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Original article
Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries
  1. Lorraine B Ware1,2,
  2. Zhiguo Zhao3,
  3. Tatsuki Koyama3,
  4. Ryan M Brown1,
  5. Matthew W Semler1,
  6. David R Janz4,
  7. Addison K May5,
  8. Richard D Fremont6,
  9. Michael A Matthay7,
  10. Mitchell J Cohen8,9,
  11. Carolyn S Calfee7
  1. 1 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  3. 3 Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  4. 4 Department of Medicine, Section of Pulmonary/Critical Care and Allergy/Immunology, Louisiana State University School of Medicine in New Orleans, New Orleans, Louisiana, USA
  5. 5 Department of Surgical Science, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  6. 6 Department of Medicine, Meharry Medical College, Nashville, Tennessee, USA
  7. 7 Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, California, USA
  8. 8 Department of Surgery, Denver Health Medical Center, Denver, Colorado, USA
  9. 9 University of Colorado, Aurora, Colorado, USA
  1. Correspondence to Dr Lorraine B Ware, Vanderbilt University Medical Center, T1218 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2650, USA; lorraine.ware{at}vanderbilt.edu

Abstract

Background Acute respiratory distress syndrome (ARDS) is common after severe traumatic injuries but is underdiagnosed and undertreated. We hypothesized that a panel of plasma biomarkers could be used to diagnose ARDS in severe trauma. To test this hypothesis, we derived and validated a biomarker panel in three independent cohorts and compared the diagnostic performance to clinician recognition of ARDS.

Methods Eleven plasma biomarkers of inflammation, lung epithelial and endothelial injury were measured in a derivation cohort of 439 severe trauma patients. ARDS status was analyzed by two-investigator consensus, and cases were required to meet Berlin criteria on intensive care unit (ICU) day 1. Controls were subjects without ARDS during the first 4 days of study enrollment. A multivariable logistic regression model was used to generate probabilities for ARDS. A reduced model with the top two performing markers was then tested in two independent validation cohorts. To assess clinical diagnosis of ARDS, medical records in the derivation cohort were systematically searched for documentation of ARDS diagnosis made by a clinical provider.

Results Among 11 biomarkers, the combination of the endothelial injury marker angiopoietin-2 (Ang-2) and the lung epithelial injury marker receptor for advanced glycation endproducts (RAGE) provided good discrimination for ARDS in the derivation cohort (area under the curve (AUC)=0.74 (95% CI 0.67 to 0.80). In the validation cohorts, the AUCs for this model were 0.70 (0.61 to 0.77) and 0.78 (0.71 to 0.84). In contrast, provider assessment demonstrated poor diagnostic accuracy for ARDS, with AUC of 0.55 (0.51 to 0.60).

Discussion A two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in severe trauma. Clinical application of this model could improve both diagnosis and treatment of ARDS in patients with severe trauma.

Level of evidence Diagnostic study, level II.

  • acute lung injury
  • ARDS
  • endothelium
  • lung epithelium
  • trauma

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/tsaco-2017-000121

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    Footnotes

    • Contributors All authors participated in study design. LBW, RMB, MWS, DRJ, AKM, RDF, MJC and CSC participated in data acquisition. LBW, ZZ, TK, MAM and CSC participated in analysis and interpretation of data. All authors were actively involved in the drafting and critical revision of the manuscript and provided final approval of the manuscript prior to submission.

    • Funding This study was funded by NIH HL103836 (LBW), HL112656 (LBW), and HL110969 (CSC).

    • Competing interests None declared.

    • Ethics approval Vanderbilt IRB and UCSF IRB.

    • Provenance and peer review Not commissioned; externally peer reviewed.