Ventilation Defect Percent Research Articles

Regional Heterogeneity of Lobar Ventilation in Asthma Using Hyperpolarized Helium-3 MRI

To determine lobar ventilation patterns in asthmatic lungs with hyperpolarized 3He magnetic resonance imaging (HP 3He MRI). Eighty-two subjects (14 normal, 48 mild-to-moderate asthma, and 20 severe asthma) underwent HP 3He MRI, computed tomography (CT), and pulmonary function testing. After registering proton to 3He images, we segmented the lungs from proton MRI and further segmented the five lung lobes (right upper lobe [RUL], right middle lobe [RML], and right lower lobe [RLL]; left upper lobe and left lower lobe [LLL]) by referring to the lobar segmentation from CT. We classified the gas volume into four signal intensity levels as follows: ventilation defect percent (VDP), low ventilation percent, medium ventilation percent, and high ventilation percent. The local signal intensity variations in the ventilated volume were estimated using heterogeneity score (Hs). We compared each ventilation level and Hs measured in the whole lung and lobar regions across the three subject groups. In mild-to-moderate asthma, the RML and RUL showed significantly greater VDP than the two lower lobes (RLL and LLL) (P ≤ .047). In severe asthma, the pattern was more variable with the VDP in the RUL significantly greater than in the RLL (P = .026). In both asthma groups, the lower lobes (RLL and LLL) showed significantly higher high ventilation percent and Hs compared to the three upper lobes (all P ≤ .015). In asthma, the RML and RUL showed greater ventilation abnormalities, and the RLL and LLL were more highly ventilated with greater local heterogeneity. These findings may facilitate guided bronchoscopic sampling and localized airway treatment in future studies.

Ventilation defect percent in helium-3 magnetic resonance imaging as a biomarker of severe outcomes in asthma

Ventilation defect percent (VDP) measured in asthmatics with hyperpolarized helium-3 MRI was more strongly associated with ED visits and hospitalizations due to asthma exacerbation than were conventional biomarkers of lung function and inflammation.

Pulmonary ventilation imaging in asthma and cystic fibrosis using oxygen-enhanced 3D radial ultrashort echo time MRI.

A previous study demonstrated the feasibility of using 3D radial ultrashort echo time (UTE) oxygen-enhanced MRI (UTE OE-MRI) for functional imaging of healthy human lungs. The repeatability of quantitative measures from UTE OE-MRI needs to be established prior to its application in clinical research. To evaluate repeatability of obstructive patterns in asthma and cystic fibrosis (CF) with UTE OE-MRI with isotropic spatial resolution and full chest coverage. Volunteer and patient repeatability. Eighteen human subjects (five asthma, six CF, and seven normal subjects). Respiratory-gated free-breathing 3D radial UTE (80 μs) sequence at 1.5T. Two 3D radial UTE volumes were acquired sequentially under normoxic and hyperoxic conditions. A subset of subjects underwent repeat acquisitions on either the same day or ≤15 days apart. Asthma and CF subjects also underwent spirometry. A workflow including deformable registration and retrospective lung density correction was used to compute 3D isotropic percent signal enhancement (PSE) maps. Median PSE (MPSE) and ventilation defect percent (VDP) of the lung were measured from the PSE map. The relations between MPSE, VDP, and spirometric measures were assessed using Spearman correlations. The test-retest repeatability was evaluated using Bland-Altman analysis and intraclass correlation coefficients (ICC). Ventilation measures in normal subjects (MPSE = 8.0%, VDP = 3.3%) were significantly different from those in asthma (MPSE = 6.0%, P = 0.042; VDP = 21.7%, P = 0.018) and CF group (MPSE = 4.5%, P = 0.0006; VDP = 27.2%, P = 0.002). MPSE correlated significantly with forced expiratory lung volume in 1 second percent predicted (ρ = 0.72, P = 0.017). The ICC of the test-retest VDP and MPSE were both ≥0.90. In all subject groups, an anterior/posterior gradient was observed with higher MPSE and lower VDP in the posterior compared to anterior regions (P ≤ 0.0021 for all comparisons). 3D radial UTE OE-MRI supports quantitative differentiation of diseased vs. healthy lungs using either whole lung VDP or MPSE with excellent test-retest repeatability. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1287-1297.

