Computed Tomography Scanning Techniques for the Evaluation of Cystic Fibrosis Lung Disease

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1 Computed Tomography Scanning Techniques for the Evaluation of Cystic Fibrosis Lung Disease Terry E. Robinson 1 1 Center of Excellence in Pulmonary Biology, Division of Pediatric Pulmonary, Stanford University Medical Center, Palo Alto, California Multidetector computed tomography (MDCT) scanners allow diagnosis and monitoring of cystic fibrosis (CF) lung disease at substantially lower radiation doses than with prior scanners. Complete spiral chest CT scans are accomplished in less than 10 seconds and scanner advances now allow the acquisition of comprehensive volumetric datasets for three-dimensional reconstruction of the lungs and airways. There are two types of CT scanning protocols currently used to assess CF lung disease: (1 ) high-resolution CT (HRCT) imaging, in which thin mm slices are obtained every 0.5, 1, or 2 cm from apex to base for inspiratory scans, and limited, spaced HRCT slices obtained for expiratory scans; and (2 ) complete spiral CT imaging covering the entire lung for inspiratory and expiratory scanning. These scanning protocols allow scoring of CF lung disease and provide CT datasets to quantify airway and air-trapping measurements. CF CT scoring systems typically assess bronchiectasis, bronchial wall thickening, mucus plugging, and atelectasis/consolidation from inspiratory scans, whereas air trapping is scored from expiratory imaging. Recently, CT algorithms have been developed for both HRCT and complete spiral CT imaging to quantify several airway indices, to determine the volume and density of the lung, and to assess regional and global air trapping. CT scans are currently acquired by either controlled-volume scanning techniques (controlledventilation infant CT scanning or spirometer-controlled CT scanning in children and adults) or by voluntary breath holds at full inflation and deflation. Keywords: HRCT; CF; spiral CT; volume control COMPUTED TOMOGRAPHY SCANNER TECHNIQUES Multidetector computed tomography (MDCT) scanners allow greater flexibility in the design of CT protocols to evaluate CF lung disease than prior scanners. Complete spiral chest CT scanning of the lungs from apex to base can now be accomplished in less than 10 seconds for 32 or more detector scanners, and less than 13 seconds for 16 detector scanners. Current scanner designs allow adjustment of CT dose parameters to limit radiation exposure and allow the CT technologist to use either thinslice high-resolution CT (HRCT) imaging or spiral CT imaging of the entire chest. Comprehensive volumetric datasets from spiral CT imaging can further provide three-dimensional (3D) reconstruction of the lungs and airways. HRCT High-resolution CT techniques sample the lung by acquiring thin, 0.5- to 1.5-mm slices every 0.5, 1, or 2 cm with gaps between slices (45). Scans are usually obtained from the apex to the base (Received in original form December 2, 2006; accepted in final form April 9, 2007 ) Correspondence and requests for reprints should be addressed to Terry E. Robinson, M.D., Center of Excellence for Pulmonary Biology, Division of Pediatric Pulmonary, Stanford University School of Medicine, 770 Welch Road, Suite 350, Palo Alto, CA ter@stanford.edu Proc Am Thorac Soc Vol 4. pp , 2007 DOI: /pats HT Internet address: of the lungs during inspiration. For expiratory scans, a smaller number of HRCT images are obtained, which are either evenly spaced from apex to the base or are obtained at anatomically determined locations. Using inspiratory and expiratory HRCT images, cystic fibrosis (CF) CT scoring systems have typically assessed bronchiectasis, bronchial wall thickening, mucus plugging, and atelectasis/consolidation from inspiratory scans, whereas air trapping is scored from expiratory imaging. Inspiratory HRCT scans acquired at intervals greater than 10 mm (typically 14 slices or less) result in significantly lower CF CT severity