Biomarkers in acute respiratory distress syndrome: from pathobiology to improving patient care

Abstract

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by alveolar flooding with protein-rich pulmonary edema fluid. Despite an improved understanding of ARDS pathogenesis, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help identify patients at highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. This review begins with a general description of biomarker use in clinical medicine. We then review evidence that supports the value of various ARDS biomarkers organized by the cellular injury processes central to ARDS development: endothelial injury, epithelial injury, disordered inflammation and coagulation, fibrosis, and apoptosis. Finally, we summarize the growing contributions of genomic and proteomic research and suggest ways in which the field may evolve in the coming years.

Keywords::

• acute lung injury
• acute respiratory distress syndrome
• biomarkers
• clinical predictor
• genomics
• proteomics

Acknowledgements

The authors would like to thank Diana Lim for her assistance with Figure 1.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by alveolar and interstitial flooding with protein-rich pulmonary edema fluid. Despite an improved understanding of ARDS pathogenesis, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited.

• While ARDS biomarkers are currently a research tool, they have many potential clinical uses including identifying high-risk patients for enrollment in clinical trials, improving our ability to predict the development of ARDS, monitoring response to therapy and risk-stratifying patients with known disease. Perhaps most importantly, biomarkers provide an important link between our understanding of ARDS pathobiology and the bedside care of patients with ARDS.

• Biomarkers of endothelial cell injury include Ang-2, Von Willebrand factor, VEGF, ICAM-1 and selectins. Ang-2, von Willebrand factor and ICAM-1 have shown promising results in retrospective studies of large randomized trials.

• Biomarkers of epithelial injury include surfactant proteins, receptor for advanced glycation end-products, club cell protein 16 and Krebs von den Lungen-6. Receptor for advanced glycation end-products and surfactant proteins have been studied in samples from large clinical trials with mixed results.

• Numerous inflammatory cytokines have been associated with both the development of ARDS and outcome. The study of inflammatory cytokines has shed light on the proinflammatory effects of conventional ventilator management and provided evidence that low tidal volume ventilation may attenuate this inflammatory response.

• Biomarkers of the coagulation and fibrinolytic cascade include protein C, thrombomodulin and plasminogen activator inhibitor-1. While results have been mixed, data from at least one large trial suggests that protein C and plasminogen activator inhibitor-1 may provide important diagnostic and prognostic information for patients with ARDS.

• Panels of biomarkers have been tested in several retrospective studies of large clinical trials with promising results. Given the complex pathobiology underlying ARDS, biomarker panels may represent a more accurate tool for prediction and prognosis.

• Genomic and proteomic discovery will play an increasingly prominent role in ARDS biomarker research in the coming years.

Notes

ARDS: Acute respiratory distress syndrome.