Abstract
BACKGROUND: Distributions of low-attenuation areas in two-dimensional (2-D) CT lung slices are used to quantify parenchymal destruction in patients with COPD. However, these segmental approaches are limited and may not reflect the true three-dimensional (3-D) tissue processes that drive emphysematous changes in the lung. The goal of this study was to instead evaluate distributions of 3-D low-attenuation volumes, which we hypothesized would follow a power law distribution and provide a more complete assessment of the mechanisms underlying disease progression. METHODS: CT scans and pulmonary function test results were acquired from an observational database for N = 12 patients with COPD and N = 12 control patients. The data set included baseline and two annual follow-up evaluations in patients with COPD. Three-dimensional representations of the lungs were reconstructed from 2-D axial CT slices, with low-attenuation volumes identified as contiguous voxels < -960 Hounsfield units. RESULTS: Low-attenuation sizes generally followed a power law distribution, with the exception of large, individual outliers termed "super clusters," which deviated from the expected distribution. Super cluster volume was correlated with disease severity (% total low attenuation, ρ = 0.950) and clinical measures of lung function including FEV(1) (ρ = -0.849) and diffusing capacity of the lung for carbon monoxide Dlco (ρ = -0.874). To interpret these results, we developed a personalized computational model of super cluster emergence. Simulations indicated disease progression was more likely to occur near existing emphysematous regions, giving rise to a biomechanical, force-induced mechanism of super cluster growth. CONCLUSIONS: Low-attenuation super clusters are defining, quantitative features of parenchymal destruction that dominate disease progression, particularly in advanced COPD.