scores and limit the ability to detect worsening scores at 2 years (1). For expiratory imaging, regional air trapping has been assessed with three or more HRCT images that can sample the upper, middle, and lower lung regions (2 5). Because the CT scanner must move and stop the patient for each slice, HRCT requires more time than spiral CT. HRCT scans typically require 2 seconds for each slice, or greater than 40 seconds for lung sizes greater than 20 cm in length, necessitating two or more scanning maneuvers. The major advantage of HRCT imaging is that high-resolution images can be obtained with lower radiation exposure compared with complete spiral CT protocols. The major disadvantages with this technique include the longer scan times necessary to sample the entire lung, the limited view of scanned lungs in only the axial plane with HRCT imaging, and the difficulties that exist in obtaining anatomically matched airways or regional parenchyma for serial HRCT scans obtained before and after specific treatments in clinical trials. HRCT imaging is an optimal technique for evaluating lung disease in infants, children, and adults with CF in a clinical setting, Using low-dose strategies (100 kvp and mas) and obtaining slices every 0.5 to 1 cm from apex to base during inspiratory and expiratory scans, optimal information can be obtained with low radiation exposure ( msv) corresponding to approximately two to three chest radiographs (ImPACT CT Patient Dosimetry Calculator, version 0.99x; National Health Service, London, UK) (6) given the dose of chest radiographs is 0.1 msv (7). Spiral CT Current multidetector scanners can provide complete volumetric datasets obtained from spiral CT protocols. Spiral CT provides contiguous thin sections through the entire chest. The scanning technique is relatively similar for all multidetector CT scanners that have 16 or more detectors. The advantage of higher detector scanners is chiefly in the thinner slice capabilities and more rapid scan acquisitions allowing for greater resolution in the Z (head to toe) direction for 3D reconstructions and shorter total scan time. Typical slice thicknesses range from 0.5 to 1.25 mm (45). The entire lung can be scanned in as little as 5 to 10 seconds (45). The major advantages of spiral CT imaging include the ability to better match airways and regional air trapping in CT scans obtained before and after specific interventions in clinical trials as well as the ability to provide comprehensive 3D assessment of lung parenchyma and airway abnormalities noted in CF. Two examples of this are presented in Figure 1, in which the lung has been segmented into specified lobes and the airways have been segmented into a tracheobronchial tree by 3D reconstruction (45).

2 Robinson: Chest CT Scanning Techniques in CF 311 Figure 1. Three-dimensional tracheobronchial airway segmentation with defined bronchial segments in two adolescents with cystic fibrosis (CF), and two- and three-dimensional lobar segmentation in a 19-year-old adolescent with CF. Computed tomography (CT) scans obtained with a spiral CT protocol using 80 kvp, 70 mas, 0.6 mm collimation, 0.5- second scan rotation, pitch 1 on a Siemens Sensation 64 CT scanner (Siemens, Malvera, PA). (A ) Diffuse enlarged bronchial airways (bronchiectasis) in the right upper lobe and lower lobes designated by the arrowheads in a 15-year-old adolescent with more severe CF lung disease compared with (B) a 19-year-old adolescent with mild CF lung disease. (C) Lobar segmentation in the 19- year-old adolescent with mild CF lung disease. LLL left lower lobe; LUL left upper lobe; RLL right lower lobe; RML right middle lobe; RUL right upper lobe. Upper images in A and B, and all images in C, were processed with Vida Diagnostics Software (Vida Diagnostics, Iowa City, IA); lower images in A and B were processed with software developed by the Stanford University Medical Center Cystic Fibrosis Post-Processing Lab (Stanford, CA). Reprinted by permission from Reference 45.

