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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Parraga, Grace

Abstract

Asthma has been understood to affect the airways in a spatially heterogeneous manner for over six decades. Computational models of the asthmatic lung have suggested that airway abnormalities are diffusely and randomly distributed throughout the lung, however these mechanisms have been challenging to measure in vivo using current clinical tools. Pulmonary structure and function are still clinically characterized by the forced expiratory volume in one-second (FEV1) – a global measurement of airflow obstruction that is unable to capture the underlying regional heterogeneity that may be responsible for symptoms and disease worsening. In contrast, pulmonary magnetic resonance imaging (MRI) provides a way to visualize and quantify regional heterogeneity in vivo, and preliminary MRI studies in patients suggest that airway abnormalities in asthma are spatially persistent and not random. Despite these disruptive results, imaging has played a limited clinical role because the etiology of ventilation heterogeneity in asthma and its long-term pattern remain poorly understood. Accordingly, the objective of this thesis was to develop a deeper understanding of the pulmonary structure and function of asthma using functional MRI in conjunction with structural computed tomography (CT) and oscillometry, to provide a foundation for imaging to guide disease phenotyping, personalized treatment and prediction of disease worsening. We first evaluated the biomechanics of ventilation heterogeneity and showed that MRI and oscillometry explained biomechanical differences between asthma and other forms of airways disease. We then evaluated the long-term spatial and temporal nature of airway and ventilation abnormalities in patients with asthma. In nonidentical twins, we observed a spatially-matched CT airway and MRI ventilation abnormality that persisted for seven-years; we estimated the probability of an identical defect occurring in time and space to be 1 in 130,000. In unrelated asthmatics, ventilation defects were spatially-persistent over 6.5-years and uniquely predicted longitudinal bronchodilator reversibility. Finally, we investigated the entire CT airway tree and showed that airways were truncated in severe asthma related to thickened airway walls and worse MRI ventilation heterogeneity. Together, these results advance our understanding of asthma as a non-random disease and support the use of MRI ventilation to guide clinical phenotyping and treatment decisions.

Summary for Lay Audience

Asthma is a chronic lung disease that causes the air a person breathes in to unevenly spread throughout their lungs. The causes of this are still not well-known because the current tools to measure lung function cannot locate where inside the lungs the air does not go. To better understand this, computer models have been created and showed that asthma lung abnormalities are randomly spread throughout the whole lungs, but magnetic resonance imaging (MRI) of the lung showed that abnormalities stay in the same lung locations over time and are not random. Despite these new results, MRI of the lungs is not used often for asthma patients because the causes of MRI measurements and how they change over long periods of time are not known. This thesis measured lung structure and function in asthma using functional MRI and structural computed tomography (CT) imaging to better understand how and why air unevenly spreads throughout the lungs in patients with asthma and create a new way to guide asthma treatments to help air spread more evenly. First, we evaluated lung biomechanics and saw different biomechanical measurements in patients with asthma compared to different lung diseases and healthy people. We then evaluated MRI and CT lung abnormalities twice over 6-7 years in two different groups of patients. Twins with asthma had a lung abnormality in the exact same location that stayed the same after 7 years. We calculated the chances of an identical abnormality like this occurring in two people to be 1-in-130,000, or less likely than the chances of someone being struck by lightning. In a larger group of non-related asthma patients, MRI and CT abnormalities remained in the same lung locations over 6.5 years and MRI abnormalities predicted future asthma worsening. Finally, we evaluated all airways we could see on CT images and saw that patients with severe asthma had less airways and this was related to thicker airway walls and worse lung function. Together, these results provide a better understanding of lung structure-function in asthma that are not random and support the use of MRI to guide patient-specific treatment.

Creative Commons License

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

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