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Theoretical non-linear modeling of exhaled nitric oxide has revealed extended flow-independent parameters that could explain where or how nitric oxide is produced in the lung and transferred to the airway gas stream. We aimed to evaluate the associations of bronchial hyperresponsiveness and bronchodilator response with extended flow-independent nitric oxide parameters. Nitric oxide (30, 50, 100, 200 ml s -1 ) was measured in 432 children with asthma on the same day with either a methacholine challenge test (n = 156) or spirometry with bronchodilator (n = 276; 96 previously diagnosed with asthma and treated with inhaled corticosteroid, 37 with acute exacerbation treated with systemic corticosteroid). We additionally included 107 healthy controls for evaluation of the suitability of the non-linear model of exhaled nitric oxide. In asthmatic children, the response-dose ratio of the methacholine challenge test was correlated positively with bronchial nitric oxide (JawNO) and airway tissue nitric oxide (CawNO) (r = 0.367 and r = 0.299, respectively; both p < 0.001), while the change in forced expiratory volume in 1 s, representing bronchodilator response, was associated positively with only JawNO (r = 0. 216, p < 0.001). On multiple regression, JawNO, CawNO, and the diffusing capacity of NO (DawNO) were significantly associated with the response-dose ratio. JawNO was significantly associated with change in forced expiratory volume in children with stable asthma but not those with acute exacerbation. Our findings suggest that bronchial hyperresponsiveness is associated with CawNO while factors other than airway tissue inflammation could affect bronchodilator response in children with mild asthma. Systemic corticosteroid use during asthma exacerbation could affect the association of bronchodilator response with extended nitric oxide parameters.

Objective: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and obstruction. AHR to stimuli that indirectly cause bronchial smooth muscle (BSM) contractions via release of endogenous mediators is thought to better reflect airway inflammation than AHR to stimuli that act directly on BSM. Fractional exhaled nitric oxide (FeNO) is a useful parameter for noninvasive clinical airway inflammation assessments. Accordingly, this study aimed to examine the relationships of mannitol and methacholine challenge test outcomes with FeNO and the influence of inhaled corticosteroid treatment in children with asthma., Methods: One hundred thirty-four asthmatic children (89 males; ages: 5-17 years, median: 9 years) underwent spirometry, FeNO measurement, serum total/specific IgE testing, and blood eosinophil count. All subjects were challenged with mannitol dry powder (MDP; AridolH, Pharmaxis, Australia) and methacholine at 7-day intervals. Data of steroid-treated and steroid-naïve children were compared., Results: Positive responses to MDP and methacholine challenge tests were observed in 74.6% and 67.2% of total subject group, respectively, and 72 children had positive response to both challenge tests. The median FeNO level, response-dose ratio (RDR) of PC 20 methacholine, and RDR of PD 15 MDP were significantly higher in the steroid-treated group than in the steroid-naïve group (p < 0.001, 0.226, and 0.004, respectively). FeNO levels associated significantly with PD 15 MDP and RDR PD 15 MDP in total subject populations (p = 0.016 and 0.003, respectively); however, a significant correlation between FeNO and RDR PD 15 MDP was observed only in the steroid-naïve group., Conclusions: Compared with AHR to methacholine, AHR to MDP more closely reflected the level of FeNO in steroid-naïve asthmatic children.

