Reference Values of Impulse Oscillometry and Its ...

Journal of Asthma, 2012; Early Online: 1–6 Copyright © 2012 Informa Healthcare USA, Inc. ISSN: 0277-0903 print/1532-4303 online DOI: 10.3109/02770903.2012.716472

Reference Values of Impulse Oscillometry and Its Utility in the Diagnosis of Asthma in Young Korean Children J UNG -Y ONG L EE , M . D ., 1,2 J U -H EE S EO , M . D ., 1,2 H YUNG Y OUNG K IM , M . D ., 1,2 Y OUNG H O J UNG , M . D ., 1,2 J I -W ON K WON , M . D ., 3 B YOUNG -J U K IM , M . D ., PH . D ., 4 H YO B IN K IM , M . D ., PH . D ., 5 S O -Y EON L EE , M . D ., PH . D ., 6 G WANG C HEON J ANG , M . D ., PH . D ., 7 D AE J IN S ONG , M . D ., PH . D ., 8 W OO K YUNG K IM , M . D ., PH . D ., 9 J UNG Y EON S HIM , M . D ., PH . D ., 10 H A -J UNG K IM , D . V . M ., PH . D ., 11 Y EE -J IN S HIN , M . D ., PH . D ., 12 J UNG -W ON P ARK , M . D ., PH . D ., 13 S ANG -H EON C HO , M . D ., PH . D ., 14 J OO -S HIL L EE , M . D ., PH . D ., 15 AND S OO -J ONG H ONG , M . D ., PH . D ., 1,2, * 1

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Childhood Asthma Atopy Center, Asan Medical Center, Department of Pediatrics, Ulsan University College of Medicine, Seoul, Korea. Research Center for Standardization of Allergic Diseases, Asan Medical Center, Department of Pediatrics, Ulsan University College of Medicine, Seoul, Korea. 3 Department of Pediatrics, Seoul National University Bundang Hospital, Seoul, Korea. 4 Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Seoul, Korea. 5 Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea. 6 Department of Pediatrics, Hallym University Sacred Heart Hospital, Seoul, Korea. 7 Department of Pediatrics, National Health Insurance Corporation Ilsan Hospital, Seoul, Korea. 8 Department of Pediatrics, Korea University Guro Hospital, Seoul, Korea. 9 Department of Pediatrics, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea. 10 Department of Pediatrics, Kangbuk Samsung Hospital, Sunkyunkwan University School of Medicine, Seoul, Korea. 11 Asan Institute for Life Sciences, Ulsan University College of Medicine, Seoul, Korea. 12 Department of Psychiatry, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 13 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. 14 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. 15 Allergy TF, Department of Immunology and Pathology, Korea National Institute of Health, Seoul, Korea. Aims. The aims of this study were (1) to determine the reference values for impulse oscillometry (IOS) and (2) to apply them to the evaluation of asthma in the general population of young Korean children. Methods. We performed a questionnaire survey and IOS measurements in 390 children aged 3–7 years in Seoul and Gyeonggi province, Korea, from July to August 2010. IOS measurements included respiratory resistance (Rrs) and respiratory reactance (Xrs) at 5, 10, 15, 20, 25, and 35 Hz, respiratory impedance (Zrs), and resonance frequency (RF) before and 15 min after inhalation of 200 μg salbutamol. To determine the reference values for IOS, 161 children defined as healthy controls were assessed. Results. The IOS measurements were presented as means and standard deviations. The reference equations for IOS variables were determined by multiple linear regression analysis taking into account their height, weight, and age (R5 ¼ 2.242 – 0.008 height (cm) – 0.005 age (months), coefficients of determination (R2) ¼ 0.213). Height had the greatest correlation with IOS variables, similar to previous studies. Positive airway obstruction was defined as R5 greater than the 95th percentile of predicted R5 from the reference equation. There was a higher percentage of children with positive airway obstruction in children with asthma than in healthy controls (27.3% vs. 6.2%). Multivariate logistic regression analysis indicated that positive airway obstruction was a significant risk factor for the diagnosis of asthma (adjusted odds ratio (aOR), 6.245; 95% confidence interval (CI), 2.270–17.175). Conclusion. This study provided reference values for IOS in young Korean children and applied the reference values to evaluate children with asthma. We suggest the 95th percentile of predicted R5 as a cut-off value for positive airway obstruction, which may increase the risk for diagnosis of asthma. Keywords asthma, impulse oscillometry, reference values, risk factors, young children

