title: High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD - results from the ECLIPSE study.
abstract: There is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling.
  
  
  
  Biomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Validated immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used. Multivariate models were used to assess the prognostic value of these biomarkers.
  
  
  
  Thirty subjects (3.0 %) died during follow-up. Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers. All collagen biomarkers were significantly elevated in non-survivors compared to survivors. Mortality risk was significantly increased for subjects with collagen remodeling biomarkers in the upper quartile, especially for the degradation fragment of collagen type IV C6M (hazard ratio 6.6 [95 % confidence interval 2.9-15.2], P < 0.0001) after adjusting for relevant confounders.
  
  
  
  Serological biomarkers of collagen remodeling were strongly associated with mortality in subjects with COPD indicating that assessment of tissue turnover in the parenchyma and small airways may be useful in the prognosis of COPD.
  
  
  
  NCT00292552 , GSK Study No. SCO104960.
authors.affiliation: Nordic Bioscience, Herlev, Denmark. jsa@nordicbioscience.com.|Section of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark. jsa@nordicbioscience.com.
authors.forename: Jannie M B
authors.initials: JM
authors.lastname: Sand
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Leeming
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Asger R
authors.initials: AR
authors.lastname: Bihlet
authors.affiliation: Section of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.|Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Lange
authors.affiliation: Respiratory Therapy Area Unit, GSK Research and Development, King of Prussia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: Respiratory Therapy Area Unit, GSK Research and Development, King of Prussia, PA, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Centre for Respiratory Medicine and Allergy, Manchester Academic Science Centre, The University of Manchester and University Hospital South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
mesh_terms: D000367:Age Factors; D000368:Aged; D056151:Airway Remodeling; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003094:Collagen / Q000097:blood*; D024141:Collagen Type IV / Q000097:blood; D018450:Disease Progression; D004417:Dyspnea / Q000097:blood / Q000401:mortality / Q000503:physiopathology; D017079:Exercise Tolerance; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis / Q000401:mortality* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000097:blood / Q000401:mortality / Q000503:physiopathology; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000401:mortality; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D024141:Collagen Type IV; D010446:Peptide Fragments; D003094:Collagen
keywords: Biomarker; COPD; Collagen; Elastin; Extracellular matrix; Mortality; Prognostic; Remodeling