Acute Respiratory Distress Syndrome Subphenotypes Research Articles

Current and evolving standards of care for patients with ARDS.

Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards – treatments that have a solid evidence base and are well established as targets for usual care – and also evolving standards – treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.

Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis

BackgroundSubphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.MethodsWe will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.DiscussionThis study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.Systematic review registrationPROSPERO (ID: CRD42019157236).

The evolution of radiographic edema in ARDS and its association with clinical outcomes: A prospective cohort study in adult patients

PurposeTo assess the longitudinal evolution of radiographic edema using chest X-rays (CXR) in patients with Acute Respiratory Distress Syndrome (ARDS) and to examine its association with prognostic biomarkers, ARDS subphenotypes and outcomes. Materials and methodsWe quantified radiographic edema on CXRs from patients with ARDS or cardiogenic pulmonary edema (controls) using the Radiographic Assessment of Lung Edema (RALE) score on day of intubation and up to 10 days after. We measured baseline plasma biomarkers and recorded clinical variables. ResultsThe RALE score had good inter-rater agreement (r = 0.83, p < 0.0001) applied on 488 CXRs from 129 patients, with higher RALE scores in patients with ARDS (n = 108) compared to controls (n = 21, p = 0.01). Baseline RALE scores were positively correlated with levels of the receptor for end-glycation end products (RAGE) in ARDS patients (p < 0.05). Baseline RALE scores were not predictive of 30- or 90-day survival. Persistently elevated RALE scores were associated with prolonged need for mechanical ventilation (p = 0.002). ConclusionsThe RALE score is easily implementable with high inter-rater reliability. Longitudinal RALE scoring appears to be a reproducible approach to track the evolution of radiographic edema in patients with ARDS and can potentially predict prolonged need for mechanical ventilation.

Erratum: Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy [Additional Corrections

Erratum: Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy [Additional Corrections

Distinct Metabolic Endotype Mirroring Acute Respiratory Distress Syndrome (ARDS) Subphenotype and its Heterogeneous Biology

Predisposing aetiologies in Acute Respiratory Distress Syndrome (ARDS), perpetuates to heterogeneous clinical course hampering therapeutic response. Therefore, physiological variables need to be identified by stratifying ARDS subphenotypes and endotype, to target ARDS heterogeneity. The present study is stimulated by the fact that the ARDS heterogeneity arises from diverse pathophysiological changes leading to distinct ARDS endotypes characterized by perturbed biological mechanism which can be exploited in terms of metabolic profile by metabolomics. Biological endotypes using (n = 464 patients and controls), mBALF and serum samples were identified by high – resolution NMR spectroscopy from two clinically diagnosed ARDS subtypes grouped under mild, moderate and severe ARDS as subphenotype1and pulmonary and extra – pulmonary ARDS as subphenotype2. The identified mBALF endotypes (isoleucine, leucine, valine, lysine/arginine, tyrosine, threonine) and serum endotypes (proline, glutamate, phenylalanine, valine) in both subphenotypes by statistical analysis were tested for their reproducibility and robustness. By combining metabolic endotypes with clinical based mortality score (APACHE and SOFA) added to their predictive performance as ARDS mortality predictors. Thus, a comprehensive set of mBALF endotypes representing compartmentalized lung milieu and serological endotypes representing systemic markers of ARDS subtypes were validated. The interlinked biological pathway of these disease specific endotype further elucidated their role as candidate biomarker in governing ARDS heterogeneous biology.

Erratum: Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy.

Erratum: Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy.

Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial

Precision medicine approaches that target patients on the basis of disease subtype have transformed treatment approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of acute respiratory distress syndrome (ARDS) have been identified in three US-based clinical trials, and these subphenotypes respond differently to positive end-expiratory pressure and fluid management. We aimed to investigate whether these subphenotypes exist in non-US patient populations and respond differently to pharmacotherapies. HARP-2 was a multicentre, randomised controlled trial of simvastatin (80 mg) versus placebo done in general intensive care units (ICUs) at 40 hospitals in the UK and Ireland within 48 h of onset of ARDS. The primary outcome was ventilator-free days, and secondary outcomes included non-pulmonary organ failure-free days and mortality. In a secondary analysis of HARP-2, we applied latent class analysis to baseline data without consideration of outcomes to identify subphenotypes, and we compared clinical outcomes across subphenotypes and treatment groups. 540 patients were recruited to HARP-2. One patient withdrew consent for the use of their data, so data from 539 patients were analysed. In our secondary analysis, a two-class (two subphenotype) model was an improvement over a one-class model (p<0·0001), with 353 (65%) patients in the hypoinflammatory subphenotype group and 186 (35%) in the hyperinflammatory subphenotype group. Additional classes did not improve model fit. Clinical and biological characteristics of the two subphenotypes were similar to previous studies. Patients with the hyperinflammatory subphenotype had fewer ventilator-free days (median 2 days [IQR 0-17] vs 18 [IQR 0-23]; p<0·0001), fewer non-pulmonary organ failure-free days (15 [0-25] vs 27 [21-28]; p<0·0001), and higher 28-day mortality (73 [39%] vs 59 [17%]; p<0·0001) than did those with the hypoinflammatory subphenotype. Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001). Specifically, within the hyperinflammatory subphenotype, patients treated with simvastatin had significantly higher 28-day survival than did those given placebo (p=0·008). A similar pattern was observed for 90-day survival. Two subphenotypes of ARDS were identified in the HARP-2 cohort, with distinct clinical and biological features and disparate clinical outcomes. The hyperinflammatory subphenotype had improved survival with simvastatin compared with placebo. These findings support further pursuit of predictive enrichment strategies in critical care clinical trials. UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health.

Evolution of ARDS biomarkers: Will metabolomics be the answer?

To date, there is no clinically agreed-upon diagnostic test for acute respiratory distress syndrome (ARDS): the condition is still diagnosed on the basis of a constellation of clinical findings, laboratory tests, and radiological images. Development of ARDS biomarkers has been in a state of continuous flux during the past four decades. To address ARDS heterogeneity, several studies have recently focused on subphenotyping the disease on the basis of observable clinical characteristics and associated blood biomarkers. However, the strong correlation between identified biomarkers and ARDS subphenotypes has yet to establish etiology; hence, there is a need for the adoption of other methodologies for studying ARDS. In this review, we will shed light on ARDS metabolomics research in the literature and discuss advances and major obstacles encountered in ARDS metabolomics research. Generally, the ARDS metabolomics studies focused on identification of differentiating metabolites for diagnosing ARDS, but they were performed to different standards in terms of sample size, selection of control cohort, type of specimens collected, and measuring technique utilized. Virtually none of these studies have been properly validated to identify true metabolomics biomarkers of ARDS. Though in their infancy, metabolomics studies exhibit promise to unfold the biological processes underlying ARDS and, in our opinion, have great potential for pushing forward our present understanding of ARDS.

Stability of ARDS subphenotypes over time in two randomised controlled trials

RationaleTwo distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over...

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy.

We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure. 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. 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. 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-liberal strategy versus 18% with fluid-conservative, whereas mortality in subphenotype 2 was 40% with fluid-liberal strategy versus 50% in fluid-conservative. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes. 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.

Latent Class Models Identify Two Subphenotypes in Respiratory Distress Syndrome with Differential Response to Positive End-Expiratory Pressure

Latent Class Models Identify Two Subphenotypes in Respiratory Distress Syndrome with Differential Response to Positive End-Expiratory Pressure

Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials

Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder. We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. 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 ALVEOLI cohort. We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days). We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials. National Institutes of Health.

Poster #115 AN ENVIRONMENTAL ANALYSIS OF GENES ASSOCIATED WITH SCHIZOPHRENIA: HYPOXIA AND VASCULAR FACTORS AS INTERACTING ELEMENTS IN THE NEURODEVELOPMENTAL MODEL

Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder.We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. 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 ALVEOLI cohort.We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days).We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials.National Institutes of Health.