Rationale Validated thresholds for clinically meaningful change in quantitative computed tomography (QCT) for fibrosis extent across algorithms remain unclear in idiopathic pulmonary fibrosis (IPF).Objectives To evaluate minimal clinically important difference (MCID) for 1-year change in QCT metrics in IPF using different algorithms than previously reported and to identify prognostically meaningful thresholds for effective risk stratification. Methods This multicenter retrospective study included IPF patients with baseline and 1-year follow-up CT. Minimal clinically important differences for change in fibrosis score (Delta FS) derived from fully automated CT quantification were estimated using an anchor-based approach with 1-year changes in FVC and diffusing capacity for carbon monoxide (DLco), and a prognostic threshold was estimated using maximally selected log-rank statistics. Prognostic significance of Delta FS was evaluated in discovery and validation cohorts. Results The discovery cohort included 524 patients (mean age = 66.8 years; 79% men), and the external validation cohort included 224 patients (mean age = 69.6 years; 83% men). Anchor-based MCIDs were 2.72% for FVC and 4.52% for DLco, with a prognostic threshold of 4.05%. In the discovery cohort, 1-year Delta FS were independently associated with transplant-free survival (TFS), with greater risk when Delta FS exceeded MCID or prognostic thresholds (all, P < .001). In the validation cohort, Delta FS remained associated with TFS (adjusted hazard ratio [aHR] = 1.11; 95% CI, 1.04-1.18), and all prespecified Delta FS thresholds were prognostic for overall TFS, with the prognostic threshold of Delta FS >= 4.05% showing the most consistent associations with overall (aHR = 2.78; 95% CI, 1.36-5.68) and 3-year TFS (aHR = 2.88; 95% CI, 1.11-7.48). Conclusion One-year change in FS and its thresholds were significantly associated with TFS, supporting annual CT follow-up with predefined QCT thresholds for monitoring and risk stratification in IPF.
Background Emphysema, a major component of COPD characterised by progressive alveolar destruction, lacks effective medical therapies. Hepatocyte growth factor (HGF) possesses potent regenerative functions, but its therapeutic potential remains unrealised due to challenges in achieving targeted delivery and sustained lung expression. Methods We first assessed associations between HGF expression and emphysema severity using human datasets, lung tissue, and both elastase-induced and cigarette-smoke-induced murine models. We repurposed a clinical-stage SM102 lipid nanoparticles platform to deliver human HGF mRNA in murine models, evaluating therapeutic efficacy via intratracheal instillation in the elastase model. After optimising nebulisation, we assessed efficacy in the cigarette-smoke model. We investigated underlying mechanisms via single-cell RNA sequencing (scRNA-seq), which we validated in patient-derived lung organoids. Results HGF expression displayed a biphasic pattern across the emphysema spectrum, with upregulation in milder disease states and marked reduction in advanced emphysema. Intratracheal delivery of HGF mRNA lipid nanoparticles restored lung function and attenuated alveolar destruction in the elastase model. Nebulised delivery achieved efficient pulmonary distribution and demonstrated comparable therapeutic efficacy in the cigarette-smoke model, including improved lung function, reduced inflammation, and decreased apoptosis. scRNA-seq analysis detected enhanced alveolar type II (AT2) cell proliferation and differentiation in the elastase model and human organoids. Conclusion This study provides proof-of-concept evidence for a therapeutic strategy for emphysema. Using a clinical-stage lipid nanoparticle platform, we demonstrate that HGF mRNA therapy is effective via both direct instillation and optimised nebulisation, prompting structural and functional recovery by activating endogenous repair pathways in AT2 cells.
