New Developments in Imaging Idiopathic Pulmonary Fibrosis With Hyperpolarized Xenon Magnetic Resonance Imaging

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that is ultimately fatal. Although the diagnosis of IPF has been revolutionized by high-resolution computed tomography, this imaging modality still exhibits significant limitations, particularly in assessing disease progression and therapy response. The need for noninvasive regional assessment has become more acute in light of recently introduced novel therapies and numerous others in the pipeline. Thus, it will likely be valuable to complement 3-dimensional imaging of lung structure with 3-dimensional regional assessment of function. This challenge is well addressed by hyperpolarized (HP) Xe magnetic resonance imaging (MRI), exploiting the unique properties of this inert gas to image its distribution, not only in the airspaces, but also in the interstitial barrier tissues and red blood cells. This single-breath imaging exam could ultimately become the ideal, noninvasive tool to assess pulmonary gas-exchange impairment in IPF. This review article will detail the evolution of HP Xe MRI from its early development to its current state as a clinical research platform. It will detail the key imaging biomarkers that can be generated from the Xe MRI examination, as well as their potential in IPF for diagnosis, prognosis, and assessment of therapeutic response. We conclude by discussing the types of studies that must be performed for HP Xe MRI to be incorporated into the IPF clinical algorithm and begin to positively impact IPF disease diagnosis and management.

Figure 1:

Different clinical trajectories in idiopathic pulmonary fibrosis (IPF). Disease begins with a subclinical period in which only radiographic findings of disease may be present, followed by a symptomatic period consisting of both pre-diagnosis and post-diagnosis clinical phases. The rate of decline and progression to death may be rapid (line A), slow (lines C and D), or mixed (curve B), with periods of relative stability interposed with periods of acute decline (star). (Figure reprinted with permission of the American Thoracic Society. Copyright ^© 2018 American Thoracic Society. Ley, B., Collard, H. R. & King, T. E. Clinical Course and Prediction of Survival in Idiopathic Pulmonary Fibrosis. 2011 Am. J. Respir. Crit. Care Med. 183, 431–440. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society)

Figure 2:

Axial and sagittal reformats of HRCT (a) compared to 3D UTE (b), and 3D radial image acquired at longer echo time (TE = 2.1 ms). The HRCT is acquired during breath-hold, while the MRI scans were acquired over 5.5 min of free-breathing. Fibrosis patterns and extent are well appreciated on UTE and follow what is seen on HRCT. However, at the longer 2.1 ms echo time these patterns are no longer well visualized on MRI. Nonetheless, HRCT images exhibit substantially higher spatial resolution and reduced respiratory motion. (Images reprinted courtesy of Johnson et al, Optimized 3D ultrashort echo time pulmonary MRI. Magn. Reson. Med. 70, 1241-1250 (2013) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 3:

¹²⁹Xe ventilation MRI reveals heterogeneity associated with traction bronchiectasis. Evidence of high signal intensity in lower lobe airways, bilaterally in A and within the right lower lobe in B. These findings relate to regions of traction bronchiectasis seen on the associated computed tomography scan. (Reprinted from Nick Weatherley PhD thesis University of Sheffield 2018)

Figure 4:

Microstructural changes in IPF revealed with hyperpolarized ¹²⁹Xe apparent diffusion coefficient images. Honeycomb cysts (red arrow) and traction bronchiectasis (white arrows) are evident by virtue of their elevated apparent diffusion coefficient (ADC), reflective of airspace enlargement and enhanced ¹²⁹Xe mobility. The location of these abnormalities is consistent with findings on CT imaging. (Images courtesy of the University of Sheffield)

Figure 5:

¹²⁹Xe magnetic resonance spectrum showing signal intensity in human lungs. (A) NMR spectrum obtained when exciting the gas- and dissolved-phase ¹²⁹Xe equally, showing that the dissolved phase ¹²⁹Xe signal is only 1-2% as large as gas; (B) When the dissolved phase is selectively excited the barrier and RBC spectral peaks are better appreciated. (Figure reprinted from Cleveland et al, Hyperpolarized ¹²⁹Xe MR imaging of alveolar gas uptake in humans. PLoS One, 5. 1-8 (2010)

Figure 6:

The first 3D images of dissolved-phase xenon in human lungs. (A) Select, 15-mm-thick slices of the 3D dissolved-phase ¹²⁹Xe image, left-to-right showing anterior-to-posterior cuts; (B) Geometrically corresponding 15-mm-thick slices of the 3D gas-phase HP ¹²⁹Xe image in the same volunteer; (C) Dissolved-phase in color, overlaid on the grayscale ventilation image. (Figure reprinted from Cleveland et al, Hyperpolarized ¹²⁹Xe MR imaging of alveolar gas uptake in humans. PLoS One, 5. 1-8 (2010)

Figure 7:

Quantitative ¹²⁹Xe spectroscopy applied to patients with idiopathic pulmonary fibrosis in a study by Kaushik et al. (A) Dissolved-phase ¹²⁹Xe spectrum showing greatly reduced ¹²⁹Xe transfer to the RBC phases in patients with IPF; (B) This was quantified by the RBC:barrier ratio, for which the average in IPF subjects was 0.16 +/− 0.03, compared to 0.55 +/− 0.13 in healthy volunteers (P=0.0002). (Figure reprinted from Kaushik et al, Measuring diffusion limitation with a perfusion-limited gas-Hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis. J. Appl. Physiol. 117, 577-585 (2014)

