Longitudinal Changes in Airway Mucus Plugs and Forced Expiratory Volume in 1 Second in COPD

TO THE EDITOR:

A rapid decline in forced expiratory volume in 1 second (FEV₁) is a hallmark of chronic obstructive pulmonary disease (COPD) progression. Airway-occluding mucus plugs (MP) are observed in 41%-67% of individuals with COPD and are associated with decreased FEV₁ in cross-sectional studies.^1-3 While the formation of MPs is dynamic, with some persisting and others resolving over time,¹ the impact of changes in MPs on FEV₁ decline in COPD remains unknown. We hypothesized that persistent MPs are associated with a rapid decline in FEV₁.

We analyzed participants of the COPDGene study who smoked ≥10 pack-years and were diagnosed with COPD by spirometry at baseline.⁴ MPs were surveyed on computed tomography (CT) scans at baseline (phase 1) and 5-year follow-up (phase 2).³ Participants were categorized into four MP change categories: Persistently negative (no MP at either phase), Resolved (MP present only at phase 1), Newly formed (MP present only at phase 2), and Persistently positive (MP present at both phases).¹ We used multivariable regression models to examine associations between MP change categories and FEV₁ decline. Details are provided in the Supplementary Methods.

Among 4,363 participants with mucus plug assessment at baseline, 2,118 had 5-year follow-up CT and spirometry data (Figure S1). The MP change status was as follows: Persistently negative, 934 (44.1%); Resolved, 341 (16.1%); Newly formed, 417 (19.7%); Persistently positive, 426 (20.1%). Tables S1, S2, and S3 show participants’ characteristics at phases 1 and 2 and those excluded from the study, respectively. Table S4 shows participants’ representativeness.

Compared to the Persistently negative group (reference), the FEV₁ decline was faster by 23.2 ml/year (95%-CI: 15.0, 31.4) and 17.7 ml/year (95%-CI: 11.3, 24.1) in the Persistently positive and Newly formed groups, respectively, while no significant difference was observed in the Resolved group (2.2 ml/year; 95%-CI: −5.3, 9.6) (Figure 1A-B, Table S5). When including an interaction term between the MP change category and smoking status, the steepest decline in FEV₁ occurred in the Persistently positive group’s participants who resumed smoking and the slowest was in the Resolved group’s participants who quit smoking (Figure 1C).

Figure 1.

(A) Unadjusted post-bronchodilator FEV₁ in mL at the baseline and 5-year follow-up visits by mucus plug change category. (B) Estimated marginal means of post-bronchodilator FEV₁ (mL/year) changes by mucus plug change category (negative numbers indicate decline). Marginal means are estimated by a multivariable linear regression model adjusting for age, sex, race, BMI, height, pack-years, change in smoking status, baseline FEV₁, history of asthma, history of congestive heart failure, CT measures of wall thickness and emphysema and baseline mucus plug score. (C) Estimated marginal means with the same multivariable model, including interaction between mucus plug change and smoking status change. Error bars represent 95% confidence intervals. See Table S5 for complete results.

Persistent and newly formed MPs were associated with a faster decline in FEV₁, which was more pronounced among those who resumed or continued smoking. The main limitations included cohort attrition during follow-up and a study population limited to two races and heavy tobacco use. Recent asthma trials indicated that medical therapy could reduce MPs.⁵ Further research into the biology, clinical implications, and interventions targeting this pathology in COPD is warranted.