Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Parraga, Grace

Abstract

Novel biologic therapies, such as anti-interleukin-5 receptor α (anti-IL-5Rα) or benralizumab, have been developed to treat patients with severe eosinophilic asthma who experience frequent exacerbations, poor quality of life and increased risk of mortality. Whether this therapy results in disease modifying activity, specifically in the asthmatic airways and pulmonary vasculature, is still poorly understood. Pulmonary structure and function may be evaluated using computed tomography (CT) and hyperpolarized noble gas magnetic resonance imaging (MRI), respectively. Computed tomography has previously been utilized to measure airway dimensions, mucus occlusions and pulmonary blood volumes. In contrast, hyperpolarized gas MRI allows for the in vivo visualization and quantification of ventilation abnormalities, which are thought to reflect airway abnormalities such as airway inflammation and mucus plugging. Therefore, CT and MRI are poised to non-invasively evaluate the pulmonary structural and functional changes in eosinophilic asthma patients initiated on anti-IL-5Rα therapy. The overarching objective of this thesis was to use hyperpolarized 129Xe MRI and chest CT to evaluate pulmonary function and structure following continuous anti-IL-5Rα therapy and to compare with pre-treatment measurements to better our understanding of the mechanisms responsible for improved asthma control and airflow obstruction. We first determined the upper limit of normal and minimal clinically important difference for 129Xe MRI ventilation defect percent (VDP) and showed that the upper limit of normal varied with age and the minimal clinically important difference was 2%. Next, we measured 129Xe MRI VDP after a single dose of anti-IL-5Rα and showed that VDP improvements were influenced by baseline CT mucus plugs. We evaluated a subset of these same participants after 2.5-years of continuous treatment and revealed that early 129Xe MRI VDP improvements were sustained and that there was a near complete resolution of CT mucus plugs. Finally, we measured pulmonary blood volumes following 2.5-years of therapy and showed that there was a normalization and redistribution of blood from the larger to smaller vessels in eosinophilic asthma. Together, these results point towards mechanisms that may be responsible for improvements in airflow obstruction and asthma control and suggest that anti-IL-5Rα results in disease-modifying activity in patients with eosinophilic asthma.

Summary for Lay Audience

Patients with eosinophilic asthma have difficulty breathing, which means they must be treated with very strong medications. Unfortunately, many of these patients still end up in the hospital because of their breathing trouble. New treatments, such as anti-IL-5Rα, have improved breathing problems in these patients, but the reasons for these changes are still not understood. This thesis used structural computed tomography (CT) and functional magnetic resonance imaging (MRI) to better understand how lung structure and function change after treatment with anti-IL-5Rα. First, we needed to know how much MRI ventilation needed to change before the patient would feel a difference, which we saw was 2%. Next, we measured MRI ventilation before and after one dose of treatment and saw that patients with many mucus plugs had more improvements in MRI ventilation. In the same groups of patients, we saw that the MRI ventilation changes after one treatment were still improved after 2.5 years, and that mucus plugs were gone. Finally, we measured volumes of blood in the lungs after 2.5 years of treatment. We saw that blood had moved from the larger blood vessels to the smaller blood vessels and that blood volumes in asthma patients after treatment were the same as blood volumes in healthy people. Together, these results tell us that airway function and structure, and blood vessel volumes improve after treatment with anti-IL-5Rα. These improvements may be causing improvements in breathing and this may help us understand which patients will get better using this medication.

Creative Commons License

Creative Commons Attribution-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.

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