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Hyperpolarized (HP) gas pulmonary MR ventilation images are typically quantified using ventilation defect percent (VDP); however, the test-retest variability of VDP has not been systematically established in multi-center trials. Herein, we perform a systematic review of the test-retest literature on the variability of VDP, and similar metrics, generated from HP MRI. This review utilizes the Medline, EMBASE, and EBM Reviews databases and includes studies that assessed the variability of HP MRI VDP. The protocol was registered to PROSPERO: CRD42022328535. Imaging techniques and statistical analysis characteristics were extracted and used to group studies to evaluate the overall ability to pool data across grouped studies. The ability to pool data to provide systematic evidence was assessed using a modified COSMIN tool. A total of 22 studies with 37 distinct aims for repeated HP MRI acquisition or quantification were included. Studies were grouped into six categories based on HP gas and analysis type: repeated imaging ( 129 Xe n = 13, 3 He n = 12), interobserver repeated analysis ( 129 Xe n = 4, 3 He n = 4) or intraobserver repeated analysis ( 129 Xe n = 1, 3 He n = 2). Studies assessed variability using a variety of statistical tests including absolute difference, percent coefficient of variation, Bland-Altman limits of agreement, coefficient of reproducibility, or the intra-class correlation. Individual studies generally reported low variability of VDP (ICC range: 0.5-1.0; Bland-Altman bias range: -6.9-20%), but there was an overall inability to pool data and provide a meta-analysis due to methodological inconsistencies and small sample size. Overall, we found that VDP has low variability in most studies. However, inconsistent image acquisition and quantification methodologies between studies limits direct comparability and precludes grouping of study data for meta-analyses. Despite early efforts to standardize HP MRI acquisition, further work is necessary to standardize VDP quantification to allow broader validation and clinical implementation. Evidence Level: 2 Technical Efficacy: Stage 3., (© 2025 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: A subset of COPD patients have high levels of eosinophils in the distal airways ("airway eosinophilia")., Objectives: To compare the gene expression of type 2 inflammation in airway epithelial brushings of COPD patients with and without airway eosinophilia and to investigate the changes after inhaled corticosteroids (ICS)., Methods: Post-hoc analyses of the DISARM randomised controlled trial investigated the expression of airway inflammation (type 1, 2, and 17), IL-13, and mast cell gene signatures at baseline and after 12-week ICS treatment. Gene signatures were generated from RNA sequencing of airway epithelial brushings. Airway eosinophilia was defined as eosinophils>1% of the total leukocyte count in bronchoalveolar lavage. Gene set enrichment analyses identified upregulated canonical pathways in airway eosinophilia., Results: Among 58 COPD patients, 38% had airway eosinophilia at baseline. Patients with airway eosinophilia had more severe airflow obstruction and more radiographic emphysema than the non-eosinophilia group. Patients with airway eosinophilia showed a higher epithelial expression of type 2 airway inflammation and IL-13 and mast cell activation at baseline, but the expression of type 1 and type 17 airway inflammation was similar to patients without airway eosinophilia. The airway eosinophilia group showed an upregulation of canonical pathways related to type 2 immune response and asthma. Treatment with ICS for 12 weeks reduced the epithelial expression of type 2 inflammation and mast cell gene signatures in patients with airway eosinophilia, while this change was not significant in patients without airway eosinophilia., Conclusions: Airway eosinophilia marks a subset of COPD patients with increased airway epithelial expression of type 2 inflammation and a response to ICS treatment., (Copyright ©The authors 2025. For reproduction rights and permissions contact permissions@ersnet.org.)

Aim: To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms., Method: Adults with and without long COVID were recruited from the general community in Greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID, which was defined as persons with new or worsening respiratory symptoms following ≥12 weeks from their initial acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (n=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had no history of acute coronavirus disease 2019 (COVID-19) (n=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced., Results: A total of 56 906 cells were recovered for the downstream analysis, with 34 840 cells belonging to the pulmonary long COVID group, which strikingly showed a unique cluster of neutrophils in the pulmonary long COVID group (p<0.05). Ingenuity Pathway Analysis revealed that the neutrophil degranulation pathway was enriched across epithelial cell clusters. Differential gene expression analysis between the pulmonary long COVID and control groups demonstrated upregulation of inflammatory chemokines and epithelial barrier dysfunction across epithelial cell clusters, as well as over-expression of mucin genes across secretory cell clusters., Conclusion: A single-cell transcriptomic landscape of the small airways suggest that neutrophils may play a significant role in mediating the chronic small airway inflammation driving pulmonary symptoms of long COVID., Competing Interests: Conflict of interest: F.V. Geraveli reports grants from MiTACS Accelerate. S. Milne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi Australia, The Limbic Australia and Research Review Australia, support for attending meetings from Sanofi Australia, Chiesi Australia and AstraZeneca, and a leadership role with Thoracic Society of Australia and New Zealand (NSW/ACT). R.L. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network and Natural Sciences and Engineering Research Council Canada, consultancy fees from VIDA Diagnostics Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Thorasys Thoracic Medical Systems Inc., and support for attending meetings from Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health. C. Gilchrist reports grants from Canadian institutes of Health Research. J. Leipsic reports consultancy fees from Heartflow, and stock (or stock options) with Heartflow. J.M. Leung reports support for the present study from Canadian Institutes of Health Research, grants from Canadian Institutes of Health Research and BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from BC Lung Foundation and University of British Columbia, participation on a data safety monitoring board with Enhance Quality Safety and Patient experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership roles with Canadian Respiratory Research Network and the CanCOLD Study. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with NHLBI. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Rationale and Objectives: Hyperpolarized 129 Xe MRI quantifies ventilation-defect-percent (VDP), the ratio of 129 Xe signal-void to the anatomic 1 H MRI thoracic-cavity-volume. VDP is associated with airway inflammation and disease control and serves as a treatable trait in therapy studies. Semi-automated VDP pipelines require time-intensive observer interactions. Current convolutional neural network (CNN) approaches for quantifying VDP lack external validation, which limits multicenter utilization. Our objective was to develop an automated and externally validated deep-learning pipeline to quantify pulmonary 129 Xe MRI VDP., Materials and Methods: 1 H and 129 Xe MRI data from the primary site (Site1) were used to train and test a CNN segmentation and registration pipeline, while two independent sites (Site2 and Site3) provided external validation. Semi-automated and CNN-based registration error was measured using mean-absolute-error (MAE) while segmentation error was measured using generalized-Dice-similarity coefficient (gDSC). CNN and semi-automated VDP were compared using linear regression and Bland-Altman analysis., Results: Training/testing used data from 205 participants (healthy volunteers, asthma, COPD, long-COVID; mean age=54 ± 16y; 119 females) from Site1. External validation used data from 71 participants. CNN and semi-automated 1 H and 129 Xe registrations agreed (MAE=0.3°, R 2 =0.95 rotation; 1.1%, R 2 =0.79 scaling; 0.2/0.5px, R 2 =0.96/0.95, x/y-translation; all p < .001). Thoracic-cavity and ventilation segmentations were also spatially corresponding (gDSC=0.92 and 0.88, respectively). CNN VDP correlated with semi-automated VDP (Site1 R 2 /ρ = .97/.95, bias=-0.5%; Site2 R 2 /ρ = .85/.93, bias=-0.9%; Site3 R 2 /ρ = .95/.89, bias=-0.8%, all p < .001)., Conclusion: An externally validated CNN registration/segmentation model demonstrated strong agreement with low error compared to the semi-automated method. CNN and semi-automated registrations, thoracic-cavity-volume and ventilation-volume segmentations were highly correlated with high gDSC for the datasets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Hyperpolarized 129 Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129 Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129 Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129 Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129 Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129 Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes., Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129 Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129 Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction., Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV 1 ) (p=0.04) were different between long COVID and COVID-negative; FEV 1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern., Conclusions: We identified four 129 Xe MRI long COVID phenotypes with distinct characteristics. 129 Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care., Competing Interests: Conflicts of interest: R.L. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network, and Natural Sciences and Engineering Research Council Canada, consulting fees from VIDA Diagnostics Inc., payment or honoraria for lectures from Thorasys Thoracic Medical Systems Inc., support for attending meetings and/or travel from the Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health, and a leadership or fiduciary role for the Xenon MRI Clinical Trials Consortium (Steering Committee Member). D. Mummy reports consultancy fees from Polarean Imaging Plc. F.V. Gerayeli reports grants from MITACS Accelerate. J.A. Leipsic reports grants from GE Healthcare, consultancy fees and support for attending meetings and/or travel from Heartflow, and owns stock/stock options in Heartflow. J.M. Leung reports grants from the Canadian Institutes of Health Research and BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from the BC Lung Foundation, participation on a data safety monitoring board or advisory board for Enhance Quality Safety, and Patient Experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership or fiduciary roles for the Canadian Respiratory Research Network and CanCOLD Study. B. Driehuys reports grants from Translating Duke Health (Duke Internal Award), royalties or licenses from Polarean Imaging, a leadership or fiduciary role with Polarean Imaging, and owns stock/stock options in Polarean Imaging. L.G. Que reports grants from Translating Duke Health (Duke Internal Award) and a leadership or fiduciary role as a member of the Xe MRI Consortium. M. Castro reports grants from the NIH, ALA, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi and Theravance, consulting fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines and GSK, payment or honoraria for lectures, presentations, manuscript writing or educational events from Amgen, AstraZeneca, Genentech, Regeneron, Sanofi-Aventis and Teva, and owns stock/stock options in Aer Therapeutics. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for the NHLBI. P.J. Niedbalski reports grants from the Scleroderma Foundation (New Investigator Grant) and American Heart Association (CDA 930177), and consultancy fees, payment or honoraria for lectures, and support for attending meetings and/or travel from Polarean Imaging Plc. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Purpose of Review: Spirometry is a validated tool in the diagnosis of obstructive airways disease. However, it may be insufficiently sensitive in detecting airflow limitation in the small airways. This review highlights common clinical scenarios wherein airflow limitation may be missed or overlooked., Recent Findings: This article covers recent literature on the interpretation of lung function test, focusing on detection of mild obstructive airways disease. It also sheds light on the contextual difficulties of defining mild airflow limitation on spirometry., Summary: We highlight the consensus definition of mild obstructive airways disease and emphasize that this definition does not necessarily mean mild in certain disease-specific contexts. Several spirometric findings outside of a reduced forced expiratory volume in one second/forced vital capacity ratio should raise suspicion of mild obstruction., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Irritant-induced asthma (IIA) may develop after acute inhalational exposure in individuals without preexisting asthma. The effect of bronchial thermoplasty to treat intractable, worsening IIA has not yet been described. We evaluated a previously healthy 52-year-old man after inhalation of an unknown white powder. His pulmonary function and symptoms/quality of life worsened over 4 years, despite maximal guidelines-based asthma therapy. We acquired 129 Xe MRI and pulmonary function test measurements on three occasions including before and after bronchial thermoplasty treatment. Seven months after bronchial thermoplasty, improved MRI ventilation and oscillometry small airway resistance were observed. Spirometry and asthma control did not improve until 19 months after bronchial thermoplasty, 5.5 years postexposure. Together, oscillometry measurements of the small airways and 129 Xe MRI provided effort-independent, sensitive, and objective measurements of response to therapy. Improved MRI and oscillometry small airway resistance measurements temporally preceded improved airflow obstruction and may be considered for complex asthma cases., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: R. L. E. discloses personal consulting fees from VIDA Diagnostics and Thorasys Thoracic Medical Systems, outside the submitted work. G. P. discloses investigator-initiated grants from GSK, Novartis, and AstraZeneca PLC, funding from the Ontario Ministry of Health and Long-term Care, and honoraria from AstraZeneca PLC, outside the submitted work. None declared (M. J. M., J. J. H., H. K. K., C. A. M.), (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: The minimal clinically important difference (MCID) and upper limit of normal (ULN) for MRI ventilation defect percent (VDP) were previously reported for hyperpolarized 3 He gas MRI. Hyperpolarized 129 Xe VDP is more sensitive to airway dysfunction than 3 He, therefore the objective of this study was to determine the ULN and MCID for 129 Xe MRI VDP in healthy and asthma participants., Materials and Methods: We retrospectively evaluated healthy and asthma participants who underwent spirometry and 129 XeMRI on a single visit; participants with asthma completed the asthma control questionnaire (ACQ-7). The MCID was estimated using distribution- (smallest detectable difference [SDD]) and anchor-based (ACQ-7) methods. Two observers measured VDP (semiautomated k-means-cluster segmentation algorithm) in 10 participants with asthma, five-times each in random order, to determine SDD. The ULN was estimated based on the 95% confidence interval of the relationships between VDP and age., Results: Mean VDP was 1.6 ± 1.2% for healthy (n = 27) and 13.7 ± 12.9% for asthma participants (n = 55). ACQ-7 and VDP were correlated (r = .37, p = .006; VDP = 3.5·ACQ + 4.9). The anchor-based MCID was 1.75% while the mean SDD and distribution-based MCID was 2.25%. VDP was correlated with age for healthy participants (p = .56, p =.003; VDP = .04·Age-.01). The ULN for all healthy participants was 2.0%. By age tertiles, the ULN was 1.3% ages 18-39 years, 2.5% for 40-59 years and 3.8% for 60-79 years., Conclusion: The 129 Xe MRI VDP MCID was estimated in participants with asthma; the ULN was estimated in healthy participants across a range of ages, both of which provide a way to interpret VDP measurements in clinical investigations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: A proportion of coronavirus disease 2019 (COVID-19) survivors experience persistent dyspnoea without measurable impairments in lung function. We performed a systematic review and meta-analysis to determine relationships between dyspnoea and imaging abnormalities over time in post-COVID-19 patients., Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we analysed studies published prior to 15 September 2022 and indexed by Google Scholar, PubMed and LitCOVID which assessed chest imaging in adults ≥3 months after COVID-19. Demographic, chest imaging, spirometric and post-COVID-19 symptom data were extracted. The relationships between imaging abnormalities and dyspnoea, sex and age were determined using a random effects model and meta-regression., Results: 47 studies were included in the meta-analysis (n=3557). The most prevalent computed tomography (CT) imaging abnormality was ground-glass opacities (GGOs) (44.9% (95% CI 37.0-52.9%) at any follow-up time-point). Occurrence of reticulations significantly decreased between early and late follow-up (p=0.01). The prevalence of imaging abnormalities was related to the proportion of patients with dyspnoea (p=0.012). The proportion of females was negatively correlated with the presence of reticulations (p=0.001), bronchiectasis (p=0.001) and consolidations (p=0.025). Age was positively correlated with imaging abnormalities across all modalities (p=0.002) and imaging abnormalities present only on CT (p=0.001) (GGOs (p=0.004) and reticulations (p=0.001)). Spirometric values improved during follow-up but remained within the normal range at all time-points., Conclusions: Imaging abnormalities were common 3 months after COVID-19 and their occurrence was significantly related to the presence of dyspnoea. This suggests that CT imaging is a sensitive tool for detecting pulmonary abnormalities in patients with dyspnoea, even in the presence of normal spirometric measurements., Competing Interests: Conflict of interest: R.L. Eddy receives personal consulting fees from VIDA Diagnostics Inc., and lecture honoraria from AstraZeneca, outside the submitted work. S. Milne reports grants from British Columbia Lung Association, CHEST Foundation, Genome British Columbia, Mitacs and Michael Smith Health Research BC, and financial support from Chiesi Australia, outside the submitted work. D.D. Sin has received an honorarium for speaking engagements for COPD from GSK, AstraZeneca and Boehringer Ingelheim, and chairs a DSMB for an NHLBI-sponsored clinical trial in COPD, outside the submitted work. E. Guinto, F.V. Gerayeli and H. Lee do not declare any conflicts of interest., (Copyright ©The authors 2023.)

Background: We previously showed in patients with poorly controlled eosinophilic asthma that a single dose of benralizumab resulted in significantly improved Asthma Control Questionnaire (ACQ-6) score and 129 Xe MRI ventilation defect percent (VDP) 28 days postinjection, and 129 Xe MRI VDP and CT airway mucus occlusions were shown to independently predict this early ACQ-6 response to benralizumab., Research Question: Do early VDP responses at 28 days persist, and do FEV 1 , fractional exhaled nitric oxide, and mucus plug score improve during a 2.5 year treatment period?, Study Design and Methods: Participants with poorly controlled eosinophilic asthma completed spirometry, ACQ-6, and MRI, 28 days, 1 year, and 2.5 years after initiation of treatment with benralizumab; chest CT was acquired at enrollment and 2.5 years later., Results: Of 29 participants evaluated at 28 days post-benralizumab, 16 participants returned for follow-up while on therapy at 1 year, and 13 participants were evaluable while on therapy at 2.5 years post-benralizumab initiation. As compared with 28 days post-benralizumab, ACQ-6 score (2.0 ± 1.4) significantly improved after 1 year (0.5 ± 0.6, P = .02; 95% CI, 0.1-1.1) and 2.5 years (0.5 ± 0.5, P = .03; 95% CI, 0.1-1.1). The mean VDP change at 2.5 years (-4% ± 3%) was greater than the minimal clinically important difference, but not significantly different from VDP measured 28 days post-benralizumab. Mucus score (3 ± 4) was significantly improved at 2.5 years (1 ± 1, P = .03; 95% CI, 0.3-5.5). In six of eight participants with previous occlusions, mucus plugs vanished or substantially diminished 2.5 years later. VDP (P < .001) and mucus score (P < .001) measured at baseline, but not fractional exhaled nitric oxide or FEV 1 , independently predicted ACQ-6 score after 2.5 years., Interpretation: In poorly controlled eosinophilic asthma, early MRI VDP responses at 28 days post-benralizumab persisted 2.5 years later, alongside significantly improved mucus scores and asthma control., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Outside eosinophilia, current clinical asthma phenotypes do not show strong relationships with disease pathogenesis or treatment responses. While chest x-ray computed tomography (CT) phenotypes have previously been explored, functional MRI measurements provide complementary phenotypic information., Purpose: To derive novel data-driven asthma phenotypic clusters using functional MRI airway biomarkers that better describe airway pathologies in patients., Study Type: Retrospective., Population: A total of 45 patients with asthma who underwent post-bronchodilator 129 Xe MRI, volume-matched CT, spirometry and plethysmography within a 90-minute visit., Field Strength/sequence: Three-dimensional gradient-recalled echo 129 Xe ventilation sequence at 3 T., Assessment: We measured MRI ventilation defect percent (VDP), CT airway wall-area percent (WA%), wall-thickness (WT, WT* [*normalized for age/sex/height]), lumen-area (LA), lumen-diameter (D, D*) and total airway count (TAC). Univariate relationships were utilized to select variables for k-means cluster analysis and phenotypic subgroup generation. Spirometry and plethysmography measurements were compared across imaging-based clusters., Statistical Tests: Spearman correlation (ρ), one-way analysis of variance (ANOVA) or Kruskal-Wallis tests with post hoc Bonferroni correction for multiple comparisons, significance level 0.05., Results: Based on limited common variance (Kaiser-Meyer-Olkin-measure = 0.44), four unique clusters were generated using MRI VDP, TAC, WT* and D* (52 ± 14 years, 27 female). Imaging measurements were significantly different across clusters as was the forced expiratory volume in 1-second (FEV 1 % pred ), residual volume/total lung capacity and airways resistance. Asthma-control (P = 0.9), quality-of-life scores (P = 0.7) and the proportions of severe-asthma (P = 0.4) were not significantly different. Cluster1 (n = 15/8 female) reflected mildly abnormal CT airway measurements and FEV 1 with moderately abnormal VDP. Cluster2 (n = 12/12 female) reflected moderately abnormal TAC, WT and FEV 1 . In Cluster3 and Cluster4 (n = 14/6 female, n = 4/1 female, respectively), there was severely reduced TAC, D and FEV 1 , but Cluster4 also had significantly worse, severely abnormal VDP (7 ± 5% vs. 41 ± 12%)., Data Conclusion: We generated four proof-of-concept MRI-derived clusters of asthma with distinct structure-function pathologies. Cluster analysis of asthma using 129 Xe MRI in combination with CT biomarkers is feasible and may challenge currently used paradigms for asthma phenotyping and treatment decisions., Evidence Level: 3 TECHNICAL EFFICACY: Stage., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129 Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129 Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function., Research Question: Does 129 Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response?, Study Design and Methods: MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28 days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and 28., Results: Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P < .001), and peripheral airway resistance (P = .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n = 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P < .001) and day 0 CT scan mucus score (P < .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection., Interpretation: 129 Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab., Trial Registry: ClinicalTrials.gov; No.: NCT03733535; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Hard data labels for automated algorithm training are binary and cannot incorporate uncertainty between labels. We proposed and evaluated a soft labeling methodology to quantify opacification and percent well-aerated lung (%WAL) on chest CT, that considers uncertainty in segmenting pulmonary opacifications and reduces labeling burden., Materials and Methods: We retrospectively sourced 760 COVID-19 chest CT scans from five international centers between January and June 2020. We created pixel-wise labels for >27,000 axial slices that classify three pulmonary opacification patterns: pure ground-glass, crazy-paving, consolidation. We also quantified %WAL as the total area of lung without opacifications. Inter-user hard label variability was quantified using Shannon entropy (range=0-1.39, low-high entropy/variability). We incorporated a soft labeling and modeling cycle following an initial model with hard labels and compared performance using point-wise accuracy and intersection-over-union of opacity labels with ground-truth, and correlation with ground-truth %WAL., Results: Hard labels annotated by 12 radiologists demonstrated large inter-user variability (3.37% of pixels achieved complete agreement). Our soft labeling approach increased point-wise accuracy from 60.0% to 84.3% (p=0.01) compared to hard labeling at predicting opacification type and area involvement. The soft label model accurately predicted %WAL (R=0.900) compared to the hard label model (R=0.856), but the improvement was not statistically significant (p=0.349)., Conclusion: Our soft labeling approach increased accuracy for automated quantification and classification of pulmonary opacification on chest CT. Although we developed the model on COVID-19, our intent is broad application for pulmonary opacification contexts and to provide a foundation for future development using soft labeling methods., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm 3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning., (© 2022 Asian Pacific Society of Respirology.)

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., (© 2021 International Society for Magnetic Resonance in Medicine.)

Patient-specific localisation of ventilation defects using hyperpolarised gas magnetic resonance imaging (MRI) introduces the possibility of regionally targeted bronchial thermoplasty (BT) for the treatment of severe asthma. We aimed to demonstrate that BT guided by MRI to ventilation defects reduces the number of radiofrequency activations while resulting in improved asthma quality-of-life and control scores that are non-inferior to standard BT. In a 1-year pilot randomised controlled trial, 14 patients with severe asthma who were clinically eligible to receive BT underwent hyperpolarised gas MRI to characterise ventilation defects and were randomised to MRI-guided or standard BT. End-points were improved Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, the proportion of AQLQ and ACQ responders and the number of radiofrequency activations and bronchoscopy sessions. Participants who underwent MRI-guided BT received 53% fewer radiofrequency activations than those who had standard BT (p=0.003). At 12 months, the mean improvement from baseline was similar between the MRI-guided group (n=5) and the standard group (n=7) for AQLQ score (MRI-guided: 1.8, 95% CI 0.1-3.5, p=0.04; standard: 0.7, 95% CI -0.9-2.3, p=0.30) (p=0.25) and ACQ-5 score (MRI-guided: -1.4, 95% CI -2.6- -0.2, p=0.03; standard: -0.7, 95% CI -1.3-0.0, p=0.04) (p=0.17). A similar proportion of participants in both groups achieved a clinically relevant improvement in AQLQ score (MRI-guided: 80%; standard: 71%) and ACQ-5 score (MRI-guided: 80%; standard: 57%). Hyperpolarised gas MRI-guided BT reduced the number of radiofrequency activations, and resulted in asthma quality of life and control improvements at 12 months that were non-inferior to standard BT., Competing Interests: Conflict of interest: S. Svenningsen reports personal fees from AstraZeneca and Novartis, grants from Cyclomedica and personal fees from Polarean, outside the submitted work. Conflict of interest: P. Nair reports grants and personal fees from AstraZeneca, grants from Novartis, grants and personal fees from Teva, grants from Sanofi, grants and personal fees from Roche, personal fees from Novartis, Merck and Equillium, and grants from Foresee, outside the submitted work. Conflict of interest: R.L Eddy has nothing to disclose. Conflict of interest: M.J. McIntosh has nothing to disclose. Conflict of interest: M. Kjarsgaard has nothing to disclose. Conflict of interest: H.F. Lim has nothing to disclose. Conflict of interest: D.G. McCormack has nothing to disclose. Conflict of interest: G. Cox has nothing to disclose. Conflict of interest: G. Parraga reports grants from Astra Zeneca and Novartis, outside the submitted work., (Copyright ©The authors 2021.)