Background: Thymus and activation-regulated chemokine (TARC), a member of the CC chemokine family, plays a crucial role in Th2-specific inflammation. We aimed to determine the concentration of sputum TARC in children with asthma and eosinophilic bronchitis (EB) and its relation with eosinophilic inflammation, pulmonary function, and bronchial hyper-responsiveness., Methods: In total, 90 children with asthma, 38 with EB, and 45 control subjects were enrolled. TARC levels were measured in sputum supernatants using an ELISA. We performed pulmonary function tests and measured exhaled fractional nitric oxide, eosinophil counts in blood, and sputum and serum levels of total IgE in all children., Results: Sputum TARC levels were significantly higher in children with asthma than in either children with EB (p=0.004) or the control subjects (p=0.014). Among patients with asthma, sputum TARC concentration was higher in children with sputum eosinophilia than in those without sputum eosinophilia (p=0.035). Sputum TARC levels positively correlated with eosinophil counts in sputum, serum total IgE levels, exhaled fractional nitric, and the bronchodilator response. Negative significant correlations were found between sputum TARC and FEV1/FVC (the ratio of forced expiratory volume in one second and forced expiratory vital capacity) or PC 20 (the provocative concentration of methacholine causing a 20% decrease in the FEV 1 )., Conclusion: Elevated TARC levels in sputum were detected in children with asthma but not in children with EB. Sputum TARC could be a supportive marker for discrimination of asthma from EB in children showing characteristics of eosinophilic airway inflammation., (Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor and an acute-phase protein. It has gained attention as a new biomarker reflecting tissue inflammation and damage in a variety of diseases. Aim of this study is to investigate the role of PTX3 in childhood asthma.In total, 260 children (140 patients with asthma and 120 controls) were enrolled. PTX3 levels were measured in sputum supernatants using enzyme-linked immunosorbent assay test. We performed spirometry and methacholine challenge tests and measured the total eosinophil count and the serum levels of total IgE and eosinophil cationic protein (ECP) in all subjects.Sputum PTX3 concentration was significantly higher in children with asthma than in control subjects (P < 0.001). Furthermore, sputum PTX3 levels correlated with atopic status and disease severity among patients with asthma. A positive significant correlation was found between sputum PTX3 and the bronchodilator response (r = 0.25, P = 0.013). Sputum PTX3 levels were negatively correlated with forced expiratory volume in 1 second (FEV1) (r = -0.30, P = 0.001), FEV1/forced vital capacity (FVC) (r = -0.27, P = 0.002), and FEF25-75 (r = -0.392, P < 0.001), which are indicators of airway obstruction and inflammation. In addition, the PTX3 concentration in sputum showed negative correlations with post-bronchodilator (BD) FEV1 (r = -0.25, P < 0.001) and post-BD FEV1/FVC (r = -0.25, P < 0.001), which are parameters of persistent airflow limitation reflecting airway remodeling.Sputum PTX3 levels increased in children with asthma, suggesting that PTX3 in sputum could be a candidate molecule to evaluate airway inflammation and remodeling in childhood asthma., Competing Interests: There are no financial or other issues that might lead to conflict of interest.

Background: We aimed to systematically review observational studies investigating the relationship between vitamin D levels and allergic rhinitis (AR)., Methods: Studies were selected if they evaluated the relationship between vitamin D levels and AR, and included studies that evaluated other allergic conditions if those studies also contained data on AR. We assessed the incidence and prevalence of AR according to vitamin D levels and compared vitamin D levels in patients with AR to levels in controls., Results: Nineteen studies were selected. Of these, only seven focused solely on AR; 10 studies evaluated the other allergic diseases as well as AR; and two studies evaluated asthma primarily, but also included data on patients with AR. The pooled odds ratios (ORs) for the incidence of AR according to vitamin D levels were not statistically significant for either children or adults. Lower vitamin D levels were associated with a higher AR prevalence only in children (pooled OR [95% confidence interval (CI)], 0.75 [0.58, 0.98]). The pooled mean vitamin D level in patients with AR was lower than that of controls only in children (pooled means difference [95% CI], -7.63 [-13.08, -2.18])., Conclusions: Prior vitamin D levels were not related to developing AR, but lower vitamin D levels were associated with a higher AR prevalence only in children. There is insufficient evidence to support vitamin D supplementation for AR prevention. However, physicians should consider evaluating patients for vitamin D deficiency during AR management, especially in children., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Clusterin is a sensitive cellular biosensor of oxidative stress and has been studied as a biomarker for inflammation-associated diseases. Clusterin levels in childhood asthma have not been evaluated., Objectives: (1) To evaluate sputum clusterin levels in children with asthma compared to a control group. (2) To assess the relationships between sputum clusterin levels and airway inflammation, pulmonary function, and bronchial hyperresponsiveness., Methods: This study included 170 children aged 5-18 years with stable asthma (n = 91), asthma exacerbation (n = 29), or no asthma (healthy controls; n = 50). Induced sputum, pulmonary function, and methacholine challenge tests were performed. Stable asthma was classified into two groups according to the severity. Clusterin levels in sputum were measured using an enzyme-linked immunosorbent assay., Results: Children with stable asthma had a higher clusterin level than healthy controls [4540 (3872-5651) pg/mL vs. 3857 (1054-4369) pg/mL, P < 0.001]. The clusterin level was also more elevated in eosinophil-dominant sputum than in non-eosinophilic sputum in stable asthma [5094 (4243-6257) pg/mL vs. 4110 (1871-4839) pg/mL, P = 0.0017]. Clusterin levels were associated with asthma severity. Paradoxically, clusterin levels were lower during asthma exacerbation than in stable asthma [1838 (350-4790] pg/mL vs. 4540 (3872-5651) pg/mL, P < 0.001]. Clusterin levels were strongly correlated with the methacholine concentration that caused a 20% decrease in the forced expiratory volume in 1 s (r = -0.617, P < 0.001); there was no significant correlation between clusterin levels and other pulmonary function parameters., Conclusions and Clinical Relevance: Clusterin levels were altered in children with stable asthma and asthma exacerbation because of its antioxidant and anti-inflammatory effects. Clusterin may be a marker that reflects airway inflammation and severity of symptoms, and it can be used in the assessment and management of childhood asthma., (© 2015 John Wiley & Sons Ltd.)

