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1 Department of Pediatric Pulmonology and Allergology, Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands; and 2 Department of Radiology, Meander Medical Center, Amersfoort, The Netherlands
Correspondence and requests for reprints should be addressed to Harm A.W.M. Tiddens, M.D., Ph.D., Erasmus MC–Sophia Children's Hospital, Department of Pediatric Pulmonology and Allergology, P.O Box 2060, 3000CB Rotterdam, The Netherlands. E-mail: h.tiddens{at}erasmusmc.nl
ABSTRACT
Lung function parameters have been used in most therapeutic studies to date. Thanks to improvements in cystic fibrosis (CF) therapy, these parameters have become a less sensitive endpoint in clinical studies. Computed tomography (CT) in CF can identify highly relevant structural lung changes, such as bronchiectasis and air trapping. CT scoring systems have been developed to quantify in a systematic fashion these structural changes on CT scans. Clinical studies have been conducted using CT scores as an outcome parameter. These studies suggest strongly that CT scoring is more sensitive than pulmonary function tests for the detection of relevant disease progression in CF. Bronchiectasis, which is progressive and irreversible in CF, is probably the most relevant structural change on CT scans that can be scored reliably. CT measurement of airway wall thickening is possible. Airway wall thickening is related to inflammation; thus, this endpoint is of significance for interventional studies that include antiinflammatory drugs.
Key Words: computed tomography • endpoint • structure function • cystic fibrosis • bronchiectasis
Lung function parameters have been used as endpoints in most therapeutic trials in cystic fibrosis (CF) to date. Because of improvement in CF therapy, lung function parameters have become a less sensitive endpoint in clinical studies. Computed tomography (CT) in CF can identify highly relevant structural changes, such as bronchiectasis and air trapping. CT scoring systems have been developed to quantify in a systematic fashion these structural changes on CT scans. An important clinically relevant structural change that can be observed on CT is bronchiectasis. CT has been used in clinical studies as an outcome measure. In this article, we will discuss how CT-related endpoints compare with pulmonary function test (PFT)–related endpoints in longitudinal studies.
MORPHOLOGICAL CHANGES ON CT IN COHORTS
To determine whether CT-related parameters can be used as a surrogate endpoint, it is important first to focus on longitudinal observational cohort studies. These studies can inform us about the changes over time in CT scans from patients with CF receiving standard treatment. There are only a limited number of studies that have used CT to monitor patients longitudinally (1, 2). The largest cohort that is being followed is from the Erasmus Medical Center in Rotterdam, the Netherlands (2). In this CF center, since 1996, high-resolution CT (HRCT) scans have been performed every second year as part of routine clinical care, beginning at age 4. Since 2004, the first CT scan has been performed at age 2. Approximately 25 slices of the lung are made from the apex to the base. The CT scan is generally performed on the same day as the annual extensive lung function testing. Therefore, detailed information is obtained every second year at the annual checkup on both lung function and structure.
In a retrospective study, the sensitivity of lung function and CT to detect progression of CF lung disease in this cohort were compared (2). Children were included who had at least one CT scan with or without lung function testing. Hence, there were slightly more CT scans than lung function tests done because some young children who had a successful CT scan at younger than 6 years were unable to do lung function testing. All CT scans were scored in random order, and observers were blinded to the patients' identification and lung function test results. Five established semiquantitative scoring systems were used (3). In addition, airway wall dimensions were measured in a subpopulation using a semiautomated system. The changes in lung function parameters did not change significantly in a group of 48 patients over 2 years. Over a period of 4 years, lung function parameters, such as FEV1, showed an annual decrease of only 1.1% per year (unpublished data). Such low annual loss of lung function was also observed in another cohort (4). The total CT score in the Rotterdam cohort increased significantly by 1.7% per year (unpublished data). Overall, the magnitude of the changes in the CT score was nearly twice as high as the changes in lung function parameters. The most important components of the CT score that increased were the bronchiectasis and mucus plugging subscores. These findings were reproduced in a cohort of children and adults from the West Swedish CF Centre, Gothenburg, Sweden, which has been monitored since 1997 with a CT scan every third year (1). As in the Rotterdam cohort, lung function parameters did not show much change, whereas the CT score increased. Therefore, in adults as in children, CT is more sensitive than lung function parameters in detecting disease progression. In addition, for both the Rotterdam and the Gothenburg cohorts, a clear dissociation between the lung function and CT data was observed. The annual change in lung function parameters correlated only poorly with the annual change in the CT score. In almost 50% of the patients, the conclusion obtained from CT was dissociated from that of lung function.
