Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers

Abstract

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV₁ and peripheral oxygen saturation (P < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (P < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) (P < 0.001).Conclusions: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Keywords: COPD; FEV1; computed tomography; emphysema; mucus plugs.

Figure 1.

Airway mucus plugs in smokers with chronic obstructive pulmonary disease. (A) An example of two mucus plugs occluding subsegmental airways in the lower lobes identified as tubular opacifications in the axial plane (yellow and red arrowheads). (B) The mucus plugs in the coronal plane (the yellow and red arrowheads indicating the same mucus plugs as in A), revealing that the plugs extend for several millimeters and branch. (C) An example of a branching mucus plug occluding a segmental airway in the right upper lobe (yellow arrowhead), as visualized in the axial plane. (D) The same plug in the coronal plane (yellow arrowhead).

Figure 2.

Large and small plugs are identifiable on computed tomographic scans of the lungs. (A and B) Axial (A) and coronal (B) oblique images through the right lung. In A, three subsegmental mucus plugs are visible in the right middle lobe medial segment (blue arrow), lateral segment (yellow arrow), and right lower lobe medial basal segment (red arrow), with complete opacification of the airways. In B, the blue arrow corresponds with the same plug as in A, which completely opacifies the airway lumen, with patent airway proximal and distal (white arrows). An additional plug in the same segment is also visible on this image (orange arrow). (C and D) Axial (C) and coronal (D) oblique images through the left lung. In C, three mucus plugs are visible in the left lower lobe posterobasal (red arrow), lateral basal (blue arrow), and anteromedial (yellow arrow) segments. In D, the blue arrow corresponds with the same plug in the lateral basal segment as in C. Note the complete occlusion of the airway, which is patent proximal and distal to the plug (white arrows). Also note that more proximally, there are nonocclusive filling defects in the airway lumen, which are not counted as plugs.

Figure 3.

Mucus plug scores in smoker subgroups and control subjects. (A) The mucus plug score in healthy nonsmokers, smokers with preserved lung function, and smokers with chronic obstructive pulmonary disease (COPD). (B) The frequency distribution of mucus scores in smokers with COPD. ***Significant difference between the COPD group and the other two groups, P < 0.001.

Figure 4.

Mucus plugs, emphysema, and airflow obstruction in smokers. (A) The mucus plug score in smokers with preserved lung function and smokers with increasing severity of airflow obstruction classified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. (B) The fraction of smokers with high mucus scores in the subgroups with and without airflow obstruction. (C) The emphysema percentage in smokers with preserved lung function and smokers with increasing severity of airflow obstruction classified by GOLD stage. (D) The fraction of smokers with emphysema in the subgroups with and without airflow obstruction. (E) The relationships between mucus plug scores and emphysema percentage in smokers. (F) The directed acyclic graph (DAG), or causal diagram, which formed the basis for the DAG-informed logistic regression models used to assess relationships among mucus plugs, emphysema, FEV₁, and peripheral oxygen saturation. Purple circles represent the predictor and outcome variables; blue circles represent ancestors of predictor or outcomes; and red circles represent ancestors of predictor and outcomes (confounders). Green arrows represent nonconfounded causal paths, and pink arrows represent biasing paths. ***Significantly different from smokers with preserved lung function, P < 0.001. HU = Hounsfield units.

Figure 5.

The relationship between mucus plug score and lung function outcomes are modified by emphysema. (A) The relationship between mucus plug score and FEV₁% predicted is modified by emphysema. Three linear regression lines demonstrate the relationships between mucus plug scores and FEV₁% predicted in smokers grouped by tertiles of emphysema percentage. The slope of the line describing the inverse relationship between mucus plug score and FEV₁ was steeper in smokers in the lowest tertile of emphysema percentage values than in those in the highest tertile. (B) The FEV₁ values in subgroups of smokers with and without a high mucus plug score and stratified by presence or absence of emphysema. (C) The relationship between mucus plug score and resting peripheral oxygen saturation (Sp_O2-R) is modified by emphysema. The slope of the line describing the inverse relationship between mucus plug score and Sp_O2-R was steeper in smokers in the lowest tertile of emphysema percentage values than in those in the highest tertile. (D) The Sp_O2-R values in subgroups of smokers with and without a high mucus plug score and stratified by presence or absence of emphysema. (E) The relationship between mucus plug score and postexercise peripheral oxygen saturation (Sp_O2-PE) is modified by emphysema. The slope of the line describing the inverse relationship between mucus plug score and Sp_O2-PE was steeper in smokers in the lowest tertile of emphysema percentage values than in those in the highest tertile. (F) The Sp_O2-PE values in subgroups of smokers with and without a high mucus plug score and stratified by presence or absence of emphysema. dy/dx is the marginal effect of mucus score on FEV₁ in A, resting Sp_O2 in C, and postexercise Sp_O2 in E stratified by quintiles of emphysema score. **Significantly different from smokers with mucus score of less than 5, P < 0.01. ***Significantly different from smokers with mucus score of less than 5, P < 0.001. CI = confidence interval.

Figure 6.

Mucus plugs persist for 1 year in smokers with chronic obstructive pulmonary disease (COPD). (A) A Sankey bar graph of mucus plug scores in 100 smokers with COPD at baseline and at 1 year of follow-up. Patients with COPD with low mucus plug scores (tertile 1) at baseline tended to remain in the lowest tertile for mucus plug scores at 1 year, whereas patients with COPD with high mucus plug scores (tertile 3) tended to remain in the highest tertile for mucus plug scores at 1 year. (B) Data on mucus plugs in bronchopulmonary segments with no airways plugged with mucus in baseline scans; 92% of these segments continued to have no airways plugged with mucus on the Year 1 scan. (C) Data on mucus plugs in bronchopulmonary segments with at least one airway plugged with mucus in baseline scans, 67% of these segments continued to have at least one airway plugged with mucus on the Year 1 scan.