Purpose: High-sensitivity assays enabled the identification of C-reactive protein (hs-CRP) at levels that were previously undetectable. We aimed to determine if hs-CRP could reflect airway inflammation in children, by comparing hs-CRP with spirometry and impulse oscillometry (IOS) parameters and symptomatic severities., Materials and Methods: A total of 276 asthmatic children who visited Severance Children's Hospital from 2012-2014 were enrolled. Serum hs-CRP and pulmonary function tests were performed on the same day. Patients were divided into hs-CRP positive and negative groups (cut-off value, 3.0 mg/L)., Results: Of the 276 asthmatic children [median age 7.5 (5.9/10.1) years, 171 boys (62%)], 39 were hs-CRP positive and 237 were negative. Regarding spirometry parameters, we observed significant differences in maximum mid-expiratory flow, % predicted (FEF₂₅₋₇₅) (p=0.010) between hs-CRP positive and negative groups, and a negative correlation between FEF₂₅₋₇₅ and hs-CRP. There were significant differences in the reactance area (AX) (p=0.046), difference between resistance at 5 Hz and 20 Hz (R5-R20) (p=0.027), resistance at 5 Hz, % predicted (R5) (p=0.027), and reactance at 5 Hz, % predicted (X5) (p=0.041) between hs-CRP positive and negative groups. There were significant positive correlations between hs-CRP and R5 (r=0.163, p=0.008), and X5 (r=0.164, p=0.007). Spirometry and IOS parameters had more relevance in patients with higher blood neutrophil levels in comparison to hs-CRP., Conclusion: Hs-CRP showed significant correlation with FEF₂₅₋₇₅, R5, and X5. It can reflect small airway obstruction in childhood asthma, and it is more prominent in neutrophil dominant inflammation.

Effect of breastfeeding on the protective effect on asthma has been studied extensively but remains controversial. Studies regarding the effect of breastfeeding on lung function have also been conflicting. The aim of this study was to determine the influence of breastfeeding on lung function in asthmatic children. We included 555 patients who visited Severance Children's Hospital Allergy Clinic with asthma. Pulmonary function, its bronchodilator response (BDR), fractional nitric oxide, and sputum eosinophils were measured. Parents completed questionnaires with information on feeding practices, family history of allergic disease, exposure to tobacco smoke, and presence of pets. Breastfeeding duration was categorized as not breastfed, breastfed <6 months, and breastfed ≥6 months. Within the asthma group, we stratified by atopic sensitization. We also investigated whether exclusivity of breastfeeding had any modifying effect on lung function. In the asthma group, ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) significantly increased according to breastfeeding duration: 86.6 ± 8.7 for not breastfed group, 87.2 ± 8.6 for <6 months group, and 88.8 ± 7.7 for ≥6 months group. Within asthma group, only the nonatopic subjects showed a significant increase of FEV1/FVC, maximal midexpiratory flow, and decrease of maximal response to BD according to breastfeeding duration. Increase in FEV1/FVC was seen in the exclusive breastfeeding for ≥6 months group compared with those partially breastfed but FVC was significantly lower in those exclusively breastfed <6 months group compared with those partially breastfed. BDR decreased with breastfeeding duration in the nonatopic asthma group. In conclusion, longer duration of breastfeeding appears to have a favorable effect on lung function in asthmatic children, especially in nonatopic subjects.

