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DOI: 10.1148/radiol.2292021805
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(Radiology 2003;229:507-512.)
© RSNA, 2003

Thoracic Imaging

ß-Thalassemia Major: Thin-Section CT Features and Correlation with Pulmonary Function and Iron Overload1

Pek-Lan Khong, FRCR, Godfrey C. F. Chan, MD, FRCP, So-Lun Lee, MRCP, Wing Y. Au, MRCP, Daniel Y. T. Fong, PhD, Kenneth W. T. Tsang, MD, FRCP and Gaik-Cheng Ooi, MRCP, FRCR

1 From the Depts of Diagnostic Radiology (P.L.K., G.C.O.), Paediatrics (G.C.F.C., S.L.L.), and Medicine (W.Y.A., K.W.T.T.), Queen Mary Hosp; and Clinical Trials Ctr (D.Y.T.F.), Univ of Hong Kong, 102 Pokfulam Rd, Block K, Room 406, Hong Kong. Received Dec 31, 2002; revision requested Mar 10, 2003; revision received Mar 17; accepted Apr 14. Supported by Committee on Research and Conference Grants of Univ of Hong Kong. Address correspondence to P.L.K. (e-mail: plkhong@hkucc.hku.hk).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To describe and quantify thin-section computed tomographic (CT) features of the lung in patients with ß-thalassemia major (ß-TM) and determine the correlation between thin-section CT findings, pulmonary function test (PFT) results, and iron overload.

MATERIALS AND METHODS: Forty-one patients with ß-TM (mean age, 24.5 years) underwent thin-section CT (during full inspiration and expiration) and PFTs. Two radiologists in consensus recorded the presence of focal bronchial and parenchymal abnormalities and air trapping. A semiquantitative air trapping score (ATS) was used, and patients were separated into air trapping–negative (ATS between 0 and 3) and air trapping–positive (ATS > 3) groups for statistical analysis. Iron overload was estimated by calculating the ratio of the signal intensity (SI) of the liver to the SI of paraspinous muscle by using magnetic resonance imaging in 27 patients (66%). We performed multiple logistic regression analysis to study the influence of age, PFT findings, and SI ratio on the presence of air trapping at CT and multivariate regression analysis to study the simultaneous influence of the presence of air trapping on obstructive PFT indexes.

RESULTS: Air trapping was the predominant thin-section CT finding and was seen in 10 (24%) of 41 patients. No patient had interstitial lung disease at CT, although 11 (27%) had a restrictive spirometric pattern. Simple logistic regression analysis revealed significant associations between ATS and forced expiratory volume in the first second (FEV1), FEV1/forced vital capacity (FVC), forced expiratory flow (FEF) in the midexpiratory phase (FEF25%–75%), FEF at 50% of the FVC (FEF50%), and FEF at 75% of the FVC (FEF75%) (P = .019, .030, .007, .034, and .021, respectively) but not between ATS and SI ratio. At multiple logistic regression analysis, only FEF25%–75% was significantly associated with ATS (P = .019, adjusted odds ratio = 0.86, R2 = 41.8%). Multivariate analysis revealed that ATS did not have a significant influence on lung function indexes (P = .104), although significant effects were found with FEV1, FEF25%–75%, FEF50%, and FEF75% when examined separately.

CONCLUSION: Air trapping may be present at expiratory thin-section CT in patients with ß-TM and is associated with reduced FEF25%–75% values but not hepatic iron overload.

© RSNA, 2003

Index terms: Anemia, 57.652, **.6522 • Liver, MR, 761.121411, 761.121412 • Lung, air trapping, 60.751 • Lung, CT, 60.12118 • Lung, function


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
ß-Thalassemia major is a common inherited disorder of hemoglobin synthesis in Southern China. In Hong Kong, there are currently more than 300 patients with ß-thalassemia major (1). Iron overloading from regular blood transfusions results in organ dysfunction, the major cause of morbidity and mortality in these patients. Although effective iron chelation treatment is available, the difficulty of frequent and prolonged administration of iron-chelating agents makes compliance extremely difficult. Heart and liver dysfunction have been extensively studied owing to their early effect on survival. Pulmonary dysfunction is one of the least understood complications of ß-thalassemia major, although it is not uncommon, having been reported in up to 80% of patients with the disease (2,3). Reported abnormalities are varied and include restrictive lung disease (2–7), impaired diffusing capacity of lung for carbon monoxide (DLCO) (4,8), small-airway disease (5,9,10), and obstructive airway disease (4,5,8).

