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For other articles and previous issues click here. January 16, 2006 Imaging
Asthma Reactions to Cat Allergens — High-Resolution CT Provides
a Look at Smaller Air Passageways As CT scanning technology improvements keep coming, diagnostic imaging keeps finding new, advanced applications for them. One that is intriguing, and potentially promising, involves using high-resolution CT (HRCT) techniques to identify and target respiratory inflammation in asthmatic patients. Work in this area was described in a presentation at RSNA 2005 this past November. Jared Allen, PhD, reported results from a study showing that patients exposed to known asthma triggers—in this case, cat allergens—continue to display airway inflammation and accompanying lung function impairment as long as one day after exposure. That finding confirms what many physicians treating asthmatics have long noted anecdotally, but previously have been unable to prove clinically, according to Allen, a postdoctoral researcher at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA) and lead author of the paper, “Novel Quantitative CT Analysis Demonstrates Delayed Small Airway Reactivity Following Cat Antigen Exposure.” Being able to evaluate this previously hidden inflammation is important because while lung changes triggered by allergen exposure may not always produce immediate symptoms, they can contribute to persistent impairment in the small airways. Untreated, such lasting constriction could lead to subsequent severe attacks, Allen says. The
Costs of Epidemic Asthma Adults suffer, too. The American Lung Association says nearly 20 million Americans, or approximately 9% of the total populace, struggle with asthma. Approximately 10 million Americans have been diagnosed specifically with allergic asthma, which causes respiratory attacks triggered by exposure to environmental irritants. Direct care costs for treating asthma patients top $11.5 billion annually, including more than $5 billion in prescription drugs. Indirectly, asthma accounts for 24.5 million missed workdays each year, representing $4.6 billion in lost productivity. Animal
Allergens Allen’s study grew out of the frequently noted clinical observation that patients report feeling symptomatic even two days following an asthma attack, particularly when it’s induced by exposure to cat allergens. In many such cases, the triggering inflammation is ‘clinically silent,’ meaning that the patient’s responses typically register normal when assessed using the conventional measures of pulmonary function tests (PFT). Although asthma usually is thought of as a disease of large airway constriction (presenting as the tell-tale wheeze), given the anecdotal evidence, Allen’s research team postulated that the smaller distal airways may actually contribute more significantly to this characteristic inflammatory response than previously suspected. “Specifically studying cat allergens was important,” he says, “because the actual particle that causes cat allergies [the inflammatory response] are considered to be small enough to reach these far regions of the lung, the distal airways, where other allergen particles may affect larger airways.” The problem to date has been the lack of a direct, noninvasive way to assess small airway response. The standard test involves inserting a bronchoscope through the nose and into the lung—obviously a highly invasive procedure. HRCT offers a less invasive alternative. “We looked for a pretty well-studied model system,” says Allen. “With cat allergens, there are many studies available, many going back a good many years, so it was a good system for us to use in evaluating the utility of the HRCT approach and methodology.” Virtually all earlier tests involving animal irritants required the patients to inhale particles of the trigger substance in a laboratory setting. By contrast, the “cat room challenge” (CRC) involved placing known asthma patients in a closed room where cats had previously been allowed to roam freely, and where the cats continued to be kept (in cages) during the exposure period. “We call it a naturalized cat allergen exposure,” Allen notes. “We can document the antigen present in the room, but we get a more naturalistic response because patients stay in the room until they display a reaction and begin having symptoms.” Test
Technology In the CRC study, the researchers coupled HRCT with respiratory gating to create segmentation analyses. Patients were monitored with spirometers and coached to perform appropriate breathing maneuvers to acquire residual volume scans, with images being acquired during a breath-hold at end expiration. Allen notes that although automated respiratory gating wasn’t used during the CRC trials, “It’s an emerging technology that would be ideal for our application.” Scans were acquired on a GE Medical Systems 9800 High Speed Advantage CT scanner, which uses a 10-millimeter spiral reconstruction every 1 millimeter at 3 centimeters above and below the breastbone ridge. Because each scan required synchronizing scanning to the respiratory cycle, the average test time lasted approximately 45 minutes, but Allen points out that actual image acquisition time was quite short. “Because these studies were functional imaging, you only want to acquire images according to individual respiration,” he says. “But you want to scan fast enough that patients don’t run out of breath. So acquisition speed and resolution were important to getting reasonable, quantifiable data.” Software
Assessments The UCLA team’s segmentation software programs built on similar techniques that have been used to study other organ systems, including the heart, kidneys, brain, and liver. The software automates the image analysis process by applying anatomical landmarks and other algorithms to identify the voxels (volume elements) that represent lung tissue. This allows the software to differentiate lung structures from the ribs, the heart, and so on. Allen explains, “In a normal asthmatic patient who’s having an attack, you can see changes in their lung tissue that show that they’re trapping air; it’s something you can see with your eyes. But we were looking at very small airway structures, less than 2 millimeters in diameter, that can’t be directly visualized … so it’s much more powerful if we can use a reproducible computational technique to quantify airway changes. By having multidetection, HRCT allows us to get obviously better resolution [and thus to collect the kind of data] that allows us to gauge changes in the lung tissue.” In the CRC study, the automated lung field segmentation program created 12 highly detailed regions of interest, which were highlighted onscreen and used to derive lung attenuation curves (see the accompanying box for details). Each targeted series of images, says Allen, essentially represent tens of thousands of data points, which the computer can analyze to give the characteristics of that tissue. This, in turn, allows the researchers to address the characteristics of the CT scan in specified areas, using a random model effect to assess changes in small airway reactivity. “We looked at things like attenuation values and patterns,” notes Allen. “For instance, does the scan show a lot of open, aerated lung where you would expect to see more uniformly dense tissue? The segmentation analysis gives you the computational power to analyze the CT more deeply than what you can normally see just by looking at the scanned images.” Study
