A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0-19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared.

A stable, highly concentrated fluorous nanoemulsion formulation for in vivo cancer imaging via 19F-MRI.

Magnetic resonance imaging (MRI) is a routine diagnostic modality in oncology that produces excellent imaging resolution and tumor contrast without the use of ionizing radiation. However, improved contrast agents are still needed to further increase detection sensitivity and avoid toxicity/allergic reactions associated with paramagnetic metal contrast agents, which may be seen in a small percentage of the human population. Fluorine-19 (19F)-MRI is at the forefront of the developing MRI methodologies due to near-zero background signal, high natural abundance of 100%, and unambiguous signal specificity. In this study, we have developed a colloidal nanoemulsion (NE) formulation that can encapsulate high volumes of the fluorous MRI tracer, perfluoro-[15-crown-5]-ether (PFCE) (35% v/v). These nanoparticles exhibit long-term (at least 100 days) stability and high PFCE loading capacity in formulation with our semifluorinated triblock copolymer, M2F8H18. With sizes of approximately 200 nm, these NEs enable in vivo delivery and passive targeting to tumors. Our diagnostic formulation, M2F8H18/PFCE NE, yielded in vivo 19F-MR images with a high signal-to-noise ratio up to 100 in a tumor-bearing mouse model at clinically relevant scan times. M2F8H18/PFCE NE circulated stably in the vasculature, accumulated in high concentration of an estimated 4-9 × 1017 19F spins/voxel at the tumor site, and cleared from most organs over the span of 2 weeks. Uptake by the mononuclear phagocyte system to the liver and spleen was also observed, most likely due to particle size. These promising results suggest that M2F8H18/PFCE NE is a favorable 19F-MR diagnostic tracer for further development in oncological studies and potential clinical translation.

Same-Day Repeatability and 28-Day Reproducibility of Xenon MRI Ventilation in Children With Cystic Fibrosis in a Multi-Site Trial.

BACKGROUND: MRI with xenon-129 gas (Xe MRI) can assess airflow obstruction and heterogeneity in lung diseases. Specifically, Xe MRI may represent a sensitive modality for future therapeutic trials of cystic fibrosis (CF) therapies. The reproducibility of Xe MRI has not yet been assessed in the context of a multi-site study. PURPOSE: To determine the same-day repeatability and 28-day reproducibility of Xe MRI in children with CF. STUDY TYPE: Four-center prospective, longitudinal. POPULATION: Thirty-eight children (18 females, 47%), median interquartile range (IQR) age 12 (9-14) years old, with mild CF (forced expiratory volume in 1 second (FEV1) ≥85% predicted). FIELD STRENGTH/SEQUENCE: 3-T, two-dimensional (2D) gradient-echo (GRE) sequence. ASSESSMENT: Xe MRI, FEV1, and nitrogen multiple-breath wash-out for lung-clearance index (LCI2.5) were performed. To assess same-day reproducibility, Xe MRI was performed twice within the first visit, and procedures were repeated at 28 days. Xe hypoventilation was quantified using ventilation-defect percentage (VDP) and reader-defect volume (RDV). For VDP, hypoventilated voxels from segmented images were identified using a threshold of <60% mean whole-lung signal and expressed as a percentage of the lung volume. For RDV, hypoventilation was identified by two trained readers and expressed as a percentage. STATISTICAL TESTS: Inter-site comparisons were conducted using Kruskal-Wallis nonparametric tests with Dunn's multiple-comparisons tests. Differences for individuals were assessed using Wilcoxon matched-pairs tests. Bland-Altman tests were used to evaluate same-day repeatability, 28-day reproducibility, and inter-reader agreement. A P-value ≤0.05 was considered significant. RESULTS: Median FEV1 %-predicted was 96.8% (86%-106%), and median LCI2.5 was 6.6 (6.3-7.4). Xe MRI had high same-day reproducibility (mean VDP difference 0.12%, 95% limits of agreement [-3.2, 3.4]; mean RDV difference 0.42% [-2.5, 3.3]). At 28 days, 26/31 participants (84%) fell within the same-day 95% limits of agreement. DATA CONCLUSION: Xe MRI may offer excellent same-day and short-term reproducibility. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program.

Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV1% predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P < 0.001). In adjusted models, PSMD predicted lung function trajectory in women with asthma (ß = -0.47 Δ slope per 10-HU decrease; P = 0.03) but not men (ß = 0.11 Δ slope per 10-HU decrease; P = 0.77). The highest PSMD tertile predicted a 2.9% improvement whereas the lowest tertile predicted a 1.8% decline in FEV1% predicted among women with asthma over 5 years. Conclusions: Participants with asthma have lower PSMD, reflecting greater muscle fat infiltration. Baseline PSMD predicted lung function decline among women with asthma but not men. These data support an important role of metabolic dysfunction in lung function decline.

