Association of Radiologic PPFE Change with Mortality in Lung Cancer Screening Cohorts

TL;DR

Quantitative assessment of PPFE progression may provide a clinically relevant imaging biomarker for identifying individuals at increased respiratory risk within screening programmes.

Abstract

Background: Pleuroparenchymal fibroelastosis (PPFE) is an upper lobe predominant fibrotic lung abnormality associated with increased mortality in established interstitial lung disease. However, the clinical significance of radiologic PPFE progression in lung cancer screening populations remains unclear. We investigated whether longitudinal change in PPFE quantified on low dose CT independently associates with mortality and respiratory morbidity. Methods: We analysed longitudinal low-dose CT scans and clinical data from two lung cancer screening studies: the National Lung Screening Trial (NLST; n=7980) and the SUMMIT study (n=8561). An automated algorithm quantified PPFE volume on baseline and follow up scans. Annualised change in PPFE (dPPFE) was derived and dichotomised using a distribution based threshold to define progressive PPFE. Associations between dPPFE and mortality were evaluated using Cox proportional hazards models adjusted for demographic and clinical variables. In the SUMMIT cohort, dPPFE was also examined in relation to clinical outcomes. Findings: dPPFE independently associated with mortality in both cohorts (NLST: HR 1.25, 95% CI 1.01-1.56, p=0.042; SUMMIT: HR 3.14, 95% CI 1.66-5.97, p<0.001). Kaplan-Meier curves showed reduced survival among participants with progressive PPFE in both cohorts. In SUMMIT, dPPFE was associated with higher respiratory admissions (IRR 2.79, p<0.001), increased antibiotic and steroid use (IRR 1.55, p=0.010), and a trend towards higher mMRC scores (OR 1.40, p=0.055). Interpretation: Radiologic PPFE progression independently associates with mortality across two large lung cancer screening cohorts and with adverse clinical outcomes. Quantitative assessment of PPFE progression may provide a clinically relevant imaging biomarker for identifying individuals at increased respiratory risk within screening programmes.

Figures (4)

• Figure 1: Flowchart illustrating the selection of participants from the NLST and SUMMIT datasets. From the NLST cohort (n = 15,000; 44,722 CT scans), scans reconstructed using both lung and soft-tissue kernels were retained, followed by the selection of participants with baseline and one-year follow-up CTs and available survival data, yielding a final cohort of 7,980 participants (15,960 CT scans). From the SUMMIT cohort (n = 13,035; 33,093 CT scans), participants with baseline and two-year follow-up CTs and available follow-up information were included. After excluding individuals without ILA data, the final SUMMIT cohort comprised 8,561 participants (17,122 CT scans).
• Figure 2: Kaplan–Meier survival by longitudinal PPFE progression. NLST (ten-year follow-up) and SUMMIT (two-year follow-up) cohorts comparing overall survival between participants with progressive ($\Delta$PPFE $\geq$ 0.41 cm$^3$/year) and non-progressive PPFE change. Shaded areas indicate 95% confidence intervals and tick marks denote censoring. Numbers at risk are displayed below each plot. Participants with progressive $\Delta$PPFE exhibited significantly reduced survival in both cohorts (log-rank p$<$0.001 for both NLST and SUMMIT), consistent with multivariable Cox models (Table \ref{['tab_multi_cox_two_cohorts']}) in which $\Delta$PPFE remained independently associated with mortality.
• Figure 3: Representative examples of automated PPFE quantification on axial CT images from the NLST and SUMMIT cohorts. The first column shows the original CT images, and the second column shows the corresponding CT images with automated PPFE segmentation overlaid. Highlighted regions (red) indicate PPFE identified by the automated segmentation model in the upper lung zones. The first row shows images from a 65-year-old female participant in the NLST cohort with a quantified PPFE volume of 8.85 cm$^{3}$. The second row shows images from a 55-year-old male participant in the SUMMIT cohort with a quantified PPFE volume of 5.32 cm$^{3}$.
• Figure 4: Flowchart illustrating identification of baseline-only participants in SUMMIT cohort. This diagram outlines the selection of SUMMIT participants who did not undergo a follow-up CT scan. Starting from the full SUMMIT cohort (n=13,035), individuals with available baseline CT imaging were identified, after which participants with follow-up CTs were excluded. Additional exclusions were applied based on imaging quality and availability of clinical data. The final baseline-only subgroup consisted of 2,580 participants.