Comparison of hyperpolarized 3He-MRI, CT based parametric response mapping, and mucus scores in asthmatics.

Purpose: The purpose of this study was to anatomically correlate ventilation defects with regions of air trapping by whole lung, lung lobe, and airway segment in the context of airway mucus plugging in asthma. Methods: A total of 34 asthmatics [13M:21F, 13 mild/moderate, median age (range) of 49.5 (36.8-53.3) years and 21 severe, 56.1 (47.1-62.6) years] and 4 healthy subjects [1M:3F, 38.5 (26.6-52.2) years] underwent HP 3He MRI and CT imaging. HP 3He MRI was assessed for ventilation defects using a semi-automated k-means clustering algorithm. Inspiratory and expiratory CTs were analyzed using parametric response mapping (PRM) to quantify markers of emphysema and functional small airways disease (fSAD). Segmental and lobar lung masks were obtained from CT and registered to HP 3He MRI in order to localize ventilation defect percent (VDP), at the lobar and segmental level, to regions of fSAD and mucus plugging. Spearman's correlation was utilized to compare biomarkers on a global and lobar level, and a multivariate analysis was conducted to predict segmental fSAD given segmental VDP (sVDP) and mucus score as variables in order to further understand the functional relationships between regional measures of obstruction. Results: On a global level, fSAD was correlated with whole lung VDP (r = 0.65, p < 0.001), mucus score (r = 0.55, p < 0.01), and moderately correlated (-0.60 ≤ r ≤ -0.56, p < 0.001) to percent predicted (%p) FEV1, FEF25-75 and FEV1/FVC, and more weakly correlated to FVC%p (-0.38 ≤ r ≤ -0.35, p < 0.001) as expected from previous work. On a regional level, lobar VDP, mucus scores, and fSAD were also moderately correlated (r from 0.45-0.66, p < 0.01). For segmental colocalization, the model of best fit was a piecewise quadratic model, which suggests that sVDP may be increasing due to local airway obstruction that does not manifest as fSAD until more extensive disease is present. sVDP was more sensitive to the presence of a mucus plugs overall, but the prediction of fSAD using multivariate regression showed an interaction in the presence of a mucus plugs when sVDP was between 4% and 10% (p < 0.001). Conclusion: This multi-modality study in asthma confirmed that areas of ventilation defects are spatially correlated with air trapping at the level of the airway segment and suggests VDP and fSAD are sensitive to specific sources of airway obstruction in asthma, including mucus plugs.

Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at 3He MRI.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Hyperpolarized 129Xe MRI and Spectroscopy of Gas-Exchange Abnormalities in Nonspecific Interstitial Pneumonia.

