Mucus plugs revealed via imaging correlate with airflow obstruction, eosinophilia

Key takeaways:

• 58% of patients had at least one mucus plug.
• Patients with four or more mucus plugs had a median FEV₁ of about 50%.
• 82% of patients with a plug at baseline had a plug at year 3.

WASHINGTON — Providers can measure mucus plugs directly with computer tomography and indirectly with MRI imaging, according to data presented at the American Thoracic Society International Conference.

Also, mucus scores based on CT imaging correlate with changes in airflow obstruction and eosinophilia over time, Eleanor Dunican, MB, BCH, BAO, PhD (ED), consultant respiratory physician, St. Vincent’s University Hospital, said during her presentation.

The results of imaging

“Analysis of standard CT scans using computational fluid dynamics shows that even in normal lungs, there is heterogeneity in ventilation, drug deposition, and response to bronchodilation,” Dunican said. “So, looking at the lung using a more regionalized approach may provide novel insights into disease heterogeneity in asthma.”

Using hyperpolarized gas, usually xenon or helium, MRI imaging reveals heterogenous ventilation defects that not only are very strongly associated with airflow obstruction but also can persist in the same location for many years, Dunican said.

“What’s particularly interesting in asthma is that there is a predominance of these ventilation defects in patients that are eosinophilic,” Dunican said, “compared to patients that have normal eosinophils.”

While these defects tend to persist even after maximal bronchodilation among patients with eosinophilia, Dunican continued, they improve with maximal bronchodilation among patients who are not eosinophilic.

Noting that these defects persisted after bronchodilation, Dunican said they probably were not caused by smooth muscle contraction. Instead, she said, airway remodeling or mucus plugging may be the cause.

Application of CT

“Our group has been very interested in understanding the role of mucus plugging in the pathophysiology of asthma and whether CT can identify a novel mucus phenotype,” Dunican said.

Since CT can directly visualize mucus plugs, Dunican developed a score where radiologists examine each bronchopulmonary segment and assign it a 0 or 1 based on whether it has a mucus plug. Total scores for each patient can range from 0 to 20.

Next, Dunican and her colleagues applied this system to patients in the third phase of the Severe Asthma Research Program, or SARP-3, who had CT as part of their characterization.

“What we found was kind of surprising,” Dunican said. “Mucus plugging is far more common in asthma than would have previously been thought.”

Analysis found that 58% of these patients had at least one mucus plug, but there was no association between the presence or absence of mucus plugging and the presence or absence of symptoms of chronic mucus hypersecretion.

“Mucus plugging is very common, but clinically silent in asthma apart from on imagery,” Dunican said.

However, mucus plugs were associated with lower FEV₁. Median FEV₁ totals included approximately 50% for patients with four mucus plugs or more and 80% for patients with no mucus plugs.

After maximal bronchodilation therapy, 75% of the patients with four or more plugs had persistent airflow obstruction, defined as FEV₁ of less than 80%.

“Furthermore, this group was also very eosinophilic,” Dunican said. “They had markedly raised levels of sputum eosinophils and eosinophils.”

When the researchers compared baseline results with imaging at 3 years, they found very little change in mucus plug status, with some mucus plugs remaining in the exact same location.

Specifically, 82% of patients with a plug at baseline had a plug at year 3, and 71% of those with no plug at baseline were plug-free at year 3. Similarly, 65% of bronchopulmonary segments had a plug at baseline and at year 3, and 87% of bronchopulmonary segments that did not have a plug at baseline were plug-free at year 3.

“Next, we were interested in comparing change in mucus score with change in lung function over time to support the hypothesis that mucus plugging plays a role in airflow obstruction in asthma,” Dunican said.

In addition to the decreases in FEV₁, there were associations between increases in mucus plug scores and decreases in forced vital capacity (FVC) and in the ratio of FEV₁ to FVC, Dunican said.

These findings support the hypothesis that mucus plugging contributes to airflow reductions in asthma, Dunican continued, even though current asthma therapies do not target mucus plugging.

Measured as air trapping and functional small airways disease, airflow narrowing was associated with mucus plug imaging as well, Dunican said.

Increases in blood eosinophils from baseline to year 3 were associated with increases in mucus scores as well, Dunican said, indicating that eosinophils contribute to mucus formation in asthma.

Patients who had mucus plugs according to CT additionally had much higher segmental ventilation defect percent in MRI than those who did not have mucus plugs in CT, Dunican said, but many patients with ventilation defects did not have visible mucus plugs too.

“Mucus plugs explain at least some of the ventilation defects, but there are other pathologies at work,” Dunican said.

Treatment impact

After 2 and a half years of treatment with benralizumab (Fasenra, AstraZeneca), which targets IL-5, mucus scores significantly fell and total airway count increased.

Airway narrowing, lumen area and wall thickness also all improved, while the ventilation defects that were observed in MRI were reduced as well.

“This nicely translated into improvements in FEV₁ and improvements in asthma control,” Dunican said.

Tezepelumab (Tezspire, Amgen/AstraZeneca), which targets thymic stromal lymphopoietin and reduces airway eosinophil counts, was associated with improvements in mucus plug score and FEV₁ after 28 weeks of treatment as well.

Overall, Dunican said, CT and MRI both demonstrate improvements in mucus plugging with T2-directed therapies, translating into improvements in FEV₁. Also, she said, regional defects may be biomarkers for determining treatment and treatment response.