Mortality surrogates in combined pulmonary fibrosis and emphysema

Background: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. Methods: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D (LCO)) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. Results: In both IPF cohorts, CPFE patients with >= 10% emphysema had a greater smoking history and lower baseline D (LCO) compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with >= 10% emphysema, 1-year D (LCO) decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by >= 15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines >= 5% and >= 10% showed strong mortality associations. Conclusion: When assessing disease progression in IPF, D (LCO) decline should be considered in patients with >= 10% emphysema and a >= 5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.