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1 Department of Radiology, Royal Brompton Hospital, London, United Kingdom
Correspondence and requests for reprints should be addressed to Zelena A. Aziz, Department of Radiology, The London Chest Hospital, Bonner Road, London E2 9JX, UK. E-mail: Tunku.Aziz{at}bartsandthelondon.nhs.uk
ABSTRACT
Interest in the role of computed tomography (CT) as a monitoring tool in cystic fibrosis (CF) research has gained momentum in the past 5 years. This is a consequence of the rapid development of therapeutic options for CF lung disease and hence the need for sensitive outcome measures that can be applied to clinical intervention trials. The following article summarizes the proposed use of CT in a forthcoming multidose gene therapy trial. Issues surrounding dose, timing of scans, scoring, and quantification of CT morphologic features are discussed. The literature which supports the use of CT as a surrogate outcome measure is also summarized.
Key Words: computed tomography • cystic fibrosis • outcome measure
The UK Gene Therapy Consortium is currently planning a multidose gene therapy trial. At present, computed tomography (CT) is being considered as a potential end-point. As a prelude to the main trial, there will be a "run-in" period of a year, during which all potential (imaging and nonimaging) assays will be assessed. Measurements from all assays including CT will be obtained from 200 subjects at several time points over the course of a year. It is hoped the information gained will help determine primary and secondary outcome measures for the main gene therapy trial, inform power calculations, and define patient selection criteria to ensure that patients with the optimal disease severity progress through to the clinical trial. Apart from its potential role as an outcome measure, CT may have a role as a disease stratifier, identifying those patients with "clean" lungs to optimize the chances of therapy, but yet with enough disease as to provide a measurable signal.
The following paragraphs will briefly outline the thinking behind plans for how we propose to use CT.
WHY USE CT AS A POTENTIAL SURROGATE OUTCOME MEASURE?
Criteria for the validation of an imaging biomarker as a surrogate outcome measure are that (1) the presence of the imaging biomarker is linked to the severity of disease; (2) the detection and quantification of the biomarker is accurate and reproducible; (3) measured changes over time are closely coupled to the success or failure of a therapeutic effect; and (4) the imaging marker should be correlated with "true" outcomes rather than short-term measures of disease (1–4). It is clear that abnormalities demonstrated on CT do reflect the severity of disease in patients with cystic fibrosis (CF). In addition, the detection and quantification of CT features are relatively reproducible (5–10). However, the accuracy of the detection and quantification of CT abnormalities is much harder to assess in the absence of a gold standard. Most studies have used correlation with lung function (FEV1) as a means of validating CT scoring systems. However, if it is accepted that FEV1 is a blunt tool, and in particular, can be insensitive to mild or localized lung disease, then its role as a "validator" is questionable. Thus, it can often be misleading to make a statement on the suitability of a biomarker as a potential surrogate outcome measure based on the correlation, or indeed lack of correlation, with another "established" surrogate outcome measure.
Studies have shown that CT demonstrates abnormalities such as mild bronchiectasis or a mosaic attenuation pattern even when FEV1 is normal (11–13), and that disease progression can be seen on sequential CT in patients in whom FEV1 shows either stability (14) or even improvement (15). This has led to the perception that at least in some respects, CT may be superior at identifying early lung damage in patients with cystic fibrosis, and also that CT more accurately represents disease burden than FEV1. Long and coworkers demonstrated that infants (mean age of 2 years) with CF have greater airway wall thickness and lumen diameter compared with matched control subjects (9)—further evidence that CT abnormalities can be identified very early on in patients with cystic fibrosis.
Sensitivity to change, an important prerequisite of a surrogate outcome measure, has also been confirmed in several CT studies that have evaluated specific features before and after a clinical intervention; either using pulmozyme (16–18) or conventional treatment for an acute exacerbation (19–21). Mucus plugging, centrilobular nodules, and bronchial wall thickening are known to be reversible CT features after treatment for an infective exacerbation (20, 22). In two studies, air-trapping in patients with relatively mild disease improved after pulmozyme; the study by Nasr and colleagues used semiquantitative CT scoring (17), the study by Robinson and coworkers used quantitative assessment (18). No significant change was seen in air-trapping using semiquantitative scoring in a study by Robinson and coworkers (16), although a composite CT/PFT score did show significant differences between groups.
A recent study by Brody and colleagues (23) has shown that a 2-year change in overall CT score, bronchiectasis, and parenchymal disease on CT correlated significantly with the number of infective exacerbations that occurred during the 2-year period. This is the first study to show that changes in CT are coupled to what is considered to be a "true" outcome measure. Of note, the change in pulmonary function over the 2-year period did not correlate with the number of respiratory tract infections.
