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The Proceedings of the American Thoracic Society 4:321-327 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200611-181HT
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Magnetic Resonance Imaging of the Lung in Cystic Fibrosis

Talissa A. Altes1,2, Monika Eichinger3 and Michael Puderbach3

1 Department of Radiology, University of Virginia Medical Center, Charlottesville, Virginia; 2 Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and 3 Department of Radiology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

Correspondence and requests for reprints should be addressed to Talissa Altes, M.D., Department of Radiology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: altes{at}email.chop.edu

ABSTRACT

Magnetic resonance imaging (MRI) can provide regional information about lung structural changes in cystic fibrosis (CF), albeit at lower spatial and temporal resolution than computed tomography. The lack of ionizing radiation associated with MRI may make MRI an attractive alternative to computed tomography in applications in which repeated or serial scanning is desired. Furthermore, MRI can provide functional information about the lung, which may prove to be a useful outcome measure in CF. In this article, the MRI findings of CF are described, and the newer functional magnetic resonance techniques for imaging the lung are discussed.

Key Words: proton MRI • cystic fibrosis • pulmonary MRI • hyperpolarized gas MRI • lung imaging

Pulmonary function tests provide a global measure of airflow obstruction and/or restriction but provide no regional information about the lung function or information about lung structure. Although pulmonary function tests are useful, they are known to be relatively insensitive to early lung disease and to small changes in the severity of lung disease. Furthermore, pulmonary function tests are dependent upon the effort and compliance of the patient and are difficult for young children to perform. Yet, pulmonary function tests remain one of the primary outcome measures in cystic fibrosis (CF) lung disease. A decrease of FEV1 was shown to be the most important prognostic factor for the course of the disease and the most significant predictor of mortality in a study of 673 patients with CF (1). A more sensitive test that is not effort dependent and that can be done by young children would be desirable for the assessment of CF lung disease.

Chest computed tomography (CT) provides submillimeter resolution images of lung structure and has been proposed as a possible outcome measure for CF lung disease (2–4). CT has been shown to be more sensitive to early CF lung disease than pulmonary function testing, likely due to the regional nature of the information obtained (3). Despite the promising early studies related to the use of CT scanning in CF, a major drawback remains the radiation exposure associated with CT (5–9). This important issue is discussed in more detail by Huda and colleagues elsewhere in this issue (10). Radiation safety concerns may limit the utility of CT in CF lung disease for applications in which multiple CT scans are required.

Magnetic resonance imaging (MRI) has the potential to provide regional information about the lung without the use of ionizing radiation. Although conventional proton MRI has found widespread clinical application in most organs of the body, MRI of the lung lags behind because the lung is difficult to image with MRI. The strength of the magnetic resonance (MR) signal depends on the physical density of the protons in the tissue being imaged and the local environment of the protons. The lung has a low physical density and thus a low proton density, so little MR signal is generated by the lung. Furthermore, the magnetic susceptibility effects from its many air–tissue interfaces cause what little signal is generated to rapidly decay so that the lung typically appears dark on conventional proton MR images. During recent years, a variety of strategies have been developed to overcome the inherent difficulties of MRI of the lung, enabling a substantial improvement in temporal and/or spatial resolution (11–13). Although the spatial resolution of MRI is lower than CT, MRI has the advantage of improved tissue contrast characterization. Furthermore, MR can assess various aspects of pulmonary function, including lung perfusion (14, 15), blood flow (16), respiratory mechanics (17, 18), and, using an inhaled contrast agents, pulmonary ventilation (19–22). Thus, MRI is emerging as a versatile modality for morphologic and functional imaging of the lung. A drawback of MRI is that MRI in general requires a longer scan time than CT, something that is not much of an issue with older children but may preclude its use in nonsedated younger children. Most children are not claustrophobic in MR scanners, but with adults, claustrophobia is more of an issue with MRI than with CT. Although the level of structure detail possible with lung MRI may never equal that of CT, MRI may provide clinically useful information and be a sensitive, effort independent test of CF lung disease.

Research with MRI in CF lung disease lags behind that with CT. In this article, we review the common findings of CF lung disease on conventional proton MRI and discuss some of the newer MRI techniques that provide functional information about the lung.