Although the spectrum of pulmonary function abnormalities in ß-thalassemia major has been evaluated and described, there are limited reports of the morphologic features of the lung at computed tomography (CT) in these patients. In two published series, thin-section CT was performed in selected patients with ß-thalassemia major who underwent pulmonary function testing, but the findings were not described in detail (4,6). Recently, using thin-section CT, we found diffuse centrilobular nodules and air trapping in a patient with ß-thalassemia major who was subsequently confirmed to have small-airway disease at histopathologic examination (11). Thus, the purpose of our study was to describe and quantify the thin-section CT imaging features of the lung in patients with ß-thalassemia major and determine the correlation between thin-section CT findings, pulmonary function test results, and iron overload.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
Patients who had been given a diagnosis of ß-thalassemia major and who were 8 years of age or older were randomly selected from a database at our institution (at the time of this writing, the database contained information for about 80 patients) for enrollment in the study during a 6-month period between October 2001 and March 2002. Enrollment in the study was based on whether or not we were able to contact the patients by telephone. Informed consent was obtained from all patients and/or parents, and the study was approved by the institutional review board. All patients were visiting our institution for regular follow-up and blood transfusion at fixed monthly intervals. They were all undergoing chelation therapy with subcutaneous administration of desferrioxamine five to six times a week. Pulmonary function testing was performed prior to blood transfusion.

We aimed to recruit about 50 patients and contacted 54, of whom 41 (76%) consented to participate in the study (mean age, 24.5 years; age range, 9–40 years). There were 18 male patients (mean age, 24.1 years; age range, 10–39 years) and 23 female patients (mean age, 24.7 years; age range, 9–40 years). None of the patients had a history of asthma, and none were active smokers, although there were four ex-smokers who had not smoked for more than 1 year. Apart from three patients who complained of recurrent cough, all patients were asymptomatic and clinically stable at the time of examination. Pretransfusion serum hemoglobin levels ranged from 7.6 to 11.1 g/dL (76–111 g/L), with a mean of 9.4 g/dL (94 g/L). The normal range for male individuals is 13.0–18.0 g/dL (130–180 g/L); the normal range for female individuals is 11.5–16.5 g/dL (115–165 g/L).

Thin-Section CT
All patients underwent full inspiratory and expiratory thin-section CT (Light-Speed or Hi-Speed Advantage; GE Medical Systems, Milwaukee, Wis) of the thorax while they were in the supine position. Inspiratory scanning parameters included 1-mm collimation, a 10-mm section interval, 120 kV, and different milliampere second values according to patient age. Expiratory scans were obtained by using similar parameters except for a larger section interval (20 mm). Images were reconstructed with a bone algorithm and filmed by using standard lung window settings (window level, -700 HU; window width, 1,000–1,500 HU). Two radiologists with 12 and 10 years of experience in interpreting thin-section CT results (G.C.O. and P.L.K., respectively) reviewed the images together, and decisions were made in consensus. Both radiologists were aware that the images had been obtained in a cohort of patients with ß-thalassemia major but were blinded to clinical details such as treatment compliance, laboratory and pulmonary function test results, and magnetic resonance (MR) imaging findings in the liver.

Evaluation of Inspiratory Scans
With the inspiratory CT scans, each lung was evaluated for the presence of mosaic attenuation, intra- and/or interlobular septal thickening, centrilobular nodules, bronchial dilatation, and bronchial wall thickening. Mosaic attenuation was defined as the presence of alternating areas of hypo- and hyperattenuating lung parenchyma. In addition, the presence of paraspinal masses consistent with extramedullary hematopoiesis and rib widening were recorded.

Evaluation of Expiratory Scans
Expiratory scans were evaluated for the presence of air trapping. Air trapping was defined as the presence of areas of lung that failed to increase in attenuation after full expiration, as compared with the attenuation at full inspiration. Spurious areas of decreased attenuation, including the region of the minor fissure and the relatively low-attenuating apical segments of the lower lobes, as well as the air trapping in single secondary lobules that can be seen in some healthy individuals, were disregarded (12–15).

