title: Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD.
abstract: BACKGROUND
  Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD.
  
  
  METHODS
  In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro-forms of collagen type III (Pro-C3) and type VI (Pro-C6), and neutrophil elastase-generated fragments of elastin (EL-NE) according to enzyme-linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD.
  
  
  RESULTS
  Serum levels of C3M, C6M, Pro-C3, Pro-C6, and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation compared with stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59-0.89; P = .002) and Pro-C6 with survival (hazard ratio, 2.09; CI, 1.18-3.71; P = .011).
  
  
  CONCLUSIONS
  Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD.
  
  
  BACKGROUND
  No.: ISRCTN99586989; URL: www.controlled-trials.com.
authors: Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland. Electronic address: daiana.stolz@usb.ch.
authors: Daiana
authors: D
authors: Stolz
authors: Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark.
authors: Diana Julie
authors: DJ
authors: Leeming
authors: Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark.
authors: Jacob Hull Edfort
authors: JHE
authors: Kristensen
authors: Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark.
authors: Morten A
authors: MA
authors: Karsdal
authors: Pneumology, Medisch Centrum, Alkmaar, the Netherlands.
authors: Wim
authors: W
authors: Boersma
authors: Pneumology, University of Liege, Liege, Belgium.
authors: Renaud
authors: R
authors: Louis
authors: Pneumology, Institute for Pulmonary Diseases, Belgrade, Serbia.
authors: Branislava
authors: B
authors: Milenkovic
authors: Pneumology, Medical School, University of Thessaly, Greece.
authors: Konstantinos
authors: K
authors: Kostikas
authors: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors: Francesco
authors: F
authors: Blasi
authors: Pneumology, Amphia Hospital, Breda, the Netherlands.
authors: Joachim
authors: J
authors: Aerts
authors: Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark.
authors: Jannie M B
authors: JMB
authors: Sand
authors: Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Emiel F M
authors: EFM
authors: Wouters
authors: Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors: Gernot
authors: G
authors: Rohde
authors: Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, CIBER Enfermedades Respiratorias (CIBERES) Instituto de Salud Carlos III, Barcelona, Spain.
authors: Cristina
authors: C
authors: Prat
authors: Pneumology, Hospital Clinic, Barcelona, Spain.
authors: Antoni
authors: A
authors: Torres
authors: Pneumology, Medizinische Hochschule, Hannover, Germany.
authors: Tobias
authors: T
authors: Welte
authors: Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.
authors: Michael
authors: M
authors: Roth
authors: Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.
authors: Eleni
authors: E
authors: Papakonstantinou
authors: Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.
authors: Michael
authors: M
authors: Tamm
mesh_terms: D000368:Aged; D056151:Airway Remodeling / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism*; D005060:Europe / Q000453:epidemiology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology; D012129:Respiratory Function Tests / Q000379:methods; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D003094:Collagen; D004549:Elastin
keywords: COPD; acute exacerbations of COPD; collagen; elastin; extracellular matrix molecules