On the Potential Role of MRI Biomarkers of COPD to Guide Bronchoscopic Lung Volume Reduction

In patients with severe emphysema and poor quality of life, bronchoscopic lung volume reduction (BLVR) may be considered and guided based on lobar emphysema severity. In particular, x-ray computed tomography (CT) emphysema measurements are used to identify the most diseased and the second-most diseased lobes as BLVR targets. Inhaled gas magnetic resonance imaging (MRI) also provides chronic obstructive pulmonary disease (COPD) biomarkers of lobar emphysema and ventilation abnormalities. Our objective was to retrospectively evaluate CT and MRI biomarkers of lobar emphysema and ventilation in patients with COPD eligible for BLVR. We hypothesized that MRI would provide complementary biomarkers of emphysema and ventilation that help determine the most appropriate lung lobar targets for BLVR in patients with COPD. We retrospectively evaluated 22 BLVR-eligible patients from the Thoracic Imaging Network of Canada cohort (diffusing capacity of the lung for carbon monoxide = 37 ± 12%predicted, forced expiratory volume in 1 second = 34 ± 7%predicted, total lung capacity = 131 ± 17%predicted, and residual volume = 216 ± 36%predicted). Lobar CT emphysema, measured using a relative area of <-950 Hounsfield units (RA950) and MRI ventilation defect percent, was independently used to rank lung lobe disease severity. In 7 of 22 patients, there were different CT and MRI predictions of the most diseased lobe. In some patients, there were large ventilation defects in lobes not targeted by CT, indicative of a poorly ventilated lung. CT and MRI classification of the most diseased and the second-most diseased lobes showed a fair-to-moderate intermethod reliability (Cohen κ = 0.40-0.59). In this proof-of-concept retrospective analysis, quantitative MRI ventilation and CT emphysema measurements provided different BLVR targets in over 30% of the patients. The presence of large MRI ventilation defects in lobes next to CT-targeted lobes might also change the decision to proceed or to guide BLVR to a different lobar target.

Pulmonary 3He Magnetic Resonance Imaging Biomarkers of Regional Airspace Enlargement in Alpha-1 Antitrypsin Deficiency

Thoracic x-ray computed tomography (CT) and hyperpolarized 3He magnetic resonance imaging (MRI) provide quantitative measurements of airspace enlargement in patients with emphysema. For patients with panlobular emphysema due to alpha-1 antitrypsin deficiency (AATD), sensitive biomarkers of disease progression and response to therapy have been difficult to develop and exploit, especially those biomarkers that correlate with outcomes like quality of life. Here, our objective was to generate and compare CT and diffusion-weighted inhaled-gas MRI measurements of emphysema including apparent diffusion coefficient (ADC) and MRI-derived mean linear intercept (Lm) in patients with AATD, chronic obstructive pulmonary disease (COPD) ex-smokers, and elderly never-smokers. We enrolled patients with AATD (n = 8; 57 ± 7 years), ex-smokers with COPD (n = 8; 77 ± 6 years), and a control group of never-smokers (n = 5; 64 ± 2 years) who underwent thoracic CT, MRI, spirometry, plethysmography, the St. George's Respiratory Questionnaire, and the 6-minute walk test during a single 2-hour visit. MRI-derived ADC, Lm, surface-to-volume ratio, and ventilation defect percent were generated for the apical, basal, and whole lung as was CT lung area ≤-950 Hounsfield units (RA950), low attenuating clusters, and airway count. In patients with AATD, there was a significantly different MRI-derived ADC (P = .03), Lm (P < .0001), and surface-to-volume ratio (P < .0001), but not diffusing capacity of carbon monoxide, residual volume or total lung capacity, or CT RA950 (P > .05) compared to COPD ex-smokers with a significantly different St. George's Respiratory Questionnaire. In this proof-of-concept demonstration, we evaluated CT and MRI lung emphysema measurements and observed significantly worse MRI biomarkers of emphysema in patients with AATD compared to patients with COPD, although CT RA950 and diffusing capacity of carbon monoxide were not significantly different, underscoring the sensitivity of MRI measurements of AATD emphysema.

Free-breathing Functional Pulmonary MRI: Response to Bronchodilator and Bronchoprovocation in Severe Asthma

Ventilation heterogeneity is a hallmark feature of asthma. Our objective was to evaluate ventilation heterogeneity in patients with severe asthma, both pre- and post-salbutamol, as well as post-methacholine (MCh) challenge using the lung clearance index, free-breathing pulmonary 1H magnetic resonance imaging (FDMRI), and inhaled-gas MRI ventilation defect percent (VDP). Sixteen severe asthmatics (49 ± 10 years) provided written informed consent to an ethics board-approved protocol. Spirometry, plethysmography, and multiple breath nitrogen washout to measure the lung clearance index were performed during a single visit within 15 minutes of MRI. Inhaled-gas MRI and FDMRI were performed pre- and post-bronchodilator to generate VDP. For asthmatics with forced expiratory volume in 1 second (FEV1) >70%predicted, MRI was also performed before and after MCh challenge. Wilcoxon signed-rank tests, Spearman correlations, and a repeated-measures analysis of variance were performed. Hyperpolarized 3He (P = .02) and FDMRI (P = .02) VDP significantly improved post-salbutamol and for four asthmatics who could perform MCh (n = 4). 3He and FDMRI VDP significantly increased at the provocative concentration of MCh, resulting in a 20% decrease in FEV1 (PC20) and decreased post-bronchodilator (P = .02), with a significant difference between methods (P = .01). FDMRI VDP was moderately correlated with 3He VDP (ρ = .61, P = .01), but underestimated VDP relative to 3He VDP (-6 ± 9%). Whereas 3He MRI VDP was significantly correlated with the lung clearance index, FDMRI was not (ρ = .49, P = .06). FDMRI VDP generated in free-breathing asthmatic patients was correlated with static inspiratory breath-hold 3He MRI VDP but underestimated VDP relative to 3He MRI VDP. Although less sensitive to salbutamol and MCh, FDMRI VDP may be considered for asthma patient evaluations at centers without inhaled-gas MRI.

