboratory-confirmed SARS-CoV-2 infection and severe ARDS requiring ECMO who were admitted to 17 Greater Paris intensive care units between March 8 and June 3, 2020. Central regulation for ECMO indications and pooling of resources were organised for the Greater Paris intensive care units, with six mobile ECMO teams available for the region. Details of complications (including ECMO-related complications, renal replacement therapy, and pulmonary embolism), clinical outcomes, survival status at 90 days after ECMO initiation, and causes of death are reported. Multivariable analysis was used to identify pre-ECMO variables independently associated with 90-day survival after ECMO. Findings The 302 patients included who underwent ECMO had a median age of 52 years (IQR 45−58) and Simplified Acute Physiology Score-II of 40 (31−56), and 235 (78%) of whom were men. 165 (55%) were transferred after cannulation by a mobile ECMO team. Before ECMO, 285 (94%) patients were prone positioned, median driving pressure was 18 cm H 2 O (14−21), and median ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen was 61 mm Hg (IQR 54−70). During ECMO, 115 (43%) of 270 patients had a major bleeding event, 27 of whom had intracranial haemorrhage; 130 (43%) of 301 patients received renal replacement therapy; and 53 (18%) of 294 had a pulmonary embolism. 138 (46%) patients were alive 90 days after ECMO. The most common causes of death were multiorgan failure (53 [18%] patients) and septic shock (47 [16%] patients). Shorter time between intubation and ECMO (odds ratio 0·91 [95% CI 0·84−0·99] per day decrease), younger age (2·89 [1·41−5·93] for ≤48 years and 2·01 [1·01−3·99] for 49–56 years vs ≥57 years), higher pre-ECMO renal component of the Sequential Organ Failure Assessment score (0·67, 0·55−0·83 per point increase), and treatment in centres managing at least 30 venovenous ECMO cases annually (2·98 [1·46–6·04]) were independently associated with improved 90-day survival. There was no significant difference in survival between patients who had mobile and on-site ECMO initiation. Interpretation Beyond associations with similar factors to those reported on ECMO for non-COVID-19 ARDS, 90-day survival among ECMO-assisted patients with COVID-19 was strongly associated with a centre's experience in venovenous ECMO during the previous year. Early ECMO management in centres with a high venovenous ECMO case volume should be advocated, by applying centralisation and regulation...

AF designed the study, participated in data collection and analysis, performed statistical analysis and wrote the paper. AL participates in study design, data collection and analysis, performed statistical analysis and participated in writing. JM, SD, JMC, AM and CEL participated in patients' care and clinical data collection and analysis. CP participated in study design, data collection and analysis. AGM performed virology analysis. MB participated in study design, data collection and analysis and writing. All authors contributed to writing of the paper.

Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 106 UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (day (D) 0) and D7. Results Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO2/FiO2 changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [− 15.5 to 93.3] vs 25.3 [− 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI − 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment. Conclusions D0-to-D7 PaO2/FiO2 changes for intravenous UC-MSCs-versus placebo-treated adults with SARS–CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context. Trial registration: NCT04333368. Registered 01 April 2020, https://clinicaltrials.gov/ct2/history/NCT04333368.