Imaging in COPD

E. J. R. van Beek, E. A. Hoffman

Division of Physiologic Imaging, Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA Correspondence to: Edwin JR van Beek, M.D. Ph.D. F.R.C.R. Department of Radiology, Carver College of Medicine, University of Iowa, C-751 GH, 200 Hawkins Drive, Iowa City, IA 52242-1077, USA Tel: 319 384 6133; Fax: 319 356 1503; E-mail: edwin-vanbeek@uiowa.edu Key words: Chronic obstructive pulmonary disease, CT, MRI, functional imaging.

Introduction

Computed tomography (CT) has been the main approach to imaging in lung diseases, including chronic obstructive pulmonary diseases (COPD) for many decades. With the older CT systems, only axial imaging was feasible, and high resolution 1 mm slices could be obtained at 1 cm increments to give detailed images of lung structure down to 1 mm3. The subsequent development of multi-detector row CT (MDCT) has made it possible to obtain isotropic volumetric voxels, thus leading to a multiple projection approach (sagittal and coronal), while the implementation of contrast-enhanced angiography has enabled the study of pulmonary vasculature and cardiac anatomy (1). Newer techniques are now coming online, which include the application of dual-energy MDCT (which may have implications for novel contrast applications for both perfusion and ventilation imaging) as well as the progressive use of sophisticated software tools that help quantify lung disease (2). Some of this work is now also being incorporated in large-scale multicentre studies that evaluate the role of genetics in the development of COPD, given that approximately 30% of all smokers are susceptible to its effects (35). This has led to two major NIH-funded initiatives (COPD Gene and SPIROMICS), which will be briey described at the end of this study. Magnetic resonance imaging (MRI) has taken a significant ight with novel proton sequence applications, allowing greater details of the lungs to become visible. The use of gadolinium-based contrast agents has led to the development of perfusion and angiography of the pulmonary vasculature. Furthermore, hyperpolarized gas methods (using 3-Helium and 129-Xenon isotopes) have been developed for study of ventilation-based assessment of the lung and study of airow dynamics, lung microstructure, gas distribution and assessment of total alveolar surface. Although this was a major area of excitement, more recently there has been some dispute over the longer term availability of particularly 3-Helium as the medical eld competes with security devices industries.
Computed tomography

The application of MDCT has gained widespread acceptance, and in most institutions a minimum 16-slice CT

scanning system is now available, with up to 256-slice systems allowing faster imaging at increased spatial resolution (6). This has improved the versatility of CT of the chest, as greater coverage in shorter time span has decreased the problems of breathing artefacts with rotation times of 0.3 s or less. In addition, novel contrast techniques, including varying injection protocols and even inhaled contrast applications, now enable visualization of both pulmonary and systemic vascular systems, all heart chambers and ventilation of the lungs. Initial studies using dual-source CT (DSCT) have demonstrated early promising results for assessment of perfusion and ventilation CT imaging of the lung, facilitating the study of lung pathophysiology in COPD. The increased speed also enables gating of imaging within a chosen physiological cycle, including respiratory and cardiac cycles (79). This leads to the options of performing imaging with semi-dynamic reconstruction opportunities, recreating a virtual beating heart or breathing lung, which offers the study of heart and lung dynamics. It has been recognized that traditional morphological CT studies are insufcient for disease quantication, and that this may be a very important approach to study treatment effects and to monitor disease states more accurately. With the introduction of more individualized therapies as well as the realization that imaging methods may shorten the duration of clinical trials using surrogate (non-clinical) end points, it is likely that quantitative (software determined) analysis is of progressive interest. Advanced software has been developed, which allows for the study of density changes in the lungs (Fig. 1), 3D visualization of the airway tree (Fig. 2), quantication of disease states, assessment of airway wall diameters (Fig. 3), planning of pathways for interventional procedures (Fig. 4) and quantication of perfusion and ventilation. Enhanced methods include the use of cut-off values (usually at )950 or )910 HU) to detect the number of voxels that are below this threshold (1012). This is the method to determine the presence and quantify the amount of emphysema-like lung parenchyma, which can be depicted in a cumulative histogram (Fig. 5). In addition, a range of other potential indicators have been suggested, but most of these are still in a research domain.