Objective: We aimed to evaluate the association between eosinophilic inflammation in induced sputum and pulmonary function and persistent airflow limitation in children., Methods: A total of 92 asthmatic children and 72 controls were enrolled in this study. Eosinophil count (%) and eosinophil cationic protein (ECP) levels were measured in induced sputum. We performed spirometry and a methacholine challenge test, and measured total eosinophil count, total serum IgE, and serum ECP in all subjects., Results: Asthmatic children had significantly higher levels of sputum eosinophils (9% vs. 0%; P < 0.001) and sputum ECP (2.3 ± 0.7 vs. 1.6 ± 0.6 log µg/L, p < .001) than controls. Sputum ECP levels showed a significant negative correlation with post-bronchodilator (post-BD) FEV(1) (r = -0.307; p = .001) and post-BD FEV(1)/FVC (r = -0.286; p = .002), whereas sputum eosinophils showed no correlation with post-BD FEV(1) and post-BD FEV(1)/FVC. However, no significant differences in sputum ECP and sputum eosinophil counts were observed in asthmatic children with and without persistent airflow limitation., Conclusions: Our findings suggest that sputum eosinophilic inflammation, especially ECP, is associated with pulmonary function and persistent airflow limitation, which is manifested by low post-BD FEV(1)/FVC.

Aim: Asthma is a heterogeneous and complex chronic inflammatory disease of the airways. Asthma can be classified as eosinophilic asthma (EA) or noneosinophilic asthma (NEA). We investigated whether children with EA manifest different clinical characteristics than those with NEA., Methods: We enrolled 288 steroid-naive asthmatic children and classified them, based on the cell counts in induced sputum, into EA (158 children) and NEA (89 children) groups., Results: No significant differences were observed between the groups with regard to age, sex, family history of atopy, secondary smoking or asthma exacerbations. Moderate-to-severe asthma was more frequent in the EA group than in the NEA group. Blood eosinophil counts and serum eosinophil cationic protein were higher in EA patients than in NEA patients. The forced expiratory volume in 1 sec was lower in children with EA than in those with NEA (% of predicted value, 88.6 ± 18.5 vs. 93.6 ± 15.6, p < 0.05). The sputum eosinophil (in EA) and neutrophil (in NEA) counts increased with increasing asthma severity., Conclusion: Airway inflammation, especially eosinophilic inflammation, was associated with asthma severity and reduced pulmonary function in children., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

Objectives: The aim of the present study was to compare the validity of the International Study of Asthma and Allergies in Childhood (ISAAC) written (WQ) and audiovisual questionnaires (AVQ 3.0) in two age-groups (10-12 and 13-15 years, respectively)., Methods: The 13-15 year olds performed the self-completed the WQ and AVQ on the same day. The 10-12 year olds performed the self-completed the AVQ and the parent-completed WQ was completed by their parents. The methacholine challenge test was conducted in 10-12 year olds from one elementary school., Results: In 10-12 year olds, the AVQ detected a generally higher prevalence of asthma symptoms than WQ. In 13-15 year olds, this was reversed. In 10-12 year olds, poor agreement was found between the parent-completed WQ and the self-reported AVQ. In 13-15 year olds, moderate agreement was found between the self-reported WQ and AVQ. Low sensitivity was found, in predicting bronchial hyper-responsiveness (BHR) for all questions of both WQ and AVQ in 10-12 year olds. However, the AVQ had slightly higher sensitivity than WQ, with the exception of wheeze ever, although it was not statistically significant., Conclusion: The ISAAC AVQ may be another effective instrument for assessing the prevalence of asthma symptoms in children aged 10-12 years, whereas the parent-reported-WQ may underestimate the prevalence of asthma symptoms in this age-group., (Copyright © 2011 Wiley Periodicals, Inc.)

The purpose of this study was to investigate the association between body mass index (BMI) and the prevalence of wheeze using nation-wide cross-sectional study in Korean children. Total 50,200 children from 427 elementary schools were randomly selected according to residential areas (metropolitan, provincial, rural, and industrial areas) by the cluster sampling method. The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires were used to measure the prevalence of wheeze. Among 31,026 respondents, 25,322 were analyzed. BMI was classified into quartiles based on BMI-for-age percentile. In all residential areas, pets at home and visible mold or moisture were associated with an increased prevalence of wheeze in both genders. However, other living environment factors were not consistently associated among residential areas and gender. Among girls, lowest BMI was negatively associated with prevalence of wheeze and highest BMI was positively associated in all residential areas. In multilevel logistic regression analysis, environmental tobacco smoking exposure, pets at home, visible mold or moisture, and being in the lowest and highest BMI quartile were significantly associated with the prevalence of wheeze in both genders. BMI has become an important risk factor for asthma symptoms among Korean children.

Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.