STRUCTURAL CHANGES OF CF LUNG DISEASE ON PROTON MRI

Using common proton-MRI sequences, it is possible to visualize the structural changes of CF lung disease, including bronchial wall thickening, mucus plugging, bronchiectasis, air fluid levels, consolidation, and segmental/lobar destruction, albeit with lower spatial and temporal resolution than with CT (23). It seems likely that the lower spatial and temporal resolution of MRI means that MRI is less sensitive than CT to specific imaging features, such as distal bronchiectasis. This does not necessarily mean that MRI provides less useful information about CF because sensitivity to these imaging features may not be critical for the assessment of the overall burden of disease.

Bronchial Wall Thickening
The visualization of bronchial wall thickening is dependent on bronchial size, bronchial wall thickness, and bronchial wall signal. In MRI studies of normal lung, only the central airways to the level of lobar bronchi are routinely visualized, and some segmental bronchi can be identified. This is in contrast to CT, in which the sixth- to eighth-generation bronchi can be identified. In patients with CF, bronchial wall thickening of the small airways enhances their detectability by MRI so that small airways with thick walls can be visualized in the lung periphery (23) (Figure 1). The T2-weighted signal of the thickened bronchial walls in CF varies from high intensity to low intensity. Because water and edema produce a high-T2–weighted signal, it would not be surprising if the high bronchial wall signal is due to edema possibly caused by active inflammation. This is a phenomenon not observed in CT. A T1-weighted sequence allows for evaluation of the contrast enhancement of the bronchial wall. In CF, different patterns of bronchial wall contrast enhancement have been observed. In some lung regions bronchi demonstrate striking enhancement, whereas in other regions weak contrast enhancement is observed. This phenomenon may also be related to inflammatory activity within the bronchial wall, but further studies are required to improve our understanding of these phenomena (Figure 2).


Figure 1
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  		Figure 1. Transverse magnetic resonance T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE) image (a) and corresponding computed tomographic image (b) of a 14-year-old girl with cystic fibrosis. In both images, bronchial wall thickening, bronchiectasis, peripheral mucus plugging, and dorsal consolidations are demonstrated.

 

Figure 2
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  		Figure 2. T1-weighted magnetic resonance images of a 43-year-old patient with cystic fibrosis (a) pre- and (b) post-contrast media. The post-contrast images demonstrate extensive bronchial wall enhancement and permit differentiation of a thickened wall from intrabronchial secretions, with intrabronchial fluid having an air fluid level (arrow).

 
Mucus Plugging
Mucus plugging is well visualized by MRI due to the high T2-weighted signal of its fluid content (see Figure 1). Mucus plugging in central large bronchi and peripheral small bronchi can be visualized on MRI. In central mucus plugging, there is high T2-weighted signal filling the bronchus within its course. Peripheral mucus plugging shows a grape-like appearance of small T2–weighted, high-intensity areas, similar to the "tree in bud" phenomenon in small airway inflammation on CT. Mucus plugging does not show contrast enhancement; thus, mucus and bronchial wall thickening can be differentiated by the combination of T2-weighted and contrast-enhanced sequences. In CT, these two pathologic entities can not be reliably distinguished because the CT attenuation of mucus and soft tissue are similar.

Depending on the stage of disease, patients with CF have an increased risk of hemoptysis. The localization of the origin of bleeding can be crucial for the outcome of the patient. With CT, mucus and blood are similar in attenuation and cannot be distinguished. On MRI, using the combination of T1- and T2-weighted and contrast-enhanced sequences, mucus and fresh blood can be distinguished. Mucus has a high T2-weighted and a low T1-weighted signal, whereas fresh blood has low T2- and T1-weighted signals.

Bronchiectasis
The MRI appearance of bronchiectasis is dependent on bronchial level, bronchial diameter, wall thickness, wall signal, and the signal within the bronchial lumen. Central bronchiectasis is well visualized on MRI independent of wall thickening or wall signal because of the anatomically thicker wall of the central bronchi. Peripheral bronchi starting at the third to fourth generation are poorly visualized by MRI except when they are pathologic with bronchial wall thickening and/or mucus plugging.

Air Fluid Levels
Air fluid levels are indicative of active infection and occur in saccular or varicose bronchiectasis. Bronchial air fluid levels can be visualized by MRI because of the high T2-weighted signal from the fluid. Discriminating between a bronchus with an air fluid level and one with a partial mucus plug or a severely thickened wall can be difficult. However, by evaluating the signal characteristics on T1- and T2-weighted and contrast-enhanced sequences, air fluid levels can frequently be differentiated (Figure 2).

