129Xe MRI Offers Detailed View of Pulmonary Function and Huge Clinical Potential

Hyperpolarized ¹²⁹xenon gas magnetic resonance imaging (¹²⁹Xe MRI) provides an incredibly detailed view of pulmonary function — and, in doing so, appears to hold tremendous clinical promise.

¹²⁹Xe MRI offers “an unprecedented look into fundamental function of the lung,” says Jason C. Woods, PhD, director for the Center of Pulmonary Imaging Research and a professor of pulmonary medicine and radiology at the Cincinnati Children’s Hospital and University of Cincinnati.

The imaging technology, which has been used as part of medical research for nearly 2 decades, is likely to be approved in the near future by the US Food and Drug Administration (FDA), Dr Woods added.

To gain insight into the clinical implications of this imaging modality for pulmonology medicine, Pulmonology Advisor interviewed Dr Woods along with Marrissa McIntosh and Kiran Kooner, doctoral candidates at Western University in Ontario, Canada, who have published research on ¹²⁹Xe MRI.¹

¹²⁹Xe MRI Defined

What is ¹²⁹Xe MRI?

McIntosh: ¹²⁹Xe MRI is a noninvasive tool that can be used to acquire pulmonary functional images. There are 3 main applications of this, which include imaging ventilation or ventilation heterogeneity, terminal airspace geometry, and gas transfer and microvascular perfusion. ¹²⁹Xe MRI uses an inhaled contrast agent that fills unobstructed regions of the lung, and will also diffuse from the alveoli, across the alveolar interstitial barrier, into the capillary and finally into the red blood cells (RBC). Hyperpolarizing this gas magnetically aligns the gas particles so that functional regions of the lung, as well as the gas uptake in the barrier and RBC, may be imaged using MRI during a single breath-hold acquisition. Regions that gas does not reach appear dark or void of signal, and these regions are described as ventilation abnormalities or defects. Ventilation defects have been shown to be related to structural abnormalities, including emphysema, mucus plugs, and air-trapping, as well as airway inflammation and remodeling.

Kooner: Alveolar microstructure and diameter can also be measured using ¹²⁹Xe MRI as the apparent diffusion coefficient (ADC). When the hyperpolarized gas travels to the alveolar level of the pulmonary airways, its diffusion or movement is restricted by the alveolar wall. Therefore, when the alveolus is enlarged, the MRI ADC values increase with the increased movement of the gas. In various pulmonary disease states, ¹²⁹Xe MRI ADC has been observed to relate to lung fibrosis, emphysema, and air-trapping. Moreover, although the majority of inhaled ¹²⁹Xe gas remains in the airspaces of the lungs, about 1% to 2% of the xenon will dissolve into the interstitial barrier and RBC.

McIntosh: Each of these 3 compartments (airspaces, barrier, RBC) will exhibit distinct resonance frequency shifts that can be measured to examine the gas uptake and gas exchange processes in the lungs. In this way, the ¹²⁹Xe signal in the gas exchange units and capillary beds allows for evaluation of pulmonary microvasculature. ¹²⁹Xe MRI is used in pulmonology because it allows for the visualization of functional abnormalities in vivo. The image acquisition is also safe, rapid (less than 30 seconds), and benefits from ionizing radiation-free imaging and contrast. In addition, this imaging tool provides information that cannot be gleaned from standard pulmonary function testing used in clinical settings by providing 3-dimensional information about the lungs, which is important for the inherently heterogeneous nature of many pulmonary disorders and disease states.

Dr Woods: ¹²⁹Xe MRI is an MRI of hyperpolarized xenon gas in the lungs. Xenon is a stable, noble gas, so it’s nonradioactive, safe, and the fact that we can generate a large excess of magnetization in the spins (ie, hyperpolarization) allows us to have high signal on the MRI. The technique is really an unprecedented look into fundamental function of the lung; ventilation images of xenon represent where the inhaled gas goes in the lung during a near-tidal inspiration. The US Food and Drug Administration approval is on the horizon, hopefully this autumn, so it’s an exciting time for those of us who do this kind of imaging.

Novel Uses

What are some exciting, new, or novel ways in which ¹²⁹Xe MRI is being used — or might be used — in the field of pulmonology?

