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DOI: 10.1148/radiol.2401050502
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(Radiology 2006;240:236-245.)
© RSNA, 2006

Thoracic Imaging

Thin-Section CT in Patients with Cystic Fibrosis: Correlation with Peak Exercise Capacity and Body Mass Index1

Jonathan D. Dodd, MB, MSc, MRCPI, FFRRCSI, Sinead C. Barry, MISCP, PhD, Rupert B. M. Barry, MB, MRCPI, Charles G. Gallagher, MB, FRCPI, FRCPC, Stephen J. Skehan, MB, FRCPI, FFRRCSI, FRCR and James B. Masterson, MB, FFRRCSI, FRCR

1 From the Department of Radiology (J.D.D., S.J.S., J.B.M.) and The National Referral Centre for Adult Cystic Fibrosis (S.C.B., R.B.M.B., C.G.G.), St Vincent's University Hospital, Dublin, Ireland. Received March 26, 2005; revision requested May 19; revision received August 17; final version accepted September 14. Supported by the Health Research Board of Ireland, the Cystic Fibrosis Research Trust Fund of Ireland, and the Department of Radiology, St Vincent's University Hospital. Address correspondence to J.D.D., Department of Radiology, Vancouver General Hospital, 855 W 12th Ave, Vancouver, BC, Canada V6K 1R4 (e-mail: jddodd{at}partners.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Purpose: To evaluate whether thin-section chest computed tomographic (CT) findings correlate with exercise capacity, body mass index (BMI), dyspnea, and leg discomfort in patients with cystic fibrosis (CF).

Materials and Methods: Institutional ethics committee approval was obtained, and patients provided written informed consent. Twenty-two patients (13 male and nine female patients; mean age, 22 years ± 5.9; age range, 17–41 years) with stable CF underwent thin-section CT and exercise testing on a cycle ergometer. Three radiologists blinded to the clinical severity of disease and the spirometric findings of all patients independently and randomly scored all scans with a modified Bhalla scoring system. The primary measurement of the outcome of exercise testing was percentage of predicted peak O2 uptake. Univariate (Spearman rank correlation) and multivariate analyses were used to compare thin-section CT, clinical (age, sex, spirometric data, and BMI), and exercise measurements.

Results: The correlation between total thin-section CT score and percentage of predicted peak O2 uptake was stronger than the correlation between the percentage of predicted peak O2 uptake and any clinical measurement (R = –0.60, P < .01). The thin-section CT structural abnormalities that had the strongest correlation with percentage of predicted peak O2 uptake were severity of bronchiectasis and presence of sacculations or abscesses (R = –0.70 and –0.71, respectively; P < .01). Multivariate analysis showed total thin-section CT score to be the only significant predictor of exercise capacity, accounting for 42% of the variance in percentage of predicted peak O2 uptake.

Conclusion: In patients with CF, the correlation between thin-section CT score and exercise limitation is stronger than that between spirometry results or BMI and exercise limitation.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Cystic fibrosis (CF) is the most common inherited autosomal recessive disease in white people, and it has an incidence of one case per 1461 births in Ireland (1). Most patients with CF die of progressive respiratory failure, although improvements in treatment have led to increased life expectancy (2). Traditionally, patients have been monitored with spirometry and chest radiography; however, use of thin-section computed tomography (CT) is becoming more common in pulmonary assessment (3–9).

Thin-section CT is the current optimal imaging investigation used to assess structural changes in the lungs of patients with CF; however, the functional importance of these changes is unclear. Functional indexes in patients with CF are primarily measured with the well-validated Shwachman-Kulczyski clinical scoring system, which consists of four categories (general activity, nutrition, and physical examination and radiographic findings), and maximal exercise testing (generally performed on a cycle ergometer or treadmill in an exercise laboratory) (10). Exercise testing has become an important functional investigation in the examination of patients with CF, allowing physicians to evaluate the cause of exercise limitation, the magnitude of exercise-induced hypoxemia, and the need for supplemental O2. In addition, the findings of exercise testing are a good predictor of mortality and quality of life in patients with CF (11–14).