Mucus Plugs Persist in Asthma, and Changes in Mucus Plugs Associate with Changes in Airflow over Time.

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a longitudinal analysis of baseline and Year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures. Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and Year 3 (3.4 [0-20] vs. 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at Year 3 than those without baseline plugs (risk ratio, 2.8; 95% confidence interval [CI], 2.0-4.1; P < 0.001; and risk ratio, 5.0; 95% CI, 4.5-5.6; P < 0.001, respectively). The change in mucus plug score from baseline to Year 3 was significantly negatively correlated with change in FEV1% predicted (rp = -0.35; P < 0.001) and with changes in CT air trapping measures (all P values < 0.05). Conclusions: Mucus plugs identify a persistent asthma phenotype, and susceptibility to mucus plugs occurs at the subject and the bronchopulmonary segment level. The association between change in mucus plug score and change in airflow over time supports a causal role for mucus plugs in mechanisms of airflow obstruction in asthma.

Hyperpolarized 129Xe MR Spectroscopy in the Lung Shows 1-year Reduced Function in Idiopathic Pulmonary Fibrosis.

Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (129Xe) MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Materials and Methods In a prospective study, healthy volunteers and participants with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Participants with IPF were followed up with forced vital capacity percent predicted (FVC%p), diffusing capacity of the lungs for carbon monoxide percent predicted (DLco%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10%, reduction in DLco%p by at least 15%, or admission to hospice care. CT and MRI were spatially coregistered and a measure of pulmonary gas transfer (red blood cell [RBC]-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. Results Sixteen healthy volunteers (mean age, 57 years ± 14 [SD]; 10 women) and 22 participants with IPF (mean age, 71 years ± 9; 15 men) were evaluated, as follows: nine IPF progressors (mean age, 72 years ± 7; five women) and 13 nonprogressors (mean age, 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 vs 8.2% ± 5.9; P = .03) and RBC-to-barrier ratio (0.26 ± 0.06 vs 0.20 ± 0.06; P = .03) at baseline were associated with progression of IPF. Participants with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 vs 0.28 ± 0.05; P = .01) but not in fibrotic regions of the lung (0.15 ± 0.09 vs 0.14 ± 0.04; P = .62) relative to the nonprogressive group. Conclusion In this preliminary study, functional measures of gas transfer and ventilation measured with xenon 129 MRI and the extent of fibrotic structure at CT were associated with idiopathic pulmonary fibrosis disease progression. Differences in gas transfer were found in regions of nonfibrotic lung. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gleeson and Fraser in this issue.

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.

Quantitative CT Characteristics of Cluster Phenotypes in the Severe Asthma Research Program Cohorts.

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Dynamic contrast enhanced MRI for the evaluation of lung perfusion in idiopathic pulmonary fibrosis.

BACKGROUND: The objective of this work was to apply quantitative and semiquantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF). METHODS: In this prospective trial 41 subjects, including healthy control and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year; progressive IPF (IPFprog) subjects were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted forced vital capacity (FVC % pred) or diffusing capacity of the lung for carbon monoxide (D LCO % pred) measured during follow-up visits. 35 out of 41 subjects were retained for final baseline analysis (control: n=15; IPFstable: n=14; IPFprog: n=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: control versus IPF groups and control versus IPFstable versus IPFprog groups, using linear regression analysis. Each measure was compared with FVC % pred, D LCO % pred and the lung clearance index (LCI % pred) using a Spearman rank correlation. RESULTS: DCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprog compared with both IPFstable (p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV and D LCO % pred (rs= -0.48, p=0.022) and LCI % pred (rs= +0.47, p=0.015). Significant group differences were detected in age (p<0.001), D LCO % pred (p<0.001), FVC % pred (p=0.001) and LCI % pred (p=0.007). CONCLUSIONS: Global analysis obscures regional changes in pulmonary haemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

Quantitative cardiopulmonary magnetic resonance imaging in neonatal congenital diaphragmatic hernia.

