Why Do Some People Experience Asthma Symptoms Despite Treatment?

While there is no cure for asthma, many people successfully manage the condition. Others experience asthma symptoms, such as shortness of breath, despite taking medication. A new study offers insight into why some groups of patients with asthma may not respond to treatment.

In the study, published in the Journal of Allergy and Clinical Immunology, researchers focused on eosinophils, a type of cell associated with lung function and asthma. For more than a decade, as the recognition of the role of eosinophils in asthma has grown, multiple eosinophil-directed treatments, including mepolizumab, have been developed.

Medicines like mepolizumab are an important treatment option for patients with asthma who have high eosinophils because these patients tend to have chronic and severe disease even with the use of high-dose inhaler therapies, said Gabriella Wilson, MD, lead author of the study and graduating fellow in the Yale School of Medicine (YSM) Section of Pulmonary, Critical Care, and Sleep Medicine.

“We know from studying large groups of patients that these medications reduce asthma symptoms and exacerbations, but we’ve also seen in our Yale Center for Asthma and Airway Disease clinic that there is a subset of patients that don’t respond,” Wilson said.

To better understand why some people on eosinophil-directed treatments continue to have asthma flare-ups, Wilson and her team conducted a sub-study of a larger clinical trial, called MUPPITS-2, which examined the effect of mepolizumab in reducing exacerbations of asthma in 290 urban children. Wilson and her team examined the sputum of 53 children from the main trial.

“We wanted to find out how eosinophils behave functionally in the airways of children who had asthma exacerbations during the main trial compared to those who did not,” she said.

The researchers discovered that while children treated with mepolizumab had lower overall levels of sputum eosinophils, those with elevated levels of two subtypes of sputum eosinophils experienced exacerbations.

For decades, the role of eosinophils as drivers of inflammation and symptoms in asthma has been unclear and assumed to be one dimensional—a singular phenotype of cells that is unequivocally pro-inflammatory, said Geoffrey Chupp, MD, professor of medicine (pulmonary, critical care, and sleep medicine) at YSM, and corresponding author of the study.

“Dr. Wilson’s work, examining eosinophils collected from the airway of children treated with mepolizumab, exquisitely demonstrates that this paradigm is likely not correct,” he said. “The study also demonstrates the existence of multiple types of eosinophils that may be significant drivers of persistent disease activity in some patients treated with mepolizumab.”

Chupp added that the study highlighted the importance of team science, as the results were attained through collaborations with Ruth Montgomery, PhD, professor of medicine and of epidemiology (microbial diseases) at YSM, and the University of Wisconsin’s Inner City Asthma Consortium translational science team, led by William Busse, MD.

The use of the emerging technology cytometry by time-of-flight, or CyTOF, a mass spectroscopy-based instrument that is especially powerful when working with precious small-size samples from human subjects, was a key element of the research, said Montgomery, co-author of the study.

“Our group undertook multiparameter single cell analysis of the airway samples from children enrolled in the multicenter MUPPITS-2 study, coordinating sample collection and reagents, and processing across multiple centers for optimal data quality,” she said. “This wonderful collaboration at Yale started with a hallway chat with colleague Geoff Chupp and led to Dr. Wilson leading the analysis of this complex dataset and identifying eosinophil cell subsets relevant to the severity of childhood asthma.”

Through this research, Wilson hopes to raise awareness about the significance of eosinophil subtypes in disease activity and drug response. “With further study, we could potentially use airway eosinophil subtype analysis to determine which medications will and won’t work for individuals with asthma,” she said.

“Precision medicine is important in all diseases, and asthma is no different,” Wilson added. “Gaining understanding about these breakthrough exacerbations—through this study and through future research—will help us be more targeted and precise in selecting treatments for our patients.”

Other authors of “Activated Sputum Eosinophils Associated With Exacerbations in Children on Mepolizumab” include James Knight, PhD; Qing Liu, MD, PhD; Ashish Shelar, PhD; Emma Stewart; Xiaomei Wang, MD; Xiting Yan, PhD; Joshua Sanders; Cynthia Visness, PhD; Michelle Gill, MD, PhD; Rebecca Gruchalla, MD, PhD; Andrew H. Liu, MD; Meyer Kattan, MD; Gurjit K. Khurana Hershey, MD, PhD; Alkis Togias, MD; Patrice M. Becker, MD; Matthew C. Altman, MD; William W. Busse, MD; and Daniel J. Jackson, MD.

The Section of Pulmonary, Critical Care and Sleep Medicine is one of the eleven sections within Yale School of Medicine’s Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM's website, or follow them on Facebook and Twitter.