Impulse oscillometry for estimation of airway obstruction and bronchodilation in adults with mild obstructive asthma

Impulse oscillometry for estimation of airway obstruction and bronchodilation in adults with mild obstructive asthma Jung-Won Park, MD, PhD; Yong-Won Lee, MD; Young-Hee Jung, BSc; Se-Eun Park, MD; and Chein-Soo Hong, MD, PhD

Background: Clinical validity of impulse oscillometry (IOS) for the evaluation of airway obstruction and bronchodilation is a controversial issue in adults with asthma. Methods: This study enrolled 195 outpatients from October 1998 to October 2004. We performed IOS in 158 asthmatic adults, including 70 asthmatic adults with a forced expiratory volume in 1 second (FEV1) reversibility (group 1), 88 asthmatic adults with hyperresponsiveness to methacholine or sputum eosinophilia (group 2) who did not meet the FEV1 criteria, and 37 nonasthmatic adults (group 3). Results: Baseline respiratory resistance at 5 Hz (R5), respiratory resistance at 10 Hz, frequency dependency of resistance (R5 to 20), and resonance frequency were discriminative between asthmatic patients and nonasthmatic patients. The IOS parameters were decreased after bronchodilation in both asthmatic groups compared with the nonasthmatic group. Among these patients, R5 and R5 to 20 were the most discriminative parameters for evaluation of bronchodilation. Approximately one third of the patients with positive methacholine challenge test results or sputum eosinophilia manifested bronchodilation evaluated by these IOS parameters. Overall sensitivities of these parameters were comparable to FEV1 for diagnosis of bronchodilation in 158 asthmatic adults. Logistic regression analysis showed that R5 to 20 was the most reliable parameter for prediction of R5 reversibility for all asthmatic adults. Conclusions: IOS may complement the estimation of obstruction and bronchodilation for asthmatic adults. Its discriminative power for airway obstruction and sensitivities for bronchodilation were comparable to FEV1. Ann Allergy Asthma Immunol. 2007;98:546–552.

INTRODUCTION Asthma is most commonly diagnosed by forced expiratory volume in 1 second (FEV1) reversibility, but the diagnostic value of spirometry is limited; therefore, many patients require either a methacholine bronchial provocation test or other extensive studies. The American Thoracic Society recommends the increase of FEV1 by 12% and 200 mL, after administration of bronchodilation,1 but these criteria are not available in asthmatic patients with mild airway obstruction whose FEV1 values are close to normal (proportion of mild airway obstructive asthma of 60%–70%).2– 4 Furthermore, spirometry depends on the patient’s ability to perform the forced expiratory maneuver, which is difficult for children, elderly patients, and institutionalized patients.5,6 Therefore, there are increasing needs to develop new sensitive and easily applicable tests for diagnosis of airway obstruction and dilation for asthma patients.5,7–11 The forced oscillation technique (FOT) was developed to measure respiratory impedance (respiratory resistance and

Department of Internal Medicine, Institute of Allergy, Brain Korea 21 Project for Medical Science Yonsei University, College of Medicine, Seoul, Korea. Received for publication September 29, 2006. Received in revised form January 20, 2007. Accepted for publication February 8, 2007.

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reactance) simultaneously at various frequencies superimposed at the mouth during spontaneous breathing. It does not need any special breathing maneuver or any noticeable interference with respiration.12,13 This technique has been well validated to measure lung function in obstructive lung diseases7,14,15 and bronchial provocation tests in asthma.14,16,17 Several investigators have reported the clinical usefulness for evaluation of bronchodilation in asthmatic patients.9,15,18 –22 However, no consensus exists for the use of FOT for evaluation of bronchodilation in adult asthma in clinical practice.23 In this study, we evaluated the clinical validity of impulse oscillometry (IOS), which is one type of commercially available FOT, in the estimation of airway obstruction and bronchodilation in asthmatic adults with mild airway obstruction. PATIENTS AND METHODS Patients This study enrolled 195 patients from outpatient clinics of the Severance Hospital of Yonsei University from October 1998 to October 2004. Yonsei University’s medical ethics committee approved this study and obtained informed consent from the enrolled patients. All patients complained of respiratory symptoms, such as dyspnea, wheezing, or cough, and were evaluated for the presence of asthma. The patients were categorized into 3 groups according to the reversibility tests performed with a spirometer, the methacholine challenge test

