Integrated phenotyping identifies reproducible prognostic subgroups in idiopathic pleuroparenchymal fibroelastosis

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by upper-lobe-predominant fibrosis and heterogeneous prognosis. An integrated phenotype classification incorporating clinical, radiological and biological markers has not been established.

We conducted a retrospective observational study of 32 patients with idiopathic PPFE in an exploratory cohort and 37 patients in a separate validation cohort. Unsupervised k-means clustering was performed using % forced vital capacity (%FVC), residual volume/total lung capacity (RV/TLC), serum KL-6 levels, and extent of fibrotic lesions on quantitative computed tomography. Leukocyte telomere length (LTL) was measured using quantitative PCR and age-adjusted. Survival was assessed using Kaplan-Meier and Cox regression models. A simplified prognostic score was constructed using predefined clinical thresholds, and its discriminative performance was evaluated using the concordance index (C-index) with bootstrap-derived confidence intervals. Sensitivity analyses using multiple imputation were performed to assess robustness.

Two distinct phenotypic clusters were identified in the exploratory cohort (Cluster 1, n = 15; Cluster 2, n = 17). Cluster 2 showed a severe fibrotic phenotype characterized by lower %FVC, higher RV/TLC, higher KL-6 levels, and greater fibrotic extent, and was associated with significantly worse survival (adjusted hazard ratio, 8.63; 95% CI, 1.06-70.4). Similar phenotypic separation and prognostic differences were reproduced in the validation cohort. The four-variable scoring system reproducibly stratified patients into three risk categories with stepwise prognostic separation in both cohorts. The model demonstrated moderate-to-good discriminative ability, with a C-index of 0.74 (95% CI, 0.59-0.88) in the exploratory cohort and 0.84 (95% CI, 0.74-0.92) in the validation cohort. In contrast, age-adjusted LTL in PPFE was not significantly shorter than in healthy controls and was not associated with survival.

Integrated phenotyping using quantitative CT and clinical indicators identifies reproducible prognostic subgroups in idiopathic PPFE, whereas telomere shortening does not appear to play a major prognostic role. A simple scoring system may provide clinically applicable risk stratification.