Daiana Stolz1, Diana Julie Leeming2, Jacob Hull Edfort Kristensen2, Morten A Karsdal2, Wim Boersma3, Renaud Louis4, Branislava Milenkovic5, Konstantinos Kostikas6, Francesco Blasi7, Joachim Aerts8, Jannie M B Sand2, Emiel F M Wouters9, Gernot Rohde9, Cristina Prat10, Antoni Torres11, Tobias Welte12, Michael Roth13, Eleni Papakonstantinou13, Michael Tamm13. 1. Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland. Electronic address: daiana.stolz@usb.ch. 2. Nordic Bioscience, Biomarker Biology and Biomarkers, Herlev, Denmark. 3. Pneumology, Medisch Centrum, Alkmaar, the Netherlands. 4. Pneumology, University of Liege, Liege, Belgium. 5. Pneumology, Institute for Pulmonary Diseases, Belgrade, Serbia. 6. Pneumology, Medical School, University of Thessaly, Greece. 7. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. 8. Pneumology, Amphia Hospital, Breda, the Netherlands. 9. Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the Netherlands. 10. Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, CIBER Enfermedades Respiratorias (CIBERES) Instituto de Salud Carlos III, Barcelona, Spain. 11. Pneumology, Hospital Clinic, Barcelona, Spain. 12. Pneumology, Medizinische Hochschule, Hannover, Germany. 13. Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.
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. TRIAL REGISTRY: No.: ISRCTN99586989; URL: www.controlled-trials.com.
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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