The extent of air trapping was evaluated by using a well-validated semiquantitative scoring system (12–14). The area of air trapping was assessed by using a five-point scale on images obtained at the following four fixed levels in each lung (or on the images obtained closest to these levels): the aortic arch, the carina, the pulmonary venous confluence, and approximately 1 cm above the diaphragm at the lung base. A score of 0 indicated no visible air trapping; a score of 1, air trapping affecting 1%–25% of the cross-sectional area of the lung; a score of 2, air trapping affecting 26%–50% of the cross-sectional area of the lung; a score of 3, air trapping affecting 51%–75% of the cross-sectional area of the lung; and a score of 4, air trapping affecting 76%–100% of the cross-sectional area of the lung. The air trapping scores were summed to obtain a total score for each patient that ranged from 0 to 32, with the score for each lung ranging up to 16.

A threshold total score of 3 was used for air trapping because healthy individuals can have total scores of 3 or lower (15,16). For statistical analyses, the patients were separated into two groups: a group with air trapping scores of 0–3 (hereafter referred to as the air trapping–negative group) and a group with air trapping scores higher than 3 (hereafter referred to as the air trapping–positive group).

Pulmonary Function Testing
Pulmonary function testing was performed on the same day as thin-section CT in 28 (68%) of the 41 patients, while the examinations were performed a mean of 3 months apart in the other patients. All pulmonary function tests were performed by the same technician with a SensorMedics VMAX 22 spirometer (SensorMedics, Yorba Linda, Calif) according to the standard American Thoracic Society protocol (17). Results were expressed as percentages of predicted normal values (18). Pulmonary function testing included assessment of forced expiratory volume in the 1st second (FEV1), forced vital capacity (FVC), residual volume (RV), total lung capacity (TLC), forced expiratory flow in the midexpiratory phase (FEF25%–75%), forced expiratory flow at 50% and at 75% of the FVC (FEF50% and FEF75%, respectively), and DLCO as measured with a single-breath technique and corrected for hemoglobin concentration. The ratios of FEV1 to FVC and RV to TLC were also calculated. The patients were separated into the following groups: those with a restrictive pattern (ie, FEV1/FVC > 80% and TLC < 80%), those with an obstructive pattern (ie, FEV1 < 80% and FEV1/FVC < 80%), those with a mixed restrictive and obstructive pattern (ie, TLC < 80% and FEV1/FVC < 80%), and those with small-airway disease (FEF25%–75% < 50% or FEF75% < 50%). Impaired DLCO was defined as a situation where DLCO values were less than 80% of predicted values.

MR Imaging of Liver
Hepatic iron content was measured with MR imaging of the liver. Hepatic iron content data were acquired from an ongoing study of iron overload in patients with ß-thalassemia major at our institution. MR imaging of the liver was performed by using a Signa 1.5-T MR imaging unit (GE Medical Systems) with a body coil. Respiratory-gated multisection transverse abdominal images were obtained with spin-echo T1-weighted (repetition time msec/ echo time msec, 600/10; field of view, 32 cm; number of signals acquired, two) and gradient-recalled-echo T2*-weighted (700/15; field of view, 32 cm; number of signals acquired, two; flip angle, 20°) sequences. Signal intensities were measured by using a previously validated method of placing operator-defined regions of interest (average area, 9.5 mm2; size range, 8–10 mm2) over the liver and the paraspinous muscle (19). Regions of interest were placed by a radiologic technician after instruction and training by a radiologist (G.C.O.). The signal intensity values in each of three regions of interest were averaged to obtain one value. The ratio of the signal intensity of the liver to the signal intensity of the paraspinous muscles was calculated on T1-weighted and T2*-weighted MR images. Iron overload was defined as a situation where this ratio was less than 1.00 (19).

Statistical Analysis
Simple logistic regression analysis was used to examine the relationships between age; the obstructive pulmonary function indexes FEV1, FEV1/FVC, RV/TLC, FEF25%–75%, FEF50%, and FEF75%; the signal intensity ratios; and the dichotomous dependent variables absence of air trapping and presence of air trapping. We then performed a multiple logistic regression analysis by using a forward stepwise selection procedure to study the independent influences of the following variable(s) on the presence of air trapping: age, pulmonary function indexes, and signal intensity ratios. From this, we could determine the variable(s) with the strongest association with air trapping at thin-section CT.