Thoracic CT-MRI coregistration for regional pulmonary structure-function measurements of obstructive lung disease.

Recent pulmonary imaging research has revealed that in patients with chronic obstructive pulmonary disease (COPD) and asthma, structural and functional abnormalities are spatially heterogeneous. This novel information may help optimize treatment in individual patients, monitor interventional efficacy, and develop new treatments. Moreover, by automating the measurement of regional biomarkers for the 19 different anatomical lung segments, there is an opportunity to embed imaging biomarkers into clinically acceptable clinical workflows and improve lung disease clinical care. Therefore, to exploit the regional structure-function information provided by thoracic imaging, and as a first step toward this goal, our objective was to develop a fully automated registration pipeline for thoracic x-ray computed tomography (CT) and inhaled gas functional magnetic resonance imaging (MRI) whole lung and segmental structure-function biomarkers. Thirty-five patients including 15 severe, poorly controlled asthmatics and 20 COPD patients [classified according to the global initiative for chronic obstructive lung disease (GOLD) criteria)] provided written informed consent to a study protocol approved by Health Canada and underwent pulmonary function tests, MRI, and CT during a single 2-hour visit. Using this diverse patient dataset, we developed and evaluated a joint deformable registration approach to simultaneously coregister CT with both 1 H and 3 He MRI by enforcing the similarity of the deformation fields from the two individual registrations. We derived a simpler model that was equivalent to the original challenging optimization problem through variational analysis and the simpler model gave rise to an efficient numerical solver that was parallelized on a graphics processing unit. The coregistered CT-3 He MRI and whole lung/segmental lung masks were used to generate whole lung and segmental 3 He MRI ventilation defect percent (VDP). To estimate fiducial localization reproducibility, a single observer manually identified 109 pairs of CT and 3 He MRI fiducials for 35 patient images on five separate occasions and determined the fiducial localization error (FLE). CT-3 He MRI registration accuracy was evaluated using the target registration error (TRE). Whole lung VDP generated using the algorithm was compared with VDP generated using a previously validated semiautomated approach and computational efficiency was evaluated using run time. In 35 patients including 15 with severe asthma and 20 with COPD, mean forced expiratory volume in 1s (FEV1 ) was 63±24%pred and FEV1 /forced vital capacity (FVC) was 54±17%. FLE was 0.16mm and 0.34mm for 3 He MRI and CT, respectively. TRE was 4.5±2.0mm, 4.0±1.7mm, 4.8±2.3mm for asthma, COPD GOLD II, and GOLD III groups, respectively, with a mean of 4.4±2.0mm for the entire dataset. TRE was significantly improved for joint CT-1 H/3 He MRI registration compared with CT-1 H MRI rigid registration (P<0.0001). Whole lung VDP generated using the pipeline was not significantly different (P=0.37) compared to a semiautomated method with which it was strongly correlated (r=0.93, P<0.0001). The fully automated pipeline required 11±0.4 min to generate whole lung and segmental VDP. For a diverse group of patients with COPD and asthma, whole lung and segmental VDP was measured using an automated lung image analysis pipeline which provides a way to incorporate lung functional biomarkers into clinical research and patient care.

Pulmonary magnetic resonance imaging biomarkers of lung structure and function in adult survivors of bronchopulmonary dysplasia with COPD