Rationale and Objectives: 129 Xe MRI has been developed to noninvasively visualize and quantify the functional consequence of airway obstruction in asthma. Its widespread application requires evidence of intersite reproducibility and agreement. Our objective was to evaluate reproducibility and agreement of 129 Xe ventilation MRI measurements in severe asthmatics at two sites., Materials and Methods: In seven adults with severe asthma, 129 Xe ventilation MRI was acquired pre- and post-bronchodilator at two geographic sites within 24-hours. 129 Xe MRI signal-to-noise ratio (SNR) was calculated and ventilation abnormalities were quantified as the whole-lung and slice-by-slice ventilation defect percent (VDP). Intraclass correlation coefficients (ICC) and Bland-Altman analysis were used to determine intersite 129 Xe VDP reproducibility and agreement., Results: Whole-lung and slice-by-slice 129 Xe VDP measured at both sites were correlated and reproducible (pre-bronchodilator: whole-lung ICC = 0.90, p = 0.005, slice-by-slice ICC = 0.78, p < 0.0001; post-bronchodilator: whole-lung ICC = 0.94, p < 0.0001, slice-by-slice ICC = 0.83, p < 0.0001) notwithstanding intersite differences in the 129 Xe-dose-equivalent-volume (101 ± 15 mL site 1, 49 ± 6 mL site 2, p < 0.0001), gas-mixture ( 129 Xe/ 4 He site 1; 129 Xe/N 2 site 2) and SNR (40 ± 19 site 1, 23 ± 5 site 2, p = 0.02). Qualitative 129 Xe gas distribution differences were observed between sites and slice-by-slice 129 Xe VDP, but not whole-lung 129 Xe VDP, was significantly lower at site 1 (pre-bronchodilator VDP: whole-lung bias = -3%, p > 0.99, slice-by-slice bias = -3%, p = 0.0001; post-bronchodilator VDP: whole-lung bias = -2%, p = 0.59, slice-by-slice-bias = -2%, p = 0.0003)., Conclusion: 129 Xe MRI VDP at two different sites measured within 24-hours in the same severe asthmatics were correlated. Qualitative and quantitative intersite differences in 129 Xe regional gas distribution and VDP point to site-specific variability that may be due to differences in gas-mixture composition or SNR., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: The relationships between computed tomography (CT) pulmonary vascularity and MRI ventilation is not well-understood in chronic obstructive pulmonary disease (COPD) patients. Our objective was to evaluate CT pulmonary vascular and MRI ventilation measurements in ex-smokers and to investigate their associations and how such measurements change over time., Materials and Methods: Ninety ex-smokers (n = 41 without COPD 71 ± 10 years and n = 49 COPD 71 ± 8 years) provided written informed-consent to an ethics-board approved protocol and underwent imaging and pulmonary-function-tests twice, 31 ± 7 months apart. 3 He MRI was acquired to generate ventilation-defect-percent (VDP). CT measurements of the relative area-of-the-lung with attenuation <-950 Hounsfield units (RA 950 ), pulmonary vascular total-blood-volume (TBV) and percent of vessels with radius < one voxel (PV 1 ) were evaluated., Results: At baseline, there were significant differences in RA 950 (p = 0.0001), VDP (p = 0.0001), total-blood-volume (p = 0.0001) and PV 1 (p = 0.01) between ex-smokers and COPD participants as well as for VDP (p = 0.0001) in COPD participants with and without emphysema. The annual FEV 1 change (-40 ± 93 mL/year) was not different among participant subgroups (p = 0.87), but the annual RA 950 (p = 0.01) and PV 1 (p = 0.007) changes were significantly different in participants with an accelerated annual FEV 1 decline as compared to participants with a diminished annual FEV 1 decline. There were significant but weak relationships for PV 1 with FEV 1%pred (p = 0.02), FEV 1 /FVC (p = 0.001), and log RA 950 (p = 0.0001), but not VDP (p=0.20). The mean change in PV 1 was also weakly but significantly related to the change in RA 950 (p = 0.02)., Conclusion: CT pulmonary vascular measurements were significantly different in ex-smokers and participants with COPD and related to RA 950 but not VDP worsening over 2.5 years., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Although nearly 3,000 e-cigarette-related hospitalizations have been reported in North America, the long-term outcomes in these patients have not been described. We followed an 18-year-old boy who survived acute critical illness and respiratory failure related to 5 months of e-cigarette use. Chronic irreversible airflow obstruction and markedly abnormal 129 Xe MRI ventilation heterogeneity was observed and persisted 8 months after hospital discharge, despite improvement in quality-of-life and chest CT findings. Lung clearance index and oscillometry measures were also highly abnormal at 8 months postdischarge. Although 129 Xe MRI ventilation abnormalities were dominant in the lung apices and central lung regions, the pattern of ventilation defects was dissimilar to ventilation heterogeneity observed in patients with obstructive lung disease, such as asthma and COPD. Our findings underscore the long-term functional impacts of e-cigarette-related lung injury in survivors of critical illness; longitudinal evaluations may shed light on the pathophysiologic mechanisms that drive e-cigarette-related lung disease., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to "anti-T2" therapy., Research Question: Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma?, Study Design and Methods: Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%)., Results: MRI VDP was improved pre- (ΔVDP +anti-T2 : -3% ± 4%, P = .02) and post-bronchodilator (ΔVDP +anti-T2 : -3% ± 4%; P = .04) after additional anti-T2 therapy that controlled eosinophilic bronchitis (n = 2 mepolizumab, n = 2 reslizumab, n = 3 benralizumab, n = 1 dupilumab, n = 2 increased daily prednisone). A greater post-bronchodilator ΔVDP +anti-T2 was observed in those patients with median or higher percentage of sputum eosinophils at baseline (≥15.8%; P = .01). In 7 of 10 patients with asthma, residual ventilation defects persisted despite bronchodilator and anti-T2 therapy., Interpretation: Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: In patients with asthma, X-ray computed tomography (CT) has provided evidence of thickened airway walls and airway occlusions, but the total number of CT-visible airways and its relationship with disease severity is unknown. Objectives: To measure CT total airway count (TAC) in asthma and evaluate relationships with asthma severity, airway morphology, pulmonary function, and magnetic resonance imaging (MRI) ventilation. Methods: Participants underwent post-bronchodilator inspiratory CT, and prebronchodilator and post-bronchodilator spirometry and hyperpolarized 3 He MRI. CT TAC was quantified as the sum of airways in the segmented airway tree, and airway wall area percent (WA%) and lumen area were measured. MRI ventilation abnormalities were quantified as the ventilation defect percent. Measurements and Main Results: We evaluated 70 participants, including 15 Global Initiative for Asthma (GINA) steps 1 to 3, 19 GINA 4, and 36 GINA 5 participants with asthma. As compared with GINA 1 to 3, TAC was significantly diminished in GINA 4 ( P  = 0.03) and GINA 5 ( P  = 0.045). Terminal airway intraluminal occlusion was present in 5 (2 GINA 4 and 3 GINA 5) of 70 participants. Sub-subsegmental airways were CT-invisible or missing in 69 out of 70 participants; the most common number of missing sub-subsegments was 10. Participants with ≥10 missing subsegments had worse WA% ( P  < 0.0001), lumen area ( P  < 0.0001), and ventilation defect percent ( P  = 0.03) than those with <10 missing subsegments. In a multivariable model, TAC (standardized regression coefficient = 0.50; P  = 0.001) independently predicted FEV 1 ( R 2  = 0.27; P  = 0.003) and, in a separate model, TAC (standardized regression coefficient = -0.53; P  < 0.0001) independently predicted airway WA% ( R 2  = 0.32; P  = 0.0001). Conclusions: TAC was significantly diminished in participants with greater asthma severity and was related to airway wall thickness and ventilation defects. Fewer airways in severe than in mild asthma challenges our understanding of airway disease in asthma.Clinical trial registered with www.clinicaltrials.gov (NCT02351141).

Background Pulmonary imaging of chronic obstructive pulmonary disease (COPD) has focused on CT or MRI measurements, but these have not been evaluated in combination. Purpose To generate multiparametric response map (mPRM) measurements in ex-smokers with or without COPD by using volume-matched CT and hyperpolarized helium 3 ( 3 He) MRI. Materials and Methods In this prospective study ( https://clinicaltrials.gov , NCT02279329), participants underwent MRI and CT and completed pulmonary function tests, questionnaires, and the 6-minute walk test between December 2010 and January 2019. Disease status was determined by using Global initiative for chronic Obstructive Lung Disease (GOLD) criteria. The mPRM voxel values were generated by using co-registered MRI and CT labels. Kruskal-Wallis and Bonferroni tests were used to determine differences across disease severity, and correlations were determined by using Spearman coefficients. Results A total of 175 ex-smokers (mean age, 69 years ± 9 [standard deviation], 108 men) with or without COPD were evaluated. Ex-smokers without COPD had a larger fraction of normal mPRM voxels (60% vs 37%, 20%, and 7% for GOLD I, II, and III/IV disease, respectively; all P ≤ .001) and a smaller fraction of abnormal voxels, including small airways disease (normal CT, not ventilated: 5% vs 6% [not significant], 11%, and 19% [ P ≤ .001 for both] for GOLD I, II, and III/IV disease, respectively) and mild emphysema (normal CT, abnormal apparent diffusion coefficient [ADC]: 33% vs 54%, 56%, and 54% for GOLD I, II, and III/IV disease respectively; all P ≤ .001). Normal mPRM measurements were positively correlated with forced expiratory volume in 1 second (FEV 1 ) ( r = 0.65, P < .001), the FEV 1 -to-forced vital capacity ratio ( r = 0.81, P < .001), and diffusing capacity ( r = 0.75, P < .001) and were negatively correlated with worse quality of life ( r = -0.48, P < .001). Abnormal mPRM measurements of small airways disease (normal CT, not ventilated) and mild emphysema (normal CT, abnormal ADC) were negatively correlated with FEV 1 ( r = -0.65 and -0.42, respectively; P < .001) and diffusing capacity ( r = -0.53 and -0.60, respectively; P < .001) and were positively correlated with worse quality of life ( r = 0.45 and r = 0.33, respectively; P < .001), both of which were present in ex-smokers without COPD. Conclusion Multiparametric response maps revealed two abnormal structure-function results related to emphysema and small airways disease, both of which were unexpectedly present in ex-smokers with normal spirometry and CT findings. © RSNA, 2020 Online supplemental material is available for this article.

Competing Interests: Conflict of interest: R.L. Eddy has nothing to disclose. Conflict of interest: G. Parraga has nothing to disclose.

Recent pulmonary functional MRI findings of spatially and temporally persistent ventilation abnormalities in patients with asthma contrast with previous in silico modeling studies that suggest that in asthma, ventilation defects may be randomly distributed. In a case study that used pulmonary MRI, CT imaging, and pulmonary function tests, we prospectively evaluated over the course of 7 years, nonidentical female adult twins, each with a lifelong history of asthma. We evaluated pulmonary function and MRI ventilation heterogeneity at baseline and follow-up after 7 years. In both twins, there was a spatially identical MRI ventilation defect and an abnormal subsegmental left-sided upper lobe airway that persisted in the same spatial location after 7 years. If ventilation defects are randomly distributed, this bears a probability of approximately one per 130,000 people. Our MRI observations in related patients with asthma suggest that ventilation abnormalities may not be randomly distributed in patients with asthma and persist distal to airway abnormalities for long periods of time., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: PN reports grants from AZ, Novartis, Teva and Sanofi; personal fees from Roche, Teva, Novartis and Knopp; and grants and personal fees from GSK, outside the submitted work.

Background Longitudinal progression to irreversible airflow limitation occurs in approximately 10% of patients with asthma, but it is difficult to identify patients who are at risk for this transition. Purpose To investigate 6-year longitudinal changes in hyperpolarized helium 3 ( 3 He) MRI ventilation defects in study participants with mild-to-moderate asthma and identify predictors of longitudinal changes in postbronchodilator forced expiratory volume in 1 second (FEV 1 ) reversibility Materials and Methods Spirometry and hyperpolarized 3 He MRI were evaluated in participants with mild-to-moderate asthma in two prospectively planned visits approximately 6 years apart. Participants underwent methacholine challenge at baseline (January 2010 to April 2011) and pre- and postbronchodilator evaluations at follow-up (November 2016 to June 2017). FEV 1 and MRI ventilation defects, quantified as ventilation defect volume (VDV), were compared between visits by using paired t tests. Participants were dichotomized by postbronchodilator change in FEV 1 at follow-up, and differences between reversible and not-reversible groups were determined by using unpaired t tests. Multivariable models were generated to explain postbronchodilator FEV 1 reversibility at follow-up. Results Eleven participants with asthma (mean age, 42 years ± 9 [standard deviation]; seven men) were evaluated at baseline and after mean 78 months ± 7. Medications, exacerbations, FEV 1 (76% predicted vs 76% predicted; P = .91), and VDV (240 mL vs 250 mL; P = .92) were not different between visits. In eight of 11 participants (73%), MRI ventilation defects at baseline were at the same location in the lung at follow-up MRI. In the remaining three participants (27%), MRI ventilation defects worsened at the same lung locations as depicted at baseline methacholine-induced ventilation. At follow-up, postbronchodilator FEV 1 was not reversible in six of 11 participants; the concentration of methacholine to decrease FEV 1 by 20% (PC 20 ) was greater in FEV 1 -irreversible participants at follow-up ( P = .01). In a multivariable model, baseline MRI VDV helped to predict postbronchodilator reversibility at follow-up ( R  2 = 0.80; P < .01), but PC 20 , age, and FEV 1 did not ( R  2 = 0.63; P = .15). Conclusion MRI-derived, spatially persistent ventilation defects predict postbronchodilator reversibility 78 months ± 7 later for participants with mild-to-moderate asthma in whom there were no changes in lung function, medication, or exacerbations. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

Background: Intraluminal contributor(s) to airflow obstruction in severe asthma are patient-specific and must be evaluated to personalize treatment. The occurrence and functional consequence of airway mucus in the presence or absence of airway eosinophils remain undetermined., Objective: The objective of this study was to understand the functional consequence of airway mucus in the presence or absence of eosinophils and to identify biomarkers of mucus-related airflow obstruction., Methods: Mucus plugs were quantified on CT scans, and their contribution to ventilation heterogeneity (using MRI ventilation defect percent [VDP]) was evaluated in 27 patients with severe asthma. Patients were dichotomized based on sputum eosinophilia such that the relationship between mucus, eosinophilia, and ventilation heterogeneity could be investigated. Fractional exhaled nitric oxide (Feno) and related cytokines in sputum were measured., Results: Mucus plugging was present in 100% of asthma patients with sputum eosinophils and 36% of those without sputum eosinophils (P = .0006) and was correlated with MRI VDP prebronchodilator (r = 0.68; P = .0001) and postbronchodilator (r = 0.72; P < .0001). In a multivariable regression, both mucus and eosinophils contributed to the prediction of postbronchodilator MRI VDP (R 2  = 0.75; P < .0001). Patients with asthma in whom the mucus score was high had raised Feno (P = .03) and IL-4 (P = .02) values. Mucus plugging correlated with Feno (r = 0.63; P = .005)., Conclusions: Both airway eosinophils and mucus can contribute to ventilation heterogeneity in patients with severe asthma. Patients in whom mucus is the dominant cause of airway obstruction have evidence of an upregulated IL-4/IL-13 pathway that could be identified according to increased Feno level., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The biomechanical properties of the lung are necessarily dependent on its structure and function, both of which are complex and change over time and space. This makes in vivo evaluation of lung biomechanics and a deep understanding of lung biomarkers, very challenging. In patients and animal models of lung disease, in vivo evaluations of lung structure and function are typically made at the mouth and include spirometry, multiple-breath gas washout tests and the forced oscillation technique. These techniques, and the biomarkers they provide, incorporate the properties of the whole organ system including the parenchyma, large and small airways, mouth, diaphragm and intercostal muscles. Unfortunately, these well-established measurements mask regional differences, limiting their ability to probe the lung's gross and micro-biomechanical properties which vary widely throughout the organ and its subcompartments. Pulmonary imaging has the advantage in providing regional, non-invasive measurements of healthy and diseased lung, in vivo. Here we summarize well-established and emerging lung imaging tools and biomarkers and how they may be used to generate lung biomechanical measurements., Methods: We review well-established and emerging lung anatomical, microstructural and functional imaging biomarkers generated using synchrotron x-ray tomographic-microscopy (SRXTM), micro-x-ray computed-tomography (micro-CT), clinical CT as well as magnetic resonance imaging (MRI)., Findings: Pulmonary imaging provides measurements of lung structure, function and biomechanics with high spatial and temporal resolution. Imaging biomarkers that reflect the biomechanical properties of the lung are now being validated to provide a deeper understanding of the lung that cannot be achieved using measurements made at the mouth., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Developed over six decades ago, pulmonary oscillometry has re-emerged as a noninvasive and effort-independent method for evaluating respiratory-system impedance in patients with obstructive lung disease. Here, we evaluated the relationships between hyperpolarized 3 He ventilation-defect-percent (VDP) and respiratory-system resistance, reactance and reactance area (A X ) measurements in 175 participants including 42 never-smokers without respiratory disease, 56 ex-smokers with chronic-obstructive-pulmonary-disease (COPD), 28 ex-smokers without COPD and 49 asthmatic never-smokers. COPD participants were dichotomized based on x-ray computed-tomography (CT) evidence of emphysema (relative-area CT-density-histogram ≤ 950HU (RA 950 ) ≥ 6.8%). In asthma and COPD subgroups, MRI VDP was significantly related to the frequency-dependence of resistance (R 5-19 ; asthma: ρ = 0.48, P = 0.0005; COPD: ρ = 0.45, P = 0.0004), reactance at 5 Hz (X 5 : asthma, ρ = -0.41, P = 0.004; COPD: ρ = -0.38, P = 0.004) and A X (asthma: ρ = 0.47, P = 0.0007; COPD: ρ = 0.43, P = 0.0009). MRI VDP was also significantly related to R 5-19 in COPD participants without emphysema (ρ = 0.54, P = 0.008), and to X 5 in COPD participants with emphysema (ρ = -0.36, P = 0.04). A X was weakly related to VDP in asthma (ρ = 0.47, P = 0.0007) and COPD participants with (ρ = 0.39, P = 0.02) and without (ρ = 0.43, P = 0.04) emphysema. A X is sensitive to obstruction but not specific to the type of obstruction, whereas the different relationships for MRI VDP with R 5-19 and X 5 may reflect the different airway and parenchymal disease-specific biomechanical abnormalities that lead to ventilation defects., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Ventilation heterogeneity is a hallmark finding in obstructive lung disease and may be evaluated using a variety of methods, including multiple-breath gas washout and pulmonary imaging. Such methods provide an opportunity to better understand the relationships between structural and functional abnormalities in the lungs, and their relationships with important clinical outcomes. We measured ventilation heterogeneity and respiratory impedance in 100 subjects [50 patients with asthma, 22 ex-smokers, and 28 patients with chronic obstructive pulmonary disease (COPD)] using oscillometry and hyperpolarized 3 He magnetic resonance imaging (MRI) and determined their relationships with quality of life scores and disease control/exacerbations. We also coregistered MRI ventilation maps to a computational airway tree model to generate patient-specific respiratory impedance predictions for comparison with experimental measurements. In COPD and asthma patients, respectively, forced oscillation technique (FOT)-derived peripheral resistance (5-19 Hz) and MRI ventilation defect percentage (VDP) were significantly related to quality of life (FOT: COPD ρ = 0.4, P = 0.004; asthma ρ = -0.3, P = 0.04; VDP: COPD ρ = 0.6, P = 0.003; asthma ρ = -0.3, P = 0.04). Patients with poorly controlled asthma (Asthmatic Control Questionnaire >2) had significantly increased resistance (5 Hz: P = 0.01; 5-19 Hz: P = 0.006) and reactance (5 Hz: P = 0.03). FOT-derived peripheral resistance (5-19 Hz) was significantly related to VDP in patients with asthma and COPD patients (asthma: ρ = 0.5, P < 0.001; COPD: ρ = 0.5, P = 0.01), whereas total respiratory impedance was related to VDP only in patients with asthma (resistance 5 Hz: ρ = 0.3, P = 0.02; reactance 5 Hz: ρ = -0.5, P < 0.001). Model-predicted and FOT-measured reactance (5 Hz) were correlated in patients with asthma (ρ = 0.5, P = 0.001), whereas in COPD patients, model-predicted and FOT-measured resistance (5-19 Hz) were correlated (ρ = 0.5, P = 0.004). In summary, in patients with asthma and COPD patients, we observed significant, independent relationships for FOT-measured impedance and MRI ventilation heterogeneity measurements with one another and with quality of life scores. NEW & NOTEWORTHY In 100 patients, including patients with asthma and ex-smokers, 3 He MRI ventilation heterogeneity and respiratory system impedance were correlated and both were independently related to quality of life scores and asthma control. These findings demonstrated the critical relationships between respiratory system impedance and ventilation heterogeneity and their role in determining quality of life and disease control. These observations underscore the dominant role that abnormalities in the lung periphery play in ventilation heterogeneity that results in patients' symptoms.

Purpose To measure regional specific ventilation with free-breathing hydrogen 1 ( 1 H) magnetic resonance (MR) imaging without exogenous contrast material and to investigate correlations with hyperpolarized helium 3 ( 3 He) MR imaging and pulmonary function test measurements in healthy volunteers and patients with asthma. Materials and Methods Subjects underwent free-breathing 1 H and static breath-hold hyperpolarized 3 He MR imaging as well as spirometry and plethysmography; participants were consecutively recruited between January and June 2017. Free-breathing 1 H MR imaging was performed with an optimized balanced steady-state free-precession sequence; images were retrospectively grouped into tidal inspiration or tidal expiration volumes with exponentially weighted phase interpolation. MR imaging volumes were coregistered by using optical flow deformable registration to generate 1 H MR imaging-derived specific ventilation maps. Hyperpolarized 3 He MR imaging- and 1 H MR imaging-derived specific ventilation maps were coregistered to quantify regional specific ventilation within hyperpolarized 3 He MR imaging ventilation masks. Differences between groups were determined with the Mann-Whitney test and relationships were determined with Spearman (ρ) correlation coefficients. Statistical analyses were performed with software. Results Thirty subjects (median age: 50 years; interquartile range [IQR]: 30 years), including 23 with asthma and seven healthy volunteers, were evaluated. Both 1 H MR imaging-derived specific ventilation and hyperpolarized 3 He MR imaging-derived ventilation percentage were significantly greater in healthy volunteers than in patients with asthma (specific ventilation: 0.14 [IQR: 0.05] vs 0.08 [IQR: 0.06], respectively, P < .0001; ventilation percentage: 99% [IQR: 1%] vs 94% [IQR: 5%], P < .0001). For all subjects, 1 H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation (ρ = 0.54, P = .002) and hyperpolarized 3 He MR imaging-derived ventilation percentage (ρ = 0.67, P < .0001) as well as with forced expiratory volume in 1 second (FEV 1 ) (ρ = 0.65, P = .0001), ratio of FEV 1 to forced vital capacity (ρ = 0.75, P < .0001), ratio of residual volume to total lung capacity (ρ = -0.68, P < .0001), and airway resistance (ρ = -0.51, P = .004). 1 H MR imaging-derived specific ventilation was significantly greater in the gravitational-dependent versus nondependent lung in healthy subjects (P = .02) but not in patients with asthma (P = .1). In patients with asthma, coregistered 1 H MR imaging specific ventilation and hyperpolarized 3 He MR imaging maps showed that specific ventilation was diminished in corresponding 3 He MR imaging ventilation defects (0.05 ± 0.04) compared with well-ventilated regions (0.09 ± 0.05) (P < .0001). Conclusion 1 H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation and ventilation defects seen by using hyperpolarized 3 He MR imaging. © RSNA, 2018 Online supplemental material is available for this article.

Rationale: Inflammation and smooth muscle dysfunction are integral components of severe asthma that contribute to luminal obstruction causing airflow limitation, ventilation heterogeneity, and symptoms. This is important for guiding treatment decisions directed at the inflammatory (e.g., anti-T-helper cell type 2 monoclonal antibodies) and noninflammatory, smooth muscle-mediated (e.g., bronchial thermoplasty) components of severe asthma., Objectives: To investigate the contribution of eosinophilic bronchitis and smooth muscle dysfunction to magnetic resonance imaging (MRI) ventilation heterogeneity in patients with severe asthma., Methods: We measured the inhaled hyperpolarized gas MRI response to salbutamol as a marker of smooth muscle dysfunction, and sputum eosinophils as a marker of airway inflammation, and their contributions to ventilation heterogeneity (quantified as the ventilation defect percent [VDP]) in 27 patients with severe asthma. Spirometry and forced oscillation airway resistance measurements were also acquired pre- and postsalbutamol. Patients were dichotomized on the basis of sputum eosinophilia, and pre- and postsalbutamol VDP and physiological measurements were evaluated., Measurements and Main Results: MRI VDP improved with salbutamol inhalation in patients in whom sputum eosinophilia was uncontrolled (≥3%, n = 16) (P = 0.002) and in those in whom it was controlled (<3%, n = 11) (P = 0.02), independent of improvements in FEV 1 , indicating smooth muscle response. In those patients in whom sputum eosinophilia was uncontrolled, greater VDP persisted postsalbutamol (P = 0.004). Postsalbutamol VDP correlated with sputum eosinophils (r = 0.63; P = 0.005)., Conclusions: In patients with severe asthma, MRI regionally identifies the inflammatory and noninflammatory components of airway disease. Ventilation heterogeneity persists postsalbutamol in patients with uncontrolled eosinophilic bronchitis, which may be the functional consequence of airway inflammation.