Asthma and atopy have a complex background that may result from the interaction of genes and the environment. Interleukin (IL)-10 is known to play various roles in immune-regulating and anti-inflammatory responses. The aim of this study was to evaluate the possible effect of the IL-10 promoter polymorphisms on susceptibility to childhood asthma. We recruited 333 patients with atopic asthma, 55 with nonatopic asthma, and 248 normal controls. We performed a genetic association study of three genetic polymorphisms (IL-10 -1082A>G, IL-10 -819T>C, and IL-10 -592A>C) of the IL-10 promoter. There was no difference between atopic asthma, nonatopic asthma, and normal controls with respect to allele, genotype, or haplotype frequencies of these IL-10 polymorphisms. However, the -1082A>G polymorphism and ATA haplotype in the IL-10 promoter gene were associated with airway hyper responsiveness (AHR) and the -819T>C, -592A>C, and ATA and ACC haplotypes were also shown to be related to serum eosinophil cationic protein (ECP). Our results suggest that the polymorphisms within the IL-10 promoter may have a disease-modifying effect in the asthmatic airway.

Background: To date, there is little evidence to support an association between symptoms of pediatric allergic disorders and psychosocial factors in the general population, particularly in Asian countries. The current study aims to investigate the relationship between psychosocial factors and symptoms of allergic disorders and to investigate the association between behavior problems and biomarkers of atopy., Methods: A cross-sectional survey of parental responses to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and the Korean version of the Child Behavior Checklist (CBCL) was conducted from one elementary school in Seoul, Korea. Skin prick tests for 18 major allergens were also performed., Results: A total of 780 children with valid CBCL surveys were included in the study. Externalizing problems were significantly larger in children with asthmatic symptoms, while internalizing problems were significantly larger in children with symptoms of both asthma and allergic rhinitis. Social adaptations were significantly lower in children with symptoms of allergic rhinitis and atopic dermatitis. Boys with more positive allergens via the skin prick tests showed larger internalizing problems., Conclusions: While school children with allergic symptoms have been reported to have more difficulties with psychosocial adaptation, the patterns of psychosocial problems varied somewhat according to the types of atopic disorder. There was a positive relationship between atopy and behavior problems, especially in boys., (Copyright © 2010 S. Karger AG, Basel.)

Purpose: Classic cystic fibrosis is now known part of cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders. These include a wide spectrum, from multi-system disorders, such as cystic fibrosis, to mono-symptomatic conditions, such as chronic pancreatitis or congenital bilateral absence of the vas deferens. However, respiratory disease is considered typical for the multi system disorder, cystic fibrosis, and is the major cause of morbidity and mortality. The purpose of this study was to evaluate the potential effects of CFTR gene mutations in Korean children with asthma., Materials and Methods: We selected 14 mutations identified in Korea and each of the 48 children with and without asthma were genotyped for the case-control study., Results: No significant differences were found in genotype and allele frequencies of the 9 polymorphisms observed between the non-asthma and asthma groups. In a haplotype determination based on a Bayesian algorithm, 8 haplotypes were assembled in the 98 individuals tested. However, we also did not find any significant differences in haplotype frequencies between the non-asthma and asthma groups., Conclusion: We have concluded that this study did not show any evidence in support of providing that CFTR genetic variations significantly contribute to the susceptibility of asthma in Korean children.

Recently the prevalence of both asthma and obesity have increased substantially in many countries. The aim of this study was to evaluate the role of retinol-binding protein (RBP) 4 in childhood asthma and its association with atopy markers, pulmonary function, and bronchial hyperresponsiveness in relation to obesity. We studied 160 children between the ages 6 to 10 yr, including 122 asthmatics and 38 controls. The body mass index, pulmonary function tests, and methacholine challenge tests were measured on the same day. Total eosinophil count, serum total IgE, serum eosinophil cationic protein, and serum RBP4 were measured in all subjects. There was no difference in serum RBP4 levels between the asthmatics and the control group. In all subjects or subgroups, serum RBP4 was not associated with total eosinophil count, serum total IgE, serum eosinophil cationic protein, or PC(20). There was no relationship between serum RBP4 and pulmonary function in female asthmatics. Forced expiratory volume in 1 second/forced vital capacity (FVC) and forced expiratory flow between 25% and 75% of FVC contributed to serum RBP4 in male asthmatics. Our findings show an association between RBP4 and pulmonary function in prepubertal male asthmatics. This relationship may indirectly affect the high prevalence of childhood asthma in males.

