Background Subphenotypes have been identified within heterogeneous syndromes such as asthma and breast cancer, with important therapeutic implications. Whether subphenotypes exist within the acute respiratory distress syndrome (ARDS), another heterogeneous syndrome, is unknown. Methods We applied latent class modeling to identify subphenotypes using clinical and biological data from two NHLBI ARDS randomized controlled trials; modeling was conducted independently in each cohort. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the second cohort. Findings Independent latent class models indicated that a two-class (i.e. two subphenotype) model was optimal for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (Phenotype 2) that was characterized by higher plasma levels of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate, and a higher prevalence of sepsis, compared to Phenotype 1. Subjects in Phenotype 2 had higher mortality and fewer ventilator-free and organ failure-free days in both cohorts. In the second cohort, the effects of ventilation strategy on mortality, ventilator and organ failure-free days differed significantly by phenotype (p=0.003–0.049 for interactions). Interpretation Latent class models identify two subphenotypes within ARDS, one of which is characterized by more severe inflammation, shock, and metabolic acidosis and by significantly worse clinical outcomes. Response to treatment in a randomized trial of PEEP strategies differed based on subphenotype. Identification of ARDS subphenotypes may be useful in selecting patients for clinical trials. Funding National Institutes of Health

Rationale: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure.Objectives: To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification.Methods: We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. Measurements and Main Results:We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90-day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-conservative strategy versus 18% with fluid-liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A threevariable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes.Conclusions: This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches.

Background-Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.Methods-We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with

UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health.

OBJECTIVE:The Patient Health Questionnaire depression scale (PHQ-9) is a well-validated, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criterion-based measure for diagnosing depression, assessing severity and monitoring treatment response. The performance of most depression scales including the PHQ-9, however, has not been rigorously evaluated in different racial/ethnic populations. Therefore, we compared the factor structure of the PHQ-9 between different racial/ethnic groups as well as the rates of endorsement and differential item functioning (DIF) of the 9 items of the PHQ-9. The presence of DIF would indicate that responses to an individual item differ significantly between groups, controlling for the level of depression. MEASUREMENTS:A combined dataset from 2 separate studies of 5,053 primary care patients including non-Hispanic white (n =2,520), African American (n =598), Chinese American (n =941), and Latino (n =974) patients was used for our analysis. Exploratory principal components factor analysis was used to derive the factor structure of the PHQ-9 in each of the 4 racial/ethnic groups. A generalized MantelHaenszel statistic was used to test for DIF. RESULTS:One main factor that included all PHQ-9 items was found in each racial/ethnic group with a coefficients ranging from 0.79 to 0.89. Although endorsement rates of individual items were generally similar among the 4 groups, evidence of DIF was found for some items. CONCLUSIONS:Our analyses indicate that in African American, Chinese American, Latino, and non-Hispanic white patient groups the PHQ-9 measures a common concept of depression and can be effective for the detection and monitoring of depression in these diverse populations.