Xenon-129 magnetic resonance: a paradigm shift, an expensive toy or another tool for the pulmonologist?

Extract

The human lung is a complex organ with multiple anatomical compartments, varied tissue constituents and an intricate fractal structure optimised for gas exchange [1]. This sophistication makes objective measurement of the severity of chronic lung disease challenging [2]. Traditional functional measurements like spirometry and structural assessments using high-resolution computed tomography (HRCT) only offer fragmentary insight into severity, akin to the parable of the six blind men and the elephant (in this parable, six men touch different parts of an elephant and describe it wildly differently, arguing over who is right until a wise person explains they each perceive only a fragment of the whole truth).

Shareable abstract

The current place of ¹²⁹Xe magnetic resonance in evaluation of lung disease in children with primary ciliary dyskinesia and similar airway diseases, and a proposed monitoring pathway in combination with existing tools https://bit.ly/4eF8SGG

The human lung is a complex organ with multiple anatomical compartments, varied tissue constituents and an intricate fractal structure optimised for gas exchange [1]. This sophistication makes objective measurement of the severity of chronic lung disease challenging [2]. Traditional functional measurements like spirometry and structural assessments using high-resolution computed tomography (HRCT) only offer fragmentary insight into severity, akin to the parable of the six blind men and the elephant (in this parable, six men touch different parts of an elephant and describe it wildly differently, arguing over who is right until a wise person explains they each perceive only a fragment of the whole truth). A composite assessment is vital for tracking progression, estimating prognosis and assessing therapeutic efficacy and clinical trial outcomes. This is even more critical in paediatric lung disease, where the inherent plasticity of the developing lung provides a critical therapeutic window to attenuate or reverse long-term structural and functional sequelae [3]. Since the turn of the century, numerous advances have improved quantification of lung disease severity, particularly in children with cystic fibrosis (CF) [4].

However, quantifying and tracking disease progression in primary ciliary dyskinesia (PCD) remains challenging. Although CF and PCD both impair mucociliary clearance, their pathophysiology differs. CF predominantly increases mucus viscosity, whereas PCD results from structural/functional defects in motile cilia with secondary mucus changes from inflammation [5]. Whilst some overlap exists, the pattern of symptoms also differs between PCD and CF with symptoms in PCD being almost perpetual from birth, reflecting continuous mucociliary impairment rather than episodic decline.

Similar to CF, spirometry is insensitive to early/mild small airway obstruction in PCD [6]. Many children maintain near–normal forced expiratory volume in 1 s (FEV₁) despite significant symptoms and spirometry may underestimate ongoing disease progression (e.g. bronchiectasis). Although chest HRCT is the gold standard to assess bronchiectasis, serial scanning is not recommended [7] due to cumulative radiation exposure [8], making early structural monitoring especially challenging.

Multiple breath washout (MBW) assesses ventilation inhomogeneity and is particularly useful for assessing peripheral airways. Lung clearance index (LCI) is the most widely used parameter derived from MBW [9]. LCI has been shown to be more sensitive than spirometry in detecting functional and structural changes in the lung in CF [4, 10], and is now widely used clinically and in CF trials. The use of LCI in PCD has a more complex history with some earlier studies using sulfur hexafluoride (SF₆) washout showing poor correlation with structural (HRCT) and functional (FEV₁) parameters [11]. However, a recent systematic review of 14 studies [12] reported that LCI is more sensitive than FEV₁ in detecting structural changes in PCD, akin to CF lung disease.

Sensitivity towards early lung disease and standardised protocols have led to increased adoption of MBW [13] particularly in paediatrics given it avoids forced expiration or complex manoeuvres. However, LCI amalgamates all structural and functional information into a single metric. Opening previously non-ventilated regions (e.g. through physiotherapy) may paradoxically worsen LCI, whilst completely non-ventilated areas, (e.g. atelectasis with complete airway blockage) may not contribute to LCI at all.

Oscillometry is another non-invasive technique nearing wider clinical use. Despite complex underlying principles, it is simple to perform [14], and well suited to paediatrics. Technical standards have been published [15]. Parameters derived from oscillometry have been found to be related to quality of life (QoL-PCD) [16], and development of bronchiectasis [17] in small cross-sectional studies in PCD.

While these techniques provide deeper insight into lung health in PCD than spirometry, imaging techniques such as HRCT are required for precise localising information. Standard (proton (¹H)) magnetic resonance (MR) has historically been impractical in paediatric lung imaging, partly due to low water density limiting available MR signal. MR using inhaled noble gases, 3-Helium (³He) and 129-Xenon (¹²⁹Xe), as “contrast agents” surmount this limitation. These isotopes have non-zero nuclear spins, making them responsive to magnetic fields and MR sequences can “visualise” them [18], following “hyperpolarisation” (i.e. nuclear spins being aligned far beyond normal (thermal) levels).

³He and ¹²⁹Xe are inherently safe, non-toxic and chemically inert, though xenon does have an anaesthetic effect at high concentrations due to its solubility in parenchymal tissue and blood. A major advantage of hyperpolarised gas MR is its ability to accurately quantify and visually represent areas of ventilation defects (inhomogeneities) integrating assessment of both lung structure and function.

In this issue of ERJ Open Research, Schofield et al. [19] report the use of ¹²⁹Xe-MR to assess ventilation distribution defects alongside ¹H-MR for structural evaluation in children with PCD. In this cross-sectional study, they found functional abnormalities (raised ventilation defect percentage (VDP)) on ¹²⁹Xe-MR in 71.4% of the children, and in about 75% of those with normal FEV₁ z-score. The authors conclude that ¹²⁹Xe-MR detects ventilation abnormalities in most children with PCD, even when spirometry appears normal. It is commendable that the authors attempted to correlate data with QoL-PCD and ultrastructural abnormalities, starting to provide useful insights into the various pheno- and genotypes of PCD [20]. However, LCI was not evaluated in the study. Wee et al. [21] investigated ¹²⁹Xe-MR in PCD and showed strong positive correlation between VDP and LCI. Although they used a higher VDP cut-off than the current study, all participants had elevated VDP, while only 53% had abnormal LCI and 19% had abnormal FEV₁%.