Bronchopulmonary dysplasia (BPD) is an emerging risk factor for chronic obstructive pulmonary disease. For BPD survivors, there are no guidelines for the management of lung disease that is often misdiagnosed as asthma. Pulmonary magnetic resonsance imaging (MRI) provides clinically-relevant lung biomarkers of ventilation abnormalities and emphysema. Here our objective was to quantify lung MRI biomarkers in adults with BPD to understand the underlying pathophysiologies responsible for their symptoms and abnormal pulmonary-function. We hypothesized that MRI measurements would be abnormal and reflect emphysema, not airways disease. Patients aged 20–29 year and born ≤32 weeks gestational age were included and those with MRI contraindications were excluded. A 25-year-old female never-smoker born <28 weeks gestation (S1) and a 27-year-old male ex-smoker born ~30 weeks gestation (S2) provided written-informed-consent and underwent pulmonary-function-tests and MRI. Lung abnormalities were quantified using ventilation defect percent (VDP), apparent diffusion coefficients (ADC) and mean linear intercept (Lm). Forced expiratory volume-in 1 sec (S1 = 46%pred/S2 = 33%pred), residual-volume (S1 = 192%pred/S2 = 267%pred) and diffusing-capacity-of-the-lung-for-carbon-monoxide (S1 = 73%pred/S2 = 72%pred) were abnormal. Chest–X-ray and computed tomography (CT) revealed mild structural abnormalities, while MRI VDP (S1 = 6%/S2 = 10%), ADC (S1 = 0.36 cm2/s/S2 = 0.37 cm2/s) and Lm (S1 = 400 μm/S2 = 430 μm) were markedly abnormal with ventilation defects spatially concordant with regions of low MRI signal-intensity and greater Lm, reflecting emphysema and/or gas-trapping. In BPD survivors, MRI biomarkers have the potential to serve as intermediate endpoints and help evaluate therapy.

Ultrashort echo time MRI biomarkers of asthma.

To develop and assess ultrashort echo-time (UTE) magnetic resonance imaging (MRI) biomarkers of lung function in asthma patients. Thirty participants including 13 healthy volunteers and 17 asthmatics provided written informed consent to UTE and pulmonary function tests in addition to hyperpolarized-noble-gas 3T MRI and computed tomography (CT) for asthmatics only. The difference in MRI signal-intensity (SI) across four lung volumes (full-expiration, functional-residual-capacity [FRC], FRC+1L, and full-inspiration) was determined on a voxel-by-voxel basis to generate dynamic proton-density (DPD) maps. MRI ventilation-defect-percent (VDP), UTE SI, and DPD values as well as CT radiodensity were determined for whole lung and individual lobes. Mean SI at full-expiration (P < 0.01), FRC (P < 0.05), and DPD (P < 0.01) were greater in healthy volunteers compared to asthmatics. In asthmatics, UTE SI at full-expiration and DPD were correlated with FEV1 /FVC (SI r = 0.73/P = 0.002; DPD r = 0.75/P = 0.003), RV/TLC (SI r = -0.57/P = 0.02), or RV (DPD r = -0.62/P = 0.02), CT radiodensity (SI r = 0.83/P = 0.006; DPD r = 0.71/P = 0.01), and lobar VDP (SI rs = -0.33/P = 0.02; DPD rs = -0.47/P = 0.01). In patients with asthma, UTE SI and dynamic proton-density were related to pulmonary function measurements, whole lung and lobar VDP, as well as CT radiodensity. Thus, UTE MRI biomarkers may reflect ventilation heterogeneity and/or gas-trapping in asthmatics using conventional equipment, making this approach potentially amenable for clinical use. 2 J. Magn. Reson. Imaging 2017;45:1204-1215.

Noncystic Fibrosis Bronchiectasis: Regional Abnormalities and Response to Airway Clearance Therapy Using Pulmonary Functional Magnetic Resonance Imaging

Evidence-based treatment and management for patients with bronchiectasis remain challenging. There is a need for regional disease measurements as focal distribution of disease is common. Our objective was to evaluate the ability of magnetic resonance imaging (MRI) to detect regional ventilation impairment and response to airway clearance therapy (ACT) in patients with noncystic fibrosis (CF) bronchiectasis, providing a new way to objectively and regionally evaluate response to therapy. Fifteen participants with non-CF bronchiectasis and 15 age-matched healthy volunteers provided written informed consent to an ethics board-approved Health Insurance Portability and Accountability Act-compliant protocol and underwent spirometry, plethysmography, computed tomography (CT), and hyperpolarized 3He MRI. Bronchiectasis patients also completed a Six-Minute Walk Test, the St. George's Respiratory questionnaire, and Patient Evaluation Questionnaire (PEQ), and returned for a follow-up visit after 3weeks of daily oscillatory positive expiratory pressure use. CT evidence of bronchiectasis was qualitatively reported by lobe, and MRI ventilation defect percent (VDP) was measured for the entire lung and individual lobes. CT evidence of bronchiectasis and abnormal VDP (14 ± 7%) was observed for all bronchiectasis patients and no healthy volunteers. There was CT evidence of bronchiectasis in all lobes for 3 patients and in 3 ± 1 lobes (range = 1-4) for 12 patients. VDP in lobes with CT evidence of bronchiectasis (19 ± 12%) was significantly higher than in lobes without CT evidence of bronchiectasis (8 ± 5%, P = .001). For patients, VDP in lung lobes with (P < .0001) and without CT evidence of bronchiectasis (P = .006) was higher than in healthy volunteers (3 ± 1%). For all patients, mean PEQ-ease-bringing-up-sputum (P = .048) and PEQ-patient-global-assessment (P = .01) were significantly improved post-oscillatory positive expiratory pressure. An improvement in regional VDP greater than the minimum clinical important difference was observed for 8 of the 14 patients evaluated. There was CT and MRI evidence of structure-function abnormalities in patients with bronchiectasis; in approximately half, there was evidence of ventilation improvements after airway clearance therapy.

Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients

BackgroundCystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV1. Methods11 healthy controls (age 6–16years) and 11 patients with mild CF (age 8–16years, Forced Expiratory Volume (FEV1) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV1>85%. Each subject was imaged via hyperpolarized 129Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV1 and VDP were compared between the groups. ResultsFEV1 for controls was 100.3%±8.5% (mean±sd) and for CF patients was 97.9%±16.0% (p=0.67). VDP was 6.4%±2.8% for controls and 18.3%±8.6% for CF (p<0.001). When considering the 9 CF patients with normal FEV1 (>85%), the mean FEV1 was 103.1%±12.3% (p=0.57 compared to controls) and VDP was 15.4%±6.3% (p=0.002). ConclusionsHyperpolarized 129Xe MRI demonstrated ventilation defects in CF patients with normal FEV1 and more effectively discriminated CF from controls than FEV1. Thus 129Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression.

Three-dimensional ultrasound measurements of carotid vessel wall and plaque thickness and their relationship with pulmonary abnormalities in ex-smokers without airflow limitation.

The relationship between carotid disease and modestly abnormal airflow in ex-smokers without chronic obstructive pulmonary disease (COPD) is not well-understood. We generated 3D ultrasound measurements of carotid vessel-wall-plus-plaque thickness (VWT) and vessel wall volume (VWV) to quantify and evaluate such carotid ultrasound measurements in ex- and never-smokers without airflow limitation. These patients did not fulfill the diagnostic criteria for COPD. We also investigated the relationship of carotid atherosclerosis with pulmonary phenotypes of COPD. We evaluated 61 subjects without a clinical diagnosis of pulmonary or vascular diseases including 34 never-smokers (72 ± 6year) and 27 ex-smokers (73 ± 9year). We measured mean VWT ([Formula: see text]) and mean VWT specific to carotid regions-of-interest ([Formula: see text]) and evaluated potential differences between ex- and never-smokers. Carotid ultrasound and pulmonary disease measurement relationships were also evaluated using correlation coefficients (r) and multivariate regression analyses. Ex-smokers had a significantly greater [Formula: see text] (p = 0.003) and [Formula: see text] (p < 0.00001) than never-smokers, whereas a significant difference between the two groups was not detected by VWV (p = 1.0). There were significant correlations between the ventilation defect percent (VDP) measured by MRI with [Formula: see text] (r = 0.42, p = 0.001) and [Formula: see text] (r = 0.56, p = 0.00001). Multivariate regression models showed that VDP significantly predicted [Formula: see text] (β = 0.38, p = 0.004) and [Formula: see text] (β = 0.50, p = 0.00001). VWT-based measurements detected differences in vessel-wall-plus-plaque burden in ex- and never-smokers, which were not revealed using VWV. There were significant correlations between cardiovascular and pulmonary disease biomarkers in these ex-smokers who did not have a clinical diagnosis of pulmonary or carotid disease.

Semiautomated Ventilation Defect Quantification in Exercise-induced Bronchoconstriction Using Hyperpolarized Helium-3 Magnetic Resonance Imaging: A Repeatability Study

This study aimed to compare the performance of a semiautomated ventilation defect segmentation approach, adaptive K-means, with manual segmentation of hyperpolarized helium-3 magnetic resonance imaging in subjects with exercise-induced bronchoconstriction (EIB). Six subjects with EIB underwent hyperpolarized helium-3 magnetic resonance imaging and spirometry tests at baseline, post exercise, and recovery over two separate visits. Ventilation defects were analyzed by two methods. First, two independent readers manually segmented ventilation defects. Second, defects were quantified by an adaptive K-means method that corrected for coil sensitivity, applied a vesselness filter to estimate pulmonary vasculature, and segmented defects adaptively based on the overall low-intensity signals in the lungs. These two methods were then compared in four aspects: (1) ventilation defect percent (VDP) measurements, (2) correlation between spirometric measures and measured VDP, (3) regional VDP variations pre- and post exercise challenge, and (4) Dice coefficient for spatial agreement. The adaptive K-means method was ~5 times faster, and the measured VDP bias was under 2%. The correlation between predicted forced expiratory volume in 1 second over forced vital capacity and VDP measured by adaptive K-means (ρ = -0.64, P <0.0001) and by the manual method (ρ = -0.63, P <0.0001) yielded almost identical 95% confidence intervals. Neither method of measuring VDP indicated apical/basal or anterior dependence in this small study cohort. Compared to the manual method, the adaptive K-means method provided faster, reproducible, comparable measures of VDP in EIB and may be applied to a variety of lung diseases.

