Management of COPD:Is there a role for quantitative imaging?

While the recent development of quantitative imaging methods have led to their increased use in the diagnosis and management of many chronic diseases, medical imaging still plays a limited role in the management of chronic obstructive pulmonary disease (COPD). In this review we highlight three pulmonary imaging modalities: computed tomography (CT), magnetic resonance imaging (MRI) and optical coherence tomography (OCT) imaging and the COPD biomarkers that may be helpful for managing COPD patients. We discussed the current role imaging plays in COPD management as well as the potential role quantitative imaging will play by identifying imaging phenotypes to enable more effective COPD management and improved outcomes

Quantitative Evaluation of Pulmonary Emphysema Using Magnetic Resonance Imaging and x-ray Computed Tomography

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality affecting at least 600 million people worldwide. The most widely used clinical measurements of lung function such as spirometry and plethysmography are generally accepted for diagnosis and monitoring of the disease. However, these tests provide only global measures of lung function and they are insensitive to early disease changes. Imaging tools that are currently available have the potential to provide regional information about lung structure and function but at present are mainly used for qualitative assessment of disease and disease progression. In this thesis, we focused on the application of quantitative measurements of lung structure derived from 1H magnetic resonance imaging (MRI) and high resolution computed tomography (CT) in subjects diagnosed with COPD by a physician. Our results showed that significant and moderately strong relationship exists between 1H signal intensity (SI) and 3He apparent diffusion coefficient (ADC), as well as between 1H SI and CT measurements of emphysema. This suggests that these imaging methods may be quantifying the same tissue changes in COPD, and that pulmonary 1H SI may be used effectively to monitor emphysema as a complement to CT and noble gas MRI. Additionally, our results showed that objective multi-threshold analysis of CT images for emphysema scoring that takes into account the frequency distribution of each Hounsfield unit (HU) threshold was effective in correctly classifying the patient into COPD and healthy subgroups. Finally, we found a significant correlation between whole lung average subjective and objective emphysema scores with high inter-observer agreement. It is concluded that 1H MRI and high resolution CT can be used to quantitatively evaluate lung tissue alterations in COPD subjects

Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes

Pulmonary x-ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient-relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well-summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD

Quantifying Airway Dilatation in the Lungs from Computed Tomography

Non CF bronchiectasis and idiopathic pulmonary fibrosis (IPF) are pulmonary diseases characterised by the abnormal and permanent dilatation of the airways. Computed tomography (CT) is used in clinical practice to diagnose and monitor patients with the disease. Currently, analysis of the scans is performed by manual inspection and there is no established computerised method to quantify the enlargement of airways. I developed a pipeline to quantify the cross-sectional area for a given airway track. Using an airway segmentation, my proposed algorithm measures the area at contiguous intervals along the airway arclength from the Carina to the most distal point visible on CT. I showed the use of the data generated from the pipeline in two applications. First, I proposed a novel tapering measure as the gradient of a linear regression between a logarithmic area against the arclength. The measurement was applied to airways affected by bronchiectasis. Second, I used Bayesian Changepoint Detection (BCD) with the area measurements to locate the progression of IPF along the airway track. The proposed pipeline was applied to a set of clinically acquired scans. I show a statistical difference (p = 3.4×10−4 ) in the tapering measurement between bronchiectatic (n = 53) and controlled (n = 39) airways. In addition, I report a statistical difference (p = 7.2×10−3 ) in the change in measurement between airways remaining healthy (n = 14) and airways that have become bronchiectatic (n = 5). I show the tapering measurement is reproducible independent to voxel size, CT reconstruction, and radiation dose. Using BCD, I show on simulated data (n = 14) my proposed method can detect the progression of IPF within 2.5mm. Finally, using results from BCD, I present a novel measure of IPF progression as the percentage volume change in the diseased region of the airways

Pulmonary Structure and Function in Chronic Obstructive Pulmonary Disease Evaluated using Hyperpolarized Noble Gas Magnetic Resonance Imaging

Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death worldwide and accounts for the highest rate of hospital admissions in Canada. The need for sensitive regional and surrogate measurements of lung structure and function in COPD continues to motivate the development of non-radiation based and sensitive imaging approaches, such as hyperpolarized helium-3 (3He) and xenon-129 (129Xe) magnetic resonance imaging (MRI). The static ventilation images acquired using these approaches allows us to directly visualize lung regions accessed by the hyperpolarized gas during a breath-hold, as well as quantify the regions without signal referred to as the percentage of the thoracic cavity occupied by ventilation defects (VDP). The lung micro-structure can also be probed using diffusion-weighted imaging which takes advantage of the rapid diffusion of 3He and 129Xe atoms to generate surrogate measurements of alveolar size, referred to as the apparent diffusion coefficient (ADC). Here we evaluated COPD lung structure and function using hyperpolarized gas MRI measurements longitudinally, following treatment and in early disease. In COPD ex-smokers, we demonstrated 3He VDP and ADC worsened significantly in only 2 years although there was no change in age-matched healthy volunteers, suggestive of disease progression. We also evaluated COPD ex-smokers pre- and post-bronchodilator and showed regional improvements in gas distribution following bronchodilator therapy regardless of spirometry-based responder classification; the ADC measured in these same COPD ex-smokers also revealed significant reductions in regional gas trapping post-bronchodilator. Although 3He MRI has been more widely used, the limited global quantities necessitates the transition to hyperpolarized 129Xe, and therefore we directly compared 3He and 129Xe MRI in the same COPD ex-smokers and showed significantly greater gas distribution abnormalities for 129Xe compared to 3He MRI that were spatially and significantly related to lung regions with elevated ADC. Finally, we demonstrated that ex-smokers with normal spirometry but abnormal diffusion capacity of the lung for carbon monoxide (DLCO) had significantly worse symptoms, exercise capacity and 3He ADC than ex-smokers with normal DLCO. These important findings indicate that hyperpolarized gas MRI can be used to improve our understanding of lung structural and functional changes in COPD