We also performed multivariate regression analysis to study the simultaneous influence of the presence of air trapping on the same obstructive pulmonary function indexes.

A P value of less than .05 was considered to indicate a statistically significant difference. Only two-tailed tests were used. All statistical analyses were performed by using the statistical packages SPSS for Windows (version 11.0; SPSS, Chicago, Ill) and SAS (version 8.2; SAS, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Thin-Section CT
All 41 patients successfully underwent inspiratory and expiratory thin-section CT. One patient had mild lower lobe bronchial wall thickening and bronchial dilatation in keeping with bronchiectasis. None of the patients was seen to have intra- or interlobular septal thickening, centrilobular nodules, or mosaic attenuation on the inspiratory scans.

The most prevalent thin-section CT finding was that of air trapping on the expiratory scans (Figure). Excluding those patients with air trapping scores of 1–3, we found that air trapping was present in 10 (24%) of 41 patients (mean air trapping score, 10; range, 4–18). All 10 patients had air trapping at the levels of the pulmonary venous confluence and at the lung base 1 cm above the diaphragm, and six of these patients also had air trapping in the two other levels.



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  		Figure a. Expiratory thin-section CT scans obtained in two patients with ß-thalassemia major show air trapping (arrows) at the level of (a) the inferior pulmonary veins (scan obtained in a 40-year-old woman) and (b) the lung base (scan obtained in a 20-year-old woman).

 


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  		Figure b. Expiratory thin-section CT scans obtained in two patients with ß-thalassemia major show air trapping (arrows) at the level of (a) the inferior pulmonary veins (scan obtained in a 40-year-old woman) and (b) the lung base (scan obtained in a 20-year-old woman).

 
A paraspinal mass consistent with extramedullary hematopoiesis was present in 16 (39%) of 41 patients. All patients had abnormal ribs with medullary expansion.

Pulmonary Function Test Results
Of the 41 patients examined, 38 underwent full pulmonary function testing. DLCO values were not available for three patients because of inadequate cooperation, and RV, FEF50%, and FEF75% values were not available for one patient each. Pulmonary function test results were normal in only four (10%) of 41 patients. A solitary impairment in DLCO was the most commonly observed pulmonary function abnormality; it was present in 13 (32%) of 41 patients. Eleven (27%) of 41 patients had restrictive lung disease, and DLCO was reduced in six of these patients. Of these 11 patients, seven had mild (ie, TLC between 70% and 79%), three had moderate (ie, TLC between 60% and 69%), and one had severe (ie, TLC < 60%) volume restriction. Obstructive lung disease was seen in four (10%) of 41 patients, while three patients (7%) had a mixed obstructive-restrictive pattern. Pulmonary function test results suggestive of small-airway disease were observed in four (10%) of 41 patients. Pulmonary function test results of the patients are shown in Table 1.


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  		TABLE 1. Pulmonary Function Test Results for Patients with ß-Thalassemia Major

 
All four patients with evidence of small-airway disease at pulmonary function testing had evidence of air trapping at thin-section CT. Air trapping was also present in two patients with impaired DLCO only and in one patient each with obstructive, restrictive, and mixed obstructive-restrictive lung disease.

MR Imaging of Liver
MR imaging of the liver was performed in 27 (66%) of the 41 patients in our cohort. This portion of the study was retrospective, with data already having been acquired as part of an ongoing study, and we did not recall the remaining 14 patients for MR imaging of the liver. Of the 27 patients, nine were in the air trapping–positive group and 18 were in the air trapping–negative group. The signal intensity ratios on T1-weighted MR images and the signal intensity ratios on T2*-weighted MR images, respectively, ranged between 0.21 and 1.66 and 0.06 and 0.79 (means: 0.91 and 0.21) for the air trapping–positive group and between 0.43 and 1.79 and 0.04 and 0.56 (means: 1.13 and 0.21) for the air trapping–negative group.

Statistical Analysis
The means and SDs for age, pulmonary function values, and signal intensity ra-tios for the air trapping–positive and air trapping–negative groups are shown in Table 2.