CHANGES IN AIRWAY SIZE
In CF, chronic airway inflammation leads to increased airway wall thickness and to bronchiectasis (5). For this reason, it is attractive to measure airway dimensions in CF. Techniques have been developed to measure airway dimensions on CT scans in a reproducible fashion using (semi-) automated imaging analysis techniques (6–8). For these measurements, it is important to measure airways that are cut cross-sectionally and ideally at well-defined anatomical locations. Various dimensions can be measured, such as the airway lumen area and the airway wall thickness and area. These dimensions are compared with the cross-sectional area of the adjacent pulmonary artery. Next, the ratio between these airway dimensions and those of the adjacent artery can be calculated.
In a study by de Jong and coworkers, airway dimensions were measured in a cohort of infants with CF and in a cohort of older children with CF (1). In the older children, airway dimensions were measured at the beginning and at the end of a 2-year interval. Dimensions were compared with CT scans from a control group consisting of infants and children who had a normal chest CT. These control scans were undertaken mainly to screen for pulmonary metastases in patients diagnosed with cancer. In control infants and infants with CF, the ratio between the airway lumen area and arterial area was similar initially, but with increasing age this ratio increased in the CF group relative to the control subjects, suggesting that the airways, on average, were dilated in the infants with CF. In the children 4 years and older, the airway/artery ratio in the patients with CF was nearly doubled relative to the control subjects and remained at that level with increasing age. This latter finding was somewhat surprising because patients with CF are believed to have progressive bronchiectasis. A progressive increase of the airway/artery ratio was thus expected. An explanation for this finding is that only airway–artery pairs were analyzed. Bronchiectatic airways without a clear identifiable artery were thus excluded from measurement. In addition, severely damaged airways and airways filled with mucus had to be excluded because the software was not able to analyze the dimensions of these airways. Therefore, this method introduced a selection bias because only the healthier airways were included in the analysis. Another important finding of this study was that, in the older children, airway wall thickness increased by 1% per year. This technique was therefore sensitive enough to detect very small changes in airway wall thickness.
In another study in young, sedated children, a CT scan was performed using the controlled ventilation technique. Infant PFTs were performed in the same session (9, 10). Next, airway dimensions on CT were measured. In this cohort, the airway lumen diameter–to–vessel diameter ratio was found to be larger in infants with CF relative to the control subjects. In addition, airway wall thickness–to–vessel diameter ratio was higher for subjects with CF relative to control subjects (11). In a similar study, it was concluded that infants with CF have thickened airway walls, narrowed airway lumens, and air trapping, as assessed by HRCT. In this study, measurements of airway structure correlated with airway function (12).
An important condition to detect small differences over time in airway size in a cohort of patients is that each patient is scanned with a well-defined protocol that remains unchanged during the study. In addition, the software for the scanner and the scanner itself should remain unchanged. Calibration should be used to detect any unexpected hardware- or software-related changes. To use airway dimensions as an endpoint in a multicenter study will require careful standardization and calibration.
CT CHANGES AND DISEASE SEVERITY
It is believed that the structural abnormalities on CT are closely linked to disease severity for the following reasons. First, bronchiectasis is a prominent relevant structural change in CF that can be detected reliably by CT. Indeed, CT is considered the gold-standard imaging study with which to diagnose bronchiectasis (13). In patients with chronic obstructive pulmonary disease (COPD), CT was able to preoperatively identify 87% of bronchiectatic airways that were present in the postoperative pathology specimen. Bronchiectasis is likely to reduce the quality of life in CF. In studies in COPD, the severity of bronchiectasis correlated to disease-specific quality-of-life scores (14). It is highly likely that a similar relation is present in patients with CF. In addition, it was shown in a recent substudy, in 61 of the 474 patients who participated in the Pulmozyme Early Intervention Trial (PEIT), that the risk for exacerbations requiring intravenous treatment was correlated to the severity of structural changes on CT but not to changes in PFT-related parameters (15). PEIT was a large, randomized, placebo-controlled trial that evaluated the efficacy of rhDNase in patients with CF who had a vital capacity above 85% and who were between 6 and 10 years of age. The CT score in these selected patients with well preserved lung function progressed approximately 1.25% per year over 2 years, which is below the rate of change observed in the Rotterdam and Gothenburg cohorts (1, 2). The annual rate of change in the bronchiectasis CT component score in these two studies was similar to that of the composite CT score. Therefore, bronchiectasis is closely linked to disease severity because its presence is associated with a higher risk of developing respiratory tract exacerbations.
A second reason to believe that structural abnormalities on CT are closely linked to disease severity is that the progression in the composite CT score and bronchiectasis CT score is correlated to disease conditions that are associated with a more severe course of the disease. The bronchiectasis CT score, and the composite CT score are higher for patients with pancreatic insufficiency than for patients with sufficient pancreatic function (unpublished data). In addition, it was shown by de Jong and colleagues that patients who are chronically infected with Pseudomonas aeruginosa have more severe bronchiectasis relative to patients who are not infected with P. aeruginosa (16). Third, in a recent study, the severity of structural changes on CT scans was correlated to inflammatory parameters in bronchoalveolar lavage (BAL) fluid in very young children with CF (17). In this study, inflammatory parameters were measured from BAL fluid obtained from the CT region with the most and the least severe structural changes. It was shown that the regions on CT with more severe structural changes had higher inflammatory markers in the BAL fluid.