Background Recent studies demonstrate that antifibrotic drugs previously reserved for idiopathic pulmonary fibrosis (IPF) may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively assess disease activity, progression, and therapy response across ILDs. Hyperpolarized xenon 129 (129Xe) MRI and spectroscopy have provided noninvasive measurements of regional gas-exchange abnormalities in IPF. Purpose To assess gas exchange function using 129Xe MRI in a group of study participants with nonspecific interstitial pneumonia (NSIP) compared with healthy control participants. Materials and Methods In this prospective study, participants with NSIP and healthy control participants were enrolled between November 2017 and February 2020 and underwent 129Xe MRI and spectroscopy. Quantitative imaging provided three-dimensional maps of ventilation, interstitial barrier uptake, and transfer into the red blood cell (RBC) compartment. Spectroscopy provided parameters of the static RBC and barrier uptake compartments, as well as cardiogenic oscillations in RBC signal amplitude and chemical shift. Differences between NSIP and healthy control participants were assessed using the Wilcoxon rank-sum test. Results Thirty-six participants with NSIP (mean age, 57 years ± 11 [standard deviation]; 27 women) and 15 healthy control participants (mean age, 39 years ± 18; two women) were evaluated. Participants with NSIP had no difference in ventilation compared with healthy control participants (median, 4.4% [first quartile, 1.5%; third quartile, 8.7%] vs 6.0% [first quartile, 2.8%; third quartile, 6.9%]; P = .91), but they had a higher barrier uptake (median, 6.2% [first quartile, 1.8%; third quartile, 23.9%] vs 0.53% [first quartile, 0.33%; third quartile, 2.9%]; P = .003) and an increased RBC transfer defect (median, 20.6% [first quartile, 11.6%; third quartile, 27.8%] vs 2.8% [first quartile, 2.3%; third quartile, 4.9%]; P < .001). NSIP participants also had a reduced ratio of RBC-to-barrier peaks (median, 0.24 [first quartile, 0.19; third quartile, 0.31] vs 0.57 [first quartile, 0.52; third quartile, 0.67]; P < .001) and a reduced RBC chemical shift (median, 217.5 ppm [first quartile, 217.0 ppm; third quartile, 218.0 ppm] vs 218.2 ppm [first quartile, 217.9 ppm; third quartile, 218.6 ppm]; P = .001). Conclusion Participants with nonspecific interstitial pneumonia had increased barrier uptake and decreased red blood cell (RBC) transfer compared with healthy controls measured using xenon 129 gas-exchange MRI and reduced RBC-to-barrier ratio and RBC chemical shift measured using spectroscopy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wild in this issue.

Regional Gas Exchange Measured by 129 Xe Magnetic Resonance Imaging Before and After Combination Bronchodilators Treatment in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE: To characterize changes in 129 Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE: Prospective. POPULATION: Seventeen COPD subjects (GOLD II/III classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES: Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. Three-dimensional images of ventilation, barrier uptake, and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3 T. ASSESSMENT: 129 Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect + low percent (vendef + low ) and by barrier uptake and RBC transfer relative to a healthy reference population (bar%ref and RBC%ref ). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO ), were also performed before and after treatment. STATISTICAL TESTS: Paired t-test, Pearson correlation coefficient (r). RESULTS: Baseline vendef + low was 57.8 ± 8.4%, bar%ref was 73.2 ± 19.6%, and RBC%ref was 36.5 ± 13.6%. Following treatment, vendef + low decreased to 52.5 ± 10.6% (P < 0.05), and improved in 14/17 (82.4%) of subjects. However, RBC%ref decreased in 10/17 (58.8%) of subjects. Baseline measurements of bar%ref and DLCO were correlated with the degree of post-treatment change in vendef + low (r = -0.49, P < 0.05 and r = -0.52, P < 0.05, respectively). CONCLUSION: LABA/LAMA therapy tended to preferentially improve ventilation in subjects whose 129 Xe barrier uptake and DLCO were relatively preserved. However, newly ventilated regions often revealed RBC transfer defects, an aspect of lung function opaque to spirometry. These microvasculature abnormalities must be accounted for when assessing the effects of LABA/LAMA therapy. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Ventilation defects on hyperpolarized helium-3 MRI in asthma are predictive of 2-year exacerbation frequency.

BACKGROUND: There is an unmet need for an objective biomarker to predict asthma exacerbations. OBJECTIVE: Our aim was to assess the ventilation defect percent (VDP) on hyperpolarized helium-3 magnetic resonance imaging as a predictor of exacerbation frequency following imaging. METHODS: Subjects underwent hyperpolarized helium-3 and conventional clinical measurements, including pulmonary function tests, during a period of disease stability, and exacerbations were recorded prospectively over the following 2 years. We used a Poisson regression tree model to estimate an optimal VDP threshold for classifying subjects into high- versus low-exacerbation groups and then used statistical regression to compare this VDP threshold against conventional clinical measures as predictors of exacerbations. RESULTS: A total of 67 individuals with asthma (27 males and 40 females, 28 with mild-to-moderate asthma and 39 with severe asthma) had a median VDP of 3.75% (1.2% [first quartile]-7.9% [third quartile]). An optimal VDP threshold of 4.28% was selected on the basis of the maximum likelihood estimation of the regression tree model. Subjects with a VDP greater than 4.28% (n = 32) had a median of 1.5 exacerbations versus 0.0 for subjects with a VDP less than 4.28% (n = 35). In a stepwise multivariate regression model, a VDP greater than 4.28% was associated with an exacerbation incidence rate ratio of 2.5 (95% CI = 1.3-4.7) versus a VDP less than or equal to 4.28%. However, once individual medical history was included in the model, VDP was no longer significant. Nonetheless, VDP may provide an objective and complementary quantitative marker of individual exacerbation risk that is useful for monitoring individual change in disease status, selecting patients for therapy, and assessing treatment response. CONCLUSION: VDP measured with magnetic resonance imaging shows promise as a biomarker of prospective asthma exacerbations.