WE‐FG‐206‐08: Pulmonary Functional Imaging Biomarkers of NSCLC to Guide and Optimize Functional Lung Avoidance Radiotherapy

Purpose:Functional lung avoidance radiotherapy promises optimized therapy planning by minimizing dose to well‐functioning lung and maximizing dose to the rest of the lung. Patients with NSCLC commonly present with co‐morbid COPD and heterogeneously distributed ventilation abnormalities stemming from emphysema, airways disease, and tumour burden. We hypothesized that pulmonary functional imaging methods may be used to optimize radiotherapy plans to avoid regions of well‐functioning lung and significantly improve outcomes like quality‐of‐life and survival. To ascertain the utility of functional lung avoidance therapy in clinical practice, we measured COPD phenotypes in NSCLC patients enrolled in a randomized‐controlled‐clinical‐trial prior to curative intent therapy.Methods:Thirty stage IIIA/IIIB NSCLC patients provided written informed consent to a randomized‐controlled‐clinical‐trial (https://clinicaltrials.gov/ct2/show/NCT02002052) comparing outcomes in patients randomized to standard or image‐guided radiotherapy. Hyperpolarized noble gas MRI ventilation‐defect‐percent (VDP) (Kirby et al, Acad Radiol, 2012) as well as CT‐emphysema measurements were determined. Patients were stratified based on quantitative imaging evidence of ventilation‐defects and emphysema into two subgroups: 1) tumour‐specific ventilation defects only (TSD), and, 2) tumour‐specific and other ventilation defects with and without emphysema (TSDVE). Receiver‐operating‐characteristic (ROC) curves were used to characterize the performance of clinical measures as predictors of the presence of non‐tumour specific ventilation defects.Results:Twenty‐one out of thirty subjects (70%) had non‐tumour specific ventilation defects (TSDVE) and nine subjects had ONLY tumour‐specific defects (TSD). Subjects in the TSDVE group had significantly greater smoking‐history (p=.006) and airflow obstruction (FEV1/FVC) (p=.001). ROC analysis demonstrated an 87% classification rate for smoking pack‐years, 90% for FEV1/FVC, and 56% for tumour RECIST measurements for identifying patients with non‐tumour and tumour‐specific ventilation abnormalities.Conclusion:70% of NSCLC patients had ventilation abnormalities stemming from emphysema, airways disease and tumour burden. Smoking‐history and airflow obstruction, but not RECIST, identified NSCLC patients with ventilation abnormalities appropriate for functional lung avoidance therapy.

Is ventilation heterogeneity related to asthma control?

In asthma patients, magnetic resonance imaging (MRI) and the lung clearance index (LCI) have revealed persistent ventilation heterogeneity, although its relationship to asthma control is not well understood. Therefore, our goal was to explore the relationship of MRI ventilation defects and the LCI with asthma control and quality of life in patients with severe, poorly controlled asthma.18 patients with severe, poorly controlled asthma (mean±sd 46±12 years, six males/12 females) provided written informed consent to an ethics board approved protocol, and underwent spirometry, LCI and (3)He MRI during a single 2-h visit. Asthma control and quality of life were evaluated using the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Ventilation heterogeneity was quantified using the LCI and (3)He MRI ventilation defect percent (VDP).All participants reported poorly controlled disease (mean±sd ACQ score=2.3±0.9) and highly heterogeneous ventilation (mean±sd VDP=12±11% and LCI=10.5±3.0). While VDP and LCI were strongly correlated (r=0.86, p<0.0001), in a multivariate model that included forced expiratory volume in 1 s, VDP and LCI, VDP was the only independent predictor of asthma control (R(2)=0.38, p=0.01). There was also a significantly worse VDP, but not LCI in asthma patients with an ACQ score >2 (p=0.04) and AQLQ score <5 (p=0.04), and a trend towards worse VDP (p=0.053), but not LCI in asthma patients reporting ≥1 exacerbation in the past 6 months.In patients with poorly controlled, severe asthma MRI ventilation, but not LCI was significantly worse in those with worse ACQ and AQLQ.

Hyperpolarized 3He magnetic resonance imaging ventilation defects in asthma: relationship to airway mechanics.