Figure 8:

Representative coronal gas, tissue (barrier) uptake, and RBC transfer images acquired in a healthy subject using radial hierarchical IDEAL strategy. The RBC image exhibits signal from the lung parenchyma as well as the left ventricle of the heart. (Figure reprinted from Qing et al, Regional mapping of gas uptake by blood and tissue in the human lung using hyperpolarized Xenon-129 MRI. J Magn. Reson. Imag. 2014) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 9:

HP ¹²⁹Xe gas exchange images comparing healthy volunteers to patients with IPF acquired using the 1-point Dixon method. Compared to healthy volunteers, ¹²⁹Xe transfer to RBCs could be seen to be focally impaired in base and periphery of the lungs of patients with IPF. (Reprinted from Kaushik et al, Single-breath clinical imaging of hyperpolarized 129Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition. Magn. Reson. Med. 75, 1434-1443 (2016) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 10:

Healthy reference distributions proposed for ¹²⁹Xe ventilation, barrier uptake, and RBC transfer. These data were generated from 10 healthy volunteer subjects and color bins were assigned based on a Gaussian curve fit, with each bin being assigned a width that is one standard deviation of the reference distribution. In this way normal compartments are defined as lying within one standard deviation of the reference mean (green), while “defects” are those 2 standard deviations below the mean and high barrier uptake values are represented in pink and purple colors. (Image reprinted from Wang et al, Quantitative analysis of hyperpolarized ¹²⁹Xe gas transfer MRI. Med Phys 44, 2415-2429 (2017) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 11:

Representative healthy [left] and IPF [right] subjects and the corresponding quantitative color maps and histograms of ventilation, barrier uptake and RBC transfer. Note the high degree of barrier uptake in IPF relative to the healthy subject, coupled with focal defects in ¹²⁹Xe transfer to the RBCs in the lung base and periphery. (Figure reprinted from Wang et al, Quantitative analysis of hyperpolarized ¹²⁹Xe gas transfer MRI. Med Phys 44, 2415-2429 (2017) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 11:

Representative healthy [left] and IPF [right] subjects and the corresponding quantitative color maps and histograms of ventilation, barrier uptake and RBC transfer. Note the high degree of barrier uptake in IPF relative to the healthy subject, coupled with focal defects in ¹²⁹Xe transfer to the RBCs in the lung base and periphery. (Figure reprinted from Wang et al, Quantitative analysis of hyperpolarized ¹²⁹Xe gas transfer MRI. Med Phys 44, 2415-2429 (2017) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 12:

With the exception of ¹²⁹Xe ventilation, ¹²⁹Xe gas exchange metrics such as barrier uptake, RBC transfer and RBC/barrier ratio all correlate well with FVC and DLCO. The correlation between RBC/barrier and DLCO (r=0.94) is particularly strong. (Figure reprinted from Wang et al, Using hyperpolarized ¹²⁹Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis. Thorax 73, 21-28 (2018) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 13:

Concordance and discordance between HRCT and ¹²⁹Xe gas exchange MRI and potential models of gas exchange. In a healthy lung (A), gaseous ¹²⁹Xe efficiently diffuses from the alveolus, across a thin barrier to RBCs, resulting in signal intensities in the normal range for both compartments. In IPF, some regions of barrier enhancement (B, arrows) are associated with decreased RBC transfer (diffusion block). As the disease progresses (C), scarring causes ¹²⁹Xe to stop diffusing into or through the barrier (normal or low range), while RBC transfer is dramatically reduced. This likely represents unperfused tissue. Most interesting are regions depicting the coexistence of high barrier uptake and preserved RBC transfer (D, arrow). This may represent regions of disease activity that could be responsive to therapy. Notably many of these areas appear normal on CT. (Figure reprinted from J. Wang et al, Using hyperpolarized ¹²⁹Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis. Thorax 73, 21-28 (2018) Copyright ©1999-2018 John Wiley & sons, Inc. All rights reserved

Figure 14:

Longitudinal changes in FVC, DLCO and ¹²⁹Xe spectroscopy derived RBC/TP (RBC:barrier ratio) in patients with IPF patients. Notably, the conventional metrics FVC and DLCO do not exhibit a significant change over the 12-month interval, whereas RBC:barrier shows a decreases at 6-months, which becomes statistically significant at 12 months. (Figure reprinted from Chan et al. Abstract 4353 ISMRM 2018)

Figure 15:

Example of improving ¹²⁹Xe gas exchange metrics for a patient on current therapy. This patient started anti-fibrotic therapy one month prior to baseline MRI and presented with 49% high barrier uptake, and focal RBC transfer defects at the lung bases resulting in 35% low RBC transfer. Upon return 5 months later, the percentage of lung exhibiting high barrier uptake had decreased to 30%, while the RBC transfer defects remained stable at 35% of lung volume.