Patient-specific modeling of aerosol delivery in healthy and asthmatic adults.

The magnitude and regional heterogeneity of airway obstructions in severe asthmatics is likely linked to insufficient drug delivery, as evidenced by the inability to mitigate exacerbations with inhaled aerosol medications. To understand the correlation between morphometric features, airflow distribution, and inhaled dosimetry, we perform dynamic computational simulations in two healthy and four asthmatic subjects. Models incorporate computed tomography-based and patient-specific central airway geometries and hyperpolarized 3He MRI-measured segmental ventilation defect percentages (SVDPs), implemented as resistance boundary conditions. Particles [diameters (dp) = 1, 3, and 5 µm] are simulated throughout inhalation, and we record their initial conditions, both spatially and temporally, with their fate in the lung. Predictions highlight that total central airway deposition is the same between the healthy subjects (26.6%, dp = 3 µm) but variable among the asthmatic subjects (ranging from 5.9% to 59.3%, dp = 3 µm). We found that by preferentially releasing the particles during times of fast or slow inhalation rates we enhance either central airway deposition percentages or peripheral particle delivery, respectively. These predictions highlight the potential to identify with simulations patients who may not receive adequate therapeutic dosages with inhaled aerosol medication and therefore identify patients who may benefit from alternative treatment strategies. Furthermore, by improving regional dose levels, we may be able to preferentially deliver drugs to the airways in need, reducing associated adverse side effects.NEW & NOTEWORTHY Although it is evident that exacerbation mitigation is unsuccessful in some asthmatics, it remains unclear whether or not these patients receive adequate dosages of inhaled therapeutics. By coupling MRI and computed tomography data with patient-specific computational models, our predictions highlight the large intersubject variability, specifically in severe asthma.

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

RATIONALE AND OBJECTIVES: To determine lobar ventilation patterns in asthmatic lungs with hyperpolarized 3He magnetic resonance imaging (HP 3He MRI). MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Magnetic resonance imaging with hyperpolarized agents: methods and applications.

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

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

RATIONALE AND OBJECTIVES: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Access to the Indian health service care system is not associated with early enrollment in medicaid for American Indian and Alaska Natives with cancer.

BACKGROUND: For uninsured American Indians and Alaskan Natives (AIAN) diagnosed with cancer, prompt enrollment in Medicaid may speed access to treatment and improve survival. We hypothesized that AIANs who were eligible for the Indian Health Service Care System (IHSCS) at cancer diagnosis may be enrolled in Medicaid sooner than other AIANs. METHODS: Using Washington, Oregon, and California State Cancer Registries, we identified AIANs with a primary diagnosis of lung, breast, colorectal, cervical, ovarian, stomach, or prostate cancer between 2001 and 2007. Among AIANs enrolled in Medicaid within 365 days of a cancer diagnosis, we linked cancer registry records with Medicaid enrollment data and used a multivariate logistic regression model to compare the odds of delayed Medicaid enrollment between those with (n = 223) and without (n = 177) IHSCS eligibility. RESULTS: Among AIANs who enrolled in Medicaid during the year following their cancer diagnosis, approximately 32% enrolled >1 month following diagnosis. Comparing those without IHSCS eligibility to those with IHSCS eligibility, the adjusted odds ratio (OR) for moderately late Medicaid enrollment (between 1 and 6 months after diagnosis) relative to early Medicaid enrollment (≤1 month after diagnosis) was 1.10 [95% confidence interval (CI), 0.62-1.95] and for very late Medicaid enrollment (>6 months to 12 months after diagnosis), OR was 1.14 (CI, 0.54-2.43). CONCLUSION: IHSCS eligibility at the time of diagnosis does not seem to facilitate early Medicaid enrollment. IMPACT: Because cancer survival rates in AIANs are among the lowest of any racial group, additional research is needed to identify factors that improve access to care in AIANs.

