Evaluating Small Airways Disease in Asthma and COPD using the Forced Oscillation Technique and Magnetic Resonance Imaging

Obstructive lung disease, including asthma and chronic obstructive pulmonary disease (COPD), is characterized by heterogeneous ventilation. Unfortunately, the underlying structure-function relationships and the relationships between measurements of heterogeneity and patient quality-of-life in obstructive lung disease are not well understood. Hyperpolarized noble gas MRI is used to visualize and quantify ventilation distribution and the forced oscillation technique (FOT) applies a multi-frequency pressure oscillation at the mouth to measure respiratory impedance to airflow (including resistance and reactance). My objective was to use FOT, ventilation MRI and computational airway tree modeling to better understand ventilation heterogeneity in asthma and COPD. FOT-measured respiratory system impedance was correlated with MRI ventilation heterogeneity and both were related to quality-of-life in asthma and COPD. FOT-measurements and model-predictions of reactance and small-airways resistance were correlated in asthma and COPD respectively. This study is the first to demonstrate the relationships between FOT-measured impedance, MRI ventilation heterogeneity, and patient quality-of-life

A tree-parenchyma coupled model for lung ventilation simulation

International audienceIn this article we develop a lung-ventilation model. The parenchyma is described as an elastic homogenized media. It is irrigated by a space-filling dyadic resistive pipe network, which represents the tracheo-bronchial tree. In this model the tree and the parenchyma are strongly coupled. The tree induces an extra viscous term in the system constitutive relation, which leads, in the finite element framework, to a full matrix. We consider an efficient algorithm that takes advantage of the tree dyadic structure to enable a fast matrix-vector product computation. This framework can be used to model both free and mechanically induced respiration, in health and disease. Patient-specific lung geometries acquired from CT scans are considered. Realistic Dirichlet boundary conditions can be deduced from surface registration on CT images. The model is compared to a more classical exit-compartment approach. Results illustrate the coupling between the tree and the parenchyma, at global and regional levels, and how conditions for the purely 0D model can be inferred. Different types of boundary conditions are tested, including a nonlinear Robin model of the surrounding lung structures

Comparison of Image Registration Based Measures of Regional Lung Ventilation from Dynamic Spiral CT with Xe-CT

Purpose: Regional lung volume change as a function of lung inflation serves as an index of parenchymal and airway status as well as an index of regional ventilation and can be used to detect pathologic changes over time. In this article, we propose a new regional measure of lung mechanics --- the specific air volume change by corrected Jacobian. Methods: 4DCT and Xe-CT data sets from four adult sheep are used in this study. Nonlinear, 3D image registration is applied to register an image acquired near end inspiration to an image acquired near end expiration. Approximately 200 annotated anatomical points are used as landmarks to evaluate registration accuracy. Three different registration-based measures of regional lung mechanics are derived and compared: the specific air volume change calculated from the Jacobian (SAJ); the specific air volume change calculated by the corrected Jacobian (SACJ); and the specific air volume change by intensity change (SAI). Results: After registration, the mean registration error is on the order of 1 mm. For cubical ROIs in cubes with size 20 mm $\times$ 20 mm $\times$ 20 mm, the SAJ and SACJ measures show significantly higher correlation (linear regression, average $r^2=0.75$ and $r^2=0.82$) with the Xe-CT based measure of specific ventilation (sV) than the SAI measure. For ROIs in slabs along the ventral-dorsal vertical direction with size of 150 mm $\times$ 8 mm $\times$ 40 mm, the SAJ, SACJ, and SAI all show high correlation (linear regression, average $r^2=0.88$, $r^2=0.92$ and $r^2=0.87$) with the Xe-CT based sV without significant differences when comparing between the three methods. Conclusion: Given a deformation field by an image registration algorithm, significant differences between the SAJ, SACJ, and SAI measures were found at a regional level compared to the Xe-CT sV in four sheep that were studied

Caractérisation biomécanique expérimentale du tissu pulmonaire avec et sans agrafes afin de caractériser le phénomène de fuite d’air apparaissant à la suite d’une résection pulmonaire

