Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.

Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline.

Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping.

Measurements and main results: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively.

Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Trial registration: ClinicalTrials.gov NCT00608764.

Keywords: FEV1; lung function; parametric response mapping.

Figure 1.

Graphic representation of the parametric response mapping (PRM) methodology. Chronic obstructive pulmonary disease of GOLD (Global Initiative for Chronic Obstructive Lung Disease) grades 1–4 are shown in rows. Inspiratory and expiratory computed tomography (CT) images, respectively, are shown on the left. PRM emphysema (PRM^Emph) voxels in red and PRM functional small airways (PRM^fSAD) voxels in yellow are shown on the right. Although every voxel receives an individual categorical assignment, in this example PRM^Emph and PRM^fSAD are distributed throughout the lung. Greater intensity of color indicates more voxels classified in each category.

Figure 2.

Change in FEV₁ (ml/yr) between visit 1 and visit 2 by disease stage. Figures show the proportion of subjects in each disease stage group with varying levels of change in FEV₁ (ml/yr) over a 5-year period for GOLD (Global Initiative for Obstructive Lung Disease) 0, mean −41.8 (47.7) ml/yr; GOLD grades 1 and 2 combined, mean −48.0 (SD, 60.0) ml/yr; and GOLD grades 3 and 4 combined, mean −25.3 (SD, 43.3) ml/yr.