In patients with asthma, magnetic resonance imaging (MRI) provides direct measurements of regional ventilation heterogeneity, the etiology of which is not well‐understood, nor is the relationship of ventilation abnormalities with lung mechanics. In addition, respiratory resistance and reactance are often abnormal in asthmatics and the frequency dependence of respiratory resistance is thought to reflect ventilation heterogeneity. We acquired MRI ventilation defect maps, forced expiratory volume in one‐second (FEV 1), and airways resistance (Raw) measurements, and used a computational airway model to explore the relationship of ventilation defect percent (VDP) with simulated measurements of respiratory system resistance (Rrs) and reactance (Xrs). MRI ventilation defect maps were experimentally acquired in 25 asthmatics before, during, and after methacholine challenge and these were nonrigidly coregistered to the airway tree model. Using the model coregistered to ventilation defect maps, we narrowed proximal (9th) and distal (14th) generation airways that were spatially related to the MRI ventilation defects. The relationships for VDP with Raw measured using plethysmography (r = 0.79), and model predictions of Rrs>14 (r = 0.91, P < 0.0001) and Rrs>9 (r = 0.88, P < 0.0001) were significantly stronger (P = 0.005; P = 0.03, respectively) than with FEV 1 (r = −0.68, P = 0.0001). The slopes for the relationship of VDP with simulated lung mechanics measurements were different (P < 0.0001); among these, the slope for the VDP‐Xrs0.2 relationship was largest, suggesting that VDP was dominated by peripheral airway heterogeneity in these patients. In conclusion, as a first step toward understanding potential links between lung mechanics and ventilation defects, impedance predictions were made using a computational airway tree model with simulated constriction of airways related to ventilation defects measured in mild‐moderate asthmatics.

Regional Heterogeneity of Chronic Obstructive Pulmonary Disease Phenotypes: Pulmonary 3He Magnetic Resonance Imaging and Computed Tomography

Pulmonary ventilation may be visualized and measured using hyperpolarized 3He magnetic resonance imaging (MRI) while emphysema and its distribution can be quantified using thoracic computed tomography (CT). Our objective was to phenotype ex-smokers with COPD based on the apical-to-basal distribution of ventilation abnormalities and emphysema to better understand how these phenotypes change regionally as COPD progresses. We evaluated 100 COPD ex-smokers who provided written informed consent and underwent spirometry, CT and 3He MRI. 3He MRI ventilation imaging was used to quantify the ventilation defect percent (VDP) for whole-lung and individual lung lobes. Regional VDP was used to generate the apical-lung (AL)-to-basal-lung (BL) difference (ΔVDP); a positive ΔVDP indicated AL-predominant and negative ΔVDP indicated BL-predominant ventilation defects. Emphysema was quantified using the relative-area-of-the-lung ≤−950HU (RA950) of the CT density histogram for whole-lung and individual lung lobes. The AL-to-BL RA950 difference (ΔRA950) was generated with a positive ΔRA950 indicating AL-predominant emphysema and a negative ΔRA950 indicating BL-predominant emphysema. Seventy-two ex-smokers reported BL-predominant MRI ventilation defects and 71 reported AL-predominant CT emphysema. BL-predominant ventilation defects (AL/BL: GOLD I = 18%/82%, GOLD II = 24%/76%) and AL-predominant emphysema (AL/BL: GOLD I = 84%/16%, GOLD II = 72%/28%) were the major phenotypes in mild-moderate COPD. In severe COPD there was a more uniform distribution for ventilation defects (AL/BL: GOLD III = 40%/60%, GOLD IV = 43%/57%) and emphysema (AL/BL: GOLD III = 64%/36%, GOLD IV = 43%/57%). Basal-lung ventilation defects predominated in mild-moderate GOLD grades, and a more homogeneous distribution of ventilation defects was observed in more advanced grade COPD; these differences suggest that over time, regional ventilation abnormalities become more homogenously distributed during disease progression.

Ventilation Heterogeneity in Never-smokers and COPD:: Comparison of Pulmonary Functional Magnetic Resonance Imaging with the Poorly Communicating Fraction Derived From Plethysmography