3 312 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL In Figure 1, two patients with CF with and without significant bronchiectasis are presented. The segmented airway in the Figure 1A reveals significant advanced bronchiectasis (arrowheads) in contrast to minimal airway disease in the subject with in Figure 1B. Another advantage of spiral CT scans is that more airways can be identified and accurately measured with quantitative CT algorithms compared with HRCT imaging (8). Spiral CT scans can further allow quantification of air trapping for all lung regions and can provide a calculation of total lung volume by CT assessment. The major disadvantages of spiral CT imaging includes the higher radiation dose compared with HRCT protocols and the slight decreased resolution of CT images compared with HRCT scans. Spiral CT is an optimal technique for research protocols that can provide comprehensive serial assessment of the lung for CF research. New approaches with lower dose scans are now possible with multidetector CT scanners. Using low-dose strategies (100 kvp and mas) for inspiratory and expiratory spiral scans, the total radiation exposure is approximately equivalent to 0.5-year background radiation exposure at sea level (1.5 msv) (ImPACT CT Patient Dosimetry Calculator, version 0.99x) (6). Promising capabilities of these low-dose scanning approaches include the potential to provide quantitative airway measurements out to the fifth and sixth generation airways for each lobe, and regional air-trapping measurements by lung zone and, in the near future, by lobe (45). With these techniques, it is anticipated that regional abnormalities will be better detected, structural changes in CF lung disease will be picked up earlier, and the effects of specific therapeutic interventions will be more readily ascertained during clinical research trials in children and adults with CF. LUNG VOLUME CONTROL CT scan acquisition, especially expiratory CT imaging, is impacted by the lung volume at which the scans are obtained (45). Expiratory lung volumes near functional residual capacity lead to significantly higher quantitative air-trapping values and lower lung density values compared with CT scanning obtained at near residual volume (4, 9). Obtaining expiratory CT scans at different lung volumes on serial studies can lead to erroneous air-trapping and lung attenuation values, limiting the ability of CT scanning Figure 2. (A ) Volitional breath-hold computed tomography (CT) scanning technique. Note: each plateau of lung volume represents different highresolution CT scan acquisitions in a well-coached subject with CF instructed to take maximal inspiratory breath holds. Maximal differences in lung volume for some scans amounted to 0.9 L. (B) Spirometer-controlled CT scanning technique. Note: inspiratory CT scan obtained at set goal of 95% slow vital capacity (SVC). ERV expiratory reserve volume.

4 Robinson: Chest CT Scanning Techniques in CF 313 to detect changes after an intervention. Quantitative airway measurements are also affected by the degree of inspiratory lung inflation (10). Children younger than approximately 5 years cannot perform the necessary maneuvers to provide inspiratory and expiratory CT scans. For children from 5 to 8 years of age, cooperation will frequently limit the quality of CT scans. Older subjects can perform the necessary maneuvers, but without standardized volume control techniques, lung volumes continue to vary at all ages. CT scans can be acquired by either standardized controlledvolume techniques (controlled-ventilation infant CT scanning [11 17] and spirometer-controlled CT [2 5, 18, 19]) or by volitional breath holds which are directed by the CT technologist during inspiratory or expiratory CT imaging (20 42). An example of a volitional breath-hold chest CT scan is presented in Figure 2A and contrasted with a volume-controlled scan in Figure 2B. Volitional breath-hold CT scans may result in inconsistent lung volume acquisition, especially with expiratory imaging. Volume-controlled scans provide reproducible CT imaging, especially for expiratory scanning. Controlled-ventilation infant CT scan acquisition is described elsewhere in this symposium by Long (pp ). Spirometer-controlled CT scanning uses a portable spirometer unit that alerts the CT technologist when the subject s lung volume has reached a precise user-defined inspiratory or expiratory lung volume (Figure 3). Before CT scanning, supine spirometry is performed to obtain supine lung volume measurements (slow vital capacity [SVC], inspiratory capacity, and expiratory reserve volume). Inspiratory and expiratory thresholds as a given percentage of the SVC are then determined for planned scan acquisition. For inspiratory scans, the threshold is set at 95% or more of SVC. For expiratory scans, the threshold is typically set to lung volumes corresponding to 5 to 12% of SVC, which decreases the chances of obtaining erroneously higher airtrapping values that have been reported for scans obtained near functional residual capacity (4). With volitional breath-hold CT scans, it is essential that the technologist practice both inspiratory and expiratory breath-hold maneuvers, typically in the supine position, before CT scan acquisition to minimize lung volume variability as much as possible. Figure 3. (A ) Spirometer-controlled chest computed tomography (CT) diagram indicating scan acquisitions at near full inflation, near functional residual capacity (nfrc), and near residual volume (nrv). Note: Spirometer-controlled scans are routinely done at 95% of slow vital capacity (SVC) and nrv corresponding to 5 12% of the supine SVC. Corresponding matched axial CT slices: (B) inspiratory scan at 95% SVC), (C) expiratory scan nfrc, and (D) expiratory scan nrv. Note regions (*) (pulmonary lobules) with different degrees of air trapping best visualized with expiratory CT scans obtained at nrv.

