Neutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality - a cohort study

Allan Klitgaard Sørensen, Dennis Back Holmgaard, Lone Hagens Mygind, Julia Johansen, Court Pedersen, Allan Klitgaard Sørensen, Dennis Back Holmgaard, Lone Hagens Mygind, Julia Johansen, Court Pedersen

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and progressive decline in pulmonary function. Neutrophil-to-lymphocyte ratio (NLR), YKL-40 and calprotectin are biomarkers of inflammation and predict mortality in patients with different inflammatory diseases. We aimed to investigate the correlation between levels of these three biomarkers and neutrophil granulocyte and lymphocyte count in patients with moderate to very severe COPD stratified by use of systemic glucocorticoids. Furthermore, we studied the ability of these biomarkers to predict all-cause mortality.

Methods: 386 patients with moderate to very severe COPD were followed prospectively for 10 years. Patients were divided into two groups according to systemic glucocorticoid use at baseline. Correlations between biomarkers were assessed by Spearman's Rho, and mortality was evaluated in uni- and multivariate Cox regression analyses with hazard ratios (HR) and 95% confidence intervals (CI).

Results: Plasma calprotectin was positively correlated with neutrophil granulocyte count and NLR. No significant association was found between plasma YKL-40 and the cellular biomarkers, irrespective of glucocorticoid treatment. In the group not treated with systemic glucocorticoids, plasma calprotectin [HR 1.002 (95% CI 1.000 - 1.004)], NLR [HR 1.090 (1.036 - 1.148)] and lymphocyte count [HR 0.667 (0.522 - 0.851)] were significantly associated with higher mortality. In the group treated with systemic glucocorticoids, higher plasma YKL-40 was significantly associated with mortality in univariate Cox regression analysis [HR 1.006 (1.003 - 1.008)].

Conclusions: Calprotectin was related to neutrophil granulocyte count and NLR in patients with moderate to very severe COPD in stable phase and not in treatment with systemic glucocorticoids. Lymphopenia, higher plasma calprotectin and higher NLR were independent predictors of increased all-cause mortality in this group. Our data also suggests that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality.

Trial registration: ClinicalTrials.gov NCT00132860.

Keywords: COPD; Calprotectin; Glucocorticoids; Lymphopenia; Mortality; Neutrophil-to-lymphocyte ratio; Prognosis; YKL-40.

Figures

Figure 1
Figure 1
Relationship between calprotectin and neutrophil granulocyte count, lymphocyte count* and NLR stratified by glucocorticoid use. Spearman’s rank correlation coefficient (Rho) and corresponding p-values are displayed in the top right corner of each plot. *An outlier of lymphocytes = 30 × 109/L was removed from the graph in the non-glucocorticoid group for aesthetic purposes.
Figure 2
Figure 2
Relationship between YKL-40 and neutrophil granulocyte count, lymphocyte count* and NLR stratified by glucocorticoid use. Spearman’s rank correlation coefficient (Rho) and corresponding p-values are displayed in the top right corner of each plot. *An outlier of lymphocytes = 30 × 109/L was removed from the graph in the non-glucocorticoid group for aesthetic purposes.
Figure 3
Figure 3
Kaplan-Meier survival estimates for each biomarker in the group not treated with systemic glucocorticoids. Calprotectin dichotomized at median (135.5 ng/mL). NLR dichotomized at median (2.83). Neutrophil count dichotomized at upper limit of reference value (7 × 109/L). Lymphocyte count dichotomized at lower limit of reference value (1.3 × 109/L). YKL-40 dichotomized at 75th age corrected percentile. NLR: Neutrophil-to-lymphocyte ratio.
Figure 4
Figure 4
Kaplan-Meier survival estimates for each biomarker in the group treated with systemic glucocorticoids. Calprotectin dichotomized at median of non-glucocorticoid group (135.5 ng/mL). NLR dichotomized at median of non-glucocorticoid group (2.83). Neutrophil granulocyte count dichotomized at upper limit of reference value (7 × 109/L). Lymphocyte count dichotomized at lower limit of reference value (1.3 × 109/L). YKL-40 dichotomized at 75th age corrected percentile. NLR: Neutrophil-to-lymphocyte ratio.

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