Airway fractal dimension predicts respiratory morbidity and mortality in COPD

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling. Characterization of airway changes on computed tomography has been challenging due to the complexity of the recurring branching patterns, and this can be better measured using fractal dimensions.

Methods: We analyzed segmented airway trees of 8,135 participants enrolled in the COPDGene cohort. The fractal complexity of the segmented airway tree was measured by the Airway Fractal Dimension (AFD) using the Minkowski-Bougliand box-counting dimension. We examined associations between AFD and lung function and respiratory morbidity using multivariable regression analyses. We further estimated the extent of peribronchial emphysema (%) within 5 mm of the airway tree, as this is likely to affect AFD. We classified participants into 4 groups based on median AFD, percentage of peribronchial emphysema, and estimated survival.

Results: AFD was significantly associated with forced expiratory volume in one second (FEV1; P < 0.001) and FEV1/forced vital capacity (FEV1/FVC; P < 0.001) after adjusting for age, race, sex, smoking status, pack-years of smoking, BMI, CT emphysema, air trapping, airway thickness, and CT scanner type. On multivariable analysis, AFD was also associated with respiratory quality of life and 6-minute walk distance, as well as exacerbations, lung function decline, and mortality on longitudinal follow-up. We identified a subset of participants with AFD below the median and peribronchial emphysema above the median who had worse survival compared with participants with high AFD and low peribronchial emphysema (adjusted hazards ratio [HR]: 2.72; 95% CI: 2.20-3.35; P < 0.001), a substantial number of whom were not identified by traditional spirometry severity grades.

Conclusion: Airway fractal dimension as a measure of airway branching complexity and remodeling in smokers is associated with respiratory morbidity and lung function change, offers prognostic information additional to traditional CT measures of airway wall thickness, and can be used to estimate mortality risk.

Trial registration: ClinicalTrials.gov identifier: NCT00608764.

Funding: This study was supported by NIH K23 HL133438 (SPB) and the COPDGene study (NIH Grant Numbers R01 HL089897 and R01 HL089856). The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion and GlaxoSmithKline.

Keywords: COPD; Pulmonology.

Conflict of interest statement

Conflict of interest: SPB received research funds to his institute from ProterixBio during the course of the study. EAH is a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. JMR owns stocks from VIDA Diagnostics, Inc., and received personal fees from Science24Seven and Boehringer Ingelheim. RSJE received consulting fees from Boehringer Ingelheim and is co-owner of Quantitative Imaging Solutions. GRW received grants from Boehringer Ingelheim and BTG Interventional Medicine; consults for Boehringer Ingelheim, Genentech, PulmonX, Regeneron, Toshiba, and GlaxoSmithKline; co-owns Quantitative Imaging Solutions, advises for ModoSpira; and received grants and consulting fees from Janssen Pharmaceuticals. GRW’s spouse works for Biogen, which is focused on developing therapies for fibrotic lung disease. MKH received personal fees from GlaxoSmithKline, Boehringer Ingeheim, and AstraZeneca, and non-financial support from Novartis and Sunovion. MTD received personal fees and other from Boehringer Ingeheim, GlaxoSmithKline, AstraZeneca, and Boston Scientific; other from Novartis, Yungjin, PneumRx/BTG, and Pulmonx; and personal fees from Genentech. JDN received grants from Siemens Healthineers and Hoffman La-Roche, and personal fees from VIDA Diagnostics, Inc. JDN has a software patent issued (US14690391).

Figures

Figure 1. Airway Fractal Dimension, Peribronchial Emphysema, and Survival.

(A) Group definitions based on median values of AFDs and percentage of peribronchial emphysema (PBE) estimated in 8,030 COPD subjects. Participants were stratified into high and low above the median for each metric. (B) Distribution of severity of airflow obstruction by GOLD criteria in each group. (C) Kaplan-Meier survival curves for the 4 groups based on AFD and percentage of peribronchial emphysema.

Figure 2. Impact of loss versus narrowing of airways on AFD.

Panel showing change in AFD sequentially with loss of small airway branches (A) and with progressive narrowing of airways (B). Changes shown are by simulation in a representative subject’s airways. The 3D images are projected as 2D for representation.

Figure 3. Segmented airway tree and AFD in representative participants who are nonsmoking and healthy, or with combinations of different degrees of AFD and emphysema.