Pour traiter les patients atteints d'un cancer du poumon, les chirurgiens thoraciques retirent la tumeur cancéreuse à l’aide d’une agrafeuse chirurgicale. À la suite de cette opération de résection pulmonaire, 28-60% des patients développent une fuite d’air. Cette fuite engendre une augmentation de la durée d’hospitalisation et une augmentation des coûts de soins de santé. Au niveau clinique, la résection des lobes supérieurs entraine des fuites plus conséquentes que la résection des lobes inférieurs. Une seule étude numérique corrobore ce constat clinique et l’explique comme résultant d’une augmentation de la contrainte sur le tissu pulmonaire restant post-résection, qui doit s’adapter à la forme en ogive de la cage thoracique. Très peu d’études se sont intéressées à étudier la cause de ces fuites, cependant quelques études expérimentales déclarent que la fuite se produirait aux extrémités de la ligne d’agrafe et qu’elle serait de nature biomécanique. Ce projet a donc pour objectif de caractériser biomécaniquement et visuellement les tissus pulmonaires avec et sans agrafes afin d'acquérir des connaissances sur les fuites d'air après une résection pulmonaire. Un banc expérimental a été conçu pour ventiler mécaniquement 11 poumons porcins frais ex vivo. La ventilation cyclique se fait par une pompe à seringue contrôlée en pression remplie d'air. Un microcontrôleur contrôle et enregistre la pression pulmonaire et le volume d'air pompé. Simultanément, deux stéréo-caméras capturent des images à intervalles réguliers de la surface costale déformée des poumons. Les images brutes sont ensuite utilisées pour calculer les déplacements et les déformations tridimensionnelles à l'aide de la méthode de corrélation d'images digitales. Une première caractérisation a permis d’identifier où se présente la fuite d’air par une observation visuelle et une documentation par photographie de poumons immergés et ventilés. Une deuxième investigation a permis de contrôler puis mesurer les pressions et les volumes en tout temps pour identifier les lobes les plus propices à la fuite ainsi que les conséquences du retrait d’un lobe sur la mécanique pulmonaire via l’évaluation de la compliance (variation de volume en réponse à une variation de pression). Enfin, une combinaison novatrice de la technique de corrélation d’images digitales appliquée sur les poumons ventilés a permis de comparer les patrons de déformation principale, avant et après agrafage, pour déterminer une possible correspondance entre la localisation des fuites et la zone de déformation principale maximale. Les résultats montrent notamment que la fuite d’air se développe au niveau des trous des pattes des agrafes du rang intérieur de la ligne d’agrafe, suite à un déchirement de la plèvre de la surface costale qui expose le tissu pulmonaire. Le lobe inférieur fuit statistiquement plus facilement, i.e. à des pressions moins élevées (p-value<0.046), que le lobe supérieur même dans des conditions ex vivo. Ce résultat concorde avec les observations cliniques et celles de l’étude numérique mais offre aussi un complément d’information puisque le résultat existe même sans l’influence de la cage thoracique. Les conséquences de la chirurgie de résection est évaluée par la compliance. Elle diminue seulement de 9 % entre l’état sain et les états réséqués. Ce résultat contraire à la littérature qui associe la diminution de compliance au volume de tissu réséqué. Enfin, l’étude des patrons de déformation principal montrent que le poumon gonfle en priorité au niveau de ses bords en développant une déformation 6 fois plus élevée que le tissu situé proche de l’arrivée d’air. L’étude des patrons de déformation en cisaillement montre une répartition non homogène de cisaillements non nul : le poumon ne se déforme pas de manière équibiaxiale comme un ballon de fête. Enfin, la comparaison des mesures de déformation principale avec les localisations de fuites semble corroborer l’hypothèse que la fuite se développe à la suite d’une fracture de la plèvre annoncée par un maximum de déformation proche de la ligne d’agrafe. Ces résultats suggèrent que les patrons de déformations sont essentiels pour comprendre les mécanismes de rupture de la ligne d’agrafe et devraient faire l'objet d'une enquête plus approfondie. Ce travail expérimental caractérise avec précision la physiologie des fuites d'air post-résection pulmonaire. Il fournit de nouvelles données à la littérature sur les changements de la compliance pulmonaire, à basse pression, sous ventilation par pression positive. D'autres études devraient viser à valider ces résultats à différentes pressions de ventilation. Les conclusions liées à ces études pourraient influencer les pratiques de pression appliquées aux drains thoraciques postopératoires déjà controversées. L’utilisation de la corrélation d’images digitales appliquée à l’ensemble du poumon est novatrice et fournit des résultats pertinents sur la biomécanique pulmonaire. Les patrons de déformation sont donc essentiels pour comprendre les mécanismes de fuites d’air au niveau des lignes d'agrafes et devraient faire l'objet d'études plus approfondies.----------ABSTRACT To treat patients with lung cancer, thoracic surgeons remove the cancerous tumor using a surgical stapler. Following this lung resection operation, 28-60% of patients develop an air leak. This leakage leads to an increase in the length of hospitalization and increased health care costs. Clinically, resections of upper lobes result in more leakage than resections of lower lobes. A single numerical study corroborates this clinical finding and explains it as a result of increased stress on the remaining lung tissue after resection, which has to adapt to fit the ogive shape of the rib cage. Very few studies have investigated the cause of these leaks, however a few experimental studies state that leaks would occur at the extremities of staple lines and would be biomechanical in nature. The objective of this project is therefore to biomechanically and visually characterize lung tissue with and without staples in order to gain knowledge about air leaks after lung resection. An experimental bench was designed to mechanically ventilate 11 fresh porcine lungs ex vivo. Cyclic ventilation is performed by a pressure-controlled syringe pump filled with air. A microcontroller monitors and records lung pressure and volume of air pumped. Simultaneously, two stereo-cameras capture images at regular intervals of the deformed costal surface of the lungs. The raw images are then used to calculate the three-dimensional displacements and deformations using the Digital Image Correlation method. An initial characterization has identified where air leakage occurs by visual observation and photographic documentation of immersed and ventilated lungs. A second investigation made it possible to control and measure pressures and volumes at all times to identify the lobes most likely to leak as well as the consequences of lobectomies on lung mechanics by calculating lungs compliance (variation of volume in response to a variation of pressure). Finally, an innovative combination of the digital image correlation technique applied to ventilated lungs has made it possible to compare the principal strain patterns, before and after stapling, to determine a possible relationship between the location of leaks and the zone of maximum principal strain. In particular, air leaks develop at staple holes from inner row of staple line, as a result of torn visceral pleura on the costal surface exposing lung tissue. Lower lobes statistically leak more easily, i.e. at lower pressures (p-value<0.046), than upper lobes even under ex vivo conditions. This result is consistent with the clinical and numerical study observations but also provides additional information since it exists even without the influence of the rib cage. The consequences of the resection surgery are evaluated by compliance. It decreases only by 9 % between healthy and resected states. This result is contrary to the literature which associates the decrease in compliance with the volume of resected tissue. Finally, the study of principal strain patterns shows that lung inflates primarily at its edges, developing a strain 6 times higher than the tissue located near the air supply. The study of shear strain patterns shows a non-homogeneous distribution of non-zero shear strains: lung does not deform equibiaxially like a party balloon. Finally, the comparison of principal strain patterns with observed leak locations seems to corroborate our hypothesis that the leak develops following a fracture of the pleura announced by a maximum principal strain close to the staple line. These results suggest that strain patterns are essential to understanding the staple line failure mechanisms and should be further investigated. This experimental work accurately characterizes the physiology of air leaks after lung resection. It provides new data to the literature on changes in lung compliance at low pressure under positive pressure ventilation. Further studies should aim to validate these results at different ventilation pressures. These studies findings may influence the already controversial pressure practices applied to postoperative chest drains supposed to reduce the leak. The use of digital image correlation applied to the entire lung is innovative and provides relevant results on lung biomechanics. Strain patterns are therefore essential for understanding the mechanisms of air leaks at staple lines and should be further investigated

