Prognostic factors affecting survival of idiopathic pulmonary fibrosis : clinical, physiologic, pathologic and molecular aspects

Abstract

[한글]

[영문]Background:Idiopathic pulmonary fibrosis (IPF) is a diffuse, relentlessly progressive parenchymal lung disease. Its etiology is unknown and it is associated with irreversible respiratory failure, and eventually, considerable morbidity and mortality. Previous studies identified factors of IPF that are related with an increased risk of mortality. These reported prognostic markers include age at diagnosis, sex, symptomatic period prior to diagnosis, a history of cigarette smoking, pulmonary function, level of dypsnea, extent of ground-glass and reticular opacities upon high-resolution computed tomography (HRCT) scanning, lymphocytes in bronchoalveolar lavage fluid (BAL), and response to steroids (e.g. immunosuppression). We examined these clinical and physiological markers in IPF patients. In addition, we investigated whether the histopathologic marker as phosphorylated Smad 2/3 (p-Smad 2/3), tumor growth factor-β (TGF-β) receptor II (TβRII), and the molecular marker polymorphism of the TGF-β1 codon 10 are associated with the progression of IPF patients. The C-reactive protein (CRP), as well as pulmonary function parameters, were also investigated as potential prognostic factors of IPF.Methods:A total of 86 IPF patients who underwent definitive surgical lung biopsy from January 1995 to December 2009 at Severance Hospital, Yonsei University College of Medicine, in Seoul, Korea, were examined. The patients were diagnosed with IPF, as defined by ATS/ERS guidelines. Clinical and physiologic parameters were investigated in these patients. For each patient, we performed immunohistochemical staining for p-Smad 2/3 and TβRII and genotyping of the TGF-β1 codon 10 polymorphism in surgical lung biopsy tissue, retrospectively. The change of pulmonary function during the follow-up period was also evaluated. To make an accurate estimate, changes in pulmonary function parameters were divided by the follow-up duration of each patient.Cox’s proportional hazards models and Kaplan-Meier estimates were used to assess the effect of clinical factors (age, sex, symptom duration at diagnosis, smoking status, amount of smoking, CRP, and treatment response), physiologic parameters (PaO2, PaCO2, FVC, FEV1, and DLCO), histopathological factors (cellularity and fibrosis degree), molecular factors (grade of immunohistochemical staining of p-Smad2/3, TβRII, and the polymorphism in TGF-β1 codon 10), and the change of pulmonary function parameters (FVC, FEV1, and DLCO).Results:The IPF patients consisted of 55 (64.0%) men and 31 (34.0%) women. The mean ± standard deviation age was 61.3 ± 8.9 years. Age at diagnosis, gender, symptom duration at diagnosis, and smoking status did not show significant association with prognosis survival rate. However, the amount of cigarette smoking and severe reduction in the percentages of predicted forced vital capacity (FVC) and diffusion lung capacity of carbon monoxide (DLCO) at diagnosis were associated with poor prognosis (amount of smoking: p = 0.002, FVC: p = 0.013, and DLCO: p = 0.023). Contrary to our expectations, cellularity, fibrosis, expression level of p-Smad2/3 and TβRII and genotype of the TGF-β1 codon 10 polymorphism did not have a statistically significant association with the prognosis of IPF. On the other hand, an abrupt decrease in follow-up pulmonary function parameters and increased level of CRP concentration at diagnosis were significantly associated with poor survival (Δ FVC (L): p = 0.001, Δ FVC (% prep): p = 0.001, Δ FEV1 (L): p = 0.007, Δ FEV1 (% prep): p = 0.006, Δ DLCO (%): p = 0.000, and CRP: p = 0.013).Conclusion: This study confirms that initial pulmonary function parameters, amount of smoking, and the abrupt decrease of lung function parameters are associated with the poor survival in IPF patients. In addition, increased levels of CRP concentration were associated with poor survival of IPF patients in this study. We believe that larger studies are required to confirm such prognostic factors as CRP in IPF patients.