Chest
Volume 147, Issue 6, June 2015, Pages 1539-1548
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Original Research: Critical Care
Distinct Molecular Phenotypes of Direct vs Indirect ARDS in Single-Center and Multicenter Studies

https://doi.org/10.1378/chest.14-2454Get rights and content

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.

Section snippets

Single-Center Study

Patients were drawn from the Validation of Biomarkers in Acute Lung Injury Diagnosis (VALID) study, a prospective cohort of critically ill patients at Vanderbilt University Medical Center, a tertiary care medical center. The inclusion and exclusion criteria for VALID have been described previously and are summarized in e-Appendix 1. Patients were enrolled in VALID on ICU day 2.14 The study was approved by the Vanderbilt University Institutional Review Board (#051065).

Patients were followed for

Patient Characteristics

Table 1 compares the patient characteristics in the two cohorts, stratified by direct vs indirect ARDS. In the single-center cohort, there were no significant differences in demographics between patients with direct and indirect ARDS; however, there were significant differences in severity of illness, with higher proportions of patients with indirect ARDS receiving vasopressors. Likewise, there was a trend toward higher APACHE II scores in indirect ARDS. Although the Pao2/Fio2 ratio was lower

Acknowledgments

Author contributions: C. S. C. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. C. S. C. and L. B. W. contributed to the study design, data cleaning and analysis, data interpretation, drafting and revision of the manuscript, and final approval of the manuscript; D. R. J. and K. N. K. contributed to the data collection and cleaning, data interpretation, and critical revision and final approval of the

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    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.

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