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Editorials |
1 From the Department of Radiology, MLC-5031, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. Received December 23, 2003; accepted January 2, 2004. Address correspondence to the author (e-mail: alan.brody@cchmc.org).
Index terms: Computed tomography (CT), in infants and children, 60.1211, 60.12118 • Computed tomography (CT), thin-section, 60.12118 • Editorials • Fibrosis, cystic, 60.252 • Lung, CT, 60.1211, 60.12118 • Lung, function
In 1986, Jacobsen and colleagues (1) compared computed tomographic (CT) scans and chest radiographs in 12 patients with cystic fibrosis (CF). In that study, they found that the identification of bronchiectasis increased from 50% to 90% with CT compared with radiography of the chest. Detection of mucus plugging increased from 33% to 58%, and that of hilar adenopathy increased from 8% to 75%. Included in that article (1) is the following provocative sentence: "If bronchocoele formation, including mucoid impaction is recognized and treated early, permanent bronchiectasis may be prevented." Since that time, authors have further evaluated the use of CT for the assessment of lung disease in CF. Detection of abnormalities (2,3), correlation between CT scores and other measures of lung disease (4,5), and response to treatment (6–8) have all been evaluated, with positive results.
It is now approximately 18 years since the study of Jacobsen et al was published, and the primary means of imaging lung disease in CF remains chest radiography. An update on CF published in Radiology in 1997 (9) contained no recommendations for imaging. Current recommendations for the radiologist’s role in the care of people with CF include chest radiography for surveillance and as needed for pulmonary exacerbations (10). No recommendations are listed for use of CT.
In this issue of Radiology, de Jong and colleagues (11) present an evaluation of five scoring systems used for quantification of CT findings in patients with CF, as well as measurements of bronchial and arterial size. It may seem odd to see a careful analysis of scoring systems when CT is not a routine tool in the care of patients with CF. Furthermore, these scoring systems are time intensive, with the authors estimating 15 minutes of a radiologist’s time for each study. This raises a number of questions for the radiologist. Why has CT remained so little used in the care of patients with CF? What is the role of CT in the care of patients with CF? What is the importance of scoring systems, and when should they be used?
The study of de Jong and colleagues (11) reflects an increasing interest in the use of CT in the care of patients with CF. An understanding of the factors that have contributed to this increase in interest will allow us to answer the questions just posed. The first factor is that care of patients with CF is changing, moving from a standardized pattern of care with limited clinical choices to an increasingly broad range of therapeutic options. The second factor is the realization that pulmonary function tests (PFTs), the mainstay of lung evaluation in patients with CF, are less robust measures than previously thought and in particular are insensitive to mild and localized lung disease. The third factor is the increasing interest in the use of imaging as an outcome surrogate for research studies and patient evaluation. This editorial will briefly explore these topics.
Changes in Care of Patients with CF
Much of the increased interest in the use of CT in the care of patients with CF comes from changes in the therapeutic options available for them. Between 1969 and 1995, life expectancy for patients with CF more than doubled from 14 to 30 years (12). A major factor in this improved life expectancy was the development of a network of CF care centers and the adoption of a uniform standard of care that includes regular evaluations and early treatment of worsening lung status. During this period, therapeutic options were limited. The mainstays of pulmonary care were chest physiotherapy and oral antibiotics, with hospital admission and intravenous antibiotics for pulmonary exacerbations. Physiotherapy was routine for all patients with CF. The identification of a pulmonary exacerbation that required treatment was largely based on a subjective assessment of the patient’s clinical status by the patient and the physician. With few branch points in the algorithm for care of patients with CF, there was little need for additional information from imaging or other evaluations.
The development of recombinant human deoxyribonuclease (DNase) in the early 1990s marked a turning point (13). DNase decreases viscosity of mucus, and thus clearance of the usually tenacious mucus found in patients with CF improves. A new option became available for patients with CF. This was followed by the development of inhaled tobramycin and a growing number of other potential new therapies. The Cystic Fibrosis Therapeutics Development Network of the Cystic Fibrosis Foundation was developed to deal with the increasing number of therapies that require evaluation (14).
Today, therapeutic options that are being developed for the treatment of the lung affected by CF include gene therapy, compounds that traffick (target) and potentiate the mutated CF protein, alternate chloride channel stimulators, new antibiotics, and antiinflammatory agents. Each of these must be evaluated in clinical trials in order to determine its effect on lung disease in CF. Methods of testing new therapies for effectiveness in a cohort of patients and methods of evaluating effectiveness in individuals are an important priority in improvement of healthcare of patients with CF. This presents an important potential role for imaging.
An additional change is the increasing understanding that care must begin early if it is to be most effective. Once bronchiectasis and parenchymal damage have occurred, the damage cannot be undone. The vicious cycle of increased susceptibility to infection followed by increased damage and further increase in infections can only be moderated, not stopped. The most effective therapies will be those that can maintain normal airways and lungs. Assessment of such therapies requires a method for evaluation of the lung status in asymptomatic infants and children.
Clinical Evaluation with PFTs
PFTs have been the mainstay of clinical evaluation of lung disease in CF. The severity of lung disease in CF is usually evaluated with measurement of the subject’s forced expiratory volume in 1 second (FEV1) and comparison of the value with an appropriate normal reference value. This approach is limited in patients with mild lung disease in whom the FEV1 value usually is normal despite the presence of abnormal airways and an exaggerated inflammatory response (15,16).