Exercise testing has some limitations. For instance, it requires highly trained personnel and sophisticated laboratory equipment that may be unavailable at many institutions. Many patients are unwilling or unable to undergo exercise testing (15). Furthermore, a small mortality rate is associated with exercise testing (16). Thus, surrogate markers of exercise limitation would be useful in patient evaluation. The best-known correlates of exercise limitation are forced expiratory volume in 1 second (FEV1) and body mass index (BMI) (17,18). Neither correlate is a particularly good indicator of exercise limitation. We hypothesized that because there is good correlation between thin-section CT findings and clinical scores (a component of which is "general activities"), thin-section CT might provide a better correlate of exercise limitation than FEV1 or BMI. Thus, the purpose of this study was to determine if a correlation exists between thin-section CT findings and exercise capacity, BMI, dyspnea, and leg discomfort in patients with CF.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Patient Population
All patients had documented clinical, radiologic, or genotypic features typical of CF, as well as abnormal sweat test results (sweat chloride level > 60 mmol/L). Thin-section CT was performed biennially as part of scheduled long-term patient assessment at the Irish National Referral Centre for Adult Cystic Fibrosis. All patients in Ireland who are older than 17 years are referred to the center, which at the time of this writing provides multidisciplinary care for 250 patients. Twenty-two patients referred for thin-section CT were randomly selected to undergo prospective exercise testing (13 male and nine female patients; mean age, 22 years ± 5.9 [standard deviation]; age range, 17–41 years). Because the exercise test is rigorous, patients were excluded if they (a) had symptoms or signs of an infective acute exacerbation of respiratory problems at thin-section CT or between thin-section CT and exercise testing, (b) had unstable spirometric findings at thin-section CT (>10% decrease in FEV1 compared with the baseline value), (c) were referred for thin-section CT because of a severe or unresolved exacerbation of respiratory problems, or (d) refused or were unable to undergo exercise testing (refusal to exercise by patients with CF has been related to the presence of chronic illness, complex medical therapies, and individual and family perceptions of exercise and its benefits [15]). The institutional ethics committee approved this study. All patients provided written informed consent.

Thin-Section CT Protocol and Scoring
Thin-section (1-mm section thickness, 10-mm interval) CT scans were obtained with a spiral CT unit (Somatom Plus 4; Siemens, Erlangen, Germany); patients were examined in the supine position. Inspiratory scans were obtained during suspended deep inspiration from the apices to the costophrenic angles. Expiratory scans were obtained during full expiration at three levels: the top of the aortic arch, the carina, and 2 cm above the diaphragm. Examination parameters were 140 kVp and 140 mA; scans were reconstructed with a high-spatial-frequency bone algorithm and a 512 x 512 matrix. Window width and center settings were 2000 HU and –700 HU, respectively.

Inspiratory scans were scored independently by two consultant radiologists (S.J.S., J.B.M., with 10 and 20 years of experience, respectively, reading thin-section chest CT scans). Mosaic perfusion and air trapping were scored independently by a chest radiology fellow (J.D.D.) with 2 years experience reading thin-section CT scans. All scans were read in random order unrelated to test date. All radiologists were blinded to the clinical severity of disease, spirometric findings, and exercise limitations of all patients.

CT scans were scored by using a modified Bhalla scoring system (19). Abnormalities were defined according to recommendations of the Nomenclature Committee of the Fleischner Society (20). Bronchiectasis was characterized by a bronchus with an internal diameter larger than its accompanying pulmonary artery, lack of tapering of the bronchial lumen for more than 2 cm, and visualization of a bronchus within 1 cm of the costal pleura. Peribronchial thickening was characterized by a bronchial wall thicker than 1 mm. Mucus plugging was characterized by the visualization of mucus plugs in large airways or the presence of peripheral tree-in-bud or centrilobular nodules. Sacculations were classified as dilated bronchi with a cystic or saccular appearance. A bulla was defined as a round focal airspace larger than 1 cm in diameter that was demarcated by a thin wall. Emphysema was indicated by areas of decreased attenuation, with disruption of the underlying vascular pattern and absence of well-defined walls. Consolidation was defined as increased lung opacification that obscured the underlying parenchyma. We modified the image score by assessing mosaic perfusion on inspiratory scans and air trapping on expiratory scans. Areas of hyperlucency with hypovascularity on inspiratory scans indicated mosaic perfusion. Areas of hyperlucency on expiratory scans indicated air trapping. Observers ignored hyperlucent areas in the plane of the minor fissure, in the apical segments of the lower lobes, and in isolated single secondary pulmonary lobules, as these findings can occur in healthy individuals (21). The extent and severity of abnormalities were scored with the scoring system described in Table 1. The total score was derived by adding the scores for each abnormality, and scores ranged from 0 to 31. When two observers scored individual abnormalities, the average score was calculated. A score of 0 indicated a normal Bhalla score; a score of 1–10, a mild Bhalla score; a score of 11–21, a moderate Bhalla score; and a score of 22–31, a severe Bhalla score.