5 314 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL CT SCANNING TECHNIQUES IN PUBLISHED RESEARCH TRIALS Since 1997, several authors have used controlled-ventilation infant CT scans to assess early lung disease in infants with CF (11 17). Several authors have also used spirometer-controlled CT imaging in children and adults with CF, ages 6 to 42 years, with mild to severe lung disease (2 5, 18, 19). Controlled-volume infant CT and spirometer-controlled CT protocols have been used to demonstrate significant improvement in total HRCT scores after intravenous antibiotics and airway clearance therapy for a pulmonary exacerbation in infants and children with CF (2, 17). Spirometer-controlled CT scanning has also been used to demonstrate greater quantitative air trapping in children with mild CF lung disease compared with normal control subjects, and improvement in quantitative air trapping and a composite HRCT/pulmonary function test score after 1 year of dornase alfa therapy during a 1-year Pulmozyme (Genentech, South San Francisco, CA) intervention study in children with mild CF lung disease (2 5, 18, 19). Volitional breath-hold CT imaging has been used in seven CF intervention studies (22, 26, 28, 33 36, 39). Of these seven studies, there has been only one study using an HRCT scoring system that has demonstrated a significant difference after a specific therapeutic intervention (28) other than antibiotic therapy for a pulmonary exacerbation in children and adults with CF (22, 34). Volitional CT scanning has also been used in an ongoing natural history study of children and adults with CF followed at Sophia Children s Hospital in the Netherlands (31, 32, 38, 41, 42). Both HRCT and volumetric CT images have been used by the radiologist to score CF disease severity with different CF CT scoring systems (1, 2, 5, 9, 12 14, 17, 19 43). In addition, both types of scanning format have been used with quantitative CT post-processing techniques, such as CT airway measurements (8, 14, 15, 31) and quantitative air-trapping measurements (3 5, 15). Several CT scoring systems have been previously reviewed (31). Recently developed CT algorithms can quantify several airway indices on either HRCT or spiral CT scans, including bronchial wall thickness, luminal diameter, wall area, and luminal area, as well as determine the volume and density of the lung for inspiratory and expiratory CT images, and assess regional and global air trapping (4, 8, 15). With these quantitative CT algorithms, two authors have reported that large airways can accurately be measured, but the accuracy of smaller airway measurements become limited when airway lumen diameters are smaller than 2.5 to 3.5 mm (43, 44). This approximates airway sizes comparable to segmental and subsegmental airways for older children and adults. CONCLUSIONS Because of advances in CT technology in the last 10 years, CT scanning in CF children and adults has become much easier and more efficient. CT scanning protocols are now available that provide comprehensive assessment of CF lung disease with lower radiation exposure. New scanning techniques provide greater flexibility to design specific CT protocols to address early and progressive disease using CF scoring systems and quantitative CT outcome measures. Conflict of Interest Statement : T.E.R. is currently the principal investigator on a Novartis and Cystic Fibrosis Foundation Therapeutic Development Network Grant. 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