Biomarkers for Chronic Obstructive Pulmonary Disease

By Dahl, Morten

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, chronic lung inflammation, and extrapul-monary systemic effects. In chronic lung inflammation, elevated protease and oxidant levels are believed to contribute to degradation of lung tissue and progression of COPD. When evaluating therapies for COPD or defining different patterns of the disease, markers that could provide insights into these destructive inflammatory processes would therefore be helpful.Newbiomarkers for COPD are being explored, including those in exhaled breath, induced sputum, bronchoalveolar lavage fluid, lung biopsy, and serum (1, 2).Abiomarker is defined as a biological marker that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (3). Biomarkers can be genetic polymorphisms that contribute new pathogenic insights intoCOPD(4) or parameters that may be used for the assessment of disease severity or effects of therapy. Compared with markers measured in other sample material, biomarkers determined in serum are reliably measured using equipment that is cost-effective and readily available in clinical settings. However, these markers may be modulated by morbidities other than COPD and thus may, in some circumstances, represent epiphe-nomena unrelated to the COPD phenotype. In this issue of the Journal (pp. 1207- 1214), Sin and colleagues report on a new biomarker for COPD, surfactant protein (SP)-D. This marker is relatively specific for the lungs and can be measured in serum (5). SP-D synthesis is mainly restricted to pulmonary tissues, as illustrated by mRNA expression and protein staining studies (http://t1dbase.org/page/GeneOverview/ display/?gene_id5 6441 and http://www.proteinatlas.org/tissue_ profile.php?antibody_id54578&spot_order5 2). Since SP-D is elevated in the circulation in response to lung pathology (6), this protein could provide a useful lung-specific marker of COPD (5).

Examining 289 patients with COPD in a randomized controlled trial, Sin and colleagues found that serum SP-D levels increased during the 4 weeks when inhaled corticosteroids, long-acting beta[sub]2[/sub]-agonists, and theophylline products were withdrawn. In contrast, 4 weeks of treatment with either fluticasone or fluticasone/salmeterol was associated with reduced serum SP-D, indicating that an inhaled corticosteroid in conjunction with a long- acting beta[sub]2[/sub]-agonist can decrease circulating levels of SP-D. The changes observed in serum SP-D with withdrawal and institution of therapy could be due to (1) changes in SP-D leakage from the lungs into the circulation, (2) changes in extrapulmonary SP-D production, or (3) changes in SP-D clearance from the circulation. Although none of these can be totally excluded, the first hypothesis seems the most likely as SP-D is primarily produced in the lungs, corticosteroids in this trial were delivered in lung, and other lung pathologies also are associated with elevated serum SP-D (6, 7).

SP-D is a pattern-recognition molecule, which binds sugar moieties of microorganisms and apoptotic cells in the lungs and mediates their clearance by the innate immune system (6, 7). Because mice without SP-D develop emphysema, and recombinant SP-D can reduce this and other lung injuries (8, 9), SP-D as a serum marker of COPD could link to critical pathologic events in the development of COPD. Further studies of SP-D and other lung-specific markers for COPD are needed to confirm the present findings and to further evaluate the potential utility of SP-D and lung-specific serum markers in clinical COPD.

Sin and colleagues also demonstrated that the withdrawal-and treatment-related changes in SP-D levels were associated with changes in the patient’s FEV[sub]1[/sub]% predicted and St. George’s Respiratory Questionnaire score, thereby fulfilling important validation criteria for new potential biomarkers in COPD (10) and demonstrating that (1) levels of the marker are associated with clinical outcome, (2) therapeutic interventions have effects on the marker, and (3) treatment-related changes in the marker are associated with positive changes in clinical outcomes. The small benefits observed in lung function and health status with inhaled corticosteroids are consistent with results from previous trials indicating that inhaled corticosteroids with or without a long- acting beta[sub]2[/sub]-agonists may be considered for certain subgroups of patients with COPD (11). The data need confirmation, but seem to support the hypothesis that a treatment strategy directed at normalization of serum SP-D and potentially other COPD biomarkers could improve lung function, health status, and symptom control in COPD.

In contrast to previous studies (12, 13), Sin and colleagues found no effect of inhaled fluticasone or combination therapy on serum levels of C-reactive protein (CRP), a systemic bio-marker of reduced lung function, and morbidity and mortality in COPD (14, 15). Sin and coworkers previously found that CRP levels were increased 71% after withdrawal of inhaled corticosteroids, whereas 8 weeks of inhaled fluticasone reduced serum CRP by 29%. Further research in this area is required to conclusively determine whether CRP can be used as biomarker to assess the efficacy of COPD therapy.

InCOPD, biomarkers seemless well investigated than markers in asthma, where exhaled nitric oxide and, to a lesser degree, sputum eosinophils have been used to guide therapy (16). Currently, these measurements are too expensive and complex for routine analysis. With theEuropeanRepiratory Society/American Thoracic Society task force’s recent work on markers in COPD (2) and with Sin and coworkers’ pharmacologic trial on SP-D, biomarkers in COPD appear to be an important emerging field.

Conflict of Interest Statement: M.D. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Am J Respir Crit Care Med Vol 177. pp 1177-1179, 2008

Internet address: www.atsjournals.org

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MORTEN DAHL, M.D.

Herlev University Hospital

Copenhagen, Denmark

Copyright American Thoracic Society Jun 1, 2008

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