CYFRA 21-1 Predicts Progression in Idiopathic Pulmonary Fibrosis: A Prospective Longitudinal Analysis of the PROFILE Cohort

Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. To determine the relationship between serum concentrations of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE) study. CYFRA 21-1 was identified by immunohistochemistry in samples of human lung obtained at surgery. Concentrations of CYFRA 21-1 were measured using an ELISA-based assay in serum samples collected at baseline, 1 month, and 3 months from 491 individuals with an incident diagnosis of IPF who were enrolled in the PROFILE study and from 100 control subjects at baseline. Study subjects were followed for a minimum of 3 years after their first blood draw. CYFRA 21-1 localizes to hyperplastic epithelium in IPF lung tissue. Peripheral CYFRA 21-1 concentrations were significantly higher in subjects with IPF than in healthy control subjects in both the discovery ( = 132) (control: 0.96 ± 0.81 ng/ml; vs. IPF: 2.34 ± 2.15 ng/ml;  < 0.0001) and validation ( = 359) (control: 2.21 ± 1.54 ng/ml; and IPF: 4.13 ± 2.77 ng/ml;  < 0.0001) cohorts. Baseline concentrations of CYFRA 21-1 were able to distinguish individuals at risk of 12-month disease progression (C-statistic, 0.70; 95% confidence interval, 0.61-0.79;  < 0.0001) and were predictive of overall mortality (hazard ratio, 1.12 [95% confidence interval, 1.06-1.19] per 1 ng/ml increase in CYFRA 21-1;  = 0.0001). Furthermore, 3-month change in concentrations of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.