Abstract
ABSTRACT: For effective clinical management of cystic fibrosis (CF) lung disease it is important to closely monitor the start and progression of lung damage. The aim of this study was to investigate the ability of high-resolution computed tomography (HRCT) scoring systems and pulmonary function tests (PFT) to detect changes in lung disease.
Abstract
CF children (n=48) had two HRCT scans in combination with two PFT 2 yrs apart. Their scans were scored using five scoring systems (Castile, Brody, Helbich, Santamaria and Bhalla). "Sensitivity" was defined as the ability to detect disease progression.
Abstract
In this group of children, HRCT scores worsened. PFT remained unchanged or improved. Of the HRCT parameters, mucous plugging and the severity, extent and peripheral extension of bronchiectasis worsened significantly. Relationships between changes in HRCT scores and PFT were weak. Substantial structural lung damage was evident in some children who had normal lung function.
Abstract
These data show that high-resolution computed tomography is more sensitive than pulmonary function tests in the detection of early and progressive lung disease, and suggest that high-resolution computed tomography may be useful in the follow up of cystic fibrosis children and as an outcome measure in studies that aim to reduce lung damage. Eur Respir J 2004; 23: 93-97. 

In cystic fibrosis (CF), chronic bacterial infection leads to progressive structural lung damage and to pulmonary dysfunction. It is generally accepted that early and aggressive therapy could delay the progression of lung disease. To evaluate the efficacy of such treatment it is important to monitor the progression of lung damage closely. Pulmonary function tests (PFT) are considered the gold standard for the monitoring of lung disease in children of aged o6 yrs. However, since lung function is only indirectly related to lung structure, it is likely that high-resolution computed tomography (HRCT) is more sensitive than PFT in the detection of structural changes compared with PFT [1] . Some CF centres have adapted periodic HRCT on a routine basis to evaluate the progression of CF lung disease in combination with PFT. However, it is unclear what method should be used to analyse the HRCT and whether HRCT is more sensitive in detecting pulmonary disease progression in CF. It could be that PFT and HRCT provide complementary information and should be performed in parallel to assess progression. The aim of this study was to investigate the sensitivity of five different HRCT-scoring systems and PFT to detect changes in CF structural lung disease over time.
Methods

Study population
Since 1996, Sophia Children9s Hospital (Rotterdam, The Netherlands), a tertiary academic hospital has monitored CF patients using annual PFT and biennial HRCT scans. All children with CF who had two HRCT scans (HRCT1 and HRCT2) in combination with two routine PFT (PFT1 and PFT2) were selected for this follow-up study (n=48). CF was diagnosed by a positive sweat test and/or genotyping for known CF mutations and/or an abnormal potential difference measured across the nasal mucosa. The ethical review board of the hospital approved the study.
Lung structure
All HRCT scans were acquired using a GE Prospeed SX scanner (General Electric Medical Systems, Milwaukee, WI, USA). During the scanning procedure, children were not sedated, they were scanned in the supine position, and instructed to take a deep breath and hold it for o5 s. A complete HRCT series contained y25 1-mm thick slices at 10-mm intervals from lung apex to lung base. Scanning parameters were 120 kV, 160 mA (v9 yrs of age 120 mA), 1-s scanning time and a field of view of 350 mm (v9 yrs of age 250 mm). Scans were reconstructed with a detail reconstruction algorithm (General Electric Medical Systems) and printed using window width -600 Hounsfield units (HU) and window level 1,500 HU. All HRCT scans were scored in random order by an experienced single observer blinded as to the date of the scan, patient identification and the PFT. Five different HRCT-scoring systems were used: CASTILE et al. [2] , BRODY et al. [3] , HELBICH et al. [4] , SANTAMARIA et al. [5] , and BHALLA et al. [6] . In a previous study, in which the observer of this study participated, these five scoring systems were shown to be reliable between and within observers [7] . All slices were used to score the lung lobes and the lingula [2, 3] or the bronchopulmonary segments of the lung [4] [5] [6] . The systems score bronchiectasis, bronchial wall thickening, mucous plugging, atelectasis, bulla, cysts, consolidation, acinar nodules, septal thickening and/or air trapping in a semiquantitative fashion. A score of zero means "no abnormalities" in each system. Maximal scores are 92, 100, 27, 29 and 25 for Castile, Brody, Helbich, Santamaria and Bhalla scores, respectively.