McIntosh: The most recent advancements in ¹²⁹Xe MRI have been focused on dissolved phase imaging and spectroscopy, which involves the imaging techniques used to target the gas transfer and microvascular perfusion processes. There is much exciting and novel research being conducted to increase our understanding of the physiological mechanisms or pathophysiology relating to observed decreases or increases in these ¹²⁹Xe MRI signals in the interstitial barrier and RBC.

Kooner: ¹²⁹Xe magnetic resonance spectroscopy has been used to detect functional and vascular abnormalities in patients with post-acute coronavirus disease 2019 [COVID-19] syndrome or long-COVID, which also were shown to relate to exercise limitation and post-exertional dyspnea in these patients.^2,3 Interestingly, this ¹²⁹Xe MRI technique was also utilized to detect an asymptomatic atrial septal defect, which revealed that an increased RBC signal might be reflective of erythrocytosis in this patient.⁴ It will be exciting to see how the field continues to advance this particular technique and what we may learn about the relationships between ventilation and perfusion as a result.

Dr Woods: ¹²⁹Xe MRI has now been used in pediatric and adult lung imaging research for nearly 2 decades, so we have a wealth of prior knowledge of how ventilation can be quantified, and how it changes with exercise and treatment. With that said, there are myriad new ways that it’s being used in pulmonary medicine right now. There are 3 examples that can help illustrate this. In lung disease resulting from cystic fibrosis (CF),⁵ we’re just now gaining insight into how ventilation changes with highly effective CF transmembrane conductance regulator modulator treatment, via a multi-site clinical trial funded by the CF Foundation [ClinicalTrials.gov Identifier: NCT03482960]. Another example is in chronic obstructive pulmonary disease (COPD),⁶ where both airways and alveoli are affected; by measuring the apparent diffusion coefficient of the xenon gas during a brief breath hold, we can measure the actual alveolar-airspace size in the lungs. Alveolar-airspace measurements have big implications in future therapies to regrow alveoli. The last example is in diseases that affect the pulmonary capillary bed, like pulmonary hypertension.⁷ We can now measure the xenon dissolved in the interstitium/membrane and red blood cells separately, which allows an unprecedented look into actual gas exchange on a voxel-by-voxel basis. This means we can “see” areas with poor oxygen transfer and be able to measure changes with treatment, even regionally.

Clinical Implications

Recent research suggests ¹²⁹Xe MRI can measure asthma control following an initial dose of benralizumab, and the technique can also provide a detailed understanding of the lung’s response to endobronchial valve replacement.Why are these findings important? What are the potential clinical implications?

McIntosh: ¹²⁹Xe MRI has been used to evaluate and predict therapeutic response to benralizumab¹ as well as provide treatment targets for bronchial thermoplasty and endobronchial valve replacement.⁸ These findings are important because they suggest that the integration of imaging findings into clinical decision-making may help improve pulmonary disease management by improving patient quality-of-life quicker, slowing disease progression earlier, and reducing patient and healthcare costs. This will help achieve the overarching goal of delivering the right intervention, to the right patient, at the right time.

Dr Woods: The findings are important because it’s the first time we’ve been able to sensitively measure ventilation changes over time and with treatment, particularly with regional changes as sensitive as global changes. The clinical implications have largely to do with not only improved medicine, but in increasing the effectiveness of personalized medicine. If a patient treated with benralizumab responds well, we can measure that. If another patient doesn’t respond, we can switch drugs and determine more easily what works for that patient.

Limiting Factors

What are the limitations of ¹²⁹Xe MRI in pulmonology? How might these be addressed?

McIntosh: There are technological and clinical limitations of ¹²⁹Xe MRI in pulmonology. Hyperpolarization of the gas and image acquisition requires specialized equipment, including a polarizer, radiofrequency coil and MRI with multinuclear capabilities, as well as highly trained staff, for both image acquisition and image analysis. Although ¹²⁹Xe is cheaper than ³He gas, which has dominated the research field for decades, acquiring ¹²⁹Xe MRI still costs approximately $300/scan.