The above-mentioned arguments strongly support that CT can detect structural changes that are clinically relevant for patients with CF. Of these changes, bronchiectasis is at present probably the most relevant structure that can be used in a clinical trial. The progression of bronchiectasis can be easily tracked on CT (Figure 1). Whether any therapy is able to prevent the development of bronchiectasis or halt further progression of bronchiectasis is, however, speculative.
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How do the annual changes in CT score and PFT parameters as observed in the Rotterdam cohort studies translate to sample sizes required in a placebo-controlled clinical study? The PEIT study aimed to show a treatment benefit in FEV1 of 3% between the placebo and the rhDNase arm. To run the same study today, at least 1,000 patients would be required (Figure 2A). This is the consequence of better treatment compared with 10 years ago, resulting in decreased annual loss of lung function parameters. However, assuming that rhDNase would be effective to reduce the progression of structural damage as observed on CT by 3%, only 150 patients would be required (Figure 2B). The better sensitivity of CT relative to lung function to detect disease progression can reduce sample size in clinical studies substantially (unpublished data).
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To date, CT scan scores have been used as an endpoint in only a few small intervention studies (18–20). In a small double-blind, placebo-controlled study of rhDNase, a difference was detected between the groups using a compound score that included both CT score components and lung function parameters (18). This approach of combining CT and lung function parameters in a model that makes physiological sense is interesting and might increase sensitivity to detect a treatment effect in an intervention study.
In another small placebo-controlled pilot study in young children, the effect of rhDNase was evaluated with CT scans over a treatment period of 100 days, In this study, only five slices were made, which reduced the sensitivity of CT as an endpoint. The results show, however, a significant improvement in the CT score for patients who were treated with rhDNase relative to the control group (20).
In a third short placebo-controlled study, CT and lung function were used to evaluate the effect of Tobramycin solution for inhalation (TOBI; Novartis, Basel, Switzerland). In this study, the change in different CT subscores from baseline to the end of study was used as endpoint. Five slices at inspiration and expiration were taken. Trends toward improvements were observed in some paired observations, but these changes were not significant (21).
In a fourth study, inspiratory and expiratory HRCT was used to assess the safety of aerosolized adenoassociated virus serotype 2 vector containing the CF transmembrane regulator (CFTR) cDNA in patients with CF (22). In this multicenter, double-blind, placebo-controlled trial, no significant changes in CT scores were observed. However, there were trends toward worsening of the parenchymal opacity score in the placebo group and toward worsening of the bronchiectasis and hyperinflation scores in the virus-treated group. These studies are too small to be conclusive, but they supply interesting and useful information that can be used to design larger scale studies.
No interventional studies have been done in CF to date that include the automated measurements of airway dimensions as an endpoint. However, in subjects with asthma, an interesting study was done that included the measurement of airway wall thickness on CT scans to evaluate the effect of inhaled steroids (23). Steroid-naive patients with asthma were treated with inhaled beclomethasone for 12 weeks. CT scans and lung function tests were done before and after treatment. Airway dimensions were measured at a well-defined anatomical position (i.e., the cross-sectional cut right upper apical bronchus). Airway dimensions were corrected for body surface area. As could be expected, lung function improved with treatment. In addition, airway wall thickness decreased. This study supports the idea that airway wall thickness measurements on CT can be used to monitor the effect of antiinflammatory drugs.
In conclusion, CT scoring is highly likely to be more sensitive than PFTs to detect relevant disease progression in CF. Bronchiectasis, which is progressive and generally irreversible in CF, is probably the most relevant structural change on CT scans that can be scored reliably. CT measurement of airway wall thickening is possible. Airway wall thickening is related to inflammation; thus, this endpoint may be relevant for intervention studies of antiinflammatory drugs. Future advancements of imaging techniques will inevitably lead to more accurate and more sensitive analysis of CT images that can be used in outcome research for CF.
FOOTNOTES
Conflict of Interest Statement: H.A.W.M.T. acted as a member of two ad hoc advisory boards for Novartis and received within the last 3 years honoraria and travel expenses for lectures and workshops from Hoffman–La-Roche and Genentech. The BV Kindergeneeskunde of the Erasmus MC–Sophia Children's Hospital has in the last 3 years received research grants from Hoffman–La-Roche. P.A.d.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form November 29, 2006; accepted in final form March 2, 2007)
REFERENCES
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