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  		Table 1. Modified Bhalla CT Scoring System

 
Exercise Testing Protocol
Because all patients did not undergo thin-section CT and exercise testing on the same day, exclusion criteria were reapplied at exercise testing. Exercise testing was performed within 6 weeks of thin-section CT (mean, 13 days ± 16 [standard deviation]; range, 0–41 days) for all patients. Testing was performed by one of three research fellows with at least 1 year of experience in clinical exercise testing (J.D.D., S.C.B., R.B.M.B.) in an exercise laboratory; a standardized protocol that was highly reproducible in all patients was used (22). Patients were asked to avoid engaging in strenuous activity for at least 24 hours before testing and to avoid consuming food or caffeinated drinks for 2 hours before testing. Testing was performed on an electrically braked cycle ergometer (Excalibur Sport; Lode, Groningen, the Netherlands) while the subject breathed room air.

Each patient mounted the cycle ergometer and wore a nose clip and mouthpiece connected to the recording computer. Resting measurements were obtained over a 4-minute period. This was followed by a 2-minute warm-up period (set at a 15-W workload) and the exercise phase, in which the workload increased by 15 W/min in a ramp fashion (workload is gradually increased as opposed to incrementally increased) until exhaustion. Patients were instructed to use speedometer feedback to maintain a cadence of 50–70 rpm.

Electrocardiogram leads were attached to the chest, which enabled continuous heart rate monitoring. Arterial O2 desaturation was monitored with pulse oximetry (Sat-Trak; Sensor Medics, Yorba Linda, Calif). Each patient's mouthpiece was connected to a heated wire flowmeter. The flow signal was digitally integrated to yield tidal volume, and respired gases were continually analyzed by rapidly responding O2 (paramagnetic) and CO2 (infrared) analyzers. All equipment was calibrated before each exercise study by using calibration syringes and precision O2 and CO2 gas mixtures.

All patients were instructed in the same manner for all tests to ensure consistency. Patients were told to exercise until exhaustion or until they were unable to maintain a cadence of more than 50 rpm. BMI was measured at the time of the exercise test.

Dyspnea and Leg Discomfort
The Borg category scale is a visual analog scale used to assess dyspnea and leg discomfort (0 = no symptoms, 10 = maximal symptoms) that has been validated during exercise (23). Dyspnea and leg discomfort were assessed at the end of exercise. Subjects were asked "How breathless do you feel?" and "How much leg discomfort do you feel?" and they pointed to the appropriate number on the scale. Patients were familiarized with the scale before testing.

Spirometry
Spirometry was performed immediately before exercise testing with a spirometer (Pneumocheck; Welch Allyn, Skaneateles Falls, NY). FEV1, forced vital capacity (FVC), ratio of FEV1 to FVC, and mean forced expiratory flow at 25%–75% of FVC were measured with previously described techniques, and predicted normal values were used to calculate percentage predicted values (24,25).

Data and Statistical Analysis
Percentage of predicted peak O2 uptake was the primary measurement of the outcome of exercise and was calculated as follows: {AOU/[0.83 x h2.7 x (1 – 0.007 x a) x (1 – 0.25 x s)] } x 100, where a is age (measured in years), AOU is actual O2 uptake, h is height (measured in meters), and s is sex (s = 0 for male patients, s = 1 for female patients) (26). Secondary measurements of exercise outcome included peak O2 uptake, exercise duration, peak workload, peak CO2 output, end-tidal CO2, minute ventilation, tidal volume, respiratory rate, arterial O2 desaturation, and heart rate. Percentage of predicted peak heart rate was calculated as follows: {HRactual/[210 – (0.66 x a)] } x 100, where HRactual is the actual heart rate (26). Peak O2 uptake, peak CO2 output, minute ventilation, tidal volume, and respiratory rate were measured breath by breath with standard formulas (26). Minute ventilation and tidal volume were expressed at standard body temperature and pressure with saturated conditions. O2 uptake and CO2 output were expressed at standard body temperature and pressure with dry conditions.