for gene–environment interactions and change the natural course of asthma (3, 4). However, lung function in young children is not easy to accurately measure because conventional spirometry, which is the most widely used method in school-aged children, requires effort-dependent maneuvers, such as maximal forced inspiration and expiration. For this reason, impulse oscillometry (IOS), which is a forced oscillation technique (FOT) that requires only passive cooperation, has been noticed to measure lung function in young children (5). Using IOS, respiratory impedance (Zrs), which comprises respiratory resistance

I NTRODUCTION Assessment of lung function in early life is important for early detection of asthma (1, 2). This might make early intervention possible around the time of the critical period *Corresponding author: Soo-Jong Hong, MD, PhD, Department of Pediatrics, Childhood Asthma Atopy Center, Research Center for Standardization of Allergic Diseases, Asan Medical Center, Ulsan University College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Korea; Tel: þ82-2-3010-3379; Fax: þ82-2-473-3725; E-mail: [email protected]

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(Rrs, energy required to propagate the pressure wave through the airways) and respiratory reactance (Xrs, amount of recoil generated against pressure wave), can be easily measured (6, 7). However, IOS is not used widely among young children as a routine test in clinical practice. In order to apply IOS in this age group, the reference values must be established and the utility of IOS in each disease group must be proven. Although previous studies have proposed reference values of IOS in young children (8–14), the numbers are limited and there are only few studies concerning Korean children (10). Studies including children with asthma have failed to suggest consistent results according to different definitions of asthma (8, 15–18). Children with asthma diagnosed by a physician had larger Rrs than healthy control subjects (15, 16), whereas children classified as asthmatic or healthy based on questionnaire exhibited no significant difference in Rrs (8, 17). Furthermore, the utility of IOS has not yet been evaluated in the general population of young children. This study was designed (1) to determine the reference values for IOS and (2) to apply them to the evaluation of asthma in the general population of young Korean children. M ATERIALS

AND

M ETHODS

Subjects This was a retrospective cross-sectional study of young children aged 3–7 years. All subjects were attending 1 of 16 kindergartens in Seoul and Gyeonggi province during July to August 2010. We initially recruited 985 young children. The parents of 919 children (response rate ¼ 93.3%) responded to the questionnaire. We aimed to perform IOS on these children around 4 years of age. A total of 394 children were approved to take the IOS measurements. Four children could not be assessed due to poor cooperation (success rate of IOS ¼ 99.0%). According to the exclusion criteria based on European Respiratory Society (ERS) guidelines (19, 20), 229 children were excluded and 161 children were included as the “healthy controls”. The exclusion criteria included (1) physician diagnosed asthma, (2) wheezing in the last 12 months, (3) premature birth (gestational age < 37 weeks), (4) low birth weight (birth weight < 1500 g), (5) environmental tobacco smoke (ETS) exposure, (6) obesity (body mass index 25 kg/m2), and (7) currently taking medication for upper respiratory infection. The study was approved by the Institutional Review Board of Asan Medical Center. Written consent was obtained from all parents following a detailed explanation of the study. Data Collection Data from a physical examination, questionnaire responses, and IOS measurements were collected. The Korean versions of the modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and an environmental questionnaire were used for screening and were answered by the parents (21–23). The two study questionnaires comprised of items that investigated three