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  		TABLE 2. Pulmonary Function Values, Age, and SI Ratios for Patients in Air Trapping-Positive and Air Trapping-Negative Groups

 
At simple logistic regression analysis, there were statistically significant negative associations between FEV1, FEV1/FVC, FEF25%–75%, FEF50%, FEF75%, and air trapping score (Table 3). With multiple logistic regression, only FEF25%–75% was significantly associated with air trapping score (P = .019; adjusted odds ratio = 0.86; 95% CI = 0.75, 0.97; R2 = 41.8%). Hepatic iron overload and age did not have additional influence on air trapping score.


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  		TABLE 3. Results of Simple Logistic Regression Analysis of Relationships between Obstructive Pulmonary Function Indexes, Patient Age, and SI Ratios and the Dependent Variables of Presence and Absence of Air Trapping

 
Results of multivariate regression analysis indicated that the presence of air trapping did not have significant influence (P = .104) on any of the obstructive lung function parameters that were tested as dependent variables (FEV1, FEV1/FVC, RV/TLC, FEF25%–75%, FEF50%, and FEF75%), although statistically significant effects were found with FEV1, FEF25%–75%, FEF50%, and FEF75% when the lung function parameters were examined separately (Table 4).


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  		TABLE 4. Results of Multivariate Regression Analysis of Relationships between Air Trapping and Obstructive Pulmonary Function Indexes

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
In our study, we quantitatively evaluated the thin-section CT findings in patients with ß-thalassemia major and their correlation with parameters of pulmonary physiology, demography, and hepatic iron overload. Our data showed that about one-quarter of patients with ß-thalassemia major (ie, 10 of 41 patients) had air trapping at thin-section CT that was consistent with small-airway disease and, in particular, obstruction. There was also a negative correlation between air trapping at thin-section CT and FEF25%–75%, an indicator of small-airway disease. This negative relationship between air trapping score and FEF25%–75% has also been described in other conditions, such as asthma and bronchiolitis obliterans, in which small-airway obstruction is the predominant pathologic process (14,20–23).

Although a few investigations of patients with ß-thalassemia major have involved thin-section CT (4,6), to our knowledge, air trapping has not been described as a feature of ß-thalassemia major. The most likely explanation for this is that expiratory scanning, which improves the accuracy of CT for the diagnosis of air trapping, was not performed and air trapping was therefore undetected (13,15,16,22,23). Air trapping is observed in patients with obstructive lung diseases such as emphysema, asthma (24), bronchiolitis obliterans (16,21,25), and bronchiectasis (23,26). It has also been described in sarcoidosis (27), rheumatoid arthritis (28), and Langerhans cell histiocytosis (29); in all of these diseases, its presence was attributed to small-airway disease.

Only four patients in our study fulfilled the criteria of small-airway disease on the basis of pulmonary function test results, and all four had evidence of air trapping at thin-section CT. Other authors have observed air trapping in the presence of normal pulmonary function test results and have concluded that thin-section CT is more sensitive than pulmonary function testing for detecting small-airway obstruction (20,27,28). This can be explained by the ability of thin-section CT to depict subtle density differences in focal areas in the lung parenchyma that may not be reflected in the pulmonary function indexes, which measure the function of the lung as a whole.

Although iron deposits have been found in the macrophages in alveoli and in the perivascular tissue of patients with ß-thalassemia major at postmortem examination (30,31), the relationship between iron deposition in the lungs and pulmonary dysfunction is unclear (31). The proposed mechanisms of airway obstruction in ß-thalassemia major include oxidative damage as a result of free iron deposition within the airway epithelium (10,11). This theory is supported by the identification of iron-laden macrophages and lymphocyte alveolitis within the bronchial mucosa and in bronchoalveolar lavage fluid, suggesting that free iron deposition is a toxic mechanism.

Other suggested mechanisms are bronchial hyperactivity (32) and chronic immunologic factors (6) related to blood transfusion and disproportionate and/or excessive alveolar growth relative to airway growth caused by hypoxemia or hypoxia, a chronic abnormality in patients with ß-thalassemia major (33). It is known that serum ferritin levels do not necessarily reflect total body iron stores because they vary during the process of chelation and because ferritin is an acute-phase protein as well as a product of hepatocellular damage (34). It is therefore not surprising that reports of correlation of serum ferritin levels with pulmonary function have been contradictory; some researchers have shown a positive correlation (3,6,7), while others have not (4,5,9,10).

