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 progres-
sive 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 evalu-
ate 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
briefly described at the end of this study.
Magnetic resonance imaging (MRI) has taken a signif-
icant flight 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 pulmo-
nary vasculature. Furthermore, hyperpolarized gas meth-
ods (using 3-Helium and 129-Xenon isotopes) have been
developed for study of ventilation-based assessment of the
lung and study of airflow 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 field
competes with security devices industries.
Computed tomography
The application of MDCT has gained widespread accep-
tance, and in most institutions a minimum 16-slice CT
1/2009 n IMAGING DECISIONS
scanning system is now available, with up to 256-slice
systems allowing faster imaging at increased spatial reso-
lution (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 tech-
niques, 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 prom-
ising results for assessment of perfusion and ventilation CT
imaging of the lung, facilitating the study of lung patho-
physiology 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 breath-
ing lung, which offers the study of heart and lung
dynamics.
It has been recognized that traditional morphological
CT studies are insufficient for disease quantification, 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 surro-
gate (non-clinical) end points, it is likely that quantita-
tive (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), quantification of
disease states, assessment of airway wall diameters (Fig. 3),
planning of pathways for interventional procedures (Fig. 4)
and quantification 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 sug-
gested, but most of these are still in a research domain.
12 n IMAGING IN COPD
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 auto-
matic labelling software (Pulmonary Workstation 2, VIDA
Diagnostics, Coralville, IA, USA).
Furthermore, recent studies have focused on the semi-
automated 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 radiol-
ogy technologists. A simple tape-recorded message will not
suffice! 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 flow volumes enables the estimation of
true pulmonary perfusion, capillary transit times and cap-
illary flow distributions. This technique has been per-
formed 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 non-
smoking 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 sufficient signal to obtain the images. This has
traditionally been difficult in lung imaging, due to a lack of
protons and due to inhomogeneity of the magnet field at
the air/tissue interface. Newer methods have improved the
visualization of lung parenchyma, making use of new
sequences and novel contrast methods, including gadolin-
ium 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 interpreta-
tion of pulmonary perfusion, breathing dynamics and
imaging of gas flow. Many of these methods are already
IMAGING DECISIONS n 1/2009

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 field 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,
inflammation or tumour), whereas calcification will lead to
signal voids.
1/2009 n IMAGING DECISIONS
IMAGING IN COPD n 13
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 assess-
ment, 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 benefit
patient care in future.
Intravenous contrast agents (which are gadolinium-
based) 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 emphy-
sema 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
14 n IMAGING IN COPD
j Fig. 5. Cumulative histogram analysis in a group of
patients according to GOLD criteria demonstrating a left-
ward shift of the curve with higher numbers of voxels with
density below )950 HU in correlation with worse pulmonary
function test results.
j Fig. 6. Patient with emphysema demonstrating exten-
sive 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).
j Fig. 8. Time course of signal change during inspiration of
3-He MRI, allowing for airflow quantification. From reference
(42).
under development, there are current issues related to
availability, costs and need for hardware (including RF
coils, multinuclear broadband MRI systems and polariz-
ers), which make this technology not widely applicable at
present.
Ventilation distribution is built on the notion that any area
with signal is a reflection 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
deficiency (the latter shows a lower lobe predominance
as predicted).
It is possible to use a variety of quantification 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 hyperpo-
larized 3-He atoms during the imaging sequence, and is
capable of demonstrating airspace dimensions due to
calculation of diffusion distance within the restricted
IMAGING DECISIONS n 1/2009

airspaces (apparent diffusion coefficient, 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 reduc-
tion treatment (39).
One drawback of this technique is that this measure-
ment 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 influence on this
technique.
Dynamic ventilation imaging uses a combination of ultrafast
imaging and post-processing to reconstruct a virtual map
of gas flow over time (40, 41). The technique can be
j Fig. 9. copd gene project description.
1/2009 n IMAGING DECISIONS
IMAGING IN COPD n 15
quantified 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 concentra-
tions 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,
16 n IMAGING IN COPD
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 tech-
nique for patients with COPD (47).
COPD gene project
This ongoing multicentre NIH-funded project, with prin-
cipal 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 physio-
logically (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 identification of gene candidates, both a case
control and a family-based association strategy will be
employed. The cohort will be balanced for gender and
stratified to represent major ethnic and racial groups in the
United States. The size of the cohort has been chosen to
provide sufficient 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 confirm their effects. The
first phase of this study is a genome-wide screen using a
conventional casecontrol design (stratified by racial/
ethnic groups) as well as a case-sib cohort. Subsequent
confirmation 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 confirmed
SNPs that appear to influence risk of COPD. We will also
validate the effects of genes identified here in two external
populations and a large group of mild COPD cases
(GOLD grade 1). Over time, the phenotypic, pathophys-
iological 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
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
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 first 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
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 sub-
groups is an exciting new development and these efforts
will likely generate progressively individualized healthcare
options to patients with emphysema.
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