Prognostic value of IFN-γ, sCD163, CCL2 and CXCL10 involved in acute exacerbation of idiopathic pulmonary fibrosis

Objective: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is of concern because of its propensity for rapid deterioration and high mortality. Its aetiology and mechanism are still unclear. The aims of this study were to clarify the pathophysiology differences between AE-IPF and stable IPF (S-IPF) by comparing the serum levels of various cytokines and chemokines in the two groups and to identify those involvement in the occurrence of acute exacerbation and associated with mortality.

Methods: The study included 28 patients with AE-IPF, 32 patients with S-IPF, and 18 healthy control subjects. We measured the serum cytokine and chemokine levels in all cases by multiplex assay. Serum levels of cytokines and chemokines were compared between AE-IPF and S-IPF subjects. Logistic regression analysis was applied to identify the ability of these variables to predict acute exacerbation. Kaplan-Meier curves were used to analyse survival and Cox proportional hazard regression was used to identify predictors of survival.

Results: Levels of several cytokines and chemokines were significantly higher in both patient groups with IPF (with the exception of interleukin-2 [IL-2], chemokine cc-motif ligand 3, and RANTES [regulation upon activation normal T-cell express sequence]) than in healthy controls. Serum IL-1β (p = 0.008) and interferon (IFN)-γ (p = 0.007) levels tended to be higher in patients with AE-IPF than in those with S-IPF. The concentration of chemokine cc-motif ligand (CCL) 2 was significantly higher in bronchoalveolar lavage fluid than in serum (p = 0.001). Higher C-reactive protein, lactate dehydrogenase, percent forced vital capacity, percent diffusing capacity of the lung for carbon monoxide, and IFN-γ values in the patients with IPF were correlated with acute exacerbation status, with respective odds ratios of 1.241 (p = 0.011), 1.050 (p = 0.004), 1.043 (p = 0.001), 0.927 (p = 0.014), and 0.929 (p = 0.020). Acute exacerbation status was associated with an increased risk of mortality (hazard ratio 0.107, 95% confidence interval 0.036-0.314; p < 0.001). Univariate Cox regression demonstrated an association of IFN-γ, CCL2, C-X-C motif chemokine 10 (CXCL10) and sCD163 levels with an increased mortality risk (p = 0.015, p = 0.002, p = 0.001, and p = 0.030, respectively).

Conclusions: Our data demonstrate that serum levels of some pro-inflammatory cytokines and macrophage chemokines are upregulated during acute exacerbations of IPF and that these exacerbations are associated with the serum IFN-γ level. Chemokines and protein such as sCD163, CCL2, and CXCL10 are associated with activation of macrophages and may have a serious impact on overall survival in patients with IPF.