Consolidation
Consolidation in CF is mainly caused by alveolar filling with inflammatory fluid. The visualization of consolidation in MRI is based on the high T2-weighted signal from the inflammatory fluid. Comparable to CT, MRI is able to visualize air bronchograms as low signal areas following the course of the bronchi within the consolidation (13, 24). With disease progression, complete destruction of lung segments or of a complete lung lobe can occur, and these affected lung areas have a similar appearance on MRI as with CT (Figure 3).


Figure 3
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  		Figure 3. (a) T2-weighted magnetic resonance (MR) image of the patient shown in Figure 2 showing lobar destruction of the right upper lobe and severe bronchiectasis and wall thickening of the left lobe. (b) MR-perfusion map of the corresponding lung region showing large perfusion defects in both upper lobes and an inhomogeneous perfusion in the peripheral lower lobe zones.

 
Mosaic Pattern
On CT, a mosaic pattern of lung attenuation is a common finding in patients with CF. This pattern can be observed on inspiratory scans as areas of relative hyperlucency, which can be due to air trapping or regional hypoperfusion (mosaic perfusion). These entities can be distinguished on expiratory CT images because regions of air trapping do not change significantly in volume and thus change little in measured CT attenuation. Conversely, in areas of hypoperfusion without air trapping, the lung attenuation increases with expiration (25).

On MRI, the phenomena of air trapping is not typically apparent because even normal lung parenchyma has a very low signal, and an increase of the air content does not cause a detectable decrease in lung parenchymal signal. An approach to overcome this limitation might be the measurement of T1 relaxation times (26). Mosaic perfusion is not typically apparent on routine MR images, but MR-perfusion imaging has the potential to overcome this limitation (27).

FUNCTIONAL LUNG MR IMAGING

In addition to visualization of structural changes within the lung, MRI can provide functional assessment of pulmonary hemodynamics and ventilation. Pulmonary perfusion imaging typically requires the administration of gadolinium-based intravenous contrast. An inhaled contrast agent, either oxygen or a hyperpolarized noble gas, is required for MR lung ventilation imaging.

Pulmonary Perfusion
In CF, regional ventilatory defects cause changes in regional lung perfusion due to the reflex of hypoxic vasoconstriction or tissue destruction. A variety of MRI methods have been used to assess lung perfusion, including methods that rely on the endogenous signal from blood (28) and others that require the administration of intravenous contrast (16, 29). Using a contrast-enhanced three-dimensional MRI acquisition in 11 children with CF, it was found that MRI-perfusion defects correlated with the degree of tissue destruction (27) (Figure 3). It is plausible that reversibility of perfusion defects after a therapeutic intervention might serve as an indicator for response to therapy and might differentiate between regions with reversible and irreversible disease.

Pulmonary Flow Measurements
Parenchymal destruction can lead to dilatation and flow augmentation of bronchial arteries. Because bronchial arteries are part of the systemic circulation, they do not contribute to blood oxygenation. Thus, a higher flow in the bronchial arteries leads to a shunt-volume, which can be assessed by MRI-based flow measurements. Decreased peak blood flow velocities in the right and left pulmonary arteries were found in 10 patients with CF as compared with 15 healthy volunteers; this might represent early development of pulmonary hypertension in this patient group (30). The clinical significance of the systemic arterial shunt volume is not known.

Oxygen-enhanced MRI
Gaseous molecular oxygen is weakly paramagnetic and serves, if inhaled in high concentrations, as a contrast medium inducing a dose-dependent T1-signal increase that can be used to assess lung ventilation (22). In a recent study of five patients with CF and five healthy volunteers, the lungs of the patients with CF had an inhomogeneous appearance after the inhalation of high oxygen concentrations, suggesting inhomogeneous lung ventilation (31). Because oxygen is soluble in blood, the oxygen-enhanced MR images depict a combination of ventilation and perfusion (32). One of the difficulties with this method is that there is a relatively low difference in signal from the lung parenchyma with 21% versus 100% inspired oxygen concentration. This results in a relatively low signal-to-noise level in the MR oxygen-enhanced images.