In addition, numerous investigators have found that in patients with abnormal PFT results the correlation between PFT results and the morphologic abnormalities identified with imaging is limited (2,3,17,18).
Several reasons can be suggested for this limited correlation, and they include the fact that PFTs are effort dependent and that the presence of bronchiectasis has little effect on PFT results (19). The most important factor is that PFTs are global measures, and they reflect the overall status of both lungs. CT, which provides excellent anatomic localization, can help identify abnormalities that affect only a small portion of the lung. In one study (20), the researchers evaluated CT scans in children with normal PFT results. Thirty percent of the children had bronchiectasis, and in 16%, bronchiectasis was in four or more lobes, with the lingula considered as a separate lobe.
These findings suggest important limitations for PFTs. First, in young patients or adults with mild disease the maintenance of normal PFT results does not necessarily indicate a lack of lung damage. This limits the use of PFTs as a means of assessment of the ability of treatment to arrest progressive lung damage. Another important concern is that PFT results are commonly used to stratify subjects in research studies according to the severity of their lung disease. Many therapies can be expected to have different effects, depending on the presence or absence of bronchiectasis. Differences in lung disease that are not reflected by PFT results could confound the results of controlled research studies. These findings indicate a need for another measure of lung disease in CF.
CT has characteristics that suggest that it could provide this evaluation. Thin-section CT provides images that are similar to gross pathologic sections of the lung (21,22). New techniques have been developed that allow high-quality CT to be performed in patients at any age (23). CT is widely available, and scoring systems have been developed to quantify the imaging findings.
Outcome Surrogates and Research Studies
The most active area of current investigation in regard to the use of CT in CF is its use as an outcome surrogate for research studies. Outcome surrogates, and more specifically imaging end points, are increasingly recognized as a potentially important contribution of imaging. An imaging end point is an imaging measurement or sign that can be used as a substitute for a clinically meaningful end point. Use of outcome surrogates can decrease the time needed for research studies or the number of subjects necessary in order to obtain a statistically significant result. The Food and Drug Administration recognizes the use of accepted outcome surrogates in the process of approval for new drugs (24).
Outcome surrogates, however, must be correctly chosen in order to ensure accurate results. Robert Temple (25), associate director for medical policy, of the Center for Drug Evaluation and Research of the Food and Drug Administration suggested four criteria for a valid outcome surrogate. The surrogate must be biologically plausible, must reflect the severity of disease, must improve rapidly with effective treatment, and must be correlated with true clinical outcomes. Smith et al (26) added that detection of an imaging biomarker must be accurate, reproducible, and feasible over time.
In the case of CT, the result of the test is a graphic image. This graphic must be converted to a form that can be used in statistical analysis. This is the role of the CT score. Clearly, the imaging biomarker is of little value if this conversion cannot be reliably performed. Demonstration that a reliable conversion process exists for CT in CF is an important contribution of the article of de Jong and colleagues (11).
Validation of an outcome surrogate can be a painstaking process. Experience with outcome surrogates has shown the errors that can be made when an incorrect surrogate is chosen. Such an error occurred in the Cardiac Arrhythmia Suppression Trial (27). In that study, investigators evaluated the ability of antiarrhythmic drugs to reduce ventricular premature beats (VPBs), which can lead to ventricular tachycardia. In that study, VPBs were reduced by 70% in the patients who received antiarrhythmic drugs compared with results in those who received the placebo. The drugs therefore had the desired effect of reducing a potentially life-threatening event. When mortality was compared in the two groups, however, the patients who received antiarrhythmic drugs had a mortality rate more than twice that of those who received the placebo. In this case, the outcome surrogate (VPBs) was a poor predictor of the true clinical outcome (mortality).
A body of work supports the use of CT as an outcome surrogate. The thin-section CT criteria for bronchiectasis were developed by using a comparison of findings on thin-section CT images with results of gross pathologic analysis. This provides a strong biologic base for the use of thin-section CT to evaluate lung disease. Researchers in some studies (4,5) showed that thin-section CT scores may be correlated with clinical status in CF, and others (6–8) showed that thin-section CT scores improved after treatment for a pulmonary exacerbation in CF. Researchers in a recent study (28) addressed the correlation between thin-section CT scores and true outcomes in CF, and findings indicated that change in CT scores during 2 years is correlated (r = 0.58, P < .0001) with the number of pulmonary exacerbations.
Conclusion
The study of de Jong and colleagues completes an important step in the journey that will lead to the use of CT as an outcome surrogate for lung disease in CF. Completion of this journey should result in provision of a valuable new tool that will help improve the care that patients with CF receive. While the use of CT in CF is currently being evaluated as a research tool, the application of CT as a tool for clinical care is an exciting opportunity that will need to be addressed in order to develop useful recommendations.
The use of CT for evaluation of lung disease in CF provides useful insights into the role of imaging biomarkers in the improvement of care for patients with a chronic disease. The ultimate goal of CF research is to cure the disease. It is likely that CT will be an essential tool in demonstration of the cure of lung disease in CF when this goal is reached.
FOOTNOTES
See also the article by de Jong et al in this issue.
REFERENCES
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