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j Fig. 1. 3D isotropic voxel display of pulmonary CT scan with 3D reconstruction of the airway tree in a normal subject and a subject with smoking-related emphysema. From reference (1).

j Fig. 2. 3D display of a human airway tree using automatic labelling software (Pulmonary Workstation 2, VIDA Diagnostics, Coralville, IA, USA).

Furthermore, recent studies have focused on the semiautomated detection of texture analysis using sophisticated computer algorithms (13, 14). In order for these software tools to be accurate, quality assurance of how CT data are acquired is essential. To this extent, several steps are important. First, appropriate coaching of patients to reach adequate inspiration (total lung capacity) and expiration (residual volume) levels require more active participation and guidance by radiology technologists. A simple tape-recorded message will not sufce! Second, CT scanner calibration is important in order to retain a stable data acquisition environment, and for this purpose appropriate checks using phantoms as well as the accurate setting of the HU range for CT scanners is important. The latest projects, as described below, take these methods into consideration, and have managed to derive protocols that will help guide these studies, which will be particularly helpful in longitudinal comparisons in patients. Thus, this will facilitate the introduction of CT as a surrogate biomarker for emphysema and thus its potential utility for clinical trials (whether testing of new devices or new drug therapies).

Functional CT imaging may be performed using the introduction of either inhaled or injected contrast agents. Xenon gas has enabled the study of ventilation by its density change (approximately 60 HU). Work using a wash-in and wash-out technique, using retrospective 4D reconstruction and gating based on the respiratory cycle have allowed the study of Xenon-CT ventilation in animals and more recently in humans. Initially, this work was limited due to the z-axis coverage of CT scanners, but more recent attempts using DSCT have focused on single-breath Xenon techniques using two different kV settings (80 and 140 kV) scanning protocols allowing for greater coverage (15). Whether a single breath technique is appropriate to study ventilation is still a matter of discussion (16, 17). Dynamic imaging during central iodinated contrast injection at high ow volumes enables the estimation of true pulmonary perfusion, capillary transit times and capillary ow distributions. This technique has been performed in a number of human subject studies at functional residual capacity, and changes in these values were shown to be an early predictor for the presence of emphysema as demonstrated in healthy smokers compared with nonsmoking normal volunteers (18).
Magnetic resonance imaging

Clearly, MRI has several inherent advantages over CT, such as speed and lack of ionizing radiation, but also requires sufcient signal to obtain the images. This has traditionally been difcult in lung imaging, due to a lack of protons and due to inhomogeneity of the magnet eld at the air/tissue interface. Newer methods have improved the visualization of lung parenchyma, making use of new sequences and novel contrast methods, including gadolinium perfusion, hyperpolarized gas inhaling methods and the application of 100% oxygen subtraction as a means of visualizing ventilation. Ultrafast imaging is also capable of obtaining dynamic contrast images, leading to interpretation of pulmonary perfusion, breathing dynamics and imaging of gas ow. Many of these methods are already

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j Fig. 3. Airway segmentation of a standard pathway, demonstrating capability to analyse airway wall and lumen dimensions using advanced software (Pulmonary Workstation 2, VIDA Diagnostics, Coralville, IA, USA).

j Fig. 4. Pathway display of 3D airway tree for assistance with bronchoscopic procedure planning.

discussed in some of the other manuscripts within this issue, therefore, the current description will limit itself to applications in COPD. Proton imaging uses the large magnetic eld and the free moving protons to derive signal from changes in proton orientation due to radiofrequency pulses. Pathological processes which lead to increased water and/or cellularity, increase the number of protons (haemorrhage, oedema, inammation or tumour), whereas calcication will lead to signal voids.