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Table 1. Demographic Features of the 3 Groups Demographics Sex, M:F Age, mean ⫾ SD, y Height, mean ⫾ SD, cm Atopy, No. (%) Allergic rhinosinusitis, No. (%) Smoker, No. (%) FEV1, mean ⫾ SD, % predicted* FEV1/FVC, mean ⫾ SD, %* Positive methacholine challenge test results, No. (%) Geometric mean, mg/mL (range)† Sputum eosinophilia, No. (%)

Group 1 (n ⴝ 70)

Group 2 (n ⴝ 88)

Group 3 (n ⴝ 37)

29:41 44.6 ⫾ 14.7 162.5 ⫾ 8.5 31 (44) 38 (54) 6 (9) 81.9 ⫾ 1.7 71.6 ⫾ 1.0 53/58 (91) 0.98 (0.17–5.56) 24/46 (52)

43:45 42.4 ⫾ 13.6 165.1 ⫾ 8.3 45 (51) 51 (58) 15 (17) 88.4 ⫾ 1.3 77.7 ⫾ 1.1 78/85 (92) 1.52 (0.30–7.66) 35/57 (61)

21:16 40.6 ⫾ 14.6 164.5 ⫾ 3.5 11 (30) 20 (54) 9 (24) 100.0 ⫾ 2.5 83.3 ⫾ 1.2 0/37 0/20

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. *P ⬍ .05 between different groups. †Mean value of log transformed provocation concentration that caused a decrease in FEV1 of 20%.

(positive criterion, ⬍16 mg/mL), and induced sputum analysis (positive criteria, ⬎3% eosinophils). All bronchodilators were withheld 48 hours before the methacholine challenge and bronchodilation test. Seventy of 195 patients met the FEV1 reversibility criteria and were diagnosed as having asthma (group 1). Eighty-eight patients (group 2) who did not meet the FEV1 reversibility criteria were also diagnosed as having asthma, according to a positive response to the methacholine challenge test (n ⫽ 78) or sputum eosinophilia (n ⫽ 35). Thirty-seven patients did not meet the positive criteria of the reversibility test, the methacholine bronchial challenge test, or the induced sputum analysis and were categorized as the nonasthmatic group (group 3). The mean age, height, weight, sex ratio, and incidence of atopy, smoking, or allergic rhinitis were not different among the 3 groups. For evaluation of atopy, skin prick testing with 55 important inhalant allergens was performed. If the wheal size of any allergen was more than 3 mm compared with the negative control, we diagnosed the patient as having atopy. The demographic features of the patients are given in Table 1. Impulse Oscillometry The IOS parameters were measured before the spirometry by the MasterLab IOS system (Erich Jaeger Co, Wurtzburg, Germany). The system was calibrated through a single volume of air (3 L) at different flow rates and with a reference resistance device (0.2 kPa/L per second). The patients used nose clips and a manufacturer-provided oval hard plastic mouthpiece; patients supported their cheeks with their hands to decrease the shunt compliance. In this study, mean respiratory resistance values were calculated over a measurement period of 30 seconds in a frequency range of 5 to 35 Hz. Artifacts caused by coughing, breath holding, swallowing, or vocalization were not included. The best of 3 acceptable attempts with the lowest respiratory resistances was chosen for final data analysis. During this study, one technician measured all IOS measurements. The normal values of IOS parameters were determined by equations of multiple regres-