Linear correlations between thin-section CT findings, clinical measurements, and exercise measurements were detected with the Spearman rank correlation test. Stepwise multiple-regression analysis was performed with percentage of predicted peak O2 uptake as the dependent variable and total thin-section CT score, age, sex, BMI, percentage of predicted FEV1, and percentage of predicted FVC as independent variables. Interobserver agreement for thin-section CT scores was evaluated with the intraclass correlation coefficient. A value of more than 0.80 was considered to indicate good interobserver agreement. Assessing intraobserver variability was not the primary aim of our study; however, de Jong et al (6) showed good inter- and intraobserver reproducibility and correlation with spirometric findings by using the Bhalla scoring system. Analysis was performed by using SPSS statistical software (version 12.0; SPSS, Chicago, Ill). Results were expressed as mean ± standard deviation. A P value of less than .05 was considered to indicate a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Study Patients
Genotype data were available in only 14 patients; eight were {Delta}F508 homozygous, and six were {Delta}F508 heterozygous (Table 2). Baseline mean spirometric findings in the 22 patients were consistent with moderate CF. Percent predicted FEV1 values were mild in eight patients (83.3% ± 6.3), moderate in 10 (52.1% ± 9.1), and severe in four (33.7% ± 4.0). Mean BMI was within normal limits; however, six patients had a BMI of less than 19 kg/m2, which indicated malnourishment.


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  		Table 2. Baseline Characteristics of the Study Population

 
Prevalence of Lung Abnormalities
Thin-section CT abnormalities included bronchiectasis and peribronchial thickening in 22 (100%) patients, mucous plugging in 20 (91%), and sacculations or abscesses in 19 (86%) (Table 3). Less common abnormalities included air trapping in 14 (64%) patients, collapse or consolidation in 10 (46%), mosaic perfusion in 10 (46%), bullae in six (27%), and emphysema in two (10%). Seven patients had mild thin-section CT scores (8 ± 3), 13 had moderate scores (16 ± 3), and two had severe scores (21 ± 5). The intraclass correlation coefficient was 0.88, which indicated good interobserver agreement.


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  		Table 3. Prevalence of Thin-Section CT Abnormalities

 
End-Exercise Measurements
Mean percentage of predicted peak O2 uptake was consistent with patients with moderate exercise impairment. Percentage of predicted peak O2 uptake was normal to mild in nine patients (93.6%), moderate in 12 (61.2%), and severe in one (36.5%). The ratio of mean peak CO2 output to mean O2 uptake, which is used to determine if patients have reached their anaerobic threshold, should be more than 1; it was 1.1 ± 0.04 in this study (Table 4). The mean end-exercise dyspnea score was 4 ± 3, which indicated somewhat severe dyspnea. The mean end-exercise leg score was 5 ± 2, which indicated severe leg discomfort.


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  		Table 4. End-Exercise Measurements

 
Linear Correlation between Thin-Section CT and Clinical Measurements
Significant correlations were noted between (a) sacculations or abscesses and BMI, (b) generations of bronchial divisions and FEV1 and FVC, (c) emphysema and FEV1, mean forced expiratory flow at 25%–75% of FVC, and ratio of FEV1 to FVC, and (d) total thin-section CT score and FEV1 (Table 5). No structural thin-section CT abnormality or total thin-section CT score correlated with age or sex.


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  		Table 5. Linear Correlation between Thin-Section CT and Clinical Measurements

 
Linear Correlation between Thin-Section CT and Exercise Measurements
Several significant relationships were detected between thin-section CT abnormalities and exercise measurements (Figs 1, 2; Table 6). The strongest correlation was between total thin-section CT score and percentage of predicted peak O2 uptake. The strongest correlations between a thin-section CT abnormality and an exercise outcome measurement were between (a) severity of bronchiectasis and percentage of predicted peak O2 uptake, (b) sacculations or abscesses and percentage of predicted peak O2 uptake, and (c) collapse or consolidation and tidal volume.


Figure 1
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  		Figure 1: Graph shows correlation between thin-section CT (HRCT) Bhalla score and percentage of predicted peak O2 uptake (R = 0.60, P < .01). As thin-section CT score increases (indicating worsening structural lung disease), percentage of predicted peak O2 uptake decreases (indicating worsening exercise tolerance).