BACKGROUND: Pulmonary arterial hypertension, impaired cardiac function and lung hypoplasia are common in infants with congenital diaphragmatic hernia (CDH) and are associated with increased morbidity and mortality. Robust noninvasive methods to quantify these abnormalities in early infancy are lacking. OBJECTIVE: To determine the feasibility of MRI to quantify cardiopulmonary hemodynamics and function in infants with CDH and to investigate left-right blood flow and lung volume discrepancies. MATERIALS AND METHODS: We conducted a prospective MRI study of 23 neonates (isolated left CDH: 4 pre-repair, 7 post-repair, 3 pre- and post-repair; and 9 controls) performed on a small-footprint 1.5-tesla (T) scanner. We calculated MRI-based pulmonary arterial blood flow, left ventricular eccentricity index, cardiac function and lung volume. Using the Wilcoxon rank sum test for continuous data and Fisher exact test for categorical data, we made pairwise group comparisons. RESULTS: The right-to-left ratios for pulmonary artery blood flow and lung volume were elevated in pre-repair and post-repair CDH versus controls (flow: P<0.005; volume: P<0.05 pre-/post-repair). Eccentricity index at end-systole significantly differed between pre-repair and post-repair CDH (P<0.01) and between pre-repair CDH and controls (P<0.001). CONCLUSION: Cardiopulmonary MRI is a viable method to serially evaluate cardiopulmonary hemodynamics and function in critically ill infants and is useful for capturing left-right asymmetries in pulmonary blood flow and lung volume.

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: Results from SARP-3.

BACKGROUND: Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. OBJECTIVES: We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. METHODS: We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity. RESULTS: Greater baseline wall area percent (ß = -0.15 [95% CI = -0.26 to -0.05]; P < .01), hyperinflation percent (ß = -0.25 [95% CI = -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal ß = 10.64 [95% CI = 3.79-17.49]; P < .01; posterior-anterior ß = -9.14, [95% CI = -15.49 to -2.78]; P < .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P < .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires. CONCLUSIONS: Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

Pulmonary Functional Imaging: Part 1-State-of-the-Art Technical and Physiologic Underpinnings.

Over the past few decades, pulmonary imaging technologies have advanced from chest radiography and nuclear medicine methods to high-spatial-resolution or low-dose chest CT and MRI. It is currently possible to identify and measure pulmonary pathologic changes before these are obvious even to patients or depicted on conventional morphologic images. Here, key technological advances are described, including multiparametric CT image processing methods, inhaled hyperpolarized and fluorinated gas MRI, and four-dimensional free-breathing CT and MRI methods to measure regional ventilation, perfusion, gas exchange, and biomechanics. The basic anatomic and physiologic underpinnings of these pulmonary functional imaging techniques are explained. In addition, advances in image analysis and computational and artificial intelligence (machine learning) methods pertinent to functional lung imaging are discussed. The clinical applications of pulmonary functional imaging, including both the opportunities and challenges for clinical translation and deployment, will be discussed in part 2 of this review. Given the technical advances in these sophisticated imaging methods and the wealth of information they can provide, it is anticipated that pulmonary functional imaging will be increasingly used in the care of patients with lung disease. © RSNA, 2021 Online supplemental material is available for this article.

Relationship between Emphysema Progression at CT and Mortality in Ever-Smokers: Results from the COPDGene and ECLIPSE Cohorts.

Background The relationship between emphysema progression and long-term outcomes is unclear. Purpose To determine the relationship between emphysema progression at CT and mortality among participants with emphysema. Materials and Methods In a secondary analysis of two prospective observational studies, COPDGene (clinicaltrials.gov, NCT00608764) and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE; clinicaltrials.gov, NCT00292552), emphysema was measured at CT at two points by using the volume-adjusted lung density at the 15th percentile of the lung density histogram (hereafter, lung density perc15) method. The association between emphysema progression rate and all-cause mortality was analyzed by using Cox regression adjusted for ethnicity, sex, baseline age, pack-years, and lung density, baseline and change in smoking status, forced expiratory volume in 1 second, and 6-minute walk distance. In COPDGene, respiratory mortality was analyzed by using the Fine and Gray method. Results A total of 5143 participants (2613 men [51%]; mean age, 60 years ± 9 [standard deviation]) in COPDGene and 1549 participants (973 men [63%]; mean age, 62 years ± 8) in ECLIPSE were evaluated, of which 2097 (40.8%) and 1179 (76.1%) had emphysema, respectively. Baseline imaging was performed between January 2008 and December 2010 for COPDGene and January 2006 and August 2007 for ECLIPSE. Follow-up imaging was performed after 5.5 years ± 0.6 in COPDGene and 3.0 years ± 0.2 in ECLIPSE, and mortality was assessed over the ensuing 5 years in both. For every 1 g/L per year faster rate of decline in lung density perc15, all-cause mortality increased by 8% in COPDGene (hazard ratio [HR], 1.08; 95% CI: 1.01, 1.16; P = .03) and 6% in ECLIPSE (HR, 1.06; 95% CI: 1.00, 1.13; P = .045). In COPDGene, respiratory mortality increased by 22% (HR, 1.22; 95% CI: 1.13, 1.31; P < .001) for the same increase in the rate of change in lung density perc15. Conclusion In ever-smokers with emphysema, emphysema progression at CT was associated with increased all-cause and respiratory mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lee and Park in this issue.

Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Detection and viability of murine NK cells in vivo in a lymphoma model using fluorine-19 MRI.

Natural killer (NK) cell therapies are being increasingly used as an adoptive cell therapy for cancer because they can recognize tumor cells in an antigen-independent manner. While promising, the understanding of NK cell persistence, particularly within a harsh tumor microenvironment, is limited. Fluorine-19 (19 F) MRI is a noninvasive imaging modality that has shown promise in longitudinally tracking cell populations in vivo; however, it has not been studied on murine NK cells. In this study, the impact of 19 F labeling on murine NK cell viability and function was assessed in vitro and then used to quantify NK cell persistence in vivo. While there was no noticeable impact on viability, labeling NK cells with 19 F did attenuate cytotoxicity against lymphoma cells in vitro. Fluorescent microscopy verified 19 F labeling in both the cytoplasm and nucleus of NK cells. Lymphoma-bearing mice were given intratumoral injections of 19 F-labeled NK cells in which signal was detectable across the 6 day observation period via 19 F MRI. Quantification from the composite images detected 78-94% of the initially injected NK cells across 6 days, with a significant decrease between Days 3 and 6. Postmortem flow cytometry demonstrated retention of 19 F intracellularly within adoptively transferred NK cells with less than 1% of 19 F-containing cells identified as tumor-associated macrophages that presumably ingested nonviable NK cells. This work demonstrates that 19 F MRI offers a specific imaging platform to track and quantify murine NK cells within tumors noninvasively.

Effects of neonatal lung abnormalities on parenchymal R2 * estimates.

Infants admitted to the neonatal intensive care unit (NICU) often suffer from multifaceted pulmonary morbidities that are not well understood. Ultrashort echo time (UTE) magnetic resonance imaging (MRI) is a promising technique for pulmonary imaging in this population without requiring exposure to ionizing radiation. The aims of this study were to investigate the effect of neonatal pulmonary disease on R2 * and tissue density and to utilize numerical simulations to evaluate the effect of different alveolar structures on predicted R2 *.This was a prospective study, in which 17 neonatal human subjects (five control, seven with bronchopulmonary dysplasia [BPD], five with congenital diaphragmatic hernia [CDH]) were enrolled. Twelve subjects were male and five were female, with postmenstrual age (PMA) at MRI of 39.7 ± 4.7 weeks. A 1.5T/multiecho three-dimensional UTE MRI was used. Pulmonary R2 * and tissue density were compared across disease groups over the whole lung and regionally. A spherical shell alveolar model was used to predict the expected R2 * over a range of tissue densities and tissue susceptibilities. Tests for significantly different mean R2 * and tissue densities across disease groups were evaluated using analysis of variance, with subsequent pairwise group comparisons performed using t tests. Lung tissue density was lower in the ipsilateral lung in CDH compared to both controls and BPD patients (both p < 0.05), while only the contralateral lung in CDH (CDHc) had higher whole-lung R2 * than both controls and BPD (both p < 0.05). R2 * differences were significant between controls and CDHc within all tissue density ranges (all p < 0.05) with the exception of the 80%-90% range (p = 0.17). Simulations predicted an inverse relationship between alveolar tissue density and R2 * that matches empirical human data. Alveolar wall thickness had no effect on R2 * independent of density (p = 1). The inverse relationship between R2 * and tissue density is influenced by the presence of disease globally and regionally in neonates with BPD and CDH in the NICU. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

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.

Characterization of R2∗ and tissue density in the human lung: Application to neonatal imaging in the intensive care unit.

