Clinical Phenotypes of Interstitial Lung Disease Progression Identified by Longitudinal Quantitative CT: Support for an Inflammatory-Fibrotic Continuum

Background: Interstitial lung disease (ILD) is often managed as discrete diagnostic categories, yet many patients appear to evolve along a shared inflammatory-fibrotic continuum. Longitudinal quantitative CT enables objective characterization of disease trajectories through volumetric and densitometric metrics. Objectives: To identify and characterize clinically distinct progression phenotypes in ILD using longitudinal quantitative CT analysis. Methods: Retrospective cohort study of 16 patients with ILD undergoing serial chest CT (18 longitudinal comparisons, follow-up 0.5–19.6 months). Each comparison was quantified using a hybrid HU–Z-score method. Unsupervised K-means clustering (k=4) identified natural phenotypic groupings. Silhouette score assessed cluster quality. Results: Four clinically distinct progression phenotypes emerged: (1) Stable/Regressive (72%, n=13): mean volume change −12.5%, mean ΔZ-score −3.87; (2) True Progressive (17%, n=3): concurrent territorial expansion +68.7% and densification ΔZ +13.96, rate +2.37 Z-score units/month; (3) Hyperacute Crisis (6%, n=1): explosive progression +47.8% volume, ΔZ +22.56 over <1 month; (4) Contraction/Regression (6%, n=1): marked volume loss −38.9%, ΔZ −11.20. Within-patient trajectory analysis demonstrated phenotype transitions following treatment initiation, supporting non-static disease behavior. Clustering quality: silhouette score 0.322. Conclusions: Longitudinal quantitative CT identifies four clinically relevant progression phenotypes in ILD supporting a dynamic inflammatory-fibrotic continuum. The True Progressive Phenotype (17%) defines the clearest target for antifibrotic therapy, while the predominant Stable Phenotype (72%) supports de-escalation strategies. This objective phenotyping approach could enable earlier stage-appropriate intervention before irreversible fibrosis is established.