Single-breath imaging, using half-Fourier sequences in combination with parallel imaging have become the standard (19, 20). These sequences are T2-weighted, and therefore show increased signal of water and cells. For some areas, such as superior sulcus tumours, MRI is preferred for assessment of resectability. For other areas, such as pneumonia, mesothelioma and mediastinal assessment, MRI plays an inferior role to CT. Ultrafast imaging has also allowed the study of the respiratory dynamics, including the diaphragm and costal excursions (21, 22). Although mainly a research tool, there are applications such as diaphragm paralysis and the effects of hyper expansion in severe emphysema that may benet patient care in future. Intravenous contrast agents (which are gadoliniumbased) enable the study of vasculature, the heart and perfusion of the lungs using a combination of static and dynamic sequences (2325). Thus, the effects of emphysema on lung perfusion and heart function can be studied and integrated in the patient management process. In spite of these developments, MRI has not made it into the routine realm of clinical imaging, largely due to the lack of availability, the time required for studies and the relative ease and speed of CT. Hyperpolarized noble gas imaging, using 3-He and 129-Xe, has been a focus of development for approximately 1015 years now (26). Although these techniques are still

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j Fig. 5. Cumulative histogram analysis in a group of patients according to GOLD criteria demonstrating a leftward shift of the curve with higher numbers of voxels with density below )950 HU in correlation with worse pulmonary function test results.

j Fig. 8. Time course of signal change during inspiration of 3-He MRI, allowing for airow quantication. From reference (42).

j Fig. 6. Patient with emphysema demonstrating extensive multiple ventilation defects using hyperpolarized 3-He MRI.

j Fig. 7. Gravity effects visualized using ADC method of hyperpolarized 3-He MRI. From reference (38).

under development, there are current issues related to availability, costs and need for hardware (including RF coils, multinuclear broadband MRI systems and polarizers), which make this technology not widely applicable at present. Ventilation distribution is built on the notion that any area with signal is a reection of the delivery of 3-He gas to this area (Fig. 6). One caveat is that this is a single breath technique, and therefore may not be a full representation of ventilation, but in spite of this limitation, several studies have shown the feasibility of this technique as well as the correlation with pulmonary function tests and extent of disease (2629). A recent multicentre study showed that the estimated ventilated lung volume correlated with both CT and pulmonary function tests, although these correlations were not perfect (and it was postulated that CT and MRI are complementary techniques in this setting) (29). Other studies have shown similar results (26, 3033). In normal volunteers, more or less homogeneous ventilation distribution is seen, whereas progressive ventilation defects are present with increasingly severe emphysema, while distribution of these defects is different between smoking-related emphysema and alpha-1 antitrypsin deciency (the latter shows a lower lobe predominance as predicted). It is possible to use a variety of quantication methods, including calculation of ventilated lung volumes by subtraction of proton and hyperpolarized 3-He images, or alternatively by performing a pixel analysis. (33). Reproducibility has been shown to be within the 5% range for both techniques. Diffusion imaging visualizes the movement of hyperpolarized 3-He atoms during the imaging sequence, and is capable of demonstrating airspace dimensions due to calculation of diffusion distance within the restricted

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airspaces (apparent diffusion coefcient, ADC). Although discussion is ongoing at what level of airspaces these measurements truly occur, a close correlation with histology, ageing, gravity and extent of emphysema has been shown (Fig. 7) (27, 3438). Furthermore, by changing the duration of measurement, it is likely feasible to assess the presence of collateral ventilation, which may have an impact on novel treatments such as transbronchial valve placement for lung volume reduction treatment (39). One drawback of this technique is that this measurement can only be performed in lung regions which allow hyperpolarized 3-He gas to enter, and air trapping and mucus plugging will both have a negative inuence on this technique. Dynamic ventilation imaging uses a combination of ultrafast imaging and post-processing to reconstruct a virtual map of gas ow over time (40, 41). The technique can be

quantied by plotting signal change over time in regions of interest (42, 43), and both inspiration and expiration can be studied by selecting different acquisition times during the respiratory cycle (Fig. 8). Oxygen-sensitive imaging uses the paramagnetic effect of oxygen as a calculable decrease in the signal of 3-He due to loss of polarization (44, 45). Signal decrease will occur faster in areas where ventilation and perfusion are not appropriately matched and oxygen concentrations in the airways remain relatively high. Mapping of oxygen uptake ratios and VQ ratios is feasible, and may become a powerful method to determine regional therapies and assess therapeutic effects in individual patients. Oxygen-enhanced imaging uses the paramagnetic effects of oxygen and the difference in signal within the lung between room air and 100% oxygen (46). This method uses a prolonged period of 100% oxygen breathing,

j Fig. 9. copd gene project description.