 

Figure 2
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  		Figure 2a: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

Figure 2
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  		Figure 2b: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

Figure 2
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  		Figure 2c: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

Figure 2
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  		Figure 2d: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

Figure 2
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  		Figure 2e: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

Figure 2
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  		Figure 2f: (a) Transverse thin-section (1-mm-thick) CT scan in a 26-year-old man with mild CF, as scored by both radiologists. Abnormalities include mild bronchiectasis (straight solid arrow), peribronchial thickening (open arrow), and peripheral mucus plugging (curved arrow). (b) Corresponding exercise graph shows O2 uptake (VO2) ({circ}) and workload; there is mild exercise impairment, with a peak O2 uptake of 3.2 L/min and a peak workload of 227 W. (c) Transverse thin-section (1-mm-thick) CT scan in a 28-year-old woman with moderate CF, as scored by both radiologists. Abnormalities include moderate changes of bronchiectasis (straight arrows) and subsegmental collapse (curved arrow); note anterior deviation of the horizontal fissure. (d) Corresponding exercise graph shows O2 uptake ({square}) and workload; there is moderate exercise impairment, with a peak O2 uptake of 1.4 L/min and a peak workload of 124 W. (e) Transverse thin-section (1-mm-thick) CT scan in a 23-year-old man with severe CF, as scored by both radiologists. Thin-section CT abnormalities include severe bronchiectasis (curved arrow), severe peribronchial thickening (open arrow), and large bullae (straight solid arrow). (f) Corresponding exercise graph shows O2 uptake ({blacktriangledown}) and workload; there is severe exercise impairment, with a peak O2 uptake of 0.86 L/min and a peak workload of 72 W.

 

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  		Table 6. Linear Correlation Between Thin-Section CT and Exercise Measurements

 
Linear Correlation between Clinical and Exercise Measurements
In general, clinical measurements correlated well with exercise outcome measurements. Percentage of predicted peak O2 uptake strongly correlated with FEV1, mean forced expiratory flow at 25%–75% of FVC, and BMI (Table 7). The strongest correlations between a clinical measurement and an exercise outcome measurement were between sex and (a) peak O2 uptake, (b) exercise duration, (c) peak workload, (d) peak CO2 output, (e) minute ventilation, and (f) tidal volume.


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  		Table 7. Linear Correlation Between Clinical and Exercise Measurements

 
Stepwise Multiple-Regression Analysis of Percentage of Predicted Peak O2 Uptake, Thin-Section CT Findings, and Clinical Measurements
The total thin-section CT score enabled prediction of 42% of the variance in percentage of predicted peak O2 uptake. This was the only significant predictor of exercise limitation.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCE IN KNOWLEDGE
 References
 
Thin-section chest CT is the best imaging investigation for assessment of anatomic pulmonary changes in patients with CF (19,27,28). Studies have suggested that thin-section CT should play a wider role in the examination of patients with CF. In particular, spirometrically gated CT provides a strong correlation with spirometry, and a combined CT and spirometric score has been shown to be a sensitive marker in the detection of treatment effects (29,30). In addition, studies have shown that thin-section CT can reveal progressive lung damage despite normal or stable spirometric findings (3,5).

Whether the structural abnormalities detected at thin-section CT signify functional deficits has been the subject of limited investigation. Several studies have shown a significant correlation between CT findings and the Shwachman-Kulczyski clinical score (9,29,31). One study showed a significant correlation between chest radiographic findings and exercise capacity in patients with CF (32).

Our study showed a strong correlation between thin-section CT findings and maximal exercise capacity in patients with CF. Thin-section CT findings were shown to be better predictors of exercise limitation than previously assessed clinical measurements, such as FEV1 and BMI. Our results are consistent with currently understood pathophysiologic mechanisms of exercise limitation in patients with CF. Exercise limitation is characterized by an increase in physiologic dead space, which leads to inefficient gas exchange and a decreased percentage of predicted peak O2 uptake during exercise (33,34). This increase in physiologic dead space in older patients with CF is predominantly caused by structural abnormalities, such as bronchiectasis (35). We found the extent and severity of such abnormalities to be strong correlates of exercise limitation. Other pulmonary conditions contributing to increased physiologic dead space, such as emphysema and sacculations, also showed significant correlation with percentage of predicted peak O2 uptake.

In contrast, Edwards et al (36) recently assessed the relationship between thin-section CT and exercise capacity in children with bronchiectasis (18 of whom had CF) and found no consistent relationship between total thin-section CT score and the exercise outcome variables. However, there was strong correlation between (a) air trapping and peak O2 uptake and (b) bronchial wall thickening and arterial O2 desaturation, which suggests there is some relationship between these variables. The thin-section CT protocol used included only five sections because of appropriate concerns about radiation dose, which may have limited the range of reported abnormalities scored with thin-section CT. In addition, the extent of lung disease was possibly more severe in our cohort of patients. We used percentage of predicted peak O2 uptake as our primary measurement of exercise outcome because it relates more meaningfully to patient age, height, and sex than does the absolute value of peak O2 uptake.