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sion analysis from the data of 69 healthy individuals who had no history of smoking, respiratory symptoms, or respiratory allergy. Their mean ⫾ SD age was 27.5 ⫾ 7.4 years (range, 21–51), and the male-female ratio was 43:26. Their mean ⫾ SD values for spirometry were as follows: forced vital capacity (FVC), 3.53 ⫾ 0.93 L; FEV1, 3.09 ⫾ 0.85 L/s; FEV1 percent predicted, 99.4 ⫾ 10.8; and FEV1/FVC percent predicated, 87.5 ⫾ 6.6. Their mean ⫾ SD values for IOS parameters were as follows: resistance at 5 Hz (R5), 0.261 ⫾ 0.078 kPas/L per second; frequency dependence of resistance (R5 to 20), 0.063 ⫾ 0.049 kPas/L per second; resistance at 10 Hz (R10), 0.226 ⫾ 0.067 kPas/L per second; resistance at 20 Hz (R20), 0.199 ⫾ 0.062 kPas/L per second; reactance at 5 Hz (X5), ⫺0.102 ⫾ 0.063 kPas/L per second; and resonance frequency (RFreq), 13.43 ⫾ 3.58 Hz. These IOS parameters were not different between the younger and older patients. However, sex differences were found in the IOS parameters. In women, the IOS values were of greater magnitude: R5, 0.226 ⫾ 0.060 vs 0.294 ⫾ 0.079 kPas/L per second (P ⬍ .001); R10, 0.194 ⫾ 0.049 vs 0.257 ⫾ 0.068 kPas/L per second (P ⬍ .001); R20, 0.171 ⫾ 0.046 vs 0.225 ⫾ 0.064 kPas/L per second (P ⬍ .001); and X5, ⫺0.077 ⫾ 0.057 vs ⫺0.123 ⫾ 0.060 kPas/L per second (P ⬍ .001). However, R5 to 20 (0.055 ⫾ 0.033 vs 0.069 ⫾ 0.059 kPas/L per second; P ⫽ .18) and RFreq (13.3 ⫾ 2.6 vs 12.0 ⫾ 4.2; P ⫽ .92) were not different. The normal values of the IOS parameters were determined by equations of multiple regression analysis with the enter approach. We evaluated normal bronchodilator responses with 20 healthy individuals. The R5 (0.281 ⫾ 0.089 vs 0.267 ⫾ 0.019 kPas/L per second; P ⫽ .25), R5 to 20 (0.069 ⫾ 0.044 vs 0.063 ⫾ 0.036 kPas/L per second; P ⫽ .47), and X5 (⫺0.107 ⫾ 0.060 vs ⫺0.094 ⫾ 0.052 kPas/L per second; P ⫽ .12) were not changed by bronchodilation. Spirometry Spirometric measurement was followed up at 5 minutes after IOS measurement in all patients. A maximal expiratory flow volume measurement was obtained using a pneumotachom-

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eter system equipped with a Lilly head (MasterScreen system; Erich Jaeger Co). International criteria6 were used to determine the spirometric flow-volume curve. The patients used nose clips and were coached through the standard forced expiratory maneuver. Each data set consisted of at least 3 reproducible attempts, with no more than 8 attempts made. The best of 3 attempts was chosen for final data analysis. Albuterol was administered in 3 puffs of 100 ␮g through a pressurized metered dose inhaler. Measurement of lung function was repeated 20 minutes after albuterol administration. To evaluate the reversal of airway obstruction, we adapted the American Thoracic Society guidelines, which require an FEV1 increase of more than 12% and 200 mL, after the administration of a bronchodilator.1 Methacholine Bronchial Challenge Test Methacholine was diluted in isotonic sodium chloride solution and administered using a handheld nebulizer (Devilbis 646; Devilbis Health Care Inc, Somerset, England) connected to a Rosental dosimeter (Devilbis Health Care Inc). Each patient took 5 full inhalations from functional residual capacity without a period of breath holding after each full inspiration. The initial concentration of methacholine administered was 0.075 mg/mL, and a dose-response curve was constructed by administering a serial doubling in concentration of methacholine up to 25 mg/mL. The provocation concentration that caused a decrease in FEV1 of 20% (PC20) was calculated by linear interpolation between the last 2 points on the dose response curve. If the PC20 value was lower than 16 mg/mL, it was considered airway hyperresponsiveness positive. The methacholine challenge test was performed at 2 weeks after measurement of IOS and spirometry. Induced Sputum Analysis Sputum was induced by inhalation of 3% saline by nebulizer (ULTRA-NEB 2000; Devilbis Health Care Inc). One milliliter of sputum was mixed with an equal volume of 10% Sputolysin (0.1% dithiothreitol in phosphate-buffered saline; Calbiochem-Novobiochem Co, San Diego, CA) and mildly homogenized by vortexing for 1 minute. After incubation in a shaking water bath for 20 minutes, cells were centrifuged at 1,500 rpm for 3 minutes. Cell pellets were resuspended with saline and cytocentrifuged to a slide by Cytospin 3 (Shandon Co, Cheshire, England) at 1,000 rpm for 3 minutes. After Wright staining, inflammatory cells were counted up to 200 cells and the eosinophil percentages were calculated. If the eosinophil percentage was more than 3%, it was considered sputum eosinophil positive. Sputum analysis was performed after spirometry and IOS on the same day. Statistical Analysis Data were analyzed using SPSS statistical software (version 12.0; SPSS Inc, Chicago, IL). A 1-way analysis of variance test was used to compare data among the 3 groups, and a bivariate correlation test was used to evaluate the relation between 2 parameters. The independent t test and logistic regression analysis were used to compare the positive and