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followed by image subtraction, to yield the signal change due to oxygen shift in the lungs effectively this is ventilation, although the signal is also derived from oxygen increase in the interstitial structures and blood. Work is ongoing to demonstrate the possible utility of this technique for patients with COPD (47).
COPD gene project

the purpose of identifying subpopulations and intermediate outcome measures. It is funded by the National Heart, Lung, and Blood Institute and is coordinated by the University of North Carolina at Chapel Hill. This project is currently in its rst phase, where full protocols are being developed. Initial patient enrolment is scheduled for the fourth quarter of 2009. Imaging will be employed for phenotyping purposes, and the project is expected to be closely tied with the COPD Gene project.
Conclusions

This ongoing multicentre NIH-funded project, with principal investigators at National Jewish Hospital, Denver, CO, and Brigham and Womens Hospital, Boston, MA, aims to create a large cohort of subjects at risk for or expressing one of the various stages of COPD (GOLD grades 14). This cohort will be phenotyped both physiologically (spirometry, 6-min walk, BODE score) and radiographically (chest CT scan); genome-wide association analysis will be performed using a staged approach to identify and replicate COPD susceptibility genes. To optimize the identication of gene candidates, both a case control and a family-based association strategy will be employed. The cohort will be balanced for gender and stratied to represent major ethnic and racial groups in the United States. The size of the cohort has been chosen to provide sufcient statistical power to identify genetic risk factors in each of the ethnic and racial groups. All results will be validated in the entire cohort and in an external family-based association cohort. Our goal is to identify and correlate the phenotypic and genetic risk factors that underlie COPD. The cohort will initially be used in a cross-sectional design but will also be designed for future longitudinal follow-up. A series of case control studies will be conducted to identify genes controlling risk to COPD and conrm their effects. The rst phase of this study is a genome-wide screen using a conventional casecontrol design (stratied by racial/ ethnic groups) as well as a case-sib cohort. Subsequent conrmation of small nuclear peptides (SNP) yielding statistical signals will be carried out in a second phase of independent casecontrol analysis. Finally, we will conduct detailed analysis of genes/regions around these conrmed SNPs that appear to inuence risk of COPD. We will also validate the effects of genes identied here in two external populations and a large group of mild COPD cases (GOLD grade 1). Over time, the phenotypic, pathophysiological and genetic data collected here can be used to identify factors that control progression of COPD as these subjects are followed up prospectively. The outline of this study is depicted in Fig. 9.
Spiromics project

It is clear that efforts are currently focused on translating the recent advances in imaging, using both CT and MRI, into clinical applications. Furthermore, the integration of molecular diagnostic methods with phenotyping of subgroups is an exciting new development and these efforts will likely generate progressively individualized healthcare options to patients with emphysema.
References
1. Van Beek EJR, Hoffman EA. Functional imaging: CT and MRI. Chest Clin NA 2008; 29: 195216. 2. Flohr TG, McCollough CH, Bruder H et al. First performance evaluation of a dual-source CT (DSCT) system. Eur Radiol 2006; 16: 256268. 3. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 1977; 115: 195205. 4. Dranseld MT, Bailey WC. COPD: racial disparities in susceptibility, treatment, and outcomes. Clin Chest Med 2006; 27: 463471. 5. Vollmer WM, Enright PL, Pedula KL et al. Race and gender differences in the effects of smoking on lung function. Chest 2000; 117: 764772. 6. Mizuno N, Funabashi N, Imada M et al. Utility of 256-slice cone beam tomography for real four-dimensional volumetric analysis without electrocardiogram gated acquisition. Int J Cardiol 2007; 120: 262267. 7. Saba OI, Chon D, Beck K et al. Statis versus prospective gated nonbreath hold volumetric MDCT imaging of the lungs. Acad Radiol 2005; 12: 13711384. 8. Xu S, Taylor RH, Fichtinger G et al. Lung deformation estimation and four-dimensional CT lung reconstruction. Acad Radiol 2006; 13: 10821092. 9. Guerrero T, Sanders K, Castillo E et al. Dynamic ventilation imaging from four-dimensional computed tomography. Phys Med Biol 2006; 51: 777791. 10. Gould GA, Redpath AT, Ryan M et al. Parenchymal emphysema measured by CT lung density correlates with lung function in patients with bullour disease. Eur Respir J 1993; 6: 698704. 11. Stolk J, Dirksen A, van der Lugt AA et al. Repeatability of lung density measurements with low-dose computed tomography in subjects with alpha-1-antitrypsin deciency associated emphysema. Invest Radiol 2001; 36: 648651. 12. Shaker SB, Dirksen A, Laursen LC et al. Volume adjustment of lung density by computed tomography scans in patients with emphysema. Acta Radiol 2004; 45: 417423. 13. Uppaluri R, McLennan G, Enright P et al. AMFM a quantitative assessment of early parenchymal changes in smokers. Am J Respir Crit Care Med 1998; 157: A788. 14. Xu Y, van Beek eJR, Hwanjo Y et al. Computer-aided classication of interstitial lung diseases via MDCT: 3D adaptive multiple feature method (3D AMFM). Acad Radiol 2006; 13: 969978.