Lung function
All PFT were done within 1 month of the HRCT scanning using a Jäger diagnostic system (MasterLab, Jäger, Germany). Most scans were performed on the same day (71 of 96 scans) as the PFT. All HRCT scans were done as part of a routine check-up and thus patients were scanned in a relatively stable condition and not during an exacerbation. PFT results were expressed as percentage of predicted values: forced expiratory volume in one second (FEV1) [8] , forced vital capacity (FVC) [8] , forced expiratory flow between 25% and 75% of expiratory vital capacity (FEF25-75%) [9] , airway resistance (Raw) [10] , residual volume (RV) [10] , total lung capacity (TLC) and RV/TLC [10] . The ratio FEV1/FVC and the ratio RV/TLC were expressed as a percentage (FEV1/FVC % and RV/TLC %). Twelve patients were younger than patients studied by WANG et al. [9] in the development of the prediction equation for FEF25-75%. Body plethysmography (TLC, RV and Raw) was performed in 33 of the 48 children. Normal lung function was defined as a FEV1 of w85% predicted.
Lung structure and lung function over time
Data obtained at the first evaluation are reported as HRCT1 and PFT1, and data obtained at the second evaluation are reported as HRCT2 and PFT2. DHRCT is the annual change for a scoring system ((HRCT2-HRCT1)/ time interval). To compare the annual changes of the five HRCT-scoring systems, DHRCT was also expressed as a percentage of the maximal obtainable HRCT score for that system. DPFT is the annual change expressed as % pred for a lung function parameter ((PFT2-PFT1)/time interval). A positive value for DHRCT indicates an increase of structural abnormalities and for DPFT an improvement in lung function. DHRCT and DPFT were evaluated for the whole group and separately for children younger than and older than 10 yrs of age. DHRCT and DPFT were also evaluated as a function of age and baseline disease severity (HRCT1 and FEV1 % pred).
Statistical analysis
For the purpose of this article, the term sensitivity is not used in the statistical sense but rather as a measure of the techniques9 ability to track pulmonary disease progression in CF. It was assumed that, on average, CF lung disease would be progressive over 2 yrs and that the method that detected the largest change was most "sensitive". The relationships between HRCT1 and PFT1, HRCT2 and PFT2, between DHRCT and DPFT and between DHRCT, DPFT, HRCT1, PFT1 and age were evaluated using the Spearman correlation coefficient. t-tests (unpaired) were performed for DHRCT and DPFT to determine whether HRCT and/or PFT changed significantly in the whole group and for children below and above 10 yrs of age. Wilcoxon-signed ranks tests were used to determine which of the HRCT abnormalities changed significantly. Statistical significance was set at a p-value of v0.05. Data are presented as mean ¡ SD and range.
Results

Study population
Characteristics of the 48 children (28 male) are shown in Lung structure and lung function over time All HRCT scores worsened significantly. The mean changes for the whole group expressed as a percentage of the maximal scores were 2.6, 2.2, 3.3, 3.1 and 3.5% per year for Castile, Brody, Helbich, Santamaria, and Bhalla, respectively. Spirometric parameters (DFEV1, DFVC, DFEF25-75% and DFEV1/ FVC) did not change significantly. RV % pred, RV/TLC % and RV/TLC % pred decreased by 8.9% (p=0.004), 2.4% (p=0.0005) and 0.66% (pv0.0001) per year, respectively. Raw and TLC did not change significantly. The subgroup analysis of children below and above 10 yrs of age showed the same results, with the exception that RV % pred remained unchanged in the children w10 yrs of age. DHRCT and DPFT did not differ as a function of baseline disease severity or age, with the exception of significant relationships between age and DRV % pred (R=0.53, p=0.001) and between age and DRV/TLC % (R=0.46, p=0.008).
Study population
Of the HRCT scan parameters only mucous plugging (p=0.001) and the severity (p=0.005), extent (pv0.0001) and peripheral extension (p=0.02) of bronchiectasis worsened significantly. Of the 48 patients, the severity of bronchiectasis increased in 15, the score for the extent of bronchiectasis increased in 19 and the score for the peripheral extension of bronchiectasis increased in eight. In only three patients there was a reduction of the severity of bronchiectasis (in all three cases, the airway lumen diameter changed from y2-3-times vessel diameter to y1-2-times vessel diameter). One patient showed a reduction in the peripheral extension score.
Correlation between lung structure and lung function
Cross-sectional data showed a significant correlation between HRCT1 and first FEV1 (Rv-0.49, pv0.0001), and between HRCT2 and second FEV1 (Rv-0.58, pv0.0001). Longitudinal data showed significant but weak correlation between DPFT and DHRCT: DFEV1/FVC versus DSantamaria (R=-0.31, p=0.04), DRaw versus DHelbich (R=0.37, p=0.04), DRaw versus DSantamaria (R=0.38, p=0.03), DRV versus DBrody (R=0.35, p=0.04), DRV/TLC versus DBrody (R=0.38, p=0.03), and DRV/TLC versus DHelbich (R=0.41, p=0.02). The relationship between DFEV1/FVC and DSantamaria is shown in figure 1 .
