The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, with nearly 200,000 cases per year in the US alone, mortality rates of 25-40%, and no effective pharmacotherapies. We recently identified and validated the presence of two distinct subphenotypes (also known as endotypes) of ARDS in two large randomized controlled trials. In an independent analysis of both datasets, there was strong evidence that there are two different endotypes within ARDS: a hyper-inflammatory endotype and a hypo-inflammatory endotype. These endotypes had strikingly different (1) clinical characteristics, (2) biomarker profiles, (3) clinical outcomes, and (4) treatment responses. Most notably, significant endotype-specific treatment responses were identified within a clinical trial previously thought to be negative. However, what remains unknown is whether these endotypes respond differently to other ARDS treatments and how to translate these promising findings to the bedside; likewise, the biology of the two endotypes remains incompletely understood. In the research proposed here, we will test the innovative central hypothesis that ARDS contains two distinct endotypes of disease, with different clinical and biologic characteristics and differing responses to therapy. We propose to test this hypothesis primarily within the framework of completed and ongoing NHLBI-funded ARDS randomized controlled trials, leveraging randomization to identify endotype-specific therapeutic responses.
In Aim 1, we will use latent class analysis to identify ARDS endotypes in patients enrolled in two NHLBI-funded ARDS randomized controlled trials (the Statins for Acutely Injured Lungs (SAILS) clinical trial, already complete, and the Reevaluation Of Systemic Early neuromuscular blockade (ROSE) clinical trial, ongoing), in order to determine whether the endotypes respond differently to the therapies being tested in these trials. Also in Aim 1, we will test a practical, parsimonious model to identify ARDS endotypes in SAILS and ROSE, as well as in a more diverse ARDS cohort at UCSF.
In Aim 2, we will identify specific differences in the biology of ARDS endotypes through analysis of novel candidate protein, lipid and metabolite biomarkers as well as high-throughput genomic sequencing, in the setting of the ROSE trial. Our research group is well-qualified to conduct this research by virtue of our expertise in pathogenesis-focused studies of human ARDS, our experience with the specific methods involved in the project, and our history of effective collaboration. Completion of these aims will have a high impact by identifying endotype-specific therapeutic responses, by developing practical approaches to endotype identification that can be directly translated to increase the efficiency and yield of future randomized controlled trials in ARDS, and by improving our understanding of the diverse biology of human ARDS, enhancing the likelihood that successful new therapeutics will be identified for each endotype.

Public Health Relevance

The acute respiratory distress syndrome (ARDS) remains a common and frequently fatal cause of acute respiratory failure in critically ill patients, with no specific preventative strategies or therapies available. The goal of this project is to identify an deepen our understanding of subtypes of ARDS that may respond differently to treatments, in order to tailor therapy to individual ARDS patients and thereby improve clinical outcomes from ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL131621-01
Application #
9078734
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Reineck, Lora A
Project Start
2016-03-15
Project End
2020-02-28
Budget Start
2016-03-15
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Delucchi, Kevin; Famous, Katie R; Ware, Lorraine B et al. (2018) Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax 73:439-445
Lefrançais, Emma; Mallavia, Beñat; Zhuo, Hanjing et al. (2018) Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 3:
Sinha, Pratik; Delucchi, Kevin L; Thompson, B Taylor et al. (2018) Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med 44:1859-1869
Warren, Melissa A; Zhao, Zhiguou; Koyama, Tatsuki et al. (2018) Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Thorax 73:840-846
Calfee, Carolyn S; Delucchi, Kevin; Famous, Katie R (2017) Reply: Next Step to Understanding Subphenotypes of Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 196:796
Hendrickson, Carolyn M; Abbott, Jason; Zhuo, Hanjing et al. (2017) Higher mini-BAL total protein concentration in early ARDS predicts faster resolution of lung injury measured by more ventilator-free days. Am J Physiol Lung Cell Mol Physiol 312:L579-L585
Zhao, Zhiguo; Wickersham, Nancy; Kangelaris, Kirsten N et al. (2017) External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome. Intensive Care Med 43:1123-1131
Meyer, Nuala J; Calfee, Carolyn S (2017) Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. Lancet Respir Med 5:512-523
Famous, Katie R; Delucchi, Kevin; Ware, Lorraine B et al. (2017) Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med 195:331-338
Bos, L D; Schouten, L R; van Vught, L A et al. (2017) Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax 72:876-883

Showing the most recent 10 out of 16 publications