Combined HDL-BMI Phenotyping Provides Incremental Prognostic Value in Idiopathic Pulmonary Fibrosis

Background/Objectives: Risk stratification in idiopathic pulmonary fibrosis (IPF) remains primarily based on physiological indices, yet increasing evidence suggests that systemic metabolic and nutritional vulnerability may influence outcomes in chronic interstitial lung disease. Methods: In this longitudinal, single-center cohort, 211 patients with IPF were followed from diagnosis until death or last follow-up. Baseline lipid profiles and body mass index (BMI) were assessed. A metabolic-nutritional phenotype was constructed using high-density lipoprotein cholesterol (HDL) and BMI. Survival was analyzed using Kaplan-Meier and multivariable Cox models adjusted for GAP stage. Incremental prognostic value beyond the GAP index was evaluated using Harrell's C-index and time-dependent ROC analysis. Results: During a median follow-up of 29 months, 134 patients (63.5%) died. Lower HDL levels were associated with increased mortality in unadjusted analysis (HR = 1.45, 95% CI 1.03-2.04) but were not independently predictive after adjustment. In contrast, the combined HDL-BMI phenotype independently stratified mortality risk. Compared with HDL ≤ 1.0 mmol/L and BMI ≤ 24 kg/m², patients with HDL > 1.0 mmol/L and BMI > 24 kg/m² had significantly lower mortality (adjusted HR = 0.48, 95% CI 0.29-0.80), with stronger associations among those aged ≥ 65 years (adjusted HR = 0.37, 95% CI 0.18-0.74). The addition of HDL-BMI improved discrimination beyond GAP (C-index: 0.585 vs. 0.618; 36-month AUC: 0.633 vs. 0.675; NRI: 0.243). Conclusions: The coexistence of HDL ≤ 1.0 mmol/L and BMI ≤ 24 kg/m² identified a subgroup with poorer survival in IPF. This combined metabolic-nutritional phenotype improved mortality risk stratification beyond the GAP stage.