Uncovering underdiagnosed emphysema: comparative assessment using clinical CT and micro-CT.

OBJECTIVES: Objective quantification of emphysema on clinical computed tomography (CT) in patients with chronic obstructive pulmonary disease (COPD) relies primarily on the percentage of low attenuation area (LAA). However, this approach is limited by spatial resolution, potentially leading to underestimation of subtle disease. The mean linear intercept (MLI) is a well-established histological marker of airspace enlargement. We developed an automated micro-CT-based approach to quantify the MLI that is less labour-intensive than existing methods. Micro-CT MLI was systematically compared with clinical CT LAA and histological MLI. MATERIALS AND METHODS: The study included 89 patients with different disease severities, including never-smokers (n = 15), ever-smokers (n = 9), pre-COPD (n = 19), mild COPD (GOLD I/II, n = 18/12), and severe COPD (GOLD III/IV, n = 3/13). All patients underwent spirometry, clinical CT before surgery, and at least 4 tissue cores per explanted lung specimen were scanned with micro-CT and used for the MLI computation. Histological validation was performed in a representative subset of patients (n = 29). RESULTS: MLI computed on histology was correlated with micro-CT-based MLI (r = 0.84, p < 0.001). A similar correlation (r = 0.83, p < 0.001) was found between the LAA on clinical CT and the average MLI of a patient on micro-CT. However, 30% of patients with non-elevated LAA (≤ 5%) exhibited elevated MLI on micro-CT, indicating underdiagnosed emphysema on clinical CT. The prevalence of undetected cases was the highest among ever-smokers (22%), pre-COPD patients (26%), and patients with mild COPD (23%). CONCLUSION: Micro-CT enables sensitive quantitative detection of subtle emphysematous changes, revealing important limitations of current clinical CT-based diagnostics. KEY POINTS: Question Is LAA-based emphysema thresholding on clinical CT able to accurately detect mild emphysema? Findings Emphysematous changes were detected in 30% of patients without emphysema on clinical CT, particularly among ever-smokers, pre-COPD, and mild COPD patients. Clinical relevance Micro-CT exposes early emphysematous changes undetectable on clinical CT, enabling refined COPD phenotyping and advancing diagnostic development.