Discussion
In this study, the ability of five different HRCT-scoring systems and pulmonary function tests were compared to detect and monitor progression of lung damage in 48 children with CF.
Discussion
The most striking finding of this study is that structural abnormalities as scored on HRCT scans increased significantly, independently of the scoring system used, while lung function parameters remained unchanged or even improved. This shows that HRCT was more sensitive than PFT in monitoring CF lung disease under the assumption that CF lung disease is progressive. In addition, the authors showed that it was predominantly the severity, extent and peripheral extension of bronchiectasis that worsened significantly. The bronchiectasis most likely represents irreversible structural damage. The irreversibility of bronchiectasis is supported by the fact that none of the patients who had bronchiectasis on HRCT1 were without bronchiectasis on HRCT2.
Discussion
There are a number of possibilities why the structural abnormalities on HRCT were not reflected by the PFT. Firstly, the signal-to-noise ratio for PFT is likely to be less than that of HRCT since PFT depend more on patient cooperation than HRCT, especially for the younger children, and since PFT are more difficult to perform than a breathhold on the HRCT table. Indeed, the HRCT can be scored even when there is minor motion artefact or some variation in inflation level. Furthermore, the results of PFT are expressed as % pred with reference to a large population sample and this can introduce variability related to the pubertal growth spurt [11] . In addition, HRCT can detect local abnormalities such as small areas of atelectasis and bronchiectasis that may be functionally insignificant. PFT provide a global estimate of the lung integrity [1] . In this study RV % pred improved for the whole group, but remained unchanged for the children w10 yrs of age. The improvement in RV may, therefore, be a reflection of patient effort. For the young children it is more difficult to reach RV during expiration. However, the RV/ TLC % and RV/TLC % pred improved slightly in the children w10 yrs of age. This suggests that the improvement in RV/ TLC % pred is only partially caused by an effect of age. The second important finding of this study is that the structural damage was irreversible in most patients irrespective of their change in PFT. In many patients the change in HRCT was dissociated from changes in PFT. Approximately one-half of the patients who had improved lung function had progressive structural lung disease.
Discussion
The third important finding is that substantial structural lung damage was present on HRCT scans even in children who had lung function within the normal range. This supports the conclusions of earlier studies that conventional PFT are relatively insensitive to detect the onset and early progression of lung disease in CF [1, 7, 12] . These results indicate that the current monitoring strategy using PFT may fail to detect disease progression and suggest that studies using PFT to monitor treatment response may underestimate treatment effects. Therefore, it is possible that because of flawed outcome measures, the optimal treatment regime to minimise the progression of structural lung damage in CF patients is as yet unknown. In this study, the HRCT features that changed most over the 2-yr observation period were the severity score for bronchiectasis and mucous plugging. Selective scoring of these parameters, instead of the full range of parameters included in the currently used complex scoring systems, may be more efficient and reproducible. A simplified scoring system may prove to be adequate for patient management and therapeutic trials. Clearly, such a system should be tested in further studies against the complex scoring systems to test this hypothesis. Monitoring CF patients using HRCT carries potential risk due to the associated radiation exposure. Since the probability of cancer induction from ionising radiation is highest in the paediatric age group [13] and increases with each successive scan, the proposal to employ serial HRCT scans must be balanced against the potential radiation risk. Further research to determine the optimal scan parameters and frequency of HRCT scans for CF monitoring is required. This study has some limitations. First, only one observer did the scoring. However, in a previous study, in which this observer participated, it was shown that the within-and between-observer variability for the five scoring systems was good [7] . Secondly, clinical outcomes were not measured in these patients and thus it cannot be assessed whether the worsening on HRCT scans affected the clinical management of the patients. However, a case scenario ( fig. 2) illustrates how CT scoring could be used in a clinical setting. In this patient more aggressive therapy may have affected disease progression if it had been detected earlier. Larger prospective clinical studies in which CT scans are used in clinical decision making are required to test the importance of this conjecture.
Discussion
To the best of the authors9 knowledge, this is the first study that shows that HRCT can reveal progressive, irreversible structural damage in the lungs of cystic fibrosis patients over a 2-yr period; changes that are not associated with deterioration in lung function. Since the evolution of lung function over time may be dissociated from changes in the lung structure it may be advantageous to include high-resolution computed tomography in the standard follow-up of cystic fibrosis patients. Furthermore, these data support the use of highresolution computed tomography as a measurement tool in therapeutic trials for computed tomography patients, where the outcome measure is a slowing of progression of lung disease. Conversely, high-resolution computed tomography involves significant radiation exposure and in this era of prolonged patient survival in cystic fibrosis, the risk-benefit ratio for routine high-resolution computed tomography assessment needs to be more fully explored.

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