Kooner: Image acquisition and analysis is not yet standardized, and normal values are not established. Moreover, there is insufficient evidence about whether the integration of ¹²⁹Xe MRI truly improves patient outcomes. Due to these limitations, ¹²⁹Xe MRI is not yet approved by regulatory boards for widespread clinical or research use, except for special regulatory approval at a single center in the UK as an investigational medicinal product. Established ¹²⁹Xe MRI sites around the world have formed the ¹²⁹Xe MRI Clinical Trials Consortium, which is dedicated to facilitating clinical research, education, and awareness of the capabilities of ¹²⁹Xe MRI, to address these limitations.⁹

Dr Woods: The imaging requires specialized equipment and MRI scanners — so there’s a cost barrier for medical centers to get into the game, so to speak. And with it being a newer technology, there will be a learning curve as centers learn about the imaging and how to do it efficiently and well.

A New Horizon?

What other insights can you share regarding the applicability of ¹²⁹Xe MRI in pulmonology?

Kooner: Currently, although the use of ¹²⁹Xe MRI has been limited to research settings and clinical trials, it has been used to examine a wide range of pulmonary states, such as asthma, COPD, CF, interstitial lung disease, and lung transplantation,¹⁰ among many others. It has shown applicability in evaluating treatment response, guiding treatment intervention, phenotyping patients for precision medicine, and disease mapping. ¹²⁹Xe MRI has contributed to the growing body of evidence that pathophysiologic measurements at the site of disease are more sensitive than measurements made using conventional pulmonary function testing.

Dr Woods: With most exciting new scientific technologies and discoveries, even when we answer fundamental questions and help individual patients, scientists and physicians begin to ask new questions that build on past successes. I suspect we’ll see several new questions posed and answered about lung disease and its treatment in the coming years. It’s an exciting time to be involved in answering these fundamental questions about lung pathophysiology and improving patient outcomes.

References

1. McIntosh MJ, Kooner HK, Eddy RL, et al. Asthma control, airway mucus, and ¹²⁹Xe MRI ventilation after a single benralizumab dose. Published online March 10, 2022. Chest. 2022;S0012-3692(22)00424-X. doi:10.1016/j.chest.2022.03.003
2. Brick, P. Long COVID lung abnormalities: visualizing via CT vs 129Xenon MRI. Pulmonology Advisor. Published online June 7, 2022.
3. Grist JT, Collier GJ, Walters H, et al. Lung abnormalities depicted with hyperpolarized xenon MRI in patients with long COVID. Radiology. Published online May 24, 2022. doi:10.1148/radiol.220069
4. Matheson AM, Cunningham RSP, Bier E, et al. Hyperpolarized 129Xe Pulmonary MRI and Asymptomatic Atrial Septal Defect. Chest. 2022;161(4):e199-e202. doi:10.1016/j.chest.2021.11.020
5. Woods JC, Wild JM, Wielpütz MO, et al. Current state of the art MRI for the longitudinal assessment of cystic fibrosis. J Magn Reson Imaging. 2020;52(5):1306-1320. doi:10.1002/jmri.27030
6. Mummy DG, Coleman EM, Wang Z, et al. Regional gas exchange measured by 129 Xe magnetic resonance imaging before and after combination bronchodilators treatment in chronic obstructive pulmonary disease. J Magn Reson Imaging. 2021;54(3):964-974. doi:10.1002/jmri.27662
7. Bier EA, Alenezi F, Lu J, et al. Noninvasive diagnosis of pulmonary hypertension with hyperpolarised 129Xe magnetic resonance imaging and spectroscopy. ERJ Open Res. 2022;8(2):00035-2022. doi:10.1183/23120541.00035-2022
8. Hamedani H, Ma K, DiBardino D, et al. Simultaneous imaging of ventilation and gas exchange with hyperpolarized ¹²⁹Xe MRI for monitoring patients with endobronchial valve interventions. Am J Respir Crit Care Med. 2022;205(9):e48-e50. doi:10.1164/rccm.202106-1395IM
9. Niedbalski PJ, Hall CS, Castro M, et al. 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. Magn Reson Med. 2021;86(6):2966-2986. doi:10.1002/mrm.28985
10. Driehuys B, Mata J, Hartwig M, et al. Randomized Phase III Trial Assessing Regional Lung Function for Lung Transplant by Hyperpolarized 129Xenon Gas MRI. ERJ. 2020;56(suppl 64):2084; doi:10.1183/13993003.congress-2020.2084