Abstract Rationale Mucus plugs are increasingly recognized as a structural hallmark and key imaging marker of COPD progression. Although cross-sectional mucus burden has been linked to adverse outcomes, including mortality, the longitudinal behavior of mucus plugs and its prognostic implications remain poorly defined. Whether progressive mucus accumulation over time independently predicts mortality is unknown. Methods COPDGene participants with baseline and 5-year follow-up CT scans were analyzed. Automated segmentation quantified total mucus volume. Mucus progression was defined as an increase in total mucus volume 50 µL over 5 years. All-cause mortality was assessed through long-term follow-up. Kaplan-Meier curves evaluated survival differences. Cox proportional hazards models estimated the association between mucus progression and mortality, first unadjusted and then adjusted for age, sex, race, smoking (status and pack-years), BMI, baseline mucus burden, FEV₁, airway wall thickness (Pi10), and emphysema. Results The study included 5,123 participants (mean follow-up 12 years), of whom 1,206 (22.3%) demonstrated mucus progression (50 µL increase in total mucus volume). Mean age was 59.8 ± 8.7 years and 50% were female. Compared with non-progressors, progressors were older (61.6 vs 59.3 years, p0.001), had greater baseline smoking exposure (45.6 vs 40.7 pack-years, p0.001), and demonstrated more severe respiratory disease, including increased airway wall thickness (2.4 vs 2.2 Pi10, p0.001), lower FEV₁ (2.1 vs 2.4 L, p0.001), and greater emphysema (7.8% vs 4.5%, p0.001). Progressors also had more baseline mucus burden (≥1 lobe: 39.5% vs 25.5%) and were more likely to have GOLD 2-4 (48.8% vs 25.4%, p0.001).There were 788 deaths over follow-up. Individuals with mucus progression had significantly worse survival (log-rank p0.005). In unadjusted analysis, mucus progression was associated with a 1.95-fold increased risk of mortality (HR 1.95; 95% CI 1.68-2.25). After adjustment, mucus progression remained independently associated with mortality (HR 1.39; 95% CI 1.20-1.62; p0.005), alongside older age, lower FEV₁, and greater emphysema. Model discrimination improved from C-index 0.57 (unadjusted) to 0.73 (adjusted). Post-host sensitivity analyses demonstrated that mortality risk progressively increased across mucus-volume change thresholds from 10 to 150 µL (HR 1.19 to 1.65, p 0.05 after FDR adjustment). Conclusions Longitudinal increases in mucus burden, defined as a 50 µL rise in mucus volume over 5 years, are independently associated with higher mortality in smokers and individuals at risk for COPD. Mucus progression represents a dynamic and clinically meaningful imaging biomarker, supporting the potential role of mucus-directed interventions and motivating prospective evaluation as a targetable pathway in COPD. This abstract is funded by: This work was supported by NHLBI grants 1R01HL149877, U01 HL089897, and U01 HL089856 and by NIH contract 75N92023D00011
Estepar et al. (Fri,) studied this question.