FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial

International audienceBackground: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. Methods: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering—from day 1 to day 7—of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). Results: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, − 1.9 [− 3.3; − 0.5] vs. − 0.8 [− 5.5; − 1.1] mL/kg; estimated effect − 0.8 [− 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). Conclusions: In this unique-dosing–regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020

Accuracy of clinicians’ ability to predict the need for renal replacement therapy: a prospective multicenter study

International audiencePurpose. Identifying patients who will receive renal replacement therapy (RRT) during intensive care unit (ICU) stay is a major challenge for intensivists. The objective of this study was to evaluate the performance of physicians in predicting the need for RRT at ICU admission and at acute kidney injury (AKI) diagnosis. Methods. Prospective, multicenter study including all adult patients hospitalized in 16 ICUs in October 2020. Physician prediction was estimated at ICU admission and at AKI diagnosis, according to a visual Likert scale. Discrimination, risk stratification and benefit of physician estimation were assessed. Mixed logistic regression models of variables associated with risk of receiving RRT, with and without physician estimation, were compared. Results. Six hundred and forty-nine patients were included, 270 (41.6%) developed AKI and 77 (11.8%) received RRT. At ICU admission and at AKI diagnosis, a model including physician prediction, the experience of the physician, SOFA score, serum creatinine and diuresis to determine need for RRT performed better than a model without physician estimation with an area under the ROC curve of 0.90 [95% CI 0.86–0.94, p < 0.008 (at ICU admission)] and 0.89 [95% CI 0.83–0.93, p = 0.0014 (at AKI diagnosis)]. In multivariate analysis, physician prediction was strongly associated with the need for RRT, independently of creatinine levels, diuresis, SOFA score and the experience of the doctor who made the prediction. Conclusion. As physicians are able to stratify patients at high risk of RRT, physician judgement should be taken into account when designing new randomized studies focusing on RRT initiation during AKI

Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells

International audienceLangerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm