Granulocyte colony-stimulating factor in bronchoalveolar lavage fluid is a potential biomarker for prognostic prediction of idiopathic pulmonary fibrosis

Abstract

Background/aims: Neutrophilia is frequently observed in bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. Granulocyte colony-stimulating factor (G-CSF) is a potent neutrophil-activating glycoprotein. However, the clinical implications of G-CSF remain poorly understood.in patients with IPF. Therefore, we evaluated the relationship between the G-CSF concentration in BALF and the progression of fibrosis, including in terms of the decline in lung function and long-term survival rate.

Methods: G-CSF concentrations were measured in BALF using enzyme-linked immunosorbent assay (ELISA). The survival rate was estimated using Kaplan-Meier survival analyses.

Results: G-CSF protein levels were significantly higher in IPF (n = 87; 1.88 [0 to 5.68 pg/mL]), nonspecific interstitial pneumonia (n = 22; 0.58 [0 to 11.64 pg/mL]), and hypersensitivity pneumonitis (n = 19; 2.48 [0.46 to 5.71 pg/mL]) patients than in normal controls (n = 33; 0 [0 to 0.68 pg/mL]) (all p < 0.01). A receiver operating characteristic curve showed a difference in G-CSF levels between IPF and NC (area under the curve, 0.769): The G-CSF cut-off of 0.96 pg/mL indicated 84.9% specificity and 63.2% sensitivity for IPF. The survival rate was significantly lower in the group with G-CSF > 2.872 pg/mL than in the group with ≤ 2.872 pg/mL (hazard ratio, 2.69; p = 0.041). The annual decline in diffusing capacity of the lung for carbon monoxide was positively correlated with the G-CSF level (p = 0.018).

Conclusion: G-CSF may participate in the development of IPF and be useful for predicting the prognosis of IPF. Therefore, G-CSF should be analyzed in BALF, in addition to differential cell counts.

Keywords: Granulocyte colony-stimulating factor; Idiopathic pulmonary fibrosis; Neutrophils; Survival.

Figure 1

Granulocyte colony-stimulating factor (G-CSF) protein concentrations in bronchoalveolar lavage fluid and the receiver operator characteristic (ROC) curves. (A) The G-CSF protein was detected in 25 of 33 normal controls (NC), 82 of 87 idiopathic pulmonary fibrosis (IPF) patients, 20 of 22 nonspecific interstitial pneumonia (NSIP) patients, 18 of 19 hypersensitivity pneumonitis (HP) patients, and all 10 sarcoidosis patients. The data are presented as median values with interquartile range. (B) The ROC curve of the G-CSF protein concentration between the IPF and NC groups. A cut-off value of 0.96 pg/mL had 74.1% accuracy, 84.9% specificity, and 62.3% sensitivity for differentiating between the two groups. AUC, area under the curve.

Figure 2

Kaplan-Meier plot of 84 subjects with idiopathic pulmonary fibrosis followed for 1 to 10 years. The percent survival was significantly lower in the group with granulocyte colony-stimulating factor (G-CSF) > 2.872 pg/mL (n = 36, dotted line) than the group with G-CSF ≤ 2.872 pg/mL (n = 48, solid line) (hazard ratio, 2.69; 95% confidence interval, 1.01 to 7.15; p = 0.041).

Figure 3

Correlation between granulocyte colony-stimulating factor (G-CSF) levels and cell number in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. G-CSF protein concentrations were positively correlated with (A) diffusing capacity of the lung for carbon monoxide (DL_CO; %/year) (p = 0.018, r = 0.226) and (B) neutrophil number (p = 0.002, r = 0.325) but negatively correlated with (C) lymphocytes (p = 0.022, r = −0.246) and (D) macrophages (p = 0.008, r = −0.284).