Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is hallmarked by inflammatory processes and a progressive decline of lung function. YKL-40 is a potential biomarker of inflammation and mortality in patients suffering from inflammatory lung disease, but its prognostic value in patients with COPD remains unknown. We investigated whether high plasma YKL-40 was associated with increased mortality in patients with moderate to very severe COPD.

Methods: Four hundred and ninety-three patients with moderate to very severe COPD were followed prospectively for up to 10 years. Patients were divided into two groups according to plasma YKL-40: concentration higher than the 75th percentile for age-matched healthy subjects (i.e. high levels) and normal levels. Outcome was overall survival (OS) and was evaluated in uni- and multivariate proportional hazards Cox regression analyses and adjusted for factors affecting mortality.

Results: Median plasma YKL-40 was increased in patients with COPD (81 ng/ml, p < 0.001) compared to healthy subjects (40 ng/ml). Patients with high plasma YKL-40 had a hazard ratio (HR) of 1.42 (95% CI: 1.15-1.75, p = 0.001) for all-cause mortality. Multivariate analysis showed that YKL-40 (HR 1.38; 95% CI: 1.11-1.72, p = 0.004), age (HR 1.05; 95% CI: 1.03-1.06, p < 0.0001), Severe COPD (HR 1.35; 95 CI: 1.03-1.76, p = 0.03) very severe COPD (HR 2.19; 95% CI: 1.60 - 2.99 < 0.0001), neutrophil granulocyte count (HR 1.05; 95% CI: 1.01-1.08, p = 0.01), and a smoking history of > 40 years (HR 1.38; 95% CI: 1.11-1.71, p = 0.003) were independent prognostic markers of OS.

Conclusion: High plasmaYKL-40 is associated with increased mortality in patients with moderate to very severe COPD, suggesting a role for YKL-40 as a potential biomarker of mortality in this patient group.

Trial registration: ClinicalTrials.gov NCT00132860.

Figure 1

Plasma YKL-40 and COPD severity. Boxplots of plasma concentrations of YKL-40 in patients with COPD according to disease severity. Moderate COPD (79–50 FEV1 % predicted), severe COPD (30–50 FEV1 % predicted) and very severe COPD (< 30 FEV1 % predicted). The median score is the line in the middle of the box, and the 25^th and 75^th percentiles are the lower and upper part of the box. The whiskers are the 5^th and 95^th percentiles. Outliers are given as dots. No significant differences were found (Kruskal-Wallis test).

Figure 2

Kaplan-Meier survival curves showing the association between plasma YKL-40 and 10-year OS. Patients were dichotomized according to 75^th percentile of plasma YKL-40 in age-matched healthy subjects (A), COPD severity (B), and 40 pack years (C). P-value refers to the log-rank test for equality of strata. Moderate COPD (79–50 FEV1 % predicted), severe COPD (30–50 FEV1 % predicted) and very severe COPD (< 30 FEV1 % predicted).

Figure 3

Kaplan-Meier survival curves showing the association between plasma YKL-40 and 10 year OS in patients with different degree of disease severity. Patients were dichotomized according to the 75^th percentile of plasma YKL-40 in age-matched healthy subjects. Patients were divided into groups with moderate COPD (A), severe (B) and very severe COPD (C). P-value refers to the log-rank test for equality of strata.