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Hyperpolarized Gas Magnetic Resonance Imaging of Pediatric Cystic Fibrosis Lung Disease

Posted Feb 28, 2019 Updated Apr 10, 2023
By Giles Santyr PhD , Nikhil Kanhere MSc , Felipe Morgado MSc , Jonathan H. Rayment MDCM MSc , Felix Ratjen MD PhD , Marcus J. Couch PhD
15 min read

Conventional pulmonary function tests appear normal in early cystic fibrosis (CF) lung disease. Therefore, new diagnostic approaches are required that can detect CF lung disease in children and monitor treatment response. Hyperpolarized (HP) gas ( 129 Xe and 3 He) magnetic resonance imaging (MRI) is a powerful, emergent tool for mapping regional lung function and may be well suited for studying pediatric CF. HP gas MRI is well tolerated, reproducible, and it can be performed longitudinally without the need for ionizing radiation. In particular, quantification of the distribution of ventilation, or ventilation defect percent (VDP), has been shown to be a sensitive indicator of CF lung disease and correlates well with pulmonary function tests.

This article presents the current state of CF diagnosis and treatment and describes the potential role of HP gas MRI for detection of early CF lung disease and following the effects of interventions. The typical HP gas imaging workflow is described, along with a discussion of image analysis to calculate VDP, dosing considerations, and the reproducibility of VDP.

The potential use of VDP as an outcome measure in CF is discussed, by considering the correlation with pulmonary function measures, preliminary interventional studies, and case studies involving longitudinal imaging and pulmonary exacerbations.

Finally, emerging HP gas imaging techniques such as multiple breath washout imaging are introduced, followed by a discussion of future directions. Overall, HP gas MRI biomarkers are expected to provide sensitive outcome measures that can be used in disease surveillance as well as interventional studies involving novel CF therapies.

INTRODUCTION

Brief Review of CF

Cystic fibrosis (CF) is a monogenic, autosomal recessive genetic condition that results from loss of function mutations in the CF transmembrane conductance regulator (CFTR) gene ( ). Lung disease resulting from impaired mucociliary clearance, leading to recurrent pulmonary infections and inflammation, remains the primary cause of morbidity and mortality in these patients. Episodic worsening of respiratory symptoms, known as pulmonary exacerbations (PEx), is treated with antibiotics and is a typical manifestation of this disease. Although there is no known cure, the life span and quality of life for patients with CF have increased dramatically in the past 40 years due to improved treatments, among other factors ( ). Conventional CF therapeutic approaches include (i) targeting the cycle of infection and inflammation with inhaled antibiotics ( ) and anti-inflammatory medications ( ), (ii) improving mucociliary clearance by the rehydration of airway secretions with hypertonic saline ( ), and (iii) thinning the tenacious airway mucus with recombinant dornase alfa ( ). More recently, small molecule medications have been developed that increase the capacity of dysfunctional CFTR protein to conduct chloride and bicarbonate across the cellular membrane ( ). As new treatments become available for this disease, sensitive tests to evaluate the efficacy of different treatments, especially in children with milder pulmonary disease, will be crucial to guide treatment decisions.

Current Diagnostic Approaches and Limitations

Lung disease begins early in the life of pediatric CF patients and, if left untreated, leads to structural lung damage (e.g., bronchiectasis) that is often focal and irreversible ( ). Pulmonary function tests (PFTs), such as spirometry are performed once children are old enough to be able to properly complete the test. Spirometry measures air flow at the mouth, and the most commonly reported parameter is the forced expiratory volume in 1 second (FEV 1 ). FEV 1 is reproducible, relatively effort independent and a low FEV 1 is an excellent marker of pulmonary disability; however, the average rate of annual FEV 1 decline in children with CF is small (i.e., 1%–2.5% per year) ( ) and most children with CF have normal FEV 1 ( ). Therefore, tests that are more sensitive than spirometry are required to accurately reflect the degree of lung pathology and to monitor response to therapy in CF, especially in the early lung disease seen in pediatric patients.

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HP 129 Xe MAGNETIC RESONANCE IMAGING OF PEDIATRIC CF LUNG DISEASE

Overview of Conventional and HP Gas MRI

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General HP 129 Xe MRI Approach

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Figure 1, Representative images obtained at SickKids from a 14-year-old healthy volunteer acquired 1 year apart on a 1.5 T MRI system ( top ) and a 3 T MRI system ( bottom ), respectively. The grayscale image in the background shows the conventional 1 H MRI while the red color overlay shows the HP 129 Xe image indicating ventilated lung. Images obtained at both field strengths were acquired using a 2D gradient-recalled echo pulse sequence, with similar parameters and coil geometry. At 1.5 T, the mean whole lung SNR (±SD) was 12.0 ± 3.4 and the VDP was 1.8%. At 3 T, the SNR was 27.6 ± 8.8 and the VDP was 0.4%. Color version of figure is available online. HP, hyperpolarized; MRI, magnetic resonance imaging; SNR, signal-to-noise ratio; VDP, ventilation defect percent.