Sub Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) supports the prospective collection and analysis of phenotypic, biomarker, genetic, genomic and clinical data from subjects with COPD for

IMAGING DECISIONS n 1/2009

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15. Saba OI, Fuld MK, Krauss B et al. Dual energy MDCT for volumetric assessment of V/Q: initial experiences. Proceedings American Thoracic Society Annual Meeting, San Francisco, CA, 2007; A938. 16. Chae EJ, Seo JB, Goo HW et al. Xenon ventilation CT with a dualenergy technique of dual-source CT: initial experience. Radiology 2008; 248: 615624. 17. Mulreany DG, Simon BA, Murphy KJ, Easley RB. Volumetric Xenon-CT imaging of conventional and high-frequency oscillatory ventilation. Acad Radiol 2009; 16: 718725. 18. Alford SK, van Beek EJ, McLennan G et al.Characterization of smoking related regional alterations in pulmonary perfusion via functional CT. Proceedings American Thoracic Society Annual Meeting, San Francisco, CA, 2007; A818. 19. Sodicksen DK, Manning WJ. Simultaneous acquisition of spatial harmonics (SMASH): fast imaging with radiofrequency coil arrays. Magn Reson Med 1997; 38: 591603. 20. Pruessmann KP, Weiger M, Scheidegger MB et al. SENSE: sensitivity encoding for fast MRI. Magn Reson Med 1999; 42: 951962. 21. Swift AJ, Woodhouse N, Fichele S et al. Rapid lung volumetry using ultrafast dynamic magnetic resonance imaging during forced vital capacity maneuver: correlation with spirometry. Invest Radiol 2007; 42: 3741. 22. Eichinger M, Tetzlaff R, Puderbach M et al. Proton magnetic resonance imaging for assessment of lung function and respiratory dynamics. Eur J Radiol 2007; 64: 329334. 23. Pedersen MR, Fisher MT, van Beek EJ. MR imaging of the pulmonary vasculature an update. Eur Radiol 2006; 16: 13741386. 24. Iwasawa T, Saito K, Ogawa N et al. Prediction of postoperative pulmonary function using perfusion magnetic resonance imaging of the lung. J Magn Reson Imaging 2002; 15: 685692. 25. Fink C, Puderbach M, Ley S et al. Time-resolved echoshared parallel MRA of the lungs: observer preference study of image quality in comparison with non-echo-shared sequences. Eur Radiol 2005; 15: 20702074. 26. Fain SB, Korosec FR, Holmes JH, OHalloran R, Sorkness RL, Grist TM. Functional lung imaging using hyperpolarized gas MRI. J Magn Reson Imaging 2007; 25: 910923. 27. Fain SB, Panth SR, Evans MD et al. Early emphysematous changes in asymptomatic smokers: detection with 3He MR imaging. Radiology 2006; 293: 875883. 28. Mathew L, Evans A, Ouriadov A et al. Hyperpolarized 3He magnetic resonance imaging of chronic obstructive pulmonary disease: reproducibility at 3.0 Tesla. Acad Radiol 2008; 15: 12981311. 29. Van Beek EJR, Dahmen AM, Stavngaard T et al. Comparison of hyperpolarized 3-He MRI and HRCT in normal volunteers, patients with COPD and patients with alpha-1-antitrypsin deciency PHIL trial. Eur Resp J 2009. [in press] 30. MacFall JR, Charles HC, Black RD et al. Human lung air spaces: potential for MR imaging with hyperpolarized He-3. Radiology 1996; 200: 553558. 31. De Lange EE, Mugler JP 3rd, Brookeman JR et al. Lung air spaces: MR imaging evaluation with hyperpolarized 3He gas. Radiology 1999; 210: 851857.

