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Original Research |

Systemic biomarkers of collagen and elastin turnover are associated with clinically relevant outcomes in COPD

Daiana Stolz, Prof.; 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 FM. 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

Conflict of interest: D.J.L, J.H.E.K., M.A.K., and J.M.B.S. are full or part-time employees of Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark, the manufacturer of the assays used in this study. RL received research grants from Chiesi, GSK, Novartis and Astra Zeneca and AD Board fees from Astra Zeneca, GSK and Novartis. BM has participated in speaking activities sponsored by GSK, Astra Zeneca, Boehringer Ingelheim, Takeda and Providens and participated in industry advisory committees for Boehringer Ingelheim, GSK and Astra Zeneca. KK is an employee and shareholder of Novartis Pharma AG. He has received honoraria from Astra Zeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, MS, Novartis, Takeda and UCB, and has served on advisory boards arranged by Astra Zeneca, Chiesi, ELPEN, Novartis and Takeda. GR has received honoraria from Novartis, Bayer, Astra Zeneca, Pfizer and Chiesi. All other authors declare no conflicts of interest.

Funding: 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.

Clinical Trial Registration:www.controlled-trials.com (identifier ISRCTN99586989).

1Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland

2Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark

3Pneumology, Medisch Centrum, Alkmaar, The Netherlands

4Pneumology, University of Liege, Liege, Belgium

5Pneumology, Institute for Pulmonary Diseases, Belgrade, Serbia

6Pneumology, Medical School, University of Thessaly, Greece

7Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, Italy

8Pneumology, Amphia Hospital, Breda, The Netherlands

9Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

10Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Universitat Autònoma de Barcelona, CIBER Enfermedades Respiratorias (CIBERES) Instituto de Salud Carlos III, Spain

11Pneumology, Hospital Clinic, Barcelona, Spain

12Pneumology, Medizinische Hochschule, Hannover, Germany

Corresponding author. 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. 2016. doi:10.1016/j.chest.2016.08.1440
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Abstract

Background  Extracellular matrix remodeling (ECM) of the lung tissue releases protein fragments into the blood, where they may be detected as serological surrogate markers of disease activity in chronic obstructive pulmonary disease (COPD). We aimed 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, GOLD grades II-IV, we analyzed serum samples at stable state, exacerbation and 4 weeks after exacerbation, for a panel of 5 novel neo-epitopes including fragments of collagen type-III (C3M) and 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) by ELISA. These neo-epitopes were also measured at stable state in a derivation cohort including 100 COPD patients.

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. Degradation of collagen type-III and -VI was associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation as compared to 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 (HR 0.72[0.59-0.89] p=0.002) and Pro-C6 with survival (HR 2.09[1.18-3.71], p=0.011).

Conclusions  Serum biomarkers of ECM turnover are significantly associated with disease severity and clinically relevant outcomes in COPD.


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