Additive Lung Cancer Risk in Combined Interstitial Lung Abnormalities and Emphysema: Korean National Lung Cancer Screening Program

Abstract Rationale Interstitial lung abnormalities (ILA) and emphysema are frequently detected during lung cancer screening (LCS), but the impact of their coexistence—termed combined ILA and emphysema (CILAE)—on lung cancer risk remains unclear. Objectives To determine the prevalence of CILAE in a national LCS cohort, evaluate whether its effect on lung cancer risk is additive or multiplicative, and quantify its association with lung cancer incidence. Methods This retrospective cohort study analyzed data from the Korean national LCS program (2019–2020). Participants were categorized into four CT-defined groups: neither condition, emphysema alone, ILA alone, and CILAE. Lung cancer incidence rate ratios (IRRs) were calculated using the neither condition group as the reference. Cox proportional hazards regression, adjusted for demographic and clinical factors, assessed the interaction and risk associated with CILAE. Results Among 125600 participants, CILAE was present in 1.0% (1223/125600), ILA alone in 1.7% (2101/125600), and emphysema alone in 12.8% (16077/125600). Over a median follow-up of 2.8 years (95% confidence interval [CI]: 2.8, 2.9 years), lung cancer was diagnosed in 1.4% (1709/125600). Compared to neither condition, IRRs for lung cancer were 9.12 (95% CI: 7.39, 11.0) for CILAE, 4.51 (95% CI: 3.63, 5.44) for ILA alone, and 2.93 (95% CI: 2.66, 3.20) for emphysema alone. Adjusted HRs for lung cancer were 5.17 (95% CI: 4.21, 6.35; P<0.001) for CILAE, 3.10 (95% CI: 2.50, 3.84; P<0.001) for ILA alone, and 2.05 (95% CI: 1.83, 2.30; P<0.001) for emphysema alone. The interaction term between ILA and emphysema was not significant (adjusted hazard ratio [HR], 0.81; 95% CI: 0.60, 1.10; P=0.17), suggesting an additive rather than multiplicative effect. Conclusion CILAE was present in 1% of LCS participants and was associated with a lung cancer risk exceeding that of ILA or emphysema alone. The combined effect was additive rather than synergistic.