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Original Research: Critical Care |

Distinct Molecular Phenotypes of Direct vs Indirect ARDS in Single-Center and Multicenter StudiesMolecular Phenotypes of Direct and Indirect ARDS

Carolyn S. Calfee, MD, MAS; David R. Janz, MD; Gordon R. Bernard, MD, FCCP; Addison K. May, MD; Kirsten N. Kangelaris, MD, MAS; Michael A. Matthay, MD, FCCP; Lorraine B. Ware, MD, FCCP; the NIH NHLBI ARDS Network
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Anesthesia (Drs Calfee and Matthay), Division of Hospital Medicine, Department of Medicine (Dr Kangelaris), and Cardiovascular Research Institute (Dr Matthay), University of California San Francisco, San Francisco, CA; and the Division of Allergy, Pulmonary and Critical Care (Drs Janz, Bernard, May, and Ware), Department of Medicine, Vanderbilt University, Nashville, TN.

CORRESPONDENCE TO: Carolyn S. Calfee, MD, MAS, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, 505 Parnassus Ave, Box 0111, San Francisco, CA 94143-0111; e-mail: carolyn.calfee@ucsf.edu


Part of this article has been presented in abstract form at the American Thoracic Society International Conferences, May 17-22, 2013, Philadelphia, PA, and May 16-21, 2014, San Diego, CA.

FUNDING/SUPPORT: This work was supported by contracts with the National Heart, Lung, and Blood Institute (NHLBI) [NO1-HR-46046-64 and NO1-HR-16146-54]. Dr Calfee was supported by the National Institutes of Health (NIH) [HL090833 and HL110969]. Dr Janz was supported by the NIH [T32 HL087738]. Dr Kangelaris was supported by the NHLBI [1K23 HL116800-01]. Dr Matthay was supported by the NIH [HL51856]. Dr Ware was supported by the NIH [HL103836 and HL112656].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):1539-1548. doi:10.1378/chest.14-2454
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BACKGROUND:  ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans.

METHODS:  We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts.

RESULTS:  In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS.

CONCLUSIONS:  Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.

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