Pulmonary functional magnetic resonance imaging provides a way to quantify ventilation and its heterogeneity-a hallmark finding in chronic obstructive pulmonary disease (COPD). Unfortunately, the etiology and physiological meaning of ventilation defects and their relationship to pulmonary function and symptoms in COPD are not well understood. Another biomarker of ventilation heterogeneity is provided by the "poorly communicating fraction" (PCF), and is calculated as the ratio of total lung capacity to alveolar volume made using whole-body plethysmography. Our objective was to compare ventilation heterogeneity using hyperpolarized (3)He magnetic resonance imaging (MRI) and PCF measurements in elderly never-smokers and in ex-smokers with COPD. One hundred forty-six participants (71 ± 8 years, range = 48-87 years) provided written informed consent including 45 elderly never-smokers (71 ± 6 years, range = 61-84 years) and 101 ex-smokers with COPD (71 ± 8 years, range = 48-87 years). During a single 2-hour visit, spirometry, plethysmography, and hyperpolarized (3)He MRI were acquired. The MRI-derived ventilation defect percent (VDP) and plethysmography measurements were acquired and PCF values were calculated. Linear regression, Pearson correlations, and Bland-Altman analysis were used to evaluate the relationships for PCF and MRI VDP. PCF (P < 0.001) and VDP (P < 0.001) were significantly increased with increasing COPD severity. There was a significant relationship for VDP and PCF (r = 0.68, P < 0.001) in all subjects and COPD subjects alone (r = 0.61, P < 0.001). Bland-Altman analysis showed that PCF and VDP were significantly different (mean bias = 9.7, upper limit = 32, lower limit = -13, P < 0.001), and in severe-grade COPD, PCF overestimates of VDP were significantly greater. In elderly never-smokers and in ex-smokers with COPD, PCF and VDP are moderately correlated estimates of COPD ventilation heterogeneity that may be reflecting similar pathophysiology.

Pulmonary Artery Abnormalities in Ex-smokers with and without Airflow Obstruction

Pulmonary vascular disease is a common complication of chronic obstructive pulmonary disease (COPD), and an important risk factor for COPD exacerbations and death. We explored the relationship between pulmonary artery volumes measured using thoracic computed tomography (CT) and lung structure-function measured using spirometry, CT and magnetic resonance imaging (MRI) in 124 ex-smokers with (n = 68) and without (n = 56) airflow obstruction, and a control group of 35 never-smokers. We observed significantly greater main (p = .01), right (p = .001) and total (p = .003) pulmonary artery volumes in ex-smokers with airflow obstruction as compared to ex-smokers without airflow obstruction. There were also significantly greater pulmonary artery volumes in both ex-smoker subgroups, compared to the never-smoker subgroup (p = .008). For all participants, there were significant correlations for pulmonary artery volumes with the ratio of the forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), the diffusing capacity of the lung for carbon monoxide (DLCO%pred), airway count, MRI ventilation defect percent and MRI apparent diffusion coefficients. In ex-smokers, ventilation defect percent was significantly correlated with right (r = 0.27, p = .02) and total (r = 0.25, p = .03) pulmonary artery volumes. Multivariate zero-inflated Poisson regression analysis showed that FEV1%pred (p = .004), DLCO%pred (p = .03), the six minute walk distance (p = .04) and total pulmonary artery volume (p = .03) were significant predictors of acute exacerbations of COPD, while the number of previous exacerbations was not. In conclusion, pulmonary artery enlargement measured using thoracic CT was observed even in ex-smokers without airflow obstruction and was predictive of COPD exacerbations in ex-smokers with airflow obstruction.

Second-order Texture Measurements of 3He Ventilation MRI:: Proof-of-concept Evaluation of Asthma Bronchodilator Response

(3)He magnetic resonance imaging (MRI) can be used to quantify functional responses to asthma therapy and provocation. Ventilation imaging offers quantitative information beyond ventilation defects that have not yet been exploited. Therefore, our objective was to evaluate hyperpolarized (3)He MRI ventilation defect percent (VDP) and compare this and pulmonary function measurements to ventilation image texture features and their changes post-bronchodilator administration in patients with asthma. Volunteers with a diagnosis of asthma provided written informed consent to an ethics board-approved protocol and underwent pulmonary function tests and MRI before and after salbutamol inhalation. MR images were analyzed using VDP, and their texture was evaluated via gray-level run-length matrices. These texture classifiers were compared to VDP in responders to bronchodilation based on VDP (VDP responders) and forced expiratory volume in 1 s (FEV1) (FEV1 responders). In total, 47 patients with asthma (18 males 39 ± 13 years, FEV1 = 79 ± 21%) reported significantly improved FEV1, FEV1/forced vital capacity (FVC), residual volume (RV)/total lung capacity (TLC) (all P = .0001) and VDP (P = .01) post-salbutamol. Post-salbutamol, VDP responders and nonresponders to salbutamol were significantly different for coarse-texture features including long-run emphasis (LRE) and long-run, low gray-level emphasis (LRLGE, both P < .05) and for FEV1 responders to salbutamol, there was significantly different long-run, high gray-level emphasis (LRHGE, P = .04). There were significant relationships for VDP with LRE (R = .50, P = .0003), LRLGE (R = .34, P = .02), and LRHGE (R = .56, P = .0001). Receiver operating characteristic curves showed VDP with the strongest performance (AUC = .92), followed by coarse-texture classifier LRHGE (AUC = .83), FEV1 (AUC = .80), LRE (AUC = .66), FVC (AUC = .58), and LRLGE (AUC = .42). In patients with asthma, differences in ventilation patchiness post-salbutamol can be quantified using coarse-texture classifiers that are significantly different in bronchodilator responders.