Referral and treatment patterns among patients with stages III and IV non-small-cell lung cancer.

PURPOSE: Little is known about how referrals to different cancer specialists influence cancer care for non-small-cell lung cancer (NSCLC). Among Medicare enrollees, we identified factors of patients and their primary care physician that were associated with referrals to cancer specialists, and how the types of cancer specialists seen correlated with delivery of guideline-based therapies (GBTs). METHODS: Data from patients with stages III and IV NSCLC included in the SEER-Medicare database were linked to their physicians in the American Medical Association Masterfile database. Using logistic regression, we (1) identified patient and physician factors that were associated with referrals to cancer specialists (medical oncologists, radiation oncologists, and surgeons); (2) identified the types of referral to cancer specialists that predicted greater likelihood of receiving GBT (per National Comprehensive Cancer Network guidelines). RESULTS: A total of 28,977 patients with NSCLC diagnosed from January 1, 2000 to December 31, 2005 met eligibility criteria. Younger age, white race, higher income, and primary physician specialty other than family practice predicted higher likelihood of referrals to medical oncologists (P < .01 for all predictors). Seeing the three types of cancer specialists predicted higher likelihood of GBT (stage IIIA: odds ratio [OR] = 20.6; P < .001; IIIB: OR = 77.2; P < .001; and IV: OR = 1.2; P = .011), compared with seeing a medical oncologist only. Use of GBTs increased over the study period (42% to 48% from 2000 to 2005; P < .001). CONCLUSION: Referrals to all types of cancer specialists increased the likelihood of treatment with standard therapies, particularly in stage III patients. However, racial and income disparities still prevent optimal referrals to cancer specialists.

Lung cancer screening with low-dose computed tomography: costs, national expenditures, and cost-effectiveness.

A recent randomized trial showed that low-dose CT (LDCT) screening reduces lung cancer mortality. Health care providers need an assessment of the national budget impact and cost-effectiveness of LDCT screening before this intervention is adopted in practice. Using data from the 2009 National Health Interview Survey, CMS, and the National Lung Screening Trial (NLST), the authors performed an economic analysis of LDCT screening that includes a budget impact model, an estimate of additional costs per lung cancer death avoided attributed to screening, and a literature search of cost-effectiveness analyses of LDCT screening. They conducted a one-way sensitivity analysis, reporting expenditures in 2011 U.S. dollars, and took the health care payer and patient perspectives. LDCT screening will add $1.3 to $2.0 billion in annual national health care expenditures for screening uptake rates of 50% to 75%, respectively. However, LDCT screening will avoid up to 8100 premature lung cancer deaths at a 75% screening rate. The prevalence of smokers who qualify for screening, screening uptake rates, and cost of LDCT scan were the most influential parameters on health care expenditures. The additional cost of screening to avoid one lung cancer death is $240,000. Previous cost-effectiveness analyses have not conclusively shown that LDCT is cost-effective. LDCT screening may add substantially to the national health care expenditures. Although LDCT screening can avoid more than 8000 lung cancer deaths per year, a cost-effectiveness analysis of the NLST will be critical to determine the value of this intervention and to guide decisions about its adoption.