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negative R5 criteria group. Significance was defined at P⫽.05. The data in the “Results” section are expressed as mean ⫾ SEM. RESULTS Baseline Spirometric and IOS Parameters Baseline FEV1 and FEV1/FVC values were significantly lower in group 1 than group 2, and a difference was also found between groups 2 and 3. The baseline R5, R10, R5 to 20 , and RFreq were significantly higher in the asthmatic patients (groups 1 and 2) than group 3. R20 and X5 were not discriminative between groups 2 and 3 (Fig 1). Changes of IOS Parameters After Bronchodilation After bronchodilation, respiratory resistances at different frequencies, R5 to 20, X5, and RFreq, were improved in both asthmatic groups (P ⬍ .001). Even in group 3, the R5 (0.280 ⫾ 0.019 vs 0.248 ⫾ 0.016 kPas/L per second; P ⬍ .001), R10 (0.254 ⫾ 0.016 vs 0.213 ⫾ 0.013 kPas/L per second; P ⬍ .001), R20 (0.228 ⫾ 0.014 vs 0.192 ⫾ 0.012 kPas/L per second; P ⬍ .001), and RFreq (13.4 ⫾ 0.8 vs 11.3 ⫾ 0.6 Hz; P ⫽ .02) were decreased after bronchodilation, but not the X5 (⫺0.101 ⫾ 0.014 vs ⫺0.070 ⫾ 0.016 kPas/L per second; P ⫽ .08) and R5 to 20 (0.052 ⫾ 0.009 vs 0.056 ⫾ 0.009 kPas/L per second; P ⫽ .65). Compared with other IOS parameters, R5 and R5 to 20 were the most discriminative for bronchodilation. Absolute values of R5, R10, and R5 to 20 were prominently attenuated by bronchodilation in the asthmatic groups, and differences in their decreases were found between groups 2 and 3. The decreases in R20 and RFreq values were apparent in group 1 but not in groups 2 and 3 (Fig 2A and B). Changes of X5 were not statistically different among the 3 groups (Fig 2C). When the attenuation of respiratory resistance by bronchodilation was estimated by percentage change from baseline values, no difference was found in R20 and R5 to 20 among the 3 groups (Fig 2D). We have set the criteria of IOS parameters for bronchodilation as the mean ⫾ 2 SD change before and after bronchodilation in the 37 nonasthmatic individuals (group 3). The criteria for significant changes in R5, R10, R20, R5 to 20, and RFreq after bronchodilation were ⫺0.13, ⫺0.13, ⫺0.12, and ⫺0.11 kPa/L per second and 11.6 Hz, respectively. With these criteria, diagnostic sensitivities of R5 and R5 to 20 for evaluation of the bronchodilation in 158 asthmatic patients were 46.2% and 33.5%. The diagnostic sensitivities of respiratory resistance were attenuated at high frequencies of applied impulse. Approximately one third of group 1 showed a negative response to R5 reversibility, but 34% of group 2 who could not be diagnosed by FEV1 met the R5 reversibility criterion. Regression Analysis for Prediction of R5 Reversibility Clinical parameters were compared between R5 reversibility– positive and R5 reversibility–negative asthmatic patients by independent t test. The R5 reversibility–positive asthmatic patients were older, more likely to be female, and shorter than

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Figure 1. Baseline lung function parameters of the 3 groups. A, Percent predicted values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), respiratory resistance at 5 Hz (R5), respiratory resistance at 10 Hz (R10), respiratory resistance at 20 Hz (R20), and resonance frequency (RFreq); B, absolute unit values of respiratory resistance; C, RFreq; and D, reactance at 5 Hz (X5). *P ⬍ .01; #P ⬍ .05.

