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Original Research: COPD |

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Daiana Stolz, MD, MPH, FCCP; Diana Julie Leeming, PhD; Jacob Hull Edfort Kristensen, PhD; Morten A. Karsdal, PhD; Wim Boersma, MD; Renaud Louis, MD; Branislava Milenkovic, MD; Konstantinos Kostikas, MD; Francesco Blasi, MD; Joachim Aerts, MD; Jannie M.B. Sand, PhD; Emiel F.M. Wouters, MD; Gernot Rohde, MD; Cristina Prat, MD; Antoni Torres, MD; Tobias Welte, MD; Michael Roth, PhD; Eleni Papakonstantinou, MD, PhD; Michael Tamm, MD
Author and Funding Information

FUNDING/SUPPORT: BASCO and PROMISE-COPD were investigator-initiated studies primarily funded by the Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland and by the Swiss National Foundation (PP00-P3_128412/1). The principal investigators of all study centers had full and final control of the study design and conduct, database, statistical analysis plan, manuscript content, and publication decisions.

aClinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland

bNordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark

cPneumology, Medisch Centrum, Alkmaar, the Netherlands

dPneumology, University of Liege, Liege, Belgium

ePneumology, Institute for Pulmonary Diseases, Belgrade, Serbia

fPneumology, Medical School, University of Thessaly, Greece

gDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

hPneumology, Amphia Hospital, Breda, the Netherlands

iDepartment of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands

jMicrobiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, CIBER Enfermedades Respiratorias (CIBERES) Instituto de Salud Carlos III, Barcelona, Spain

kPneumology, Hospital Clinic, Barcelona, Spain

lPneumology, Medizinische Hochschule, Hannover, Germany

CORRESPONDENCE TO: Daiana Stolz, MD, MPH, FCCP, Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(1):47-59. doi:10.1016/j.chest.2016.08.1440
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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.

Trial Registry  No.: ISRCTN99586989; URL: www.controlled-trials.com.

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