A paper by de Jong and coworkers (8) provides further evidence for the use of CT as an outcome measure. CT scans and lung function tests were evaluated in 119 patients with CF at baseline and after a 2- or 3-year interval. CTs were scored using a system developed by Brody and colleagues that results in both a total/composite CT score and individual component scores. CT composite scores, individual component scores, and certain lung function parameters worsened with time, but the peripheral bronchiectasis score showed the largest annual numerical change in children—an increase of 1.7% per year (p < 0.0001). On the assumption that the feature (be it structural or functional) that produces the largest annual change is the most "sensitive," the authors conclude that the peripheral bronchiectasis score could be used as a useful outcome parameter in clinical studies. It is suggested by the authors that halting the progression of a particular feature that is known to be largely irreversible (such as bronchiectasis) may be more readily identifiable than looking for a therapeutic effect on a potentially reversible feature such as mucus plugging or bronchial wall thickness.
In summary, there is mounting evidence at present to consider CT as an outcome measure in clinical intervention studies. What specific CT end-point should be used is still undecided and will depend on the severity of the groups within the study population. The options are to use a total CT score encompassing all CT morphologic features, a single CT feature (such as air-trapping in patients with mild disease), or a composite score that incorporates both CT and certain lung function parameters.
NUMBER AND TIMING OF CT SCANS
The nature of clinical intervention trials necessitates, at the very least, a before and after CT scan. Multiple examinations increase the radiation dose to young adults and concerns over dose are justified, particularly in light of the increasing survival in patients with CF. A recent study has shown that the survival reduction associated with annual CT scans (interspaced high-resolution CT [HRCT] with an average estimated dose of 1 mSv using 120 kV and 120–160 mA/s) from 2 years until death is approximately 1 month and 2 years for CF cohorts, with a median survival of 26 and 50 years, respectively (24), indicating that the overall risk is relatively low but will increase as survival in patients with CF improves.
We anticipate that our patients (none of whom will be under 11 years of age) will have a single CT during the run-in period, and three or four further CTs after gene therapy. Determining the best time point at which to scan after gene therapy is difficult as the duration of effect—if any—is relatively unknown. In order not to miss a potential early effect of treatment, it is proposed that patients will be scanned at 1 month, 3 months, and 6 months after treatment. The importance of when to scan after treatment has been highlighted in a study by Moss and colleagues (25). The primary objective of the study was to determine safety and tolerability rather than efficacy of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator (CFTR) cDNA (cDNA) [tgAAVCF], but pulmonary function and HRCT abnormalities were also evaluated in the treated and placebo groups. Lung function was measured at Days 0, 30, 60, 90, and 150. HRCTs were performed at Day 0 and Day 90 only. There was significant improvement in FEV1 at Day 30 in the treated group, but at Day 90 FEV1 values had returned to baseline. At Day 90, there were no significant differences in HRCT scores when compared with baseline for both treated and placebo groups, and it may be that an early effect of [tgAAVCF] was missed by not performing an HRCT at Day 30.
CT PROTOCOLS
Contiguous Volume or Interspaced CT?
All patients in the study will have contiguous volume inspiratory HRCT. There are clear advantages to using volumetric HRCT over an interspaced technique for research studies. Generating serial images that are anatomically comparable is possible with volumetric HRCT, and this facilitates the ability to detect change in longitudinal CT studies. The increased sampling of the lung achievable with a volumetric acquisition should also improve the accuracy of scoring CT features such as bronchial dilatation and mucus plugging. In an attempt to keep radiation dose to an acceptable level, we will use a protocol that uses 1 mA/kg in conjunction with 100 kVp for all patients weighing less than 50 kg. This will result in a dose of 0.77–1.14 mSv for a contiguous volume high resolution inspiratory scan obtained on a Siemens Sensation 64 multi-slice scanner (Erlangen, Germany), similar to that of an interspaced high-resolution scan performed using conventional parameters, 0.9 mSv (120 kVp and 90 mA). For expiratory scans, we will use conventional interspaced HRCT (1-mm sections at 10-mm intervals), resulting in an overall dose of 1.4 mSv for both the inspiratory and expiratory scans. The total dose for all scans performed during the run-in and clinical trial period will fall within the intermediate risk category according to the requirements of the UK Ethics Committee (Table 1).
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The advantage of controlled-ventilation techniques is the ability to allow measurements of air trapping to be made at standardized lung volumes when evaluating serial CT scans. This is important, as the extent of air trapping demonstrated on CT is dependent on the degree of expiration. Two studies have shown that most adult patients are able to breath-hold reliably at end-expiration following rehearsed verbal instructions, and more importantly, that lung volumes at end-expiration do not change significantly between examinations. A study by Bankier and coworkers showed that in adult patients with obliterative bronchiolitis, residual volumes determined by CT software were not significantly different (p = 0.792) on repeated examinations (1,809 ml at CT1, 1,815 ml at CT2, and 1,825 ml at CT3) and that the extent of air trapping scored using visual assessment was unchanged (27). In addition, in a study comparing spirometric gated CT with automatic patient instruction, Kauczor and colleagues concluded that there were no significant differences between the mean lung density of expiratory scans in normal subjects when spirometric (–750 ± 119 HU) and the "verbal instruction" (–748 ± 119HU) sets of images were compared (28). In the absence of further studies that directly compare gated and nongated acquisition, it is difficult to be certain if expiratory lung volumes would be significantly different in adults if verbal instructions are used. At present, it is likely that non-gated acquisition will be used in the trial.