32. Guenther D, Eberle B, Hast J et al. (3)He MRI in healthy volunteers: preliminary correlation with smoking history and lung volumes. NMR Biomed 2000; 13: 182189. 33. Woodhouse N, Wild JM, Paley MN et al. Combined helium-3/proton magnetic resonance imaging measurement of ventilated lung volumes in smokers compared to never-smokers. J Magn Reson Imaging 2005; 21: 365369. 34. Woods JC, Choong CK, Yablonskiy DA et al. Hyperpolarized 3He diffusion MRI and histology in pulmonary emphysema. Magn Reson Med 2006; 56: 12931300. 35. Schreiber WG, Morbach AE, Stavngaard T et al. Assessment of lung microstructure with magnetic resonance imaging of hyperpolarized Helium-3. Respir Physiol Neurobiol 2005; 148: 2342. 36. Swift AJ, Wild JM, Fichele S et al. Emphysematous changes and normal variation in smokers and COPD patients using diffusion 3He MRI. Eur J Radiol 2005; 54: 352358. 37. Altes TA, Mata J, de Lange EE et al. Assessment of lung development using hyperpolarized helium-3 diffusion MR imaging. J Magn Reson Imaging 2006; 24: 12771283. 38. Fichele S, Woodhouse N, Swift AJ et al. MRI of Helium-3 gas in healthy lungs: posture related variations of alveolar size. J Magn Reson Imaging 2004; 20: 331335. 39. Wang C, Miller GW, Altes TA et al. Time dependence of 3He diffusion in the human lung: measurement in the long-time regime using stimulated echoes. Magn Reson Med 2006; 56: 296 309. 40. Salerno M, Altes TA, Brookeman JR et al. Dynamic spiral MRI of pulmonary gas ow using hyperpolarized (3)He: preliminary studies in healthy and diseased lungs. Magn Reson Med 2001; 46: 667 677. 41. Wild JM, Paley MN, Kasuboski L et al. Dynamic radial projection MRI of inhaled hyperpolarized 3He gas. Magn Reson Med 2003; 49: 991997. 42. Koumellis P, van Beek EJ, Woodhouse N et al. Quantitative analysis of regional airways obstruction using dynamic hyperpolarized 3He MRI preliminary results in children with cystic brosis. J Magn Reson Imaging 2005; 22: 420426. 43. Holmes HJ, Korosec FR, Du J et al. Imaging of lung ventilation and respiratory dynamics in a single ventilation cycle using hyperpolarized He-3 MRI. J Magn Reson Imaging 2007; 26: 630636. 44. Deninger AJ, Eberle B, Ebert M et al. 3(He) MRI based measurements of intrapulmonary p(O2) and its time course during apnea in healthy volunteers: rst results, reproducibility and technical limitations. NMR Biomed 2000; 13: 194201. 45. Wild JM, Fichele S, Woodhouse N et al. 3D volume-localized pO2 measurement in the human lung with 3He MRI. Magn Reson Med 2005; 53: 10551064. 46. Ohno Y, Hatabu H. Basic concepts and clinical applications of oxygen-enhanced MR imaging. Eur J Radiol 2007; 64: 320328. 47. Ohno Y, Koyama H, Nogami M et al. Dynamic oxygen-enhanced MRI versus quantitative CT: pulmonary functional loss assessment and clinical stage classication of smoking-related COPD. Am J Roentgenol 2008; 190: W93W99.

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