title: Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Anesthesia, University of California San Francisco, San Francisco, CA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA. Electronic address: carolyn.calfee@ucsf.edu.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: David R
authors.initials: DR
authors.lastname: Janz
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Addison K
authors.initials: AK
authors.lastname: May
authors.affiliation: Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Kirsten N
authors.initials: KN
authors.lastname: Kangelaris
authors.affiliation: Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Anesthesia, University of California San Francisco, San Francisco, CA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D042702:Angiopoietin-2 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D015897:Comorbidity; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism; D000094422:Secondary Data Analysis; D016032:Randomized Controlled Trials as Topic
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D015850:Interleukin-6; D016209:Interleukin-8; D037663:Pulmonary Surfactant-Associated Protein D; D014841:von Willebrand Factor