3-D lung deformation and function from respiratory-gated 4-D x-ray CT images : application to radiation treatment planning.

Many lung diseases or injuries can cause biomechanical or material property changes that can alter lung function. While the mechanical changes associated with the change of the material properties originate at a regional level, they remain largely asymptomatic and are invisible to global measures of lung function until they have advanced significantly and have aggregated. In the realm of external beam radiation therapy of patients suffering from lung cancer, determination of patterns of pre- and post-treatment motion, and measures of regional and global lung elasticity and function are clinically relevant. In this dissertation, we demonstrate that 4-D CT derived ventilation images, including mechanical strain, provide an accurate and physiologically relevant assessment of regional pulmonary function which may be incorporated into the treatment planning process. Our contributions are as follows: (i) A new volumetric deformable image registration technique based on 3-D optical flow (MOFID) has been designed and implemented which permits the possibility of enforcing physical constraints on the numerical solutions for computing motion field from respiratory-gated 4-D CT thoracic images. The proposed optical flow framework is an accurate motion model for the thoracic CT registration problem. (ii) A large displacement landmark-base elastic registration method has been devised for thoracic CT volumetric image sets containing large deformations or changes, as encountered for example in registration of pre-treatment and post-treatment images or multi-modality registration. (iii) Based on deformation maps from MOFIO, a novel framework for regional quantification of mechanical strain as an index of lung functionality has been formulated for measurement of regional pulmonary function. (iv) In a cohort consisting of seven patients with non-small cell lung cancer, validation of physiologic accuracy of the 4-0 CT derived quantitative images including Jacobian metric of ventilation, Vjac, and principal strains, (V?1, V?2, V?3, has been performed through correlation of the derived measures with SPECT ventilation and perfusion scans. The statistical correlations with SPECT have shown that the maximum principal strain pulmonary function map derived from MOFIO, outperforms all previously established ventilation metrics from 40-CT. It is hypothesized that use of CT -derived ventilation images in the treatment planning process will help predict and prevent pulmonary toxicity due to radiation treatment. It is also hypothesized that measures of regional and global lung elasticity and function obtained during the course of treatment may be used to adapt radiation treatment. Having objective methods with which to assess pre-treatment global and regional lung function and biomechanical properties, the radiation treatment dose can potentially be escalated to improve tumor response and local control