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Image Analysis and VDP Measurement

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Figure 2, (a) Conventional 1 H images and (b) HP 129 Xe MRI obtained from a 17-year-old CF patient. The yellow arrows indicate ventilation defects in the HP 129 Xe images. (c) Masks obtained following implementation of the semiautomated segmentation algorithm. Red regions depict ventilation defects, while green regions show ventilated regions. The VDP is calculated by dividing the volume of the red regions by the TCV (i.e., red + green). Color version of figure is available online. CI, cystic fibrosis; HP, hyperpolarized; MRI, magnetic resonance imaging; VDP, ventilation defect percent; TCV, thoracic cavity volume.

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Reproducibility and Dosing

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Figure 3, (a) Bland–Altman analysis of 32 VDP measurements obtained from HP 129 Xe MRI acquired within a few minutes of each other. The intrascan (same study) reproducibility of VDP was found to be high (mean difference = −0.04, 95% CI [−3.10, 3.03]). (b) Bland–Altman analysis of 47 VDP measurements obtained from repeating the semiautomated segmentation algorithm. The reproducibility of VDP measurements was found to be very high (mean difference = 0.10, 95% CI [−0.84, 1.03]). HP, hyperpolarized; MRI, magnetic resonance imaging; VDP, ventilation defect percent.

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Figure 4, (a) HP 129 Xe dose for 14 adult participants (determined by weight) and for 42 pediatric participants (determined by TLC). (b) Relationship between concentration factor and weight for adult and pediatric participants. Concentration factor is defined as volume of HP 129 Xe in the lung divided by the total volume inside the lung at the time of imaging (FRC + 1 L), represented as a percentage. (c) SNR as a function of concentration factor for a subset of 29 pediatric participants. Points below SNR = 8 provide unreliable VDP values and have been excluded from the analysis. FRC, functional residual capacity; HP, hyperpolarized; SNR, signal-to-noise ratio; TLC, total lung capacity; VDP, ventilation defect percent.

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APPLICATIONS OF HP 129 Xe MRI TO PEDIATRIC CF

Physiologic Correlations of HP Gas Imaging

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Figure 5, (a) Comparison of FEV 1 (% predicted), LCI, and VDP measured using HP 129 Xe MRI in five healthy participants and in 10 stable CF patients. Unlike FEV 1 , both VDP and LCI show a statistically significant difference between the two groups. (b) VDP as a function of LCI for the same participants as in (a). The healthy participants are shown in closed circles, while the CF patients are shown in open circles. The error bars represent the standard deviation of repeated measurements. A strong correlation is seen between VDP and LCI. (b) was reproduced with permission from Kanhere et al. ( 32 ). CF, cystic fibrosis; FEV 1 , volume in 1 second; HP, hyperpolarized; LCI, lung clearance index; MRI, magnetic resonance imaging; VDP, ventilation defect percent.

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Interventional Trials using HP Gas MRI as an Outcome Measure

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Case Study—Pulmonary Exacerbation

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Figure 6, Pulmonary exacerbation case study. Coronal center slice static ventilation images acquired using HP 129 Xe MRI (a) before and (b) after inpatient IV antibiotic treatment for a subacute decline in FEV 1 and pseudomonas aeruginosa eradication. The yellow arrows indicate areas where the ventilation defects improved after treatment (VDP decreased from 19.4% to 16.0%). This improvement was reflected in LCI, but not in FEV 1 . Color version of figure is available online. FEV 1 , volume in 1 second; HP, hyperpolarized; LCI, lung clearance index; MRI, magnetic resonance imaging. (Color version of figure is available online.)

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Case Study—Longitudinal Imaging

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Figure 7, Longitudinal imaging case study. (a) Progression of FEV 1 (% predicted) and LCI over a 2-year period. The VDP measurements from the two HP 129 Xe MRI scans are indicated ( arrows ) in this timeframe. Coronal static breath-hold HP 129 Xe images were acquired at (b) baseline (VDP = 5.1%; SNR = 19), and (c) 18 months later (SNR = 77) showing the progression of ventilation defects (VDP = 19.5%). The yellow arrows indicate areas of worsening ventilation defects at the second visit. FEV 1 , volume in 1 second; HP, hyperpolarized; LCI, lung clearance index; MRI, magnetic resonance imaging; SNR, signal-to-noise ratio. (Color version of figure is available online.)

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Multiple Breath HP Gas MRI

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r=VfreshVfresh+Vresidual, r

=

V

fresh

V

fresh

+

V

residual

,

where V fresh is the volume of fresh HP gas introduced by a washin breath and V residual is the volume of HP gas remaining in the lungs from previous breaths. Since initial preclinical studies, the speed and efficiency of washin imaging have improved to a point where clinical translation is now possible ( ). For example, images can be acquired with a variable flip angle trajectory ( ), and a computer-controlled gas delivery system can be used to dispense metered doses of HP gas mixed with O 2 ( ).

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Figure 8, Representative series of HP 129 Xe MBW images and corresponding r map acquired in a 9-year-old CF patient. Two images were acquired in the baseline breath-hold to correct for relaxation effects (first image not shown), and five images were acquired following breaths of room air (last image not shown). The mean r for the whole lung was calculated to be 0.54 ± 0.12, which represents the fractional gas replacement per breath. CF, cystic fibrosis; HP, hyperpolarized; MBW, multiple breath washout.

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FUTURE DIRECTIONS

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CONCLUSION

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ACKNOWLEDGMENTS

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Academic Radiology, Volume 26, Issue 3
Journals General Radiology
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