Introduction: IgE-dependent activation of mast cells and basophils through the high-affinity IgE receptor (Fc(epsilon)R1) is involved in the pathogenesis of allergen-induced immune responsiveness in atopic disease including bronchial asthma., Materials and Methods: We genotyped 650 children for allelic determinants at two polymorphic sites, -109T/C and E237G, in the Fc(epsilon)R1beta gene by SNP-IT assays using the SNP stream 25K system., Results: Distributions of the genotype and allele frequencies of Fc(epsilon)R1beta -109T/C and E237G polymorphisms were significantly associated with atopy (P < 0.05) and elevated serum IgE levels. However, differences in the E237G polymorphism did not reach statistical significance after adjustment for multiple comparisons. The genotypes TC or CC at -109T/C were associated with decreased forced expiratory flow(25-75%) in children with asthma (P < 0.05), but this did not reach statistical significance after correction for multiple comparisons. In addition, haplotype 1 (T-A) was associated with atopy susceptibility (P = 0.0069). Analysis of genotype distributions of haplotypes demonstrated a significantly lower PC(20) for homozygous -/- diploids compared with homozygous Ht1/Ht1 (P = 0.0261)., Conclusion: Polymorphisms in the Fc(epsilon)R1beta gene confer susceptibility to atopy in Korean children and may have a disease-modifying effect on airways of asthmatic patients.

Background: Amphiregulin, a member of the epidermal growth factor family, has been shown to promote the growth of fibroblasts, to be associated with the T-helper type 2 cell adaptive immune response, and to up-regulate mucin gene expression. We aimed to determine whether sputum amphiregulin is expressed at elevated levels in patients with asthma or eosinophilic bronchitis (EB), and whether it is associated with eosinophilic inflammation, pulmonary function, and bronchial hyperresponsiveness in children., Methods: A total of 117 children with asthma, 77 with EB, and 84 control subjects were enrolled in this study. Amphiregulin and eosinophil cationic protein (ECP) levels were measured in sputum supernatants. We performed pulmonary function and methacholine challenge tests while measuring total eosinophil count, and serum levels of total IgE and ECP in all children., Results: The children with asthma had significantly higher levels of sputum amphiregulin (mean, 10.80 pg/mL; range, 4.07 to 38.75 pg/mL) than both the children with EB (mean, 5.76 pg/mL; range, 0.61 to 21.65 pg/mL; p = 0.013) and the control subjects (mean, 6.56 pg/mL; range, 0.51 to 17.98 pg/mL; p = 0.003). Sputum amphiregulin levels positively correlated with levels of sputum eosinophils (gamma = 0.221; p = 0.007) and sputum ECP (gamma = 0.601; p < 0.0001). Negative significant correlations were found between sputum amphiregulin and FEV(1) (gamma = -0.181; p = 0.006) or post-bronchodilator therapy FEV(1) (gamma = -0.233; p = 0.002). In children with asthma who were not receiving any controller medications, sputum amphiregulin level was negatively correlated with the provocative concentration of methacholine causing a 20% fall in FEV(1) (r = -0.398; p = 0.008)., Conclusions: Our findings suggest that childhood asthma is associated with sputum amphiregulin, whereas EB is not, and that sputum amphiregulin would be a supportive marker of airway inflammation in asthma.

Impulse Oscillometry (IOS) was developed as a tool to measure lung function, and as it only requires passive cooperation, it has been successfully used in younger children. The aim of this study was to assess the utility of IOS compared to conventional spirometry for lung function measures in asthmatic Korean children aged 3 to 6 yrs. Total serum IgE levels, total eosinophil counts, and specific IgE levels were measured in 77 children with asthma and 55 control subjects. IOS and spirometry were performed in the children before and after bronchodilator administration. Asthmatic children significantly differed from control subjects in baseline resistance at 10 Hz and in their IOS-assessed bronchodilator responses through a Delta resistance at 5 Hz (mean, -27.4% vs. -13.1%; p = 0.002), 10 Hz (mean, -20.4% vs. -11.5%; p = 0.012), 20 Hz (mean, -16.4% vs. -9.4%; p = 0.016), and 35 Hz (mean, -17.2% vs. -10.2%; p = 0.020). Conventional spirometry did not show statistically significant findings. Asthmatic children significantly differed from control subjects in IOS-assessed bronchodilator response through a Delta resistance at 5 Hz, both in atopic children and in non-atopic children. For atopic children, atopic asthmatic children (n = 58) also significantly differed from atopic controls (n = 30) in baseline resistance at 10 Hz, 20 Hz, 35 Hz and impedance and in IOS-assessed bronchodilator responses through a Delta resistance at 10 Hz and 35 Hz. There were some significant correlations between bronchodilator responses of spirometric parameters and IOS parameters. IOS is useful diagnostic tool in early asthma development and might be a helpful objective outcome measure of early interventions.

