Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease leading to loss of respiratory function. The IPF-PRO Registry is a prospective multi-centre registry that provides a valuable resource to investigate biomarkers associated with disease progression in patients with IPF. Aim: To develop a biomarker-inclusive model predictive of disease progression or death in patients with IPF. Methods: Using clinical data and blood samples taken from 558 patients with IPF at enrolment into the IPF-PRO Registry, we used a machine learning-based random forest survival approach to identify demographic/clinical parameters and gene and protein expression predictive of disease progression, i.e. a composite of drop in FVC % predicted >10%, lung transplant, or death. We utilized a feature pre-selection approach, based on univariable Cox regression models in conjunction with feature correlation, to maximize feature relevance and minimize redundancy among the biomarkers. Results: The final model for prediction of the composite endpoint included, among other parameters, DLCO % predicted, body mass index, SP-D protein expression, and MIXL1 gene expression. The combination of demographic/clinical parameters and gene or protein expression outperformed prediction of the composite endpoint based on demographic/clinical parameters only. We validated the model on a separate sub-cohort of 247 patients from the IPF-PRO Registry. Conclusions: The set of biomarkers identified in this analysis may serve as a panel to predict disease progression or death in patients with IPF.
A number of model systems have been developed to study the initiating and promoting phases of neoplastic development in rat liver. Four of these protocols use diethylnitrosamine (DEN) initiation, but employ different methods of promotion. The present studies were designed to evaluate these systems under standardized laboratory conditions to determine their relative ability to induce histochemically identifiable γ-glutamyl transpeptidase positive (GGT + ) foci. Studies were also performed to examine the effects of the four promoting regimens on liver-derived serum enzymes and hepatic drug metabolism. Under standardized laboratory conditions, including the use of a single rat strain, all four systems induced GGT+ foci following DEN initiation. Within the maximum time period evaluated (8 weeks) promotion with 2-acetyl-aminofluorene and partial hepatectomy resulted in the highest number of GGT + foci/cm 2 . In addition, the hepatic mixed-function oxidase system was markedly affected by the promoting regimens. Cytochrome P-450 content was decreased (50% of control) by three of four systems. All four promotion regimens reduced benzphetamine-N-demethylase activity (20–50% of control). Ethoxycoumarin-O-deethylase activity (P-448 related) was not changed by the promotion regimens. Three of four regimens increased epoxide hydrolase activity (150–600% of control) and DT-diaphorase activity (150–200% of control). Combining DEN initiation and each of the four promotion protocols had little additional effect on hepatic drug metabolizing enzymes. It is concluded that the four systems evaluated are reproducible under standard conditions and that the promotion regimens employed cause striking alterations in hepatic microsomal drug metabolism that are largely independent of the presence or absence of focal GGT + lesions.
Introduction: IPF is a progressive and ultimately fatal interstitial lung disease with a variable clinical course. Aim: To assess relationships between clinical characteristics and death or lung transplant in patients with IPF. Methods: Data from patients with a newly established diagnosis of IPF enrolled in the US Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry from its inception on 5 June 2014 to 26 October 2017 were used to examine relationships between patient characteristics at time of enrolment and the composite outcome of all-cause death or lung transplant. Univariable associations were assessed using Cox proportional hazards models. Results: Of 662 patients enrolled, 111 events of death (91) or lung transplant (20) were observed over a follow-up period of 30 months. Older age; oxygen use at rest; oxygen use with activity; history of pulmonary hypertension; number of respiratory-related hospitalizations in the previous year; and worse disease severity based on FVC % predicted, DLco % predicted, CPI, or GAP stage were significantly associated with all-cause death or lung transplant (Table). Conclusion: Univariable analyses of data from the IPF-PRO Registry suggest that oxygen use was the strongest predictor of death or lung transplant in patients with IPF. Multivariable analyses will determine if the effect of oxygen use is independent of more well-established predictors.
Introduction: Prostasin is a serine protease expressed in alveolar epithelial cells where it regulates fluid and electrolyte balance via proteolysis of the epithelial sodium channel. Aim: Determine if circulating prostasin is associated with the presence or severity of IPF. Methods: Patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months (n=624) came from the multicenter IPF-PRO Registry. Controls (n=100) without known lung disease had a similar age and sex distribution. Plasma prostasin at enrollment was quantified by immunoassay and data were log2 transformed. Linear regression was used to compare prostasin levels in patients with IPF vs controls and, among the IPF population, determine the association of prostasin with disease severity indicated by FVC % predicted, DLCO % predicted, and composite physiologic index (CPI) (all measured at enrollment). Results: The IPF cohort was mostly male (74.4%), former smokers (64.7%), with a median age of 70. Median (Q1, Q3) FVC and DLCO % predicted were 69.2 (58.4, 79.7) and 43.2 (33.4, 51.9), respectively. About half were taking an antifibrotic (AF) drug. Prostasin levels were significantly increased in patients with IPF vs controls (log2 fold change 0.82, p<0.001), including in patients taking AF therapy. Higher prostasin levels were associated with more severe IPF (difference in disease severity per unit increase in log2-concentration: -6.33 for FVC, -9.55 for DLCO, 7.59 for CPI; all p<0.001). Associations were unchanged after adjustment for AF drug use. Conclusions: Circulating prostasin highly correlates with the presence and severity of IPF and is a candidate biomarker for severity of IPF.