Functional respiratory imaging : opening the black box

In respiratory medicine, several quantitative measurement tools exist that assist the clinicians in their diagnosis. The main issue with these traditional techniques is that they lack sensitivity to detect changes and that the variation between different measurements is very high. The result is that the development of respiratory drugs is the most expensive of all drug development. This limits innovation, resulting in an unmet need for sensitive quantifiable outcome parameters in pharmacological development and clinical respiratory practice. In this thesis, functional respiratory imaging (FRI) is proposed as a tool to tackle these issues. FRI is a workflow where patient specific medical images are combined with computational fluid dynamics in order to give patient specific local information of anatomy and functionality in the respiratory system. A robust high throughput automation system is designed in order get a workflow that is of a high quality, consistent and fast. This makes it possible to apply this technology on large datasets as typically seen in clinical trials. FRI is performed on 486 unique geometries of patients with various pathologies such as asthma, chronic obstructive lung disease, sleep apnea and cystic fibrosis. This thesis shows that FRI can have an added value in multiple research domains. The high sensitivity and specificity of FRI make it very well suited as a tool to make decisions early in the development process of a device or drug. Furthermore, FRI also seems to be an interesting technology to gain better insight in rare diseases and can possibly be useful in personalized medicine

Quantitative lung CT analysis for the study and diagnosis of Chronic Obstructive Pulmonary Disease

The importance of medical imaging in the research of Chronic Obstructive Pulmonary Dis- ease (COPD) has risen over the last decades. COPD affects the pulmonary system through two competing mechanisms; emphysema and small airways disease. The relative contribu- tion of each component varies widely across patients whilst they can also evolve regionally in the lung. Patients can also be susceptible to exacerbations, which can dramatically ac- celerate lung function decline. Diagnosis of COPD is based on lung function tests, which measure airflow limitation. There is a growing consensus that this is inadequate in view of the complexities of COPD. Computed Tomography (CT) facilitates direct quantification of the pathological changes that lead to airflow limitation and can add to our understanding of the disease progression of COPD. There is a need to better capture lung pathophysiology whilst understanding regional aspects of disease progression. This has motivated the work presented in this thesis. Two novel methods are proposed to quantify the severity of COPD from CT by analysing the global distribution of features sampled locally in the lung. They can be exploited in the classification of lung CT images or to uncover potential trajectories of disease progression. A novel lobe segmentation algorithm is presented that is based on a probabilistic segmen- tation of the fissures whilst also constructing a groupwise fissure prior. In combination with the local sampling methods, a pipeline of analysis was developed that permits a re- gional analysis of lung disease. This was applied to study exacerbation susceptible COPD. Lastly, the applicability of performing disease progression modelling to study COPD has been shown. Two main subgroups of COPD were found, which are consistent with current clinical knowledge of COPD subtypes. This research may facilitate precise phenotypic characterisation of COPD from CT, which will increase our understanding of its natural history and associated heterogeneities. This will be instrumental in the precision medicine of COPD

Statistical Shape Modelling and Segmentation of the Respiratory Airway

The human respiratory airway consists of the upper (nasal cavity, pharynx) and the lower (trachea, bronchi) respiratory tracts. Accurate segmentation of these two airway tracts can lead to better diagnosis and interpretation of airway-specific diseases, and lead to improvement in the localization of abnormal metabolic or pathological sites found within and/or surrounding the respiratory regions. Due to the complexity and the variability displayed in the anatomical structure of the upper respiratory airway along with the challenges in distinguishing the nasal cavity from non-respiratory regions such as the paranasal sinuses, it is difficult for existing algorithms to accurately segment the upper airway without manual intervention. This thesis presents an implicit non-parametric framework for constructing a statistical shape model (SSM) of the upper and lower respiratory tract, capable of distinct shape generation and be adapted for segmentation. An SSM of the nasal cavity was successfully constructed using 50 nasal CT scans. The performance of the SSM was evaluated for compactness, specificity and generality. An averaged distance error of 1.47 mm was measured for the generality assessment. The constructed SSM was further adapted with a modified locally constrained random walk algorithm to segment the nasal cavity. The proposed algorithm was evaluated on 30 CT images and outperformed comparative state-of-the-art and conventional algorithms. For the lower airway, a separate algorithm was proposed to automatically segment the trachea and bronchi, and was designed to tolerate the image characteristics inherent in low-contrast CT images. The algorithm was evaluated on 20 clinical low-contrast CT from PET-CT patient studies and demonstrated better performance (87.1±2.8 DSC and distance error of 0.37±0.08 mm) in segmentation results against comparative state-of-the-art algorithms

Focal Spot, Spring 1987

https://digitalcommons.wustl.edu/focal_spot_archives/1045/thumbnail.jp

Structure and Function of Asthma Evaluated Using Pulmonary Imaging

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