Protocol “The methacholine challenge is important because asthmatic patients’ responses, due to whatever inflammatory changes they might have, are much more sensitive to this chemical [than nonasthmatic subjects],” says Allen. “We know that when we measure the level at which they have a response, consistently people with asthma have a reaction at much lower doses. And using methacholine actually accentuates the radiological features when scanning after subsequent exposures by providing a little more airway constriction and trapped air.” Over a three-day period, 10 patients whose airways were known to be hyper-reactive to cat-induced inflammation were subjected to the CRC. Baseline PFTs and HRCTs before and after the methacholine challenge test were acquired on the morning of the first day, and subsequent assessments were compared with those baselines. After the patients were exposed to the cat room, PFTs were performed and their responses immediately monitored. Six hours later, another full PFT was administered to determine whether the patients were recovering. Says Allen, “The six-hour interval is critical because that’s considered to be part of the late phase of an asthma attack, where the inflammation starts causing problems. If patients initially have symptoms and then recover, within hours of the exposure—very often within about six hours—people will complain that they feel wheezy again. And many studies have shown that there’s a lot of inflammation that goes on in that time scale. For our study, it was important to look at whether the inflammatory symptoms persist.” The next HRCT studies were conducted after 22 hours. “Typically by this time people report being only mildly symptomatic, and conventional lung function tests are normal,” says Allen. “So we wanted to evaluate by the HRCT method to see if the same inflammation persisted.” The accompanying box details the specific CRC methodology and findings. The ability to image persistent changes that last for days after an exposure is a major step forward, Allen points out. “For instance, we can now visualize how inflammation lingers after an exposure triggers an asthma attack, and the patient seemingly recovers after a day. So we can investigate if they would be more susceptible to an additional challenge from another irritant—and would that be worse for them than if they had not had the initial challenge in the first place?” Assessing
the Results Most importantly, explains Allen, “The computer analysis shows us different patterns and distributions of air volume vs. lung tissue. This is especially crucial in asthma and emphysema, for example, where the changes in attenuation you see in CT have very important correlations to the degree of disease.” Toward
New Tests “We look pretty often at the question of how can the things we’re developing be clinically implemented, particularly the software,” he says. “The goal we have is to make the software robust enough and diverse enough that you can put it right there next to the scanner and analyze all the aspects of lung disease—maybe not in real-time but certainly postacquisition.” More immediately, he wants to draw physicians’ attention to the importance of small airways in asthma. “Across all of radiology, the technology is changing how we can look at medical imaging and evaluate things we can’t see on our own. A better understanding of the causes and complications of asthma, as afforded by this type of imaging, can lead to improved and targeted new therapies,” he says. — J. K. Bucsko is a freelance healthcare and technical writer based in Westville, N.J., and a frequent contributor to Radiology Today.
The standard methacholine challenge test (MCT) allows researchers to measure airway responsiveness immediately. Test subjects inhale an aerosol concentration and lung capacity is measured before and after the inhalations to calculate response to specific triggers. Standard spirometry measures the number of liters of air the patient can force out of the lungs within one second (called forced expiratory volume, one second, or FEV1). A normal (nonasthmatic) patient should be able to return at least 80% of the predicted air volume; a 20% decrease in respiratory measurement after MCT is considered to indicate a positive finding for a diagnosis of asthma. To track lung attenuation curves (LACs), CT series are also acquired before and after the inhalant test, and the results are plotted as a histogram correlating frequency (number of voxels) to relative density (attenuation, measured as Hounsfield Units). An asthmatic postchallenge will register decreasing attenuation and increasing frequency, showing as a leftward shift of the LAC plotted arc, which denotes air trapping in the imaged area of the lungs. This trademark shift is entirely missing in the LACs of normal patients. In the “cat room challenge” (CRC), all subjects displayed immediate FEV1 declines (mean decrease of 30 ± 11%), although six hours following their exposure to the cat room they recorded only moderate decreases in PFT results (mean decrease 10 ± 14%). However, the researchers discovered a significant leftward LAC shift, revealing the anticipated decreased attenuation between pre- and post-MCT results both for the baseline as well as for the next-day post-CRC studies. Specifically, a mean shift of -54.09Hu ± 6.80, p < 0.001 (from baseline) was documented for median attenuation and a mean shift -45.67Hu ± 5.12, p < 0.001 was recorded for its 10th percentile. In a telling trend, 22 hours after exposure in the cat room, all the test subjects’ LACs remained significantly left-shifted, even though PFTs demonstrated no significant FEV1 drop. Median attenuation showed a mean change of -15.88Hu ± 5.20 (p = 0.002) and the 10th percentile mean change was -10.42Hu ± 4.26 (p = 0.014). The MCT given after 22 hours provoked further LAC shifts of the median (-16.85Hu ± 5.40, p = 0.002) and 10th percentile (-12.81Hu ± 4.46, p = 0.004) even compared with the baseline post-MCT LAC shift. Clearly, as the study authors conclude, HRCT analysis is capable of characterizing both air trapping and sensitization to methacholine up to 22 hours after exposure to a known allergen, in spite of the patients’ return to normal spirometry measurements. “By doing CT scans with and without the methacholine challenge, we can assess both increased air trapping and airway sensitivity to subsequent irritant exposures,” says Jared Allen, PhD, a postdoctoral researcher at the David Geffen School of Medicine at UCLA. — JKB
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