Beyond Bronchodilation and Airway Inflammation Mucus

Medical therapies for COPD primarily target bronchoconstriction and inflammation. Since isoprenaline was first commercialized in 1948,¹ the bulk of therapeutic innovation in COPD can be described as inhaler device technology improvements to deliver medications and combining bronchodilators with inhaled corticosteroids, all of which require ever-increasing study cohort sizes to demonstrate statistical significance. We have little else to offer people with COPD because of an incomplete understanding of the underlying pathogenic mechanisms of the disease, animal models with poor translation of findings into humans, and a lack of private and governmental investment in COPD research and drug development. Superimposed on these challenges are the broad heterogeneity and clinical manifestations of a condition we still diagnose by a simplistic spirometric threshold. Although precision medicine is the current standard for cancer care, the COPD community is unable to link therapies so clearly to a patient-specific cause of disease. It is time for us to move beyond bronchoconstriction to focus on readily identifiable treatable traits, including dyspnea, exercise intolerance, and hypoxemia. Another evident trait should be airway mucus plugging, which drives exacerbations, loss of lung function, and mortality.^2,3

People with more severe COPD and chronic bronchitis generally have more concentrated and adherent mucus in their airways. This is caused by imbalances of airway epithelium fluid transport and elevated mucin levels, which are polymers that impart a gel-like quality to mucus. Sputum mucins align with COPD severity and contribute to disease progression.⁴ These pathologic changes are further exacerbated by chronic tobacco smoke exposure, which reduces ciliary function and affects the cystic fibrosis transmembrane conductance regulator function. As a result, mucus accumulates and will often partially or completely occlude the airway lumen, thereby impacting airway resistance, regional lung ventilation, and the distribution of inhaled therapeutics. However, the complexity of assessing mucus pathology has impeded the translation of these insights to clinical trials. Measuring mucin concentration in sputum involves intricate protocols for sample acquisition, preservation, transport, and processing, whereas quantifying mucus-related symptoms (ie, cough and phlegm) suffer from recall bias and lack of reproducibility.

Chest CT scanning, a tool recently proposed in the diagnostic workup of COPD, has proved helpful in identifying and quantifying mucus plugs in medium to large airways (ie, approximately 2–10-mm lumen diameter), and studies now report their prevalence between 41% and 67% in people with COPD.^2,3 Radiographically detected plugs are associated with lower lung function, reduced oxygen saturation and exercise capacity, and poorer health-related quality of life.³ Given the apparent association between patient-reported cough and sputum production and mucociliary dysfunction, one could assume that symptomatology could be used as a screening tool, yet up to 30% of people with COPD who have CT scan-detected mucus plugs report no cough and phlegm.² Regardless of the respiratory manifestations, though, people with mucus plugs are at increased risk for adverse outcomes such as exacerbations, all-cause mortality, and respiratory deaths (Fig 1).^2,3,5 Current CT scan-based studies of airway mucus use a visual method that requires counting the number of lung segments with mucus plugs. Although the visual evaluation is time-consuming and is prone to intraobserver and interobserver agreement variability, harmonizing CT scan protocols, standardizing coaching for patients’ inspiratory maneuvers, and training readers will enable more precise mucus plug assessment.² Although the burden of mucus plugging is not routinely included in current radiology reports, such information could be readily added with training to readers, both radiologists and pulmonologists. Given all of this, there is no ambiguity that airway mucus plugging on CT scan is highly clinically relevant.

Figure 1 –

Unadjusted cause-specific cumulative mortality by mucus plug score category. Numbers in parenthesis indicate 95% CIs for unadjusted mortality rates.⁵ Mucus plug score category: no mucus plug, 0; 1 or 2 lung segments with mucus plugs, 1–2; 3 or more lung segments with mucus plugs, 3. Reprinted with permission of the American Thoracic Society. CVD = cardiovascular disease.

Several therapies are likely effective in treating mucus pathology, including new biologics and mucolytics and more broadly accessible existing therapies for COPD, such as nebulized saline and positive expiratory pressure devices (flutter valves) that can reduce mucus plugging, although this has not been rigorously examined with CT scan.⁶ Although the molecular mechanisms of mucus pathology are complex, IL-13 and IL-5 are implicated in a mucosecretory profile of the airway epithelium by activating mucin genes MUC5B and MUC5A. The thymic stromal lymphopoietin receptor agonist activates IL-13 and IL-5, and a recent clinical trial in moderate-to-severe asthma demonstrated that, compared with placebo, a biologic that blocks thymic stromal lymphopoietin, reduced mucus plugs as measured on CT scan and improved lung function, validating the therapeutic approach.⁶ Other biologics also showed a reduction of mucus plugs on CTs in patients with severe to moderate asthma.⁷ Because those asthma trials enhanced recruitment based on Th2 inflammation phenotype, present in some patients with COPD only, other drugs should be considered. Mucolytics that break mucin disulfide cross-links decreased airway mucus plugs in animal models. Regardless of the mechanism, removing accumulated airway mucus reduces the airway microbial burden, increases expiratory airflow, improves the function of the ciliated epithelial cells, and leads to a more uniform airway distribution of our commonly used inhalers.

Further insights into the role of mucus in COPD and using CT scan-detected mucus plugs could also help speed up therapeutic development and clinical trials by reducing sample size and shortening the study duration. Additionally, CT scan-detected mucus plugs can be used in basket trials as a single end point in the context of multiple diseases, such as COPD and asthma—in the latter, mucus plugs are also clinically relevant—and platform trials (as a single COPD end point targeted with multiple therapies, such as nonmedical and medical interventions). Such broadly applied mucocentric efforts are likely to result in direct clinical improvements in people diagnosed with the disease and, more excitingly, may provide a strategy for the interception and prevention in at-high-risk individuals, those who smoke and present with symptoms but do not meet spirometric criteria for COPD.

Health care providers, investigators, funders, and industry partners in the COPD community should keep exploring alternate therapeutic approaches. It is time to break free from the repetitive cycle of testing bronchodilation and use our existing tools to focus on alternate mechanisms that may modify and even prevent disease.