Hyperpolarized Gas MRI
Hyperpolarized helium-3 is a gaseous MRI contrast agent that, when inhaled, provides a very high MR signal from the airspaces of the lung. Hyperpolarized helium MRI can be used to obtain information about lung function using static spin density imaging (19, 21, 33, 34), dynamic spin density imaging (35, 36), or oxygen-sensitive imaging (37–39). In addition, lung structure at the alveolar and distal airway level can be assessed using diffusion-weighted imaging (40–43). The majority of studies investigating the use of hyperpolarized helium MRI in CF have used static spin density imaging. Static spin density imaging, often referred to as ventilation imaging, is performed during a breath hold after the inhalation of the hyperpolarized helium-3 gas (44). Well ventilated areas of the lung receive more helium gas and thus appear brighter than poorly ventilated areas of the lung on the MR images (Figure 4). Typically, the entire lung volume can be imaged in a 4- to 20-second breath hold, but the in-plane spatial resolution is typically in the order of 3 mm and thus is lower than with CT. Because children have smaller lungs than adults, their breath hold duration is shorter, and hyperpolarized helium MRI has been successfully performed in children as young as 4 years of age without sedation (45).


Figure 4
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  		Figure 4. Conventional proton magnetic resonance (MR) and hyperpolarized helium MR ventilation images of a normal subject. A high signal is obtained from the airspaces of the lung after the inhalation of hyperpolarized helium.

 
Because no ionizing radiation is involved, hyperpolarized gas MRI may be ideal for the evaluation of pediatric lung diseases. Furthermore, in theory hyperpolarized helium is expected to be a very safe inhaled contrast agent. The polarization process does not alter the chemical properties of the helium-3 gas. Because of helium's low solubility in water and lipids, it is nearly biologically inert with little absorption into the tissues or blood (46). Mixtures of helium-4 and oxygen (heliox) are used therapeutically in patients with lung disease (46–48). To our knowledge, there is no known toxicity associated with any of the current medical uses of helium. Furthermore, in a review of the safety data from three years of hyperpolarized helium administration in 343 subjects at the University of Virginia, the rate of respiratory adverse events was approximately 7%, with all being mild (e.g., sore throat, tickle in throat, cough) and resolving spontaneously (49). Thus, both in theory and in practice, hyperpolarized helium MRI seems to be a low risk procedure.

Hyperpolarized Gas MRI in CF
The first report of hyperpolarized helium MRI in CF found extensive abnormalities of ventilation on static spin density images in four subjects with moderate to severe pulmonary CF and abnormal FEV1 (%predicted) (50). More extensive abnormalities were found on hyperpolarized helium MRI than on conventional proton MRI.

Mentore and colleagues, used static spin density imaging in a study of 31 subjects (16 healthy volunteers and 15 patients with CF) and found that the patients with CF had a significantly higher number of ventilation defects on helium MRI than the normal subjects (mean ventilation defect score, 8.2 in patients with CF vs. 1.6 in normal subjects) (p < 0.05) (51). Even the four subjects with CF with a normal FEV1 (%predicted) had significantly higher ventilation defect scores than the normal subjects (mean 6.5 CF; p = 0.0002), suggesting that hyperpolarized gas MRI may be more sensitive to ventilation abnormalities than spirometry. Moderate correlations between the ventilation defect score and spirometry were found (Figure 5). In this study, eight of the patients with CF underwent a therapeutic intervention first with nebulized albuterol followed by DNase and chest physical therapy. Repeated helium-MRI after therapy showed changes in the ventilation defect score. Thus, this study demonstrated the feasibility of using hyperpolarized helium MR as an outcome measure in the evaluation of airway clearance techniques.


Figure 5
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  		Figure 5. Coronal hyperpolarized helium magnetic resonance ventilation images from a normal subject and three patients with cystic fibrosis (CF). The patients with CF have more ventilation defects than the normal subject, and the number of defects increases with worsening FEV1 (%predicted). Reprinted by permission from Reference 51.

 
A recent study of 18 children with CF (5–17 yr of age) confirmed that hyperpolarized helium MRI can be performed by children with CF and found moderate to weak correlations between static spin density hyperpolarized helium MRI and spirometry or chest X-ray (52). It was the opinion of the authors that the weak correlations were the result of a greater sensitivity of hyperpolarized helium MRI to ventilatory abnormalities than spirometry or chest X-ray. Another recent study compared static spin density helium MRI with CT in eight adults with CF and found a strong correlation between the MRI percent ventilation and the Bhalla score (53) from CT (54) (Figure 6). The correlations between hyperpolarized helium MRI and spirometry were stronger than those between CT and spirometry. Thus, this study suggests that hyperpolarized helium MRI may represent a safe alternative to CT for the evaluation of CF lung disease.


