Advances in COPD imaging using CT and MRI: linkage with lung physiology and clinical outcomes.

Recent years have witnessed major advances in lung imaging in patients with COPD. These include significant refinements in images obtained by computed tomography (CT) scans together with the introduction of new techniques and software that aim for obtaining the best image whilst using the lowest possible radiation dose. Magnetic resonance imaging (MRI) has also emerged as a useful radiation-free tool in assessing structural and more importantly functional derangements in patients with well-established COPD and smokers without COPD, even before the existence of overt changes in resting physiological lung function tests. Together, CT and MRI now allow objective quantification and assessment of structural changes within the airways, lung parenchyma and pulmonary vessels. Furthermore, CT and MRI can now provide objective assessments of regional lung ventilation and perfusion, and multinuclear MRI provides further insight into gas exchange; this can help in structured decisions regarding treatment plans. These advances in chest imaging techniques have brought new insights into our understanding of disease pathophysiology and characterising different disease phenotypes. The present review discusses, in detail, the advances in lung imaging in patients with COPD and how structural and functional imaging are linked with common resting physiological tests and important clinical outcomes.

Review of Hyperpolarized Pulmonary Functional 129 Xe MR for Long-COVID.

The respiratory consequences of acute COVID-19 infection and related symptoms tend to resolve 4 weeks post-infection. However, for some patients, new, recurrent, or persisting symptoms remain beyond the acute phase and persist for months, post-infection. The symptoms that remain have been referred to as long-COVID. A number of research sites employed 129 Xe magnetic resonance imaging (MRI) during the pandemic and evaluated patients post-infection, months after hospitalization or home-based care as a way to better understand the consequences of infection on 129 Xe MR gas-exchange and ventilation imaging. A systematic review and comprehensive search were employed using MEDLINE via PubMed (April 2023) using the National Library of Medicine's Medical Subject Headings and key words: post-COVID-19, MRI, 129 Xe, long-COVID, COVID pneumonia, and post-acute COVID-19 syndrome. Fifteen peer-reviewed manuscripts were identified including four editorials, a single letter to the editor, one review article, and nine original research manuscripts (2020-2023). MRI and MR spectroscopy results are summarized from these prospective, controlled studies, which involved small sample sizes ranging from 9 to 76 participants. Key findings included: 1) 129 Xe MRI gas-exchange and ventilation abnormalities, 3 months post-COVID-19 infection, and 2) a combination of MRI gas-exchange and ventilation abnormalities alongside persistent symptoms in patients hospitalized and not hospitalized for COVID-19, 1-year post-infection. The persistence of respiratory symptoms and 129 Xe MRI abnormalities in the context of normal or nearly normal pulmonary function test results and chest computed tomography (CT) was consistent. Longitudinal improvements were observed in long-term follow-up of long-COVID patients but mean 129 Xe gas-exchange, ventilation heterogeneity values and symptoms remained abnormal, 1-year post-infection. Pulmonary functional MRI using inhaled hyperpolarized 129 Xe gas has played a role in detecting gas-exchange and ventilation abnormalities providing complementary information that may help develop our understanding of the root causes of long-COVID. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.

Chest CT Airway and Vascular Measurements in Females with COPD or Long-COVID.

Chest CT provides a way to quantify pulmonary airway and vascular tree measurements. In patients with COPD, CT airway measurement differences in females are concomitant with worse quality-of-life and other outcomes. CT total airway count (TAC), airway lumen area (LA), and wall thickness (WT) also differ in females with long-COVID. Our objective was to evaluate CT airway and pulmonary vascular and quality-of-life measurements in females with COPD as compared to ex-smokers and patients with long-COVID. Chest CT was acquired 3-months post-COVID-19 infection in females with long-COVID for comparison with the same inspiratory CT in female ex-smokers and COPD patients. TAC, LA, WT, and pulmonary vascular measurements were quantified. Linear regression models were adjusted for confounders including age, height, body-mass-index, lung volume, pack-years and asthma diagnosis. Twenty-one females (53 ± 14 years) with long-COVID, 17 female ex-smokers (69 ± 9 years) and 13 female COPD (67 ± 6 years) patients were evaluated. In the absence of differences in quality-of-life scores, females with long-COVID reported significantly different LA (p = 0.006) compared to ex-smokers but not COPD (p = 0.7); WT% was also different compared to COPD (p = 0.009) but not ex-smokers (p = 0.5). In addition, there was significantly greater pulmonary small vessel volume (BV5) in long-COVID as compared to female ex-smokers (p = 0.045) and COPD (p = 0.003) patients and different large (BV10) vessel volume as compared to COPD (p = 0.03). In females with long-COVID and highly abnormal quality-of-life scores, there was CT evidence of airway remodelling, similar to ex-smokers and patients with COPD, but there was no evidence of pulmonary vascular remodelling.Clinical Trial Registration: www.clinicaltrials.gov NCT05014516 and NCT02279329.

Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities.

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=-0.7; 95%CI=-0.2 to -1.2, p=0.019), St George's Respiratory Questionnaire-score (SGRQ Δ=-6; 95% CI=-1 to -11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (ß = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

Sleep-disordered breathing symptoms and their association with structural and functional pulmonary changes in children born extremely preterm.

This study aimed to evaluate symptoms of sleep-disordered breathing (SDB) among children born extremely preterm, with and without a history of bronchopulmonary dysplasia (BPD), including associations between sleep and respiratory symptoms, physical activity, pulmonary function, and pulmonary magnetic resonance imaging (MRI). This multi-center cross-sectional study enrolled children aged 7-9 years born extremely preterm with and without BPD. Participants completed the Pediatric Sleep Questionnaire (PSQ), the modified Epworth sleepiness scale, a respiratory symptom questionnaire, pedometer measurements, pulmonary function testing, and pulmonary MRI. Spearman's correlations and univariate and multivariable linear regression modelling were performed. Twenty-eight of 45 children included had a history of moderate-to-severe BPD. The prevalence of sleep-related symptoms was low, with the exception of hyperactivity and inattention. There were no differences in mean (SD) scores on sleep questionnaires in children with and without BPD (PSQ: 0.21 (0.13) vs 0.16 (0.14), p = 0.3; modified Epworth: 2.4 (2.4) vs 1.8 (2.8), p = 0.4). Multiple regression analyses examining difference in sleep scores between groups, adjusting for gestational age and intraventricular hemorrhage, found no statistical difference (p > 0.05). Greater daytime sleepiness was moderately correlated with FEV1%-predicted (r = - 0.52); no other moderate-strong associations were identified.  Conclusions: There was no evidence of clinically important differences in sleep symptoms between children with and without BPD, suggesting that sleep symptoms may be related to prematurity-related factors other than a BPD diagnosis, including airflow limitation. Further research is necessary to explore the relationship between sleep symptoms, airway obstruction, and neurobehavioral symptoms among premature-born children.  Trial registration: NCT02921308. Date of registration: October 3, 2016. What is Known: • Presence of bronchopulmonary dysplasia (BPD) may further contribute to the development of SDB, though its impact is not well-studied. • Premature-born children have a greater risk of lung structural and functional differences, including sleep-disordered breathing (SDB). What is New: • There was no difference in sleep symptoms between children with and without BPD, suggesting that sleep symptoms are related to other prematurity-related factors, such as airflow limitation. • Greater daytime sleepiness was correlated with lower FEV1 in our population, which reflects greater airflow limitation.

Chest MRI and CT Predictors of 10-Year All-Cause Mortality in COPD.

Pulmonary imaging measurements using magnetic resonance imaging (MRI) and computed tomography (CT) have the potential to deepen our understanding of chronic obstructive pulmonary disease (COPD) by measuring airway and parenchymal pathologic information that cannot be provided by spirometry. Currently, MRI and CT measurements are not included in mortality risk predictions, diagnosis, or COPD staging. We evaluated baseline pulmonary function, MRI and CT measurements alongside imaging texture-features to predict 10-year all-cause mortality in ex-smokers with (n = 93; 31 females; 70 ± 9years) and without (n = 69; 29 females, 69 ± 9years) COPD. CT airway and vessel measurements, helium-3 (3He) MRI ventilation defect percent (VDP) and apparent diffusion coefficients (ADC) were quantified. MRI and CT texture-features were extracted using PyRadiomics (version2.2.0). Associations between 10-year all-cause mortality and all clinical and imaging measurements were evaluated using multivariable regression model odds-ratios. Machine-learning predictive models for 10-year all-cause mortality were evaluated using area-under-receiver-operator-characteristic-curve (AUC), sensitivity and specificity analyses. DLCO (%pred) (HR = 0.955, 95%CI: 0.934-0.976, p < 0.001), MRI ADC (HR = 1.843, 95%CI: 1.260-2.871, p < 0.001), and CT informational-measure-of-correlation (HR = 3.546, 95% CI: 1.660-7.573, p = 0.001) were the strongest predictors of 10-year mortality. A machine-learning model trained on clinical, imaging, and imaging textures was the best predictive model (AUC = 0.82, sensitivity = 83%, specificity = 84%) and outperformed the solely clinical model (AUC = 0.76, sensitivity = 77%, specificity = 79%). In ex-smokers, regardless of COPD status, addition of CT and MR imaging texture measurements to clinical models provided unique prognostic information of mortality risk that can allow for better clinical management.Clinical Trial Registration: www.clinicaltrials.gov NCT02279329.

Pulmonary Vascular Volume by Quantitative CT in Dyspneic Smokers with Minor Emphysema.

Reduced lung diffusing capacity for carbon monoxide (DLCO) at rest and increased ventilation (⩒E)-carbon dioxide output (⩒CO2) during exercise are frequent findings in dyspneic smokers with largely preserved FEV1. It remains unclear whether low DLCO and high ⩒E-⩒CO2 are mere reflections of alveolar destruction (i.e. emphysema) or impaired pulmonary perfusion in non-emphysematous tissue contributes to these functional abnormalities. Sixty-four smokers (41 males, FEV1= 84 ± 13%predicted) underwent pulmonary function tests, an incremental exercise test, and quantitative chest computed tomography. Total pulmonary vascular volume (TPVV) was calculated for the entire segmented vascular tree (VIDA Vision™). Using the median % low attenuation area (-950 HU), participants were dichotomized into "Trace" or "Mild" emphysema (E), each group classified into preserved versus reduced DLCO. Within each emphysema subgroup, participants with abnormally low DLCO showed lower TPVV, higher ⩒E-⩒CO2, and exertional dyspnea than those with preserved DLCO (p < 0.05). TPVV (r = 0.34; p = 0.01), but not emphysema (r = -0.05; p = 0.67), correlated with lower DLCO after adjusting for age and height. Despite lower emphysema burden, Trace-E participants with reduced DLCO had lower TPVV, higher dyspnea, and lower peak work rate than the Mild-E with preserved DLCO (p < 0.05). Interestingly, TPVV (but not emphysema) correlated inversely with both dyspnea-work rate (r = -0.36, p = 0.004) and dyspnea-⩒E slopes (r = -0.40, p = 0.001). Reduced pulmonary vascular volume adjusted by emphysema extent is associated with low DLCO and heightened exertional ventilation in dyspneic smokers with minor emphysema. Impaired perfusion of non-emphysematous regions of the lungs has greater functional and clinical consequences than hitherto assumed in these subjects.

Reduced Total Airway Count and Airway Wall Tapering after Three-Years in Ex-Smokers.

Computed tomography (CT) total-airway-count (TAC) and airway wall-thickness differ across chronic obstructive pulmonary disease (COPD) severities, but longitudinal insights are lacking. The aim of this study was to evaluate longitudinal CT airway measurements over three-years in ex-smokers. In this prospective convenience sample study, ex-smokers with (n = 50; 13 female; age = 70 ± 9 years; pack-years = 43 ± 26) and without (n = 40; 17 female; age = 69 ± 10 years; pack-years = 31 ± 17) COPD completed CT, 3He magnetic resonance imaging (MRI), and pulmonary function tests at baseline and three-year follow-up. CT TAC, airway wall-area (WA), lumen-area (LA), and wall-area percent (WA%) were generated. Emphysema was quantified as the relative-area-of-the-lung with attenuation < -950 Hounsfield-units (RA950). MRI ventilation-defect-percent (VDP) was also quantified. Differences over time were evaluated using paired-samples t tests. Multivariable prediction models using the backwards approach were generated. After three-years, forced-expiratory-volume in 1-second (FEV1) was not different in ex-smokers with (p = 0.4) and without (p = 0.5) COPD, whereas RA950 was (p < 0.001, p = 0.02, respectively). In ex-smokers without COPD, there was no change in TAC (p = 0.2); however, LA (p = 0.009) and WA% (p = 0.01) were significantly different. In ex-smokers with COPD, TAC (p < 0.001), WA (p = 0.04), LA (p < 0.001), and WA% (p < 0.001) were significantly different. In all ex-smokers, TAC was related to VDP (baseline: ρ = -0.30, p = 0.005; follow-up: ρ = -0.33, p = 0.002). In significant multivariable models, baseline airway wall-thickness was predictive of TAC worsening. After three-years, in the absence of FEV1 worsening, TAC diminished only in ex-smokers with COPD and airway walls were thinner in all ex-smokers. These longitudinal findings suggest that the evaluation of CT airway remodeling may be a useful clinical tool for predicting disease progression and managing COPD.Clinical trial registration: www.clinicaltrials.gov NCT02279329.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

Pulmonary MRI and Cluster Analysis Help Identify Novel Asthma Phenotypes.

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 (FEV1 %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 FEV1 with moderately abnormal VDP. Cluster2 (n = 12/12 female) reflected moderately abnormal TAC, WT and FEV1 . In Cluster3 and Cluster4 (n = 14/6 female, n = 4/1 female, respectively), there was severely reduced TAC, D and FEV1 , 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.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

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 (~mm3 ) 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.

Pulmonary Ventilation Maps Generated with Free-breathing Proton MRI and a Deep Convolutional Neural Network.

Background Hyperpolarized noble gas MRI helps measure lung ventilation, but clinical translation remains limited. Free-breathing proton MRI may help quantify lung function using existing MRI systems without contrast material and may assist in providing information about ventilation not visible to the eye or easily extracted with segmentation methods. Purpose To explore the use of deep convolutional neural networks (DCNNs) to generate synthetic MRI ventilation scans from free-breathing MRI (deep learning [DL] ventilation MRI)-derived specific ventilation maps as a surrogate of noble gas MRI and to validate this approach across a wide range of lung diseases. Materials and Methods In this secondary analysis of prospective trials, 114 paired noble gas MRI and two-dimensional free-breathing MRI scans were obtained in healthy volunteers with no history of chronic or acute respiratory disease and in study participants with a range of different obstructive lung diseases, including asthma, bronchiectasis, chronic obstructive pulmonary disease, and non-small-cell lung cancer between September 2013 and April 2018 (ClinicalTrials.gov identifiers: NCT03169673, NCT02351141, NCT02263794, NCT02282202, NCT02279329, and NCT02002052). A U-Net-based DCNN model was trained to map free-breathing proton MRI to hyperpolarized helium 3 (3He) MRI ventilation and validated using a sixfold validation. During training, the DCNN ventilation maps were compared with noble gas MRI scans using the Pearson correlation coefficient (r) and mean absolute error. DCNN ventilation images were segmented for ventilation and ventilation defects and were compared with noble gas MRI scans using the Dice similarity coefficient (DSC). Relationships were evaluated with the Spearman correlation coefficient (rS). Results One hundred fourteen study participants (mean age, 56 years ± 15 [standard deviation]; 66 women) were evaluated. As compared with 3He MRI, DCNN model ventilation maps had a mean r value of 0.87 ± 0.08. The mean DSC for DL ventilation MRI and 3He MRI ventilation was 0.91 ± 0.07. The ventilation defect percentage for DL ventilation MRI was highly correlated with 3He MRI ventilation defect percentage (rS = 0.83, P < .001, mean bias = -2.0% ± 5). Both DL ventilation MRI (rS = -0.51, P < .001) and 3He MRI (rS = -0.61, P < .001) ventilation defect percentage were correlated with the forced expiratory volume in 1 second. The DCNN model required approximately 2 hours for training and approximately 1 second to generate a ventilation map. Conclusion In participants with diverse pulmonary pathologic findings, deep convolutional neural networks generated ventilation maps from free-breathing proton MRI trained with a hyperpolarized noble-gas MRI ventilation map data set. The maps showed correlation with noble gas MRI ventilation and pulmonary function measurements. © RSNA, 2020 See also the editorial by Vogel-Claussen in this issue.

Pulmonary Functional Imaging: Part 2-State-of-the-Art Clinical Applications and Opportunities for Improved Patient Care.

Pulmonary functional imaging may be defined as the regional quantification of lung function by using primarily CT, MRI, and nuclear medicine techniques. The distribution of pulmonary physiologic parameters, including ventilation, perfusion, gas exchange, and biomechanics, can be noninvasively mapped and measured throughout the lungs. This information is not accessible by using conventional pulmonary function tests, which measure total lung function without viewing the regional distribution. The latter is important because of the heterogeneous distribution of virtually all lung disorders. Moreover, techniques such as hyperpolarized xenon 129 and helium 3 MRI can probe lung physiologic structure and microstructure at the level of the alveolar-air and alveolar-red blood cell interface, which is well beyond the spatial resolution of other clinical methods. The opportunities, challenges, and current stage of clinical deployment of pulmonary functional imaging are reviewed, including applications to chronic obstructive pulmonary disease, asthma, interstitial lung disease, pulmonary embolism, and pulmonary hypertension. Among the challenges to the deployment of pulmonary functional imaging in routine clinical practice are the need for further validation, establishment of normal values, standardization of imaging acquisition and analysis, and evidence of patient outcomes benefit. When these challenges are addressed, it is anticipated that pulmonary functional imaging will have an expanding role in the evaluation and management of patients with lung disease.

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.

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.

Is Computed Tomography Airway Count Related to Asthma Severity and Airway Structure and Function?

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 3He 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 FEV1 (R2 = 0.27; P = 0.003) and, in a separate model, TAC (standardized regression coefficient = -0.53; P < 0.0001) independently predicted airway WA% (R2 = 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).

Reduced Cognitive Assessment Scores Among Individuals With Magnetic Resonance Imaging-Detected Vascular Brain Injury.

Background and Purpose- Little is known about the association between covert vascular brain injury and cognitive impairment in middle-aged populations. We investigated if scores on a cognitive screen were lower in individuals with higher cardiovascular risk, and those with covert vascular brain injury. Methods- Seven thousand five hundred forty-seven adults, aged 35 to 69 years, free of cardiovascular disease underwent a cognitive assessment using the Digital Symbol Substitution test and Montreal Cognitive Assessment, and magnetic resonance imaging (MRI) to detect covert vascular brain injury (high white matter hyperintensities, lacunar, and nonlacunar brain infarctions). Cardiovascular risk factors were quantified using the INTERHEART (A Global Study of Risk Factors for Acute Myocardial Infarction) risk score. Multivariable mixed models tested for independent determinants of reduced cognitive scores. The population attributable risk of risk factors and MRI vascular brain injury on low cognitive scores was calculated. Results- The mean age of participants was 58 (SD, 9) years; 55% were women. Montreal Cognitive Assessment and Digital Symbol Substitution test scores decreased significantly with increasing age (P<0.0001), INTERHEART risk score (P<0.0001), and among individuals with high white matter hyperintensities, nonlacunar brain infarction, and individuals with 3+ silent brain infarctions. Adjusted for age, sex, education, ethnicity covariates, Digital Symbol Substitution test was significantly lowered by 1.0 (95% CI, -1.3 to -0.7) point per 5-point cardiovascular risk score increase, 1.9 (95% CI, -3.2 to -0.6) per high white matter hyperintensities, 3.5 (95% CI, -6.4 to -0.7) per nonlacunar stroke, and 6.8 (95% CI, -11.5 to -2.2) when 3+ silent brain infarctions were present. No postsecondary education accounted for 15% (95% CI, 12-17), moderate and high levels of cardiovascular risk factors accounted for 19% (95% CI, 8-30), and MRI vascular brain injury accounted for 10% (95% CI, -3 to 22) of low test scores. Conclusions- Among a middle-aged community-dwelling population, scores on a cognitive screen were lower in individuals with higher cardiovascular risk factors or MRI vascular brain injury. Much of the population attributable risk of low cognitive scores can be attributed to lower educational attainment, higher cardiovascular risk factors, and MRI vascular brain injury.

Pulmonary Imaging Phenotypes of Chronic Obstructive Pulmonary Disease Using Multiparametric Response Maps.

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 (3He) 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 (FEV1) (r = 0.65, P < .001), the FEV1-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 FEV1 (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.

Expanding Applications of Pulmonary MRI in the Clinical Evaluation of Lung Disorders: Fleischner Society Position Paper.

Pulmonary MRI provides structural and quantitative functional images of the lungs without ionizing radiation, but it has had limited clinical use due to low signal intensity from the lung parenchyma. The lack of radiation makes pulmonary MRI an ideal modality for pediatric examinations, pregnant women, and patients requiring serial and longitudinal follow-up. Fortunately, recent MRI techniques, including ultrashort echo time and zero echo time, are expanding clinical opportunities for pulmonary MRI. With the use of multicoil parallel acquisitions and acceleration methods, these techniques make pulmonary MRI practical for evaluating lung parenchymal and pulmonary vascular diseases. The purpose of this Fleischner Society position paper is to familiarize radiologists and other interested clinicians with these advances in pulmonary MRI and to stratify the Society recommendations for the clinical use of pulmonary MRI into three categories: (a) suggested for current clinical use, (b) promising but requiring further validation or regulatory approval, and (c) appropriate for research investigations. This position paper also provides recommendations for vendors and infrastructure, identifies methods for hypothesis-driven research, and suggests opportunities for prospective, randomized multicenter trials to investigate and validate lung MRI methods.