main areas: (1) general characteristics including name, sex, date of birth, height, and weight; (2) a history of symptoms suggestive of asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and food allergy as in the original ISAAC questionnaire; and (3) environmental factors associated with allergic disease. All study procedures were conducted by trained researchers under the supervision of pediatric allergy specialists. IOS was performed using the Master Screen Spirometry-IOS Digital System (Jaeger Company, Würtzburg, Germany) by the same experienced operator for all children according to American Thoracic Society (ATS)/ERS recommendations (24). Children breathed normally into a mouthpiece for a short period of time during which a loudspeaker delivered a pulse-shaped pressure flow excitation to the respiratory system. Rrs (R5, R10, R15, R20, R25, R35) and Xrs (X5, X10, X15, X20, X25, X35) at 5, 10, 15, 20, 25, 35 Hz, total Zrs, and resonance frequency (RF, the frequency where the reactance equals zero) were recorded. The bronchodilator response (BDR) was assessed by repeating the measurements 15 min after inhalation of 200 μg salbutamol and was calculated as absolute change and relative change (percentage change from baseline) in IOS variables. Statistical Analysis All statistical analyses were performed using SPSS software 18.0 (SPSS Inc., Chicago, IL, USA). The t-test was used to compare variables between the two groups (healthy controls vs. excluded children and healthy controls vs. children with asthma). The reference equations for IOS variables were calculated using linear regression analysis. Risk factor analysis for asthma was conducted using multivariate logistic analysis. A p-value < .05 was considered statistically significant. R ESULTS Characteristics of the Subjects IOS measurements were performed on 390 children aged 3.50–7.17 years. We defined 161 children as healthy controls based on the exclusion criteria. The mean age of healthy controls was 5.48 0.71 years. The 229 excluded children included 33 children with diagnosed asthma, which gives an asthma prevalence of 8.5%. The 33 children with diagnosed asthma were children who had answered “yes” to the question “Have you ever been diagnosed to have asthma by a physician?” We compared the demographic characteristics of healthy controls and the excluded children (Table 1). There was a gender difference with more girls than boys in the healthy controls (p-value ¼ .044). There were no differences between the two groups in mean age, anthropometric data (weight, height, and BMI), personal history of diagnosed allergic rhinitis or atopic dermatitis, and parental history of allergic disease. Reference Values for IOS in Young Healthy Children The mean and standard deviation of Rrs and Xrs, total Zrs, and RF are shown in Table 2. In healthy controls, the

IMPULSE OSCILLOMETRY IN THE DIAGNOSIS OF ASTHMA

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T ABLE 1.—Characteristics of the healthy controls and excluded children. Subjects Number Mean age (years) Sex Male Female Height Weight BMI Diagnosis of allergic rhinitis Diagnosis of atopic dermatitis Parental history of allergic disease Diagnosis of asthma Diagnosis of allergic rhinitis Diagnosis of atopic dermatitis

Healthy controls

Excluded children

161 5.48 0.71

229 5.46 0.72

67 (41.6%) 94 (58.4%) 112.87 7.03 20.39 3.62 15.94 1.83 40/158 (25.3%) 56/160 (35.0%) 84/160 (52.5%) 7/160 (4.4%) 79/160 (49.4%) 14/160 (8.8%)

119 (52.0%) 110 (48.0%) 112.49 6.51 20.48 3.89 16.08 1.95 67/227 (29.5%) 77/227 (33.9%) 102/228 (44.7%) 11/228 (4.8%) 92/228 (40.4%) 30/228 (13.2%)


Note: BMI, body mass index.

