Biomarkers of therapeutic response in patients with chronic obstructive pulmonary disease: a critical review of the literature.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality across the world. Unfortunately, none of the current therapies, except for smoking cessation and supplemental domiciliary oxygen for hypoxaemic patients, can modify its natural course or alter survival. The pipeline for new compounds is not very promising owing to repeated failures, and many large pharmaceutical companies have abandoned COPD drug discovery altogether. One major barrier to new drug discovery is the lack of modifiable biomarkers that can be used as surrogates of clinical outcomes such as exacerbation and mortality. The only accepted marker in COPD is forced expiratory volume in 1 second (FEV(1)). However, by definition, COPD is a non-reversible or poorly reversible condition with respect to FEV(1). Thus, very few drugs except for bronchodilators have been able to address this endpoint. Of many candidate molecules, sputum neutrophil counts, exhaled corrected alveolar nitric oxide and proline-glycine-proline (PGP) and N-α-PGP, which are breakdown products of collagen, are promising lung-based biomarkers. However, their clinical utility has not been validated in large clinical trials. Promising blood biomarkers include surfactant protein D, and pulmonary- and activation-regulated chemokine (PARC/CCL-18). However, the clinical data have been inconsistent. Non-specific inflammatory biomarkers such as C-reactive protein and interleukin-6 lack specificity for COPD and thus are of limited clinical usefulness.