PURPOSE: Novel demonstration of R2∗ and tissue density estimation in infant lungs using 3D ultrashort echo time MRI. Differences between adult and neonates with no clinical indication of lung pathology is explored, as well as relationships between parameter estimates and gravitationally dependent position and lung inflation state. This provides a tool for probing physiologic processes that may be relevant to pulmonary disease and progression in newborns. METHODS: R2∗ and tissue density were estimated in a phantom consisting of standards allowing for ground truth comparisons and in human subjects (N = 5 infants, N = 4 adults, no clinical indication of lung dysfunction) using a 3D radial multiecho ultrashort echo time MRI sequence. Whole lung averages were compared between infants and adults. Dependence of the metrics on anterior-posterior position as well as between end-tidal inspiration and expiration were explored, in addition to the general relationship between R2∗ and tissue density. RESULTS: Estimates in the phantom did not differ significantly from ground truth. Neonates had significantly lower mean R2∗ (P = .006) and higher mean tissue density (P = 1.5e-5) than adults. Tissue density and R2∗ were both significantly dependent on anterior-posterior position and lung inflation state (P < .005). An overall inverse relationship was found between R2∗ and tissue density, which was similar in both neonates and adults. CONCLUSION: Estimation of tissue density and R2∗ in free breathing, nonsedated, neonatal patients is feasible using multiecho ultrashort echo time MRI. R2∗ was no different between infants and adults when matched for tissue density, although density of lung parenchyma was, on average, lower in adults than neonates.

Transverse relaxation rates of pulmonary dissolved-phase Hyperpolarized 129 Xe as a biomarker of lung injury in idiopathic pulmonary fibrosis.

PURPOSE: The MR properties (chemical shifts and R2∗ decay rates) of dissolved-phase hyperpolarized (HP) 129 Xe are confounded by the large magnetic field inhomogeneity present in the lung. This work improves measurements of these properties using a model-based image reconstruction to characterize the R2∗ decay rates of dissolved-phase HP 129 Xe in healthy subjects and patients with idiopathic pulmonary fibrosis (IPF). METHODS: Whole-lung MRS and 3D radial MRI with four gradient echoes were performed after inhalation of HP 129 Xe in healthy subjects and patients with IPF. A model-based image reconstruction formulated as a regularized optimization problem was solved iteratively to measure regional signal intensity in the gas, barrier, and red blood cell (RBC) compartments, while simultaneously measuring their chemical shifts and R2∗ decay rates. RESULTS: The estimation of spectral properties reduced artifacts in images of HP 129 Xe in the gas, barrier, and RBC compartments and improved image SNR by over 20%. R2∗ decay rates of the RBC and barrier compartments were lower in patients with IPF compared to healthy subjects (P < 0.001 and P = 0.005, respectively) and correlated to DLCO (R = 0.71 and 0.64, respectively). Chemical shift of the RBC component measured with whole-lung spectroscopy was significantly different between IPF and normal subjects (P = 0.022). CONCLUSION: Estimates for R2∗ in both barrier and RBC dissolved-phase HP 129 Xe compartments using a regional signal model improved image quality for dissolved-phase images and provided additional biomarkers of lung injury in IPF.

Improved reconstruction stability for chemical shift encoded hyperpolarized 13 C magnetic resonance spectroscopic imaging using k-t spiral acquisitions.

PURPOSE: A multiecho, field of view (FOV)-oversampled k-t spiral acquisition and direct iterative decomposition of water and fat with echo asymmetry and least-squares estimation reconstruction is demonstrated to improve the stability of hyperpolarized 13 C magnetic resonance spectroscopic imaging (MRSI) in the presence of signal ambiguities attributed to low-SNR (signal-to-noise-ratio) species, local uncertainties in metabolite peaks, and echo-to-echo signal inconsistencies. THEORY: k-t spiral acquisitions redistribute readout points to be more densely spaced radially in k-space by acquiring an FOV and matrix that are oversampled by η. These more densely spaced spiral turns constitute effective intraspiral echoes and can supplement conventional interspiral echoes to improve spectral separation and reduce spectral cross-talk to better resolve 13 C-labeled species for spectroscopic imaging. METHODS: Digital simulations and imaging phantom experiments were performed for a range of interspiral echo spacings and η using multiecho, k-t spiral acquisitions. Image spectral cross-talk artifacts were evaluated both qualitatively and quantitatively as the percent error in measured metabolite ratios. In vivo murine experiments evaluated the feasibility of multiecho, k-t spiral [1-13 C]pyruvate MRSI to reduce spectral cross-talk for 3 scenarios of different expected reconstruction stability. RESULTS: Digital simulations and imaging phantom experiments both demonstrated reduced or comparable image spectral cross-talk and percent errors in measured metabolite ratios with increasing η and better choices of echo spacings. In vivo images displayed markedly reduced spectral cross-talk in lactate images acquired with η = 7 versus η = 1. CONCLUSION: The precision of hyperpolarized 13 C metabolic imaging and quantification in the presence of low-SNR species, local uncertainties in metabolite resonances, and echo-to-echo signal inconsistencies can be improved with the use of FOV-oversampled k-t spiral acquisitions.