Figure 2. Changes of impulse oscillometry (IOS) parameters after bronchodilation. A, Changes of absolute values of respiratory resistance; B, resonance frequency (RFreq); C, reactance at 5 Hz (X5) from the baseline values; and D, percent changes of respiratory resistance, frequency dependency, and RFreq from the baseline values. *P ⬍ .01; #P ⬍ .05.

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the R5 reversibility–negative asthmatic patients. Baseline lung functions such as FEV1, FEV1/FVC, and R5 were worse and exaggerated R5 to 20 was found in the R5 reversibility– positive asthmatic patient group. However, no difference was found in methacholine PC20, sputum eosinophil percentage, or smoking status. Logistic regression analysis was performed with 5 independent parameters: age, sex, height, baseline R5 to 20, and FEV1/FVC percentage. Among these parameters, the baseline R5 to 20 value was the most reliable predictors of the R5 reversibility in 158 asthmatic patients (Table 2). DISCUSSION Many clinical studies have reported the FOT as a useful tool to evaluate airway obstruction,10,24,25 bronchodilation,15,26 –28 and methacholine bronchial challenge tests29,30 in pediatric and adult asthmatic patients. However, no consensus exists for clinical validation for bronchodilation in asthmatic patients. Our results support the hypothesis that IOS may be clinically useful for the measurement of airway obstruction and bronchodilation in adult asthma patients. The most sensitive and discriminative marker for evaluation of airway obstruction and bronchodilation in adult asthma was R5, followed by R5 to 20. This result is supported by other studies.7,20,25,29 In obstructive lung diseases, such as chronic obstructive pulmonary disease and asthma, respiratory resistance at low frequency is much higher than that of high frequency, and this phenomenon has been recognized as the R5 to 20.23,31,32 In this study, reactance at low frequency was not discriminative between asthmatic and nonasthmatic patients. The interobserver or intraindividual variabilities of X5 are higher than respiratory resistance,22,33 and contradictory results have been reported regarding the clinical efficacy of X5 for evaluation of bronchodilation11,15,19 and bronchial challenge test7,14 in asthma. Our study also showed that the discriminative powers of IOS parameters, especially R5, were comparable to those of FEV1 or FEV1/FVC in adult asthmatic patients. Baseline FEV1/FVC and IOS parameters were associated in all asthmatic patients. However, as we expected, the association is modest and discordance between spirometry and IOS param-

eters were found in some patients (data not shown). This discordance may be a reflection of the difference in the measurement of airflow obstruction. FEV1 is measured during maximal expiration from full inspiration, whereas IOS parameters are measured at spontaneous tidal breathing. Contradictory results in the diagnostic sensitivity of bronchodilation in adult asthmatic patients were reported. van Noord et al20 reported that the respiratory resistance at 6 Hz (R6) was less sensitive than FEV1 or respiratory resistance measured by plethysmography in patients with severe airway obstruction. Zerah et al34 reported comparable sensitivity and specificity between respiratory conductance measured by FOT and FEV1. Their studies have focused on differentiation of asthma from chronic obstructive pulmonary disease. However, our study was designed for differentiation of mild obstructive asthma from nonasthmatic patients with normal spirometric lung function. In this study, the overall sensitivity of IOS was comparable to FEV1. One third of group 1 patients did not meet the R5 reversibility, but in one third of group 2 patients significant bronchodilation was detected by IOS. Furthermore, 4 of 8 group 2 asthmatic patients who did not manifest responsivity to methacholine met the criterion of R5 reversibility. Other investigators have reported that FOT using respiratory resistance measured at low frequency or R5 to 20 were more sensitive than spirometry in differentiating smokers and nonsmokers,31,32 workers with and without exposure to occupational hazards,32,35 separation of healthy subjects from respiratory complainers with or without slight airway obstruction,36 and estimation of bronchodilation in patients with chronic obstructive pulmonary disease.37 These results suggest that IOS may play a complementary role in the diagnosis of airway obstruction and bronchodilation in obstructive lung diseases. Some technical limitations exist in the measurement of resistance by IOS. Resistance measured by IOS may be influenced by factors that may vary within short intervals. Part of the flow applied at the mouth can be lost in movements of the cheeks despite use of manual support,30,38 and movements of the vocal cord and pharyngeal muscles may also affect the measurement.39 The contribution of upper airway resistance to measured respiratory resistance in adults