In 2018, Smith et al. [22] published similar findings using ³HeMR in children with PCD alongside LCI using 0.2% SF₆ MBW. VDP was abnormal in all patients and showed significant correlation with LCI. Notably, some children with normal LCI had abnormal VDP. This follows on from another cross-sectional study looking at ³He-MR, SF₆ LCI and spirometry in paediatric CF [23], where unventilated volume percentage derived from ³He-MR was elevated in 89%; as opposed to elevated LCI in 47% of participants. These exciting findings led us to reconsider the place of hyperpolarised gas MR in the armamentarium of the paediatric pulmonologist, particularly in the evaluation of chronic suppurative lung disease (CSLD).

Beyond avoiding radiation exposure, ¹²⁹Xe-MR offers several advantages. Because it requires only a short breath-hold, it is feasible and well tolerated in children over six years of age, facilitating repeat measurements. Hence, parameters derived from ¹²⁹Xe-MR are potential outcome measures for clinical trials and other comparative studies, which is exciting given recent accelerated novel therapy developments in PCD and bronchiectasis [24]. However, for the clinician, the appeal is likely to be the image per se, rather than a single metric derived from it. For example, a single large ventilation defect in a particular lobe/segment may be treated differently to multiple small ventilation defects across the lung. It is potentially an excellent modality to study therapeutic effects; for example, comparing ventilation before and after chest physiotherapy (a longer-term plan of this study [19]). Therefore, it is imperative that researchers and clinicians do not fall into the trap of amalgamating rich information from images into a single number (e.g. VDP), even if such metrics are valid outcome measures. Other caveats of ¹²⁹Xe-MR also need consideration:

Standardisation: Mirroring the earlier stages of development of MBW, noble gas MR has so far also used bespoke equipment, different nomenclature (e.g. unventilated volume percentage, VDP) and different tracer gases (³He, ¹²⁹Xe). Indices from different tracer gases are not directly comparable, as a consequence of Graham's law [25]. Standardisation of equipment and wider availability is likely in the near future following approval by the US Food and Drug Administration [26].

Validation: Normative values of VDP and other indices require evaluation across broader age and sex ranges of healthy controls, and larger comparative studies across diseases are needed to validate ¹²⁹Xe-MR as a lung disease marker. This is important because ¹²⁹Xe may overestimate ventilation defects due to higher molecular mass relative to air. Consequently, phrases such as “sensitive to detect ventilation defects” [21] may not be strictly accurate in the case of ¹²⁹Xe-MR.

Within-person variability: Within-person variability of MR indices in health and disease (and exacerbations in case of chronic diseases) must be assessed through longitudinal studies. This is particularly important in conditions like PCD, where variability of spirometric indices has been described [27].

Access and cost-effectiveness: Access to hyperpolarisation technology is still limited even in high-income countries. While availability is likely to increase, cost remains a major consideration with ¹²⁹Xe-MR, and future research should evaluate its cost effectiveness relative to other imaging and monitoring techniques.

Response to therapies: Researchers and clinicians alike will want to understand how ¹²⁹Xe-MR not only correlates with other lung function tests, but also with biomarkers and endotypes across the spectrum of PCD and other CSLDs [28]. Clinical studies are needed to assess how the modality can direct clinical management and adjustment of therapies aimed at preventing disease progression.

Patient-centred approach: While clinicians value new tools that align with clinical outcomes, patients and families consistently prioritise developing effective treatments to manage symptoms and improve quality of life rather than new imaging methods [29]. Nonetheless, techniques like ¹²⁹Xe-MR are likely to play an important role in clinical trials by detecting functional changes over time. Patient voices should continue to shape research directions in PCD and CSLD.

Although we are not quite there yet, ¹²⁹Xe-MR has a potential future role in clinical practice including within the current PCD management pathway in childhood [30], as outlined in figure 1 [31].

FIGURE 1.

Proposed pathway for monitoring children and young people with primary ciliary dyskinesia (PCD) integrating structural and functional magnetic resonance (MR) imaging. ¹H-MR: proton MR spectroscopy; ¹²⁹Xe-MR: hyperpolarised Xenon-129 MR; AR: annual review; C: clinic review (and review during exacerbations); C&S: culture and sensitivity of respiratory sample; CXR: chest radiography; E-C&S: extended microbiology including C&S, fungal culture and mycobacterial culture; FEV₁: forced expiratory volume in 1 s (as part of traditional spirometry testing); HRCT: high-resolution computed tomography; LCI: lung clearance index (as part of multiple breath washout out technique); nNO: nasal nitric oxide; QoL: PCD quality of life questionnaire. ^#: If old enough and able to perform technique.

Conclusions

When considering ¹²⁹Xe-MR in comparison to other existing methods of assessing lung health Schofield et al. [19] rightly point out that a range of tools are necessary to assess the various components of lung disease in children with PCD. The question is not whether one technique is better than another or to find a single “perfect” method for investigating such a complex disease, but to understand the strengths and weaknesses of tools available and how well a techniques’ specific attributes align with each task at hand within the clinical pathways from diagnosis to monitoring the disease. Despite the caveats described above, this technique, in combination with other tools, will help us detect disease progression earlier and thereby help clinicians in prevention of lung damage (and perhaps reversal of existing damage), whilst also helping to determine impact of current and future novel therapies.