An Observational, Prospective, Multicenter Study on Hereditary Influences on Pulmonary Fibrosis Trajectories

Familial pulmonary fibrosis (FPF) is a genetically driven subset of fibrosing interstitial lung diseases (ILDs) characterised by heterogeneous phenotypes, variable clinical trajectories, and limited evidence to guide prognosis and treatment. Although antifibrotic therapies are effective in idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), data in FPF, particularly from European populations, remain scarce. The SHIFT (Hereditary Influences on Pulmonary Fibrosis Trajectories) study aims to prospectively characterize disease progression, treatment response, and outcomes in a national Italian cohort.

SHIFT is a prospective, multicenter, observational cohort study enrolling adults (≥18 years) with ILD on high-resolution computed tomography and genetic findings consistent with FPF. Participants are recruited from specialized ILD referral centers across Italy and followed every 6 months for up to 5 years. Diagnostic attribution is standardized through multidisciplinary discussion using a structured confidence framework. All treatments are prescribed according to routine clinical practice. The primary endpoint is annual relative decline in forced vital capacity (FVC). Secondary endpoints include longitudinal changes in diffusing capacity (DLCO), treatment effectiveness and safety, mortality, transplant-free survival, cancer incidence, and genotype-phenotype and genotype-treatment response associations. Longitudinal data will be analyzed using mixed-effects models, and time-to-event outcomes using survival methods. Multivariable analyses and sensitivity analyses will address confounding.