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

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

doi:10.1016/j.chest.2016.08.1440

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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), proforms 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.

Original language	English
Pages (from-to)	47-59
Number of pages	13
Journal	Chest
Volume	151
Issue number	1
DOIs	https://doi.org/10.1016/j.chest.2016.08.1440
Publication status	Published - Jan 2017

Keywords

acute exacerbations of COPD
collagen
COPD
elastin
extracellular matrix molecules
OBSTRUCTIVE PULMONARY-DISEASE
EXTRACELLULAR-MATRIX
ACUTE EXACERBATIONS
LIVER FIBROSIS
LUNG-FUNCTION
DEGRADATION
AIRWAY
INFLAMMATION

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10.1016/j.chest.2016.08.1440

Cite this

Stolz, D., Leeming, D. J., Kristensen, J. H. E., Karsdal, M. A., Boersma, W., Louis, R., Milenkovic, B., Kostikas, K., Blasi, F., Aerts, J., Sand, J. M. B., Wouters, E. F. M., Rohde, G., Prat, C., Torres, A., Welte, T., Roth, M., Papakonstantinou, E., & Tamm, M. (2017). Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD. Chest, 151(1), 47-59. https://doi.org/10.1016/j.chest.2016.08.1440

@article{790237ad65784d1092b022259eb50e89,

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), proforms 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.",

keywords = "acute exacerbations of COPD, collagen, COPD, elastin, extracellular matrix molecules, OBSTRUCTIVE PULMONARY-DISEASE, EXTRACELLULAR-MATRIX, ACUTE EXACERBATIONS, LIVER FIBROSIS, LUNG-FUNCTION, DEGRADATION, AIRWAY, INFLAMMATION",

author = "Daiana Stolz and Leeming, {Diana Julie} and Kristensen, {Jacob Hull Edfort} and Karsdal, {Morten A.} and Wim Boersma and Renaud Louis and Branislava Milenkovic and Konstantinos Kostikas and Francesco Blasi and Joachim Aerts and Sand, {Jannie M. B.} and Wouters, {Emiel F. M.} and Gernot Rohde and Cristina Prat and Antoni Torres and Tobias Welte and Michael Roth and Eleni Papakonstantinou and Michael Tamm",

year = "2017",

month = jan,

doi = "10.1016/j.chest.2016.08.1440",

language = "English",

volume = "151",

pages = "47--59",

journal = "Chest",

issn = "0012-3692",

publisher = "Elsevier",

number = "1",

}

Stolz, D, Leeming, DJ, Kristensen, JHE, Karsdal, MA, Boersma, W, Louis, R, Milenkovic, B, Kostikas, K, Blasi, F, Aerts, J, Sand, JMB, Wouters, EFM, Rohde, G, Prat, C, Torres, A, Welte, T, Roth, M, Papakonstantinou, E & Tamm, M 2017, 'Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD', Chest, vol. 151, no. 1, pp. 47-59. https://doi.org/10.1016/j.chest.2016.08.1440

TY - JOUR

T1 - Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

AU - Stolz, Daiana

AU - Leeming, Diana Julie

AU - Kristensen, Jacob Hull Edfort

AU - Karsdal, Morten A.

AU - Boersma, Wim

AU - Louis, Renaud

AU - Milenkovic, Branislava

AU - Kostikas, Konstantinos

AU - Blasi, Francesco

AU - Aerts, Joachim

AU - Sand, Jannie M. B.

AU - Wouters, Emiel F. M.

AU - Rohde, Gernot

AU - Prat, Cristina

AU - Torres, Antoni

AU - Welte, Tobias

AU - Roth, Michael

AU - Papakonstantinou, Eleni

AU - Tamm, Michael

PY - 2017/1

Y1 - 2017/1

N2 - 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), proforms 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.

AB - 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), proforms 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.

KW - acute exacerbations of COPD

KW - collagen

KW - COPD

KW - elastin

KW - extracellular matrix molecules

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - EXTRACELLULAR-MATRIX

KW - ACUTE EXACERBATIONS

KW - LIVER FIBROSIS

KW - LUNG-FUNCTION

KW - DEGRADATION

KW - AIRWAY

KW - INFLAMMATION

U2 - 10.1016/j.chest.2016.08.1440

DO - 10.1016/j.chest.2016.08.1440

M3 - Article

C2 - 27575358

VL - 151

SP - 47

EP - 59

JO - Chest

JF - Chest

SN - 0012-3692

IS - 1

ER -