Although the prevalences of asthma and obesity are increasing substantially in recent decades, very little is known about the possible association between them. We evaluated the roles of leptin, adiponectin, and resistin, which are adipokines produced by adipose tissue, on childhood asthma, and their association with pulmonary function and bronchial hyperresponsiveness. We studied 149 atopic asthmatic children, 37 non-atopic asthmatic children, and 54 healthy children. Body mass index was calculated using height and weight, which were measured on the same day that pulmonary function tests and methacholine challenge tests were performed. Skin prick tests were performed, and total eosinophil count, total serum immunoglobulin E (IgE), serum eosinophil cationic protein, leptin, adiponectin, and resistin were measured in all subjects. Atopic asthmatics had lower resistin levels compared with non-atopic asthma and control groups, but leptin and adiponectin did not show any difference among these three groups. Resistin demonstrated positive correlation with methacholine PC(20) and negative correlations with eosinophil count and serum total IgE. Leptin and adiponectin showed associations with forced expiratory volume in 1 s or forced expiratory flow between 25-75%. Multiple regression analysis revealed that resistin was a significant predictive factor for asthma. There was no direct association between asthma and leptin or adiponectin. Our findings suggest that resistin may play a negative predictive role in asthma. Adiponectin and leptin showed close associations with pulmonary function and may have disease-modifying effects in children with asthma.

Background: TNF-alpha and IL-13, two pivotal pro-inflammatory cytokines, are increased in asthmatic airways and may be linked to asthma susceptibility and/or bronchial hyperresponsiveness (BHR)., Objective: We investigated the association between the TNF-alpha-308G/A polymorphism and asthma susceptibility or asthma-related phenotypes in Korean children with asthma, and tested for a combined effect with IL-13 polymorphisms., Methods: Asthmatic children (n=719) and non-atopic healthy control children (n=243) were evaluated for asthma phenotypes including total serum IgE and BHR to methacholine. Genotypes were determined by PCR-restriction fragment length polymorphism analysis., Results: The allele frequency of TNF-alpha-308A in asthmatics (14.1%) was higher than that in control children [8.7%, odds ratio (OR) 1.72, 95% confidence interval (CI) 1.05-2.82]. Significantly lower PC(20) values were found in asthmatic children carrying one or two copies of the TNF-alpha risk allele (-308A) vs. those homozygous for the common allele (P=0.026). Combined analysis revealed that atopic asthmatic children co-inherited the risk alleles of TNF-alpha-308G/A and IL-13 +2044G/A more frequently than control children (aOR 1.91, 95% CI 1.00-3.65), and asthmatic children co-inheriting both risk alleles had significantly lower PC(20) values vs. asthmatic children homozygous for the common alleles (P=0.024)., Conclusion: The TNF-alpha promoter polymorphism (-308G/A) may be associated with asthma susceptibility and BHR in Korean children with asthma. In addition, there appears to be a synergistic effect between the TNF-alpha promoter polymorphism and an IL-13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.

Regulated upon activation in normal T cells, expressed, and secreted (RANTES) protein is abundantly expressed during atopic asthma, suggesting that it is an important mediator of this disease. The aim of this study was to evaluate the possible role of RANTES promoter polymorphisms in children with asthma. We genotyped 271 children with atopic asthma, 55 children with nonatopic asthma, and 253 control children for allelic determinants at two polymorphic sites in the promoter region at positions -403G>A and -28C>G by restriction fragment length polymorphism methods. There was no significant difference in genotype and allele frequencies of the RANTES -403G>A and -28C>G polymorphisms when the atopic asthma, nonatopic asthma, and control groups were compared. However, atopic asthmatic patients who were homozygous GG for the RANTES -28C>G tended to have lower PC20 methacholine than those carrying the wild genotype. In addition, a significantly lower PC20 was demonstrated for the homozygous haplotype -403A/-28G in asthmatic children. The polymorphisms within the RANTES promoter may have a disease-modifying effect in Korean children with asthma.

