Eosinophilic Asthma Response to Therapy: 129Xe Magnetic Resonance Imaging and Computed Tomography

Marrissa Joan McIntosh, The University of Western Ontario

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.