Shear-promoted drug encapsulation into red blood cells: a CFD model and μ-PIV analysis

The present work focuses on the main parameters that influence shear-promoted encapsulation of drugs into erythrocytes. A CFD model was built to investigate the fluid dynamics of a suspension of particles flowing in a commercial micro channel. Micro Particle Image Velocimetry (μ-PIV) allowed to take into account for the real properties of the red blood cell (RBC), thus having a deeper understanding of the process. Coupling these results with an analytical diffusion model, suitable working conditions were defined for different values of haematocrit

Ventilation and Perfusion at the Alveolar Level: Insights From Lung Intravital Microscopy

Intravital microscopy (IVM) offers unique possibilities for the observation of biological processes and disease related mechanisms in vivo. Especially for anatomically complex and dynamic organs such as the lung and its main functional unit, the alveolus, IVM provides exclusive advantages in terms of spatial and temporal resolution. By the use of lung windows, which have advanced and improved over time, direct access to the lung surface is provided. In this review we will discuss two main topics, namely alveolar dynamics and perfusion from the perspective of IVM-based studies. Of special interest are unanswered questions regarding alveolar dynamics such as: What are physiologic alveolar dynamics? How do these dynamics change under pathologic conditions and how do those changes contribute to ventilator-induced lung injury? How can alveolar dynamics be targeted in a beneficial way? With respect to alveolar perfusion IVM has propelled our understanding of the pulmonary microcirculation and its perfusion, as well as pulmonary vasoreactivity, permeability and immunological aspects. Whereas the general mechanism behind these processes are understood, we still lack a proper understanding of the complex, multidimensional interplay between alveolar ventilation and microvascular perfusion, capillary recruitment, or vascular immune responses under physiologic and pathologic conditions. These are only part of the unanswered questions and problems, which we still have to overcome. IVM as the tool of choice might allow us to answer part of these questions within the next years or decades. As every method, IVM has advantages as well as limitations, which have to be taken into account for data analysis and interpretation, which will be addressed in this review

Imaging Biomarkers of Pulmonary Structure and Function

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airflow limitations resulting from airway obstruction and/or tissue destruction. The diagnosis and monitoring of these pulmonary diseases is primarily performed using spirometry, specifically the forced expiratory volume in one second (FEV1), which measures global airflow obstruction and provides no regional information of the different underlying disease pathologies. The limitations of spirometry and current therapies for lung disease patients have motivated the development of pulmonary imaging approaches, such as computed tomography (CT) and magnetic resonance imaging (MRI). Inhaled hyperpolarized noble gas MRI, specifically using helium-3 (3He) and xenon-129 (129Xe) gases, provides a way to quantify pulmonary ventilation by visualizing lung regions accessed by gas during a breath-hold, and alternatively, regions that are not accessed - coined “ventilation defects.” Despite the strong foundation and many advantages hyperpolarized 3He MRI has to offer research and patient care, clinical translation has been inhibited in part due to the cost and need for specialized equipment, including multinuclear-MR hardware and polarizers, and personnel. Accordingly, our objective was to develop and evaluate imaging biomarkers of pulmonary structure and function using MRI and CT without the use of exogenous contrast agents or specialized equipment. First, we developed and compared CT parametric response maps (PRM) with 3He MR ventilation images in measuring gas-trapping and emphysema in ex-smokers with and without COPD. We observed that in mild-moderate COPD, 3He MR ventilation abnormalities were related to PRM gas-trapping whereas in severe COPD, ventilation abnormalities correlated with both PRM gas-trapping and PRM emphysema. We then developed and compared pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing proton (1H) MRI (FDMRI) with 3He MRI in subjects with COPD and bronchiectasis. This work demonstrated that FDMRI and 3He MRI ventilation defects were strongly related in COPD, but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with 3He MRI ventilation defects and emphysema. Based on the FDMRI biomarkers developed in patients with COPD and bronchiectasis, we then evaluated ventilation heterogeneity in patients with severe asthma, both pre- and post-salbutamol as well as post-methacholine challenge, using FDMRI and 3He MRI. FDMRI free-breathing ventilation abnormalities were correlated with but under-estimated 3He MRI static ventilation defects. Finally, based on the previously developed free-breathing MRI approach, we developed a whole-lung free-breathing pulmonary 1H MRI technique to measure regional specific-ventilation and evaluated both asthmatics and healthy volunteers. These measurements not only provided similar information as specific-ventilation measured using plethysmography, but also information about regional ventilation defects that were correlated with 3He MRI ventilation abnormalities. These results demonstrated that whole-lung free-breathing 1H MRI biomarker of specific-ventilation may reflect ventilation heterogeneity and/or gas-trapping in asthma. These important findings indicate that imaging biomarkers of pulmonary structure and function using MRI and CT have the potential to regionally reveal the different pathologies in COPD and asthma without the use of exogenous contrast agents. The development and validation of these clinically meaningful imaging biomarkers are critically required to accelerate pulmonary imaging translation from the research workbench to being a part of the clinical workflow, with the overall goal to improve patient outcomes