Figure 6
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  		Figure 6. Regional computed tomography (CT) and hyperpolarized helium magnetic resonance imaging scores in a subject with cystic fibrosis. Areas with poor hyperpolarized helium ventilation tend to have a high (worse) Bhalla score on CT and vice versa, demonstrating the regional concordance of the information obtained on CT and helium magnetic resonance. HRCT = high-resolution computed tomography; 3HeMR = hyperpolarized helium-3 magnetic resonance. Reprinted by permission from Reference 54.

 
Little work has been done in CF evaluating the other mechanisms of contrast possible with hyperpolarized gas MRI, including dynamic ventilation (55) and diffusion-weighted or oxygen-sensitive imaging. The special equipment required to perform hyperpolarized gas MRI is expensive and is not widely available, and hyperpolarized helium as a MRI contrast agent has not been approved by the U.S. Food and Drug Administration, so use of this technique is limited to a few academic medical centers. However, a method for centralized production of hyperpolarized helium and distribution of the polarized gas to geographically diverse centers has been developed that may make hyperpolarized helium more available (56, 57). Another limitation is that the rate of depolarization of the helium is dependent upon its environment, and molecular oxygen increases the rate of depolarization. Thus, in many of the studies noted in this article, the hyperpolarized helium was administered to the subject as an anoxic gas, which may be problematic in patients with severe respiratory disease. Finally, although the hyperpolarized helium MR ventilation images are striking, none of the existing methods for extracting information from these images, including human reader scoring and computer based analyses, is satisfactory (34, 51). The primary issue is that the measured signal intensity does not reflect regional ventilation alone. Other factors such as the regional transmit and receive sensitivity of the MR RF coil and the regional partial pressure of oxygen, affect the measured signal intensity, and these factors can cause as much as a 50% variation in signal intensity across the images. These factors limit the potential near-term utility of hyperpolarized gas MRI in CF.

Future Directions for MRI in CF
MRI of the lung is a promising but relatively new field. The majority of studies exploring lung MRI in CF have involved small numbers of subjects and have been observational, simply describing the imaging findings of CF. One of the issues related to using imaging as an endpoint is that the images themselves are not an endpoint. Typically, information about the disease in question has to be extracted from the images. For example, nodal size is an imaging-based endpoint used in assessing metastatic disease. With chest CT, a variety of scoring systems for CF have been proposed to do just this and to reduce a large set of images to a single number or small set of numbers that characterize the disease severity/activity. The development of imaging-based endpoints or scores for lung MRI in CF is in its infancy. First, the salient imaging features must be determined, and a method, based on human scoring or computer-based image analysis, must be devised for quantifying these features. For proton MRI, methods based on the CT scoring schemes could be developed. For the functional lung MRI techniques, new analysis methods need to be developed and specifically validated in CF. It has been proposed that to validate an endpoint or outcome surrogate, it must be shown to be accurate, reproducible, feasible over time, biologically plausible, to reflect the severity of disease, to improve rapidly with effective treatment, and correlated with true clinical outcomes (58–60). Of these characteristics, lung MRI is biologically plausible and likely feasible over time. Clinical trials are required to determine whether endpoints derived from any of the lung MRI methods discussed in this article possess the remainder of these characteristics.

CONCLUSIONS

Many of the major CF lung changes that are described on CT can be visualized by conventional proton MRI, but more subtle or smaller abnormalities cannot. Whether the additional structural detail provided by CT is necessary for the evaluation of the severity and progression of CF lung disease is not known and warrants further study. It is unknown whether the functional information provided by proton and hyperpolarized gas MRI or the structural informal provided by CT will prove to be more important in the assessment of CF. It is conceivable that CT may be better at answering some questions and MRI others. Perhaps by correlating the information from both modalities, the relationship between structural and functional abnormalities can be elucidated. These MRI techniques are relatively new, and further studies are required to more fully assess the potential utility of these techniques in CF.

FOOTNOTES

Supported by a University of Virginia Children's Hospital Seed Grant.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form November 30, 2006; accepted in final form February 23, 2007)

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