Aim: In certain patients, such as young children or individuals with cerebral palsy or severe mental retardation, it is difficult to perform forced expiratory manoeuvres to measure expiratory flow volume. In such cases, we could evaluate obstructive lung disease through the measurement of airway resistance instead of expiratory flow volume., Methods: In this study, we evaluated the correlation of Impulse Oscillometry (IOS) parameters with spirometry values and peak expiratory flow rate (PEFR) measurements to give coherence to IOS recordings in lung function exploration. Total serum IgE levels, total eosinophil counts and specific IgE levels were measured in 48 children with asthma and 66 control subjects, aged 7-15 years of age. IOS, spirometry and PEFR measurements were performed, as well as methacholine challenge. We further analyzed the correlations in atopic asthma, atopic control, nonatopic asthma and nonatopic control groups., Results: FEV(1) and PEFR showed a significant correlation with impedance and resistance (R) at 5, 10, 20 and 35 Hz, both in atopic asthmatic and in atopic control children. FVC also showed a correlation with impedance and R at 10, 20 and 35 Hz, both in atopic asthmatic and atopic control children. FEF(25-75%) did not show a correlation with resistances., Conclusion: FEV(1), FVC and PEFR were significantly correlated with IOS parameters, in both asthmatic and control subjects, especially for atopic children. IOS could be used as a suitable measure of lung function when spirometry and PEF cannot be performed.

Background: Asthma is a chronic inflammatory disease, characterized by airway inflammation, bronchial hyper-responsiveness, and airway obstruction. Although asthma induces partially reversible airway obstruction, obstruction can sometimes become irreversible. This may be a consequence of airway remodeling, which includes a number of structural changes, such as epithelial detachment, basement membrane (BM) thickening, smooth muscle hypertrophy, and new vessel formation. This study evaluated children with asthma for the presence of BM thickening., Methods: Eighteen children with asthma and 24 control subjects underwent flexible bronchoscopy with endobronchial biopsy. Light microscopy was used to measure BM thickness in paraffin-embedded biopsy sections. The association between BM thickening and age, sex, duration of asthma, asthma severity, FEV(1), FEV(1)/FVC, FEF(25-75%), methacholine PC(20), eosinophil count, and presence of atopy was examined., Results: Basement membrane thickness was greater in subjects with asthma (8.3 +/- 1.4 microM) than in control subjects (6.8 +/- 1.3 microM, P = 0.0008). Multiple regression analysis revealed that sex, FEV(1)/FVC, total IgE, and atopy (IgE for Dermatophagoides pteronyssinus >0.34 kUA/l) were significant predictive factors for BM thickness. There was no significant association between BM thickness and age, duration of asthma, FEV(1), FEF(25-75%), methacholine PC(20), eosinophil count, or asthma severity., Conclusions: Basement membrane thickening has been known to be present in children with asthma. In addition, we report an association between BM thickness and sex, FEV(1)/FVC, total IgE, and the presence of IgE specific to D. pteronyssinus.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T lymphocyte activation. The gene encoding CTLA-4 is a candidate gene for conferring susceptibility to allergic disease. The purpose of this study was to evaluate the potential effects of CTLA-4 gene polymorphisms in Korean children on asthma. We genotyped 272 children with atopic asthma, 54 children with nonatopic asthma (NAA), and 254 control children for allelic determinants at two polymorphic sites in the region at positions promoter - 318 C > T and exon 1 + 49 G > A using restriction fragment length polymorphism methods. As a result, allele and genotype frequencies of the CTLA-4 exon 1 + 49 G > A polymorphism were different to some extent between the atopic asthma children and the controls with P<0.05, which did not reach statistical significance after the correction of multiple comparisons. In addition, CTLA-4 + 49 G > A polymorphism was significantly associated with elevated serum IgE levels (P=0.01). Of the four haplotype, haplotype 1 (C-G) was only associated with atopic asthma susceptibility after the correction of multiple comparisons (P=0.01, OR=0.702, 95% CI= 0.541-0.911). Polymorphisms in the CTLA-4 gene likely confer susceptibility to atopic asthma in Korean children., ((c) 2007 Wiley-Liss, Inc.)

This study sought to evaluate the use of serum eosinophil-derived neurotoxin (EDN), which has been proposed as a marker of airway inflammation in asthma in the diagnosis and evaluation of the severity and bronchial hyperresponsiveness in childhood asthma. We studied 72 children with atopic asthma, 36 children with nonatopic asthma, and 43 healthy controls. Skin prick tests, pulmonary function tests, and methacholine challenge tests were performed, in addition to total eosinophil count, serum ECP, and EDN being measured in all subjects. EDN levels were significantly higher in the atopic asthma group than those in the nonatopic asthma group or control group (p < 0.001), as were ECP levels (p < 0.001). EDN levels differed more significantly among groups divided by asthma severity (p < 0.001) than did ECP levels for these groups (p < 0.05). For the groups divided according to bronchial hyperresponsiveness, both EDN and ECP levels were significantly different (p < 0.005 and p < 0.01, