Lung Abnormalities Detected with Hyperpolarized 129Xe MRI in Patients with Long COVID.

Background Post-COVID-19 condition encompasses symptoms following COVID-19 infection that linger at least 4 weeks after the end of active infection. Symptoms are wide ranging, but breathlessness is common. Purpose To determine if the previously described lung abnormalities seen on hyperpolarized (HP) pulmonary xenon 129 (129Xe) MRI scans in participants with post-COVID-19 condition who were hospitalized are also present in participants with post-COVID-19 condition who were not hospitalized. Materials and Methods In this prospective study, nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) were enrolled from June 2020 to August 2021. Participants underwent chest CT, HP 129Xe MRI, pulmonary function testing, and the 1-minute sit-to-stand test and completed breathlessness questionnaires. Control subjects underwent HP 129Xe MRI only. CT scans were analyzed for post-COVID-19 interstitial lung disease severity using a previously published scoring system and full-scale airway network (FAN) modeling. Analysis used group and pairwise comparisons between participants and control subjects and correlations between participant clinical and imaging data. Results A total of 11 NHLC participants (four men, seven women; mean age, 44 years ± 11 [SD]; 95% CI: 37, 50) and 12 PHC participants (10 men, two women; mean age, 58 years ±10; 95% CI: 52, 64) were included, with a significant difference in age between groups (P = .05). Mean time from infection was 287 days ± 79 (95% CI: 240, 334) and 143 days ± 72 (95% CI: 105, 190) in NHLC and PHC participants, respectively. NHLC and PHC participants had normal or near normal CT scans (mean, 0.3/25 ± 0.6 [95% CI: 0, 0.63] and 7/25 ± 5 [95% CI: 4, 10], respectively). Gas transfer (Dlco) was different between NHLC and PHC participants (mean Dlco, 76% ± 8 [95% CI: 73, 83] vs 86% ± 8 [95% CI: 80, 91], respectively; P = .04), but there was no evidence of other differences in lung function. Mean red blood cell-to-tissue plasma ratio was different between volunteers (mean, 0.45 ± 0.07; 95% CI: 0.43, 0.47]) and PHC participants (mean, 0.31 ± 0.10; 95% CI: 0.24, 0.37; P = .02) and between volunteers and NHLC participants (mean, 0.37 ± 0.10; 95% CI: 0.31, 0.44; P = .03) but not between NHLC and PHC participants (P = .26). FAN results did not correlate with Dlco) or HP 129Xe MRI results. Conclusion Nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) showed hyperpolarized pulmonary xenon 129 MRI and red blood cell-to-tissue plasma abnormalities, with NHLC participants demonstrating lower gas transfer than PHC participants despite having normal CT findings. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Parraga and Matheson in this issue.

Imaging Dynamic Expiration: Feasibility of MRI Spirometry Using Hyperpolarized Xenon Gas.

PURPOSE: To examine the feasibility of imaging-based spirometry using high-temporal-resolution projection MRI and hyperpolarized xenon 129 (129Xe) gas. MATERIALS AND METHODS: In this prospective exploratory study, five healthy participants (age range, 25-45 years; three men) underwent an MRI spirometry technique using inhaled hyperpolarized 129Xe and rapid two-dimensional projection MRI. Participants inhaled 129Xe, then performed a forced expiratory maneuver while in an MR imager. Images of the lungs during expiration were captured in time intervals as short as 250 msec. Volume-corrected images of the lungs at expiration commencement (0 second), 1 second after expiration, and 6 seconds after expiration were extracted to generate forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio pulmonary maps. For comparison, participants performed conventional spirometry in the sitting position using room air, in the supine position using room air, and in the supine position using a room air and 129Xe mixture. Paired t tests with Bonferroni corrections for multiple comparisons were used for statistical analyses. RESULTS: The mean MRI-derived FEV1/FVC value was lower in comparison with conventional spirometry (0.52 ± 0.03 vs 0.70 ± 0.05, P < .01), which may reflect selective 129Xe retention. A secondary finding of this study was that 1 L of inhaled 129Xe negatively impacted pulmonary function as measured by conventional spirometry (in supine position), which reduced measured FEV1 (2.70 ± 0.90 vs 3.04 ± 0.85, P < .01) and FEV1/FVC (0.70 ± 0.05 vs 0.79 ± 0.04, P < .01). CONCLUSION: A forced expiratory maneuver was successfully imaged with hyperpolarized 129Xe and high-temporal-resolution MRI. Derivation of regional lung spirometric maps was feasible.Keywords: MR-Imaging, MR-Dynamic Contrast Enhanced, MR-Functional Imaging, Pulmonary, Thorax, Diaphragm, Lung, Pleura, Physics Supplemental material is available for this article. © RSNA, 2021.

High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation.

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Patients 3 Months after COVID-19 Pneumonia: Preliminary Results.

Background SARS-CoV-2 targets angiotensin-converting enzyme 2-expressing cells in the respiratory tract. There are reports of breathlessness in patients many months after infection. Purpose To determine whether hyperpolarized xenon 129 MRI (XeMRI) imaging could be used to identify the possible cause of breathlessness in patients at 3 months after hospital discharge following COVID-19 infection. Materials and Methods This prospective study was undertaken between August and December of 2020, with patients and healthy control volunteers being enrolled. All patients underwent lung function tests; ventilation and dissolved-phase XeMRI, with the mean red blood cell (RBC) to tissue or plasma (TP) ratio being calculated; and a low-dose chest CT, with scans being scored for the degree of abnormalities after COVID-19. Healthy control volunteers underwent XeMRI. The intraclass correlation coefficient was calculated for volunteer and patient scans to assess repeatability. A Wilcoxon rank sum test and Cohen effect size calculation were performed to assess differences in the RBC/TP ratio between patients and control volunteers. Results Nine patients (mean age, 57 years ± 7 [standard deviation]; six male patients) and five volunteers (mean age, 29 years ± 3; five female volunteers) were enrolled. The mean time from hospital discharge for patients was 169 days (range, 116-254 days). There was a difference in the RBC/TP ratio between patients and control volunteers (0.3 ± 0.1 vs 0.5 ± 0.1, respectively; P = .001; effect size, 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum between volunteers and patients (median ± range, 567 ± 1 vs 507 ± 81 [P = .002] and 104 ± 2 vs 122 ± 17 [P = .004], respectively). Results were reproducible, with intraclass correlation coefficients of 0.82 and 0.88 being demonstrated for patients and volunteers, respectively. Participants had normal or nearly normal CT scans (mean, seven of 25; range, zero of 25 to 10 of 25). Conclusion Hyperpolarized xenon 129 MRI results showed alveolar capillary diffusion limitation in all nine patients after COVID-19 pneumonia, despite normal or nearly normal results at CT. © RSNA, 2021 See also the editorial by Dietrich in this issue.

MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies.

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.

A case series of thoracic dynamic contrast-enhanced MR lymphangiography: technique and applications.

Dynamic contrast-enhanced magnetic resonance lymphangiography is a radiation-free, high spatial resolution technique which is increasingly used to evaluate thoracic lymphatic disorders and for pre-procedural planning. DCE has the added advantage of allowing dynamic real-time evaluation of lymphatic flow. It can be employed to investigate commonly encountered clinical situations such as recurrent pleural effusions following trauma, thoracic duct injury after thoracic surgery, and exclude diseases and congenital malformations of the thoracic lymphatic system. The imaging procedure and protocol are detailed in this case series to highlight the application of dynamic contrast-enhanced magnetic resonance lymphangiography in everyday practice and its importance to guide surgical planning.

Use of high frequency jet ventilation as a refinement for imaging macaques with respiratory disease.

Imaging is used in human medicine to diagnose disease and monitor treatment efficacy. Computed tomography (CT) positron emission tomography (PET) and magnetic resonance (MR) are applied to animal models of infectious diseases to increase data quality, enhance their relevance to the clinical situation, and to address ethical issues through reduction of numbers and refinement of study designs. The time required for collection of MR and PET-CT scans means that normal breathing produces motion artefacts that can render images unacceptable. We report, for the first time, the use of high frequency jet ventilation (HFJV) for respiratory management during imaging of macaques. HFJV enables continuous gaseous exchange, resulting in cessation of spontaneous breathing motion thus providing a motionless field without the potential stresses induced by repeated breath-hold strategies.

Delayed ventilation assessment using fast dynamic hyperpolarised Xenon-129 magnetic resonance imaging.

OBJECTIVES: To investigate the use of a fast dynamic hyperpolarised 129Xe ventilation magnetic resonance imaging (DXeV-MRI) method for detecting and quantifying delayed ventilation in patients with chronic obstructive pulmonary disease (COPD). METHODS: Three male participants (age range 31-43) with healthy lungs and 15 patients (M/F = 12:3, age range = 48-73) with COPD (stages II-IV) underwent spirometry tests, quantitative chest computed tomography (QCT), and DXeV-MRI at 1.5-Tesla. Regional delayed ventilation was captured by measuring the temporal signal change in each lung region of interest (ROI) in comparison to that in the trachea. In addition to its qualitative assessment through visual inspection by a clinical radiologist, delayed ventilation was quantitatively captured by calculating a covariance measurement of the lung ROI and trachea signals, and quantified using both the time delay, and the difference between the integrated areas covered by the signal-time curves of the two signals. RESULTS: Regional temporal ventilation, consistent with the expected physiological changes across a free breathing cycle, was demonstrated with DXeV-MRI in all patients. Delayed ventilation was observed in 13 of the 15 COPD patients and involved variable lung ROIs. This was in contrast to the control group, where no delayed ventilation was demonstrated (p = 0.0173). CONCLUSIONS: DXeV-MRI offers a non-invasive way of detecting and quantifying delayed ventilation in patients with COPD, and provides physiological information on regional pulmonary function during a full breathing cycle. KEY POINTS: • Dynamic xenon MRI allows for the non-invasive detection and measurement of delayed ventilation in COPD patients. • Dynamic xenon MRI during a free breathing cycle can provide unique information about pulmonary physiology and pulmonary disease pathophysiology. • With further validation, dynamic xenon MRI could offer a non-invasive way of measuring collateral ventilation which can then be used to guide lung volume reduction therapy (LVRT) for certain COPD patients.

Magnetic resonance imaging of the time course of hyperpolarized 129Xe gas exchange in the human lungs and heart.

PURPOSE: To perform magnetic resonance imaging (MRI), human lung imaging, and quantification of the gas-transfer dynamics of hyperpolarized xenon-129 (HPX) from the alveoli into the blood plasma. MATERIALS AND METHODS: HPX MRI with iterative decomposition of water and fat with echo asymmetry and least-square estimation (IDEAL) approach were used with multi-interleaved spiral k-space sampling to obtain HPX gas and dissolved phase images. IDEAL time-series images were then obtained from ten subjects including six normal subjects and four patients with pulmonary emphysema to test the feasibility of the proposed technique for capturing xenon-129 gas-transfer dynamics (XGTD). The dynamics of xenon gas diffusion over the entire lung was also investigated by measuring the signal intensity variations between three regions of interest, including the left and right lungs and the heart using Welch's t test. RESULTS: The technique enabled the acquisition of HPX gas and dissolved phase compartment images in a single breath-hold interval of 8 s. The y-intersect of the XGTD curves were also found to be statistically lower in the patients with lung emphysema than in the healthy group (p < 0.05). CONCLUSION: This time-series IDEAL technique enables the visualization and quantification of inhaled xenon from the alveoli to the left ventricle with a clinical gradient strength magnet during a single breath-hold, in healthy and diseased lungs. KEY POINTS: • The proposed hyperpolarized xenon-129 gas and dissolved magnetic resonance imaging technique can provide regional and temporal measurements of xenon-129 gas-transfer dynamics. • Quantitative measurement of xenon-129 gas-transfer dynamics from the alveolar to the heart was demonstrated in normal subjects and pulmonary emphysema. • Comparison of gas-transfer dynamics in normal subjects and pulmonary emphysema showed that the proposed technique appears sensitive to changes affecting the alveoli, pulmonary interstitium, and capillaries.

Time-series hyperpolarized xenon-129 MRI of lobar lung ventilation of COPD in comparison to V/Q-SPECT/CT and CT.

PURPOSE: To derive lobar ventilation in patients with chronic obstructive pulmonary disease (COPD) using a rapid time-series hyperpolarized xenon-129 (HPX) magnetic resonance imaging (MRI) technique and compare this to ventilation/perfusion single-photon emission computed tomography (V/Q-SPECT), correlating the results with high-resolution computed tomography (CT) and pulmonary function tests (PFTs). MATERIALS AND METHODS: Twelve COPD subjects (GOLD stages I-IV) participated in this study and underwent HPX-MRI, V/Q-SPECT/CT, high-resolution CT, and PFTs. HPX-MRI was performed using a novel time-series spiral k-space sampling approach. Relative percentage ventilations were calculated for individual lobe for comparison to the relative SPECT lobar ventilation and perfusion. The absolute HPX-MRI percentage ventilation in each lobe was compared to the absolute CT percentage emphysema score calculated using a signal threshold method. Pearson's correlation and linear regression tests were performed to compare each imaging modality. RESULTS: Strong correlations were found between the relative lobar percentage ventilation with HPX-MRI and percentage ventilation SPECT (r = 0.644; p < 0.001) and percentage perfusion SPECT (r = 0.767; p < 0.001). The absolute CT percentage emphysema and HPX percentage ventilation correlation was also statistically significant (r = 0.695, p < 0.001). The whole lung HPX percentage ventilation correlated with the PFT measurements (FEV1 with r = - 0.886, p < 0.001*, and FEV1/FVC with r = - 0.861, p < 0.001*) better than the whole lung CT percentage emphysema score (FEV1 with r = - 0.635, p = 0.027; and FEV1/FVC with r = - 0.652, p = 0.021). CONCLUSION: Lobar ventilation with HPX-MRI showed a strong correlation with lobar ventilation and perfusion measurements derived from SPECT/CT, and is better than the emphysema score obtained with high-resolution CT. KEY POINTS: • The ventilation hyperpolarized xenon-129 MRI correlates well with ventilation and perfusion with SPECT/CT with the advantage of higher temporal and spatial resolution. • The hyperpolarized xenon-129 MRI correlates with the PFT measurements better than the high-resolution CT with the advantage of avoiding the use of ionizing radiation.

Refinement and reduction through application of a quantitative score system for estimation of TB-induced disease burden using computed tomography.

Until validated correlates of protection are identified, animal models remain the only way to test the efficacy of the new vaccines and drugs urgently needed to fight the global epidemic caused by infection with Mycobacterium tuberculosis. Non-human primates (NHP) offer the most relevant models of human tuberculosis (TB) and are central to the development process for new interventions. Efficacy evaluations are dependent on the capability of the test model to discriminate improved outcomes between treated groups after experimental exposure to M. tuberculosis and therefore the ability to measure TB-induced disease burden is central to the process. We have developed a score system that allows us to quantify the disease burden induced in macaques by infection with M. tuberculosis, based on the extent and features of disease visible on computed tomography (CT) images. The CT determined disease burden was then verified against that obtained using an established pathology-based approach. Trials of the system as a tool to measure disease burden have shown the approach capable of revealing differences between treatment groups in order to: (a) characterise outcome of infection and enable model refinement; (b) demonstrate the efficacy of drug treatment regimens by showing differences in outcome between test groups. Initial trials suggest that the imaging-based score system provides a valuable additional tool for the measurement of TB-induced disease burden that offers the opportunity to apply both refinement and reduction within studies.

Fast dynamic ventilation MRI of hyperpolarized 129 Xe using spiral imaging.

PURPOSE: To develop and optimize a rapid dynamic hyperpolarized 129 Xe ventilation (DXeV) MRI protocol and investigate the feasibility of capturing pulmonary signal-time curves in human lungs. THEORY AND METHODS: Spiral k-space trajectories were designed with the number of interleaves Nint = 1, 2, 4, and 8 corresponding to voxel sizes of 8 mm, 5 mm, 4 mm, and 2.5 mm, respectively, for field of view = 15 cm. DXeV images were acquired from a gas-flow phantom to investigate the ability of Nint = 1, 2, 4, and 8 to capture signal-time curves. A finite element model was constructed to investigate gas-flow dynamics corroborating the experimental signal-time curves. DXeV images were also carried out in six subjects (three healthy and three chronic obstructive pulmonary disease subjects). RESULTS: DXeV images and numerical modelling of signal-time curves permitted the quantification of temporal and spatial resolutions for different numbers of spiral interleaves. The two-interleaved spiral (Nint = 2) was found to be the most time-efficient to obtain DXeV images and signal-time curves of whole lungs with a temporal resolution of 624 ms for 13 slices. Signal-time curves were well matched in three healthy volunteers. The Spearman's correlations of chronic obstructive pulmonary disease subjects were statistically different from three healthy subjects (P < 0.05). CONCLUSION: The Nint = 2 spiral demonstrates the successful acquisition of DXeV images and signal-time curves in healthy subjects and chronic obstructive pulmonary disease patients. Magn Reson Med 79:2597-2606, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Ultra low dose aerosol challenge with Mycobacterium tuberculosis leads to divergent outcomes in rhesus and cynomolgus macaques.

Well characterised animal models that can accurately predict efficacy are critical to the development of an improved TB vaccine. The use of high dose challenge for measurement of efficacy in Non-human primate models brings the risk that vaccines with the potential to be efficacious against natural challenge could appear ineffective and thus disregarded. Therefore, there is a need to develop a challenge regimen that is more relevant to natural human infection. This study has established that ultra-low dose infection of macaques via the aerosol route can be reproducibly achieved and provides the first description of the development of TB disease in both rhesus and cynomolgus macaques following exposure to estimated retained doses in the lung of less than 10 CFU of Mycobacterium tuberculosis. CT scanning in vivo and histopathology revealed differences in the progression and burden of disease between the two species. Rhesus macaques exhibited a more progressive disease and cynomolgus macaques showed a reduced disease burden. The ability to deliver reproducible ultra-low dose aerosols to macaques will enable the development of refined models of M. tuberculosis infection for evaluation of the efficacy of novel tuberculosis vaccines that offers increased clinical relevance and improved animal welfare.

Route of delivery to the airway influences the distribution of pulmonary disease but not the outcome of Mycobacterium tuberculosis infection in rhesus macaques.

Non-human primates (NHP) provide a key component in the preclinical assessment pathway for new TB vaccines. In the established models, Mycobacterium tuberculosis challenge is typically delivered to airways of macaques either by aerosol or bronchoscopic instillation and therefore, an understanding of these delivery routes would facilitate the comparison of data generated from models using different challenge methods. This study compared the clinical effects, antigen-specific IFNγ response profiles and disease burden following delivery of comparable doses of M. tuberculosis to the lungs of rhesus macaques by either aerosol or bronchoscopic instillation. The outcome of infection in terms of clinical effects and overall disease burden was comparable between both routes of challenge. However, the pathology in the lungs differed as disease was localised to the site of inoculation following bronchoscopic instillation while aerosol exposure resulted in lesions being evenly distributed through the lung. Whilst the IFNγ response to PPD was similar, responses to CFP10 and ESAT6 peptide pools measured with an ex vivo ELISPOT differed with regards to responses to the N-terminal regions depending on the route of infection. Both challenge routes therefore provide valid and comparable models for evaluation of new TB vaccines, although subtle differences in host responses may occur.

MRI for definitive in utero diagnosis of cleft palate: a useful adjunct to antenatal care?

OBJECTIVE: To assess the use of fetal magnetic resonance imaging (MRI) in obtaining a definitive prenatal diagnosis of cleft palate. DESIGN: All expectant mothers with a sonographically diagnosed fetal cleft lip or a previously affected child with cleft palate were offered antenatal MRI at around 34 weeks' gestation. Images were interpreted by a consultant radiologist who was blinded to the ultrasound diagnosis. Two MRI readings were performed: one at the time of examination and one at the end of the study to elicit the radiologist's learning curve. MRI findings were correlated with the birth diagnosis. SETTING: Tertiary referral center for facial clefts--the Spires Cleft Centre, Oxford Children's Hospital, Oxford, United Kingdom. PARTICIPANTS: Study participants included 49 pregnant women between 24 and 37 weeks' gestation, four with a family history of cleft posterior palate and 45 with a facial cleft on a 20-week ultrasound. RESULTS: The positive predictive value of fetal MRI for involvement of the palate was 96%, and the negative predictive value was 80%. The accuracy in predicting palatal clefting of four different MRI signs is discussed. The radiologist's interpretation skills significantly improved between the two MRI readings. CONCLUSIONS: Fetal MRI enables us to predict accurately the extent of a cleft palate after an ultrasound diagnosis of cleft lip. With more accurate diagnosis of the severity of the cleft, we can counsel patients more precisely and plan postnatal management correctly.