Mucus Plugs Persist in Asthma, and Changes in Mucus Plugs Associate with Changes in Airflow over Time

Abstract

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a longitudinal analysis of baseline and Year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures. Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and Year 3 (3.4 [0-20] vs. 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at Year 3 than those without baseline plugs (risk ratio, 2.8; 95% confidence interval [CI], 2.0-4.1; P < 0.001; and risk ratio, 5.0; 95% CI, 4.5-5.6; P < 0.001, respectively). The change in mucus plug score from baseline to Year 3 was significantly negatively correlated with change in FEV₁% predicted (r_p = -0.35; P < 0.001) and with changes in CT air trapping measures (all P values < 0.05). Conclusions: Mucus plugs identify a persistent asthma phenotype, and susceptibility to mucus plugs occurs at the subject and the bronchopulmonary segment level. The association between change in mucus plug score and change in airflow over time supports a causal role for mucus plugs in mechanisms of airflow obstruction in asthma.

Keywords: air trapping; asthma; computed tomography; eosinophils; mucus plugs.

Figure 1.

Mucus plug identified in the same airway in baseline and Year 3 multidetector computed tomography lung scans. Yellow arrowheads indicate mucus plug, and orange arrowheads indicate blood vessel.

Figure 2.

Persistence of mucus plugs from baseline to Year 3: subject-level and segment-level susceptibility. (A) Mucus plug score in participants at baseline and Year 3. Horizontal lines indicate the mean mucus plug score. (B) Frequency distribution of mucus plug score in participants at baseline and Year 3. (C) Sankey plot showing the change in mucus plug status in participants from baseline to Year 3. (D) State transition diagram showing the transitions in mucus plug status in participants from baseline to Year 3. (E) Sankey plot showing the change in mucus plug status in bronchopulmonary segments from baseline to Year 3. (F) State transition diagram showing the transitions in mucus plug status in bronchopulmonary segments from baseline to Year 3.

Figure 3.

Regional differences in the frequency of persistent and intermittent mucus plugs at baseline and Year 3. (A) Frequency of persistent and intermittent mucus plugs in left and right lungs. (B) Frequency of persistent and intermittent mucus plugs in upper, middle/lingula, and lower lobes. (C) Frequency of persistent and intermittent mucus plugs in different bronchopulmonary segments. LIN = lingula; LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe.

Figure 4.

Relationship between change in mucus plug score and change in airflow. (A) The change in mucus plug score is significantly and negatively associated with the change in FEV₁% predicted. (B) The change in mucus plug score is significantly and negatively associated with the change in FVC% predicted. (C) The change in mucus plug score is significantly and negatively associated with the change in FEV₁/FVC. (D) The change in mucus plug score is significantly and positively associated with the change in percentage of voxels below −856 Hounsfield units (HU). (E) The change in mucus plug score is significantly and negatively associated with the change in Jacobian mean. (F) The change in mucus plug score is significantly and positively associated with the change in percentage of disease probability measure of functional small airway disease (DPM fSAD).

Figure 5.

Relationship between change in eosinophils (blood and sputum) and change in mucus plug score. (A) The change in blood eosinophils is significantly and positively associated with the change in mucus plug score. (B) The change in sputum eosinophils is significantly and positively associated with the change in mucus plug score. (C) Relationship between mucus plug score and eosinophilia adjusted for covariates. Linear regression model reports β coefficients (95% confidence interval).