Feature Article

Serum Biomarker Is Associated With COPD Exacerbations

Serum surfactant protein D may be helpful in identifying COPD patients who are at greatest risk for exacerbations.

SAN DIEGO—Serum surfactant protein D (SP-D)—a lung-derived protein that is elevated in individuals with COPD—appears to be associated with COPD exacerbations, according to David A. Lomas, MD, PhD, from the Cambridge Institute for Medical Research, UK. SP-D has been studied in many different respiratory diseases, but largely in small cohorts and with inconsistent results, explained Dr. Lomas at the 2009 International Congress of the American Thoracic Society. He stressed the importance of biomarkers in modeling COPD components, including emphysema, systemic features, and exacerbations.

Dr. Lomas suggested that SP-D is a biomarker for smoking, “and probably, therefore, for interpulmonary inflammation.” In his study, greater levels of SP-D were associated with an increased risk for exacerbations at 12 and 24 months’ follow-up.

In an effort to identify novel biomarkers of COPD components, Dr. Lomas and colleagues examined data from the ongoing ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study, which includes more than 2,000 COPD patients in Global Initiative for Chronic Obstructive Lung Disease stages II, III, and IV.

The aim of three-year long ECLIPSE study—the largest study of its kind—is to identify COPD subtypes, determine the parameters that predict disease progression in these subtypes, examine associated biomarkers that may predict disease progression, and identify novel genetic factors and/or biomarkers that are linked to both clinically relevant COPD subtypes and predict disease progression. Study procedures—which include pulmonary function measurements, computed CT, identification of biomarkers in blood, sputum, urine, and exhaled breath condensate, and health outcomes—are performed at baseline, three months, six months, and every six months thereafter.

Median Values Versus Continuous Variables
In the current study, the investigators looked at 1,837 individuals with COPD and 269 smokers without airflow obstruction (167 subjects were nonsmoking controls). SP-D levels were higher in smokers compared with that in nonsmokers—a small but statistically significant difference.

They also examined the association between SP-D and COPD exacerbations, defined by the patients as a worsening of symptoms. In 1,093 COPD patients (670 and 423 former and current smokers, respectively), there were 2,351 exacerbations (1,446 and 905 in former and current smokers, respectively; the number of exacerbations ranged from one to 11). As median values, SP-D levels were the same in patients without exacerbations and in those who had more than one exacerbation. There was no correlation between SP-D and the number of exacerbations or hospitalizations.

“Interestingly, there was a difference between those who died with COPD and those who remained alive,” Dr. Lomas pointed out. “But the numbers were quite small in the first 12 months and the difference has not yet reached statistical significance. This will be followed up as part of the cohort.”

However, in looking at SP-D as a continuous variable, Dr. Lomas and associates discovered that, for every 100-ng/mL increase in SP-D, there was an odds ratio (OR) of 1.22 for COPD exacerbations, after adjustment for gender, lung function, reversibility, and corticosteroid use. When the investigators looked at subjects with a baseline SP-D in the upper quartile, the OR was 1.42 for COPD exacerbations. Even in patients who reported no exacerbation in the year before study enrollment, an increased risk for exacerbation was present (OR, 1.23). Using an SP-D cutoff of 175.5 ng/mL (normal range was based on nonsmoking controls), subjects with high SP-D values had a greater risk (OR, 1.30) for exacerbations, after adjustment for gender, lung function, and use of inhaled corticosteroids. The investigators found similar results at 24 months’ follow-up.

Additional Findings
Because the ECLIPSE cohort is so large, Dr. Lomas and colleagues were able to determine that SP-D was not associated with gender, chronic bronchitis, emphysema scores, or use of inhaled or oral steroids. They found a weak but significant correlation between SP-D and age, as well as with BMI.

—Mary Brady Service

Suggested Reading
Lomas DA, Silverman EK, Edwards LD, et al. Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax. 2008;63(12):1058-1063.
Lomas DA, Silverman EK, Edwards LD, et al. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur Respir J. 2009 Jan 22; [Epub ahead of print].
Vestbo J, Anderson W, Coxson HO, et al, the ECLIPSE investigators. Evaluation of COPD longitudinally to identify predictive surrogate endpoints (ECLIPSE). Eur Respir J. 2008;31(4):869-873.

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