Hepatic iron content, on the other hand, gives the best quantitative estimate of total body iron stores (34), and this can be obtained noninvasively by using MR imaging (35–37). Recent studies in which measurement of the signal intensity ratio was used to estimate iron overload have not revealed statistically significant correlations with pulmonary dysfunction (4,9). Similarly, we found no such association with the presence of air trapping.

There was no evidence of interstitial lung disease in any of our patients, despite the finding of a restrictive spirometric pattern in 11 patients and a mixed obstructive-restrictive pattern in three patients. Interstitial lung disease has been documented in a cohort of patients with ß-thalassemia major in which half of the patients with a restrictive spirometric pattern had interstitial lung disease at thin-section CT (7). Our findings support the notion that restrictive lung disease in patients with ß-thalassemia major is multifactorial and is not due solely to interstitial fibrosis. Moreover, previous studies of postmortem findings have not revealed evidence of fibrosis in the lungs (unlike in patients with hemochromatosis) (30,31).

Other contributory mechanisms may include aberrant alveolar growth limiting the volume of airspaces; desferrioxamine administration leading to the production of free radicals; and platyspondyly, rib widening, and paraspinal extramedullary hematopoiesis causing reduced lung volume. The latter two factors were present in 100% and 39% of our patients, respectively. More recently, an association between patients with a restrictive spirometric pattern and the ß0/ß0 genotype, the most severe form of ß-thalassemia major, has been found (38).

Although there was a trend of increasing patient age with air trapping, the difference was not statistically significant. Given the current data, the presence of air trapping did not significantly influence any of the lung function indexes. This may be due to an insufficient number of patients for the multivariate analysis of a large number of lung function parameters. The significant influence observed when the lung function parameters were examined separately is therefore exploratory, and more patients are needed.

Thin-section CT and pulmonary function testing were not performed on the same day in 13 (32%) of 41 patients, and this may limit the accuracy of correlation between thin-section CT and pulmonary function indexes. However, all patients were clinically stable at the time of both thin-section CT and pulmonary function testing, and none had concomitant acute illnesses that may have affected the results of thin-section CT or pulmonary function testing. Because ß-thalassemia major is a chronic condition, we do not expect marked variations in thin-section CT or pulmonary function test findings over weeks or even months. We are also limited by the lack of longitudinal data and therefore cannot draw conclusions regarding the clinical importance of air trapping and small-airway disease or whether these patients will develop more severe airway obstruction with time. This is of concern, especially in view of the marked improvement in life expectancy of patients with ß-thalassemia major. Of note is the phenomenon of transfusion-induced respiratory impairment in patients with ß-thalassemia major and preexisting airway obstruction (39). These patients have been found to have worsening airway obstruction and reduced exercise tolerance after transfusion (6,31,39), and it may be necessary to identify them so as to provide the appropriate advice regarding physical exercise.

In conclusion, results of our thin-section CT and functional evaluation of patients with ß-thalassemia major demonstrated air trapping, which was associated with reduced FEF25%–75%, an indicator of small-airway disease. Iron overload and age were not significantly associated with the presence of air trapping. These findings have added a further facet to the understanding of the complex nature of pulmonary dysfunction in patients with ß-thalassemia major. Larger and longitudinal studies are required to evaluate the clinical importance of our findings.


   ACKNOWLEDGMENTS
 
The authors thank the patients and parents for participating in this study.


   FOOTNOTES
 
2 **. Multiple body systems Back

Abbreviations: DLCO = diffusing capacity of lung for carbon monoxide, FEF50% = forced expiratory flow at 50% of FVC, FEF75% = FEF at 75% of FVC, FEF25%–75% = FEF in midexpiratory phase, FEV1 = forced expiratory volume in 1st second, FVC = forced vital capacity, RV = residual volume, TLC = total lung capacity

Author contributions: Guarantor of integrity of entire study, G.C.O.; study concepts and design, P.L.K., G.C.F.C., G.C.O.; literature research, P.L.K., G.C.O.; clinical studies, G.C.F.C., S.L.L., W.Y.A., K.W.T.T.; data acquisition and analysis/interpretation, P.L.K., G.C.F.C., W.Y.A., K.W.T.T., G.C.O.; statistical analysis, P.L.K., D.Y.T.F.; manuscript preparation, P.L.K., G.C.O.; manuscript definition of intellectual content, P.L.K., G.C.F.C., S.L.L., G.C.O.; manuscript editing, revision/review, and final version approval, all authors


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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