Our findings suggest thin-section CT may be a useful surrogate of exercise testing in patients with CF. Exercise capacity is not static, and it may improve after patients with CF undergo exercise rehabilitation programs (37). If thin-section CT is to be used as a surrogate for exercise testing, CT findings must change in response to therapy. In this regard, several studies have shown that thin-section CT scores can change rapidly in response to therapeutic intervention (4,38). We suggest that irreversible structural abnormalities in patients with CF, such as bronchiectasis, contribute to baseline exercise limitation, while reversible features may account for improvements in exercise capacity after rehabilitation (37). In one study, eight patients with CF were treated with either conventional physiotherapy alone or physiotherapy and an exercise program (39). There was a significant increase in mucus plug expectoration after exercise when compared with mucus plug expectoration at rest and after physiotherapy alone. CT performed before and after exercise rehabilitation may have shown structural changes that correlated with the improvement in mucus expectoration. Future studies should be performed to evaluate whether thin-section CT scores improve in patients after exercise rehabilitation.

We found a significant correlation between sacculations or abscesses and BMI. This finding may simply reflect the fact that both sacculations and abscesses are markers of more advanced disease, and it is well known that severity of lung disease and BMI are strongly correlated in patients with CF (40). Alternatively, sacculations or abscesses may reflect increased levels of inflammatory cytokines, which are known to have a detrimental effect on the absorption of nutrients from the gastrointestinal tract in patients with severe disease (41).

The extent of mucus plugging was the strongest correlate of O2 desaturation; this is an interesting relationship and suggests this condition may have contributed to O2 desaturation. Thus, patients with extensive mucus plugging may be more likely to require supplemental O2 during exercise. Thin-section CT could be used to predict which patients will be more likely to experience O2 desaturation. Further studies are needed to assess the role of thin-section CT in patient selection for O2 supplementation before CT is applied in this way.

Radiation dose from CT remains a concern addressed in the radiological literature (42). We choose, as do many CF centers, to monitor lung disease with biennial CT examinations to minimize radiation exposure in young patients. This may change however, as recommendations for CT change and the role of CT in the care of patients with CF becomes more defined (43). The role of CT is likely to increase as it is used to assess patient response to therapeutic interventions, to investigate possible ongoing lung damage despite stable spirometric findings, and as an outcome surrogate.

Our study had some limitations. A relatively small number of patients were included in this study. Patient selection bias is common to all studies that involve exercise testing. Patients who agreed to undergo exercise testing may have been more interested in their exercise and disease status and more compliant with treatment than those who refused to undergo this test. While we found thin-section CT findings to be strong predictors of exercise limitation, other factors not detected on thin-section chest CT scans clearly contributed to exercise limitation. Although respiratory mechanisms are considered to play the primary role in exercise limitation, cardiac factors—particularly reduced stroke volume—may have affected exercise performance (44). Additionally, it has been suggested that abnormalities in the peripheral muscles of patients with CF may also contribute to exercise limitation (45,46).

In conclusion, this study shows that thin-section CT findings are independent predictors of exercise capacity in patients with CF and that the correlation between exercise capacity and CT results is stronger than that between exercise capacity and FEV1 or BMI. The major structural abnormalities that correlate with exercise limitation are severity of bronchiectasis and sacculations or abscesses. A disparity between thin-section CT findings and actual measured percentage of predicted peak O2 uptake might suggest nonrespiratory causes of exercise limitation. Our findings add further evidence that thin-section CT is able to provide functional and anatomic information in patients with CF. Future studies should be performed to assess whether thin-section CT scores change in response to exercise rehabilitation and whether thin-section CT can be used to predict which patients will benefit from supplemental O2.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Leslie E. Daly, PhD, FFPH, for statistical assistance, Samantha Alford for clerical assistance, and the CT technologists of St Vincent's University Hospital.


   FOOTNOTES
 

Abbreviations: BMI = body mass index • CF = cystic fibrosis • FEV1 = forced expiratory volume in 1 second • FVC = forced vital capacity

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, J.B.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; clinical studies, J.D.D., S.C.B., R.B.M.B., C.G.G.; statistical analysis, J.D.D., S.C.B.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 

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