SCORING AND QUANTIFICATION OF CT FEATURES
As CT is increasingly being used in clinical intervention studies, it would be desirable if there was some consensus as to a scoring system. Clear definitions of the abnormalities being scored would help ensure that observers score and report the same morphologic feature (particularly pertinent to the scoring of small airways disease which is confusingly defined in some studies as areas of hyperinflation and in others as areas of air-trapping or a mosaic attenuation pattern). The term mosaic attenuation pattern describes the presence of abnormal inhomogeneity of the lung parenchyma on inspiratory HRCT images. If the abnormal "black lung" is due to small airways disease, then expiratory images will accentuate the mosaicism because of air trapping within the abnormal lung. Thus, the term "air trapping" should be only be used if expiratory images have been acquired. Although the pathophysiology of air trapping in CF is not entirely clear, it is presumed that air trapping in patients with mild disease may be a result of bronchial hyperreactivity from inflammation or decreased airway compliance (29). In patients with more severe disease, clinical experience suggests that the process resembles an obliterative bronchiolitis. A CT pathology study (30) evaluating the association between bronchiectasis and air trapping has shown that the hyperlucency on expiratory CT adjacent to bronchiectasis represents constrictive bronchiolitis histologically. Thus in patients with more severe disease, air trapping may be a relatively fixed phenomenon and may not be a useful parameter to measure.
Most scoring systems in use have similar within- and between-observer agreement (31). A scoring system devised by Brody and coworkers and recently refined (32) has been shown to be both reproducible and sensitive to variation in the severity of CF lung disease.
Concern over the lack of perceived objectivity associated with conventional semiquantitative (nonautomated) scoring has led to interest in the use of software-driven automated techniques to quantify CT features. At present, these techniques are confined to the quantitation of bronchial wall thickness, bronchial dilatation, and air trapping.
Any method of quantification has to be accurate, that is, reflect the desired target (which in the context of CT is the morphologic feature under scrutiny). In the case of air trapping, experienced radiologists can readily identify areas of air trapping by the paucity and reduced caliber of vessels in the affected lung, which is of decreased attenuation. Regions of lung that are normally avascular and other artifactual causes of decreased attenuation are intuitively ignored. Automated methods of quantifying air trapping are either based on a fixed density threshold approach (33) or a varying threshold (13). In the latter approach, the lower density limits defining air trapping on expiratory images are set on the basis of the density distribution in the corresponding inspiratory images, but are modulated by the degree of expiration. This method is thought to provide a good descriptor of regional air trapping. If a semiquantitative scoring system is to be used, then it has to be sensitive enough to pick up small changes in air trapping. A 4-grade score for air trapping is commonly used, but this is probably too coarse to pick up small change. Scoring systems for air trapping need to have sufficient resolution, particularly at the lower end of the scale, and thus a 6-grade scoring system that showed excellent interobserver agreement (27), or even scoring air trapping to the nearest 5%, may be more appropriate.
Quantifying bronchial wall thickness accurately is difficult. Automated methods require all visible airways to be measured individually—a time-consuming process if applied to large cohorts of patients undergoing serial examinations. In addition, the problem of trying to measure wall thickness that is asymmetrical, a common feature in patients with CF because of the presence of mucus within the airways, applies to both automated and nonautomated methods. DeJong and coworkers found that quantitative bronchial measurements did not correlate significantly with either HRCT scores or PFT results (31). Despite the inherent problems, it is probably worthwhile trying to assess change in bronchial wall thickness, even if it is only a blinded side-by side comparison of "before" and "after" scans.
Two studies suggest that automated techniques may be more sensitive to small changes in air trapping (18) and bronchial wall thickness (10) than nonautomated methods. The fact that using an automated method enables a change to be demonstrated is certainly encouraging, and it seems likely that in the near future, automated methods may, become the norm, particularly for interventional studies.
SUMMARY
There is a good body of evidence at present to justify CT scanning as one of the potential outcome measurements in clinical intervention studies. Whether or not CT will be used as a primary end point in the forthcoming UK Consortium Multidose gene therapy remains undecided. Certainly, information gained from the run-in and trial periods will increase our understanding of the CT changes that occur in CF lung disease.
FOOTNOTES
Conflict of Interest Statement: Z.A.A. 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 April 4, 2007)
REFERENCES
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