F IGURE 1.—Respiratory resistance at 5 Hz as a function of height, including the regression line and 95% prediction interval.

baseline R5 and relative BDR change were 1.030 0.189 kPa/L/s and 11.803 9.562%, respectively, and the baseline X5 and relative BDR change were 0.350 0.118 kPa/L/s and 13.474 28.368%, respectively. In the BDR assessment, Rrs all decreased, and Xrs all increased significantly when p-values were calculated using a paired t-test (p < .001 except for X35, p ¼ .003). Linear regression analysis indicated that IOS variables were most strongly associated with height. The relationships between height and R5 or X5 were as follows: R5 ¼ 2.358–0.012 height (cm), coefficient of determination (R2) ¼ 0.191; X5 ¼ –0.921 þ 0.005 height (cm), R2 ¼ 0.091) (Figures 1 and 2). The reference equation of R5 as a function of height was compared with previous studies (Figure 3) (8–14). Multiple linear regression analysis of IOS variables was performed taking into account height, weight, and age. Height was the best independent factor for most of the IOS variables (except for R10 ¼ age). The reference equations for IOS variables are shown in Table 3. The reference equation for R5 was: R5 ¼ 2.242 – 0.008 height – 0.005 age, R2 ¼ 0.213. Sex, personal history of diagnosed allergic rhinitis or

F IGURE 2.—Respiratory reactance at 5 Hz as a function of height, including the regression line and 95% prediction interval.

T ABLE 2.—IOS measurements in healthy controls.

R5 R10 R15 R20 R25 R35 X5 X10 X15 X20 X25 X35 Z5 RF

Pre-bronchodilator

Post-bronchodilator

Change

Mean

SD

Mean

SD

Mean

SD

Mean

SD

1.030 0.871 0.796 0.740 0.734 0.859 0.350 0.185 0.123 0.030 0.082 0.259 1.093 20.973

0.189 0.159 0.140 0.133 0.128 0.135 0.118 0.087 0.081 0.062 0.053 0.054 0.206 2.935

0.903 0.773 0.723 0.683 0.678 0.802 0.288 0.128 0.064 0.014 0.115 0.313 0.952 18.806

0.167 0.137 0.123 0.116 0.112 0.120 0.106 0.069 0.065 0.054 0.052 0.215 0.178 3.268

0.127 0.098 0.073 0.056 0.056 0.057 0.062 0.057 0.059 0.044 0.033 0.054 0.141 2.167

0.109 0.080 0.076 0.079 0.080 0.088 0.112 0.059 0.055 0.028 0.029 0.211 0.108 1.609

11.803 10.829 8.680 6.972 7.029 6.095 13.474 25.946 – – – – 12.467 10.457

9.562 7.935 8.327 9.451 9.724 9.103 28.368 50.682 – – – – 8.696 7.841

Note: n ¼ 161; SD, standard deviation; units, kPa/L/s (for Rrs, Xrs, and Z5) or Hz (for RF).

Change (%)


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F IGURE 3.—Comparison of reference equations for respiratory resistance at 5 Hz (Klug 1998, Hellinckx 1998, Park 2011, Malmberg 2002, and this study) or 4 Hz (Stanescu 1979, Solymar 1985, and Hantos 1985) between this study and previous studies in young healthy children. T ABLE 3.—Reference equations for IOS variables.

R5 R10 R15 R20 R25 R35 X5 X10 X15 X20 X25 X35 Z5 RF

Equation

R2

RSD

P-value

2.242 – 0.008 H – 0.005 A 1.835 – 0.005 A – 0.005 H 1.633 – 0.005 H – 0.004 A 1.518 – 0.007 H 1.430 – 0.006 H 1.571 – 0.006 H 0.921 þ 0.005 H 0.813 þ 0.007 H – 0.006 W 0.643 þ 0.006 H – 0.006 W 0.396 þ 0.002 H þ 0.001 A 0.232 þ 0.003 H 0.121 þ 0.001 H 2.403 – 0.009 H – 0.005 A 39.569 – 0.165 H

0.213 0.218 0.186 0.132 0.115 0.108 0.091 0.147 0.114 0.177 0.136 0.025 0.200 0.156

0.168 0.140 0.126 0.124 0.121 0.128 0.113 0.081 0.077 0.056 0.049 0.054 0.184 2.705