Table 2. Logistic Regression Analysis for Prediction of R5 Reversibility in Asthma Demographics

Age Sex Height R5 to 20 FEV1/FVC Constant

All asthmatic patients (n ⴝ 158)

Group 1 (n ⴝ 70)

Group 2 (n ⴝ 88)

␤

P value

␤

P value

␤

P value

⫺0.030 ⫺0.157 ⫺1.028 ⫺19.58 0.030 4.09

.09 .81 .82 ⬍.001 .25 .65

⫺0.035 0.156 ⫺7.002 ⫺16.45 0.092 8.46

.23 .87 .27 ⬍.001 ⬍.05 .51

⫺0.057 ⫺0.734 1.694 ⫺32.15 ⫺0.049 9.76

.06 .51 .82 ⬍.001 .28 .54

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; R5, respiratory resistance at 5 Hz; R5 dependency of resistance.

550

to 20

, frequency

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was greater than in children.40 These limitations may contribute to a greater degree of between-observer41 and intrasubject variability using IOS compared with spirometry.22,24,42 Many FOT studies have established their positive criteria for bronchodilation. Compared with the baseline value, a 30% decrease in R10,27 a 40% decrease in the R526 or R6,20 a 10% decrease of respiratory conductance,34 and a 29% decrease in the R511 have been suggested as positive criteria for bronchodilation. Until now, there has been no consensus on the criteria of bronchodilation, and this absence may have contributed to the contradictory results on diagnostic sensitivity of FOT for bronchodilation. As seen in Figure 2, the changes of absolute values of respiratory resistance were more discriminative than percent changes from baseline respiratory resistance in this study. We have set the bronchodilation criteria of IOS resistance parameters using the mean ⫾ 2 SDs from the data of 37 nonasthmatic individuals. Because the baseline respiratory resistance is definitely lower in adults or older patients than in children,24,43,44 even small changes in resistance may be the cause of exaggerated percent changes in adult asthmatic patients. We think that changes in absolute resistance units may be more reliable than percent changes from the baseline value for evaluation of bronchodilation, at least in adult asthmatic patients. In conclusion, this study demonstrates the discrepancies between spirometric parameters and respiratory resistances measured by IOS in some adult asthmatic patients. Among the IOS parameters, R5, followed by R5 to 20, is the most sensitive and discriminative marker for the evaluation of airway obstruction and bronchodilation. Their discriminative powers for airway obstruction and sensitivities for bronchodilation were comparable to FEV1. IOS may play a complementary role in the diagnosis of airway obstruction and bronchodilation in adult asthmatic patients. ACKNOWLEDGMENTS This work was supported by the Clinical Research Center for Chronic Obstructive Airway Disease and grants 0412-CR03 to 0704 – 0001 from the Korean Ministry of Health and Welfare. REFERENCES 1. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis. 1991;144:1202–1218. 2. Cockroft D, Hargreave F. Airway hyperresponsiveness. Relevance of random population data to clinical usefulness. Am Rev Respir Dis. 1990;142:497–500. 3. Auerbach I, Springer C, Godfrey S. Total population survey of the frequency and severity of asthma in 17 year old boys in an urban area in Israel. Thorax. 1993;48:139 –141. 4. Fuhlbrigge A, Adams R, Guilbert T, et al. The burden of asthma in the United States. Am J Respir Crit Care Med. 2002;166: 1044 –1049. 5. Carvalhaes-Neto N, Lorino H, Gallinari C, et al. Cognitive assessment of lung function in the elderly. Am J Respir Crit Care Med. 1995;152:1611–1615.

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Requests for reprints should be addressed to: Jung-Won Park, MD, PhD Department of Internal Medicine Yonsei University College of Medicine Sudaemungu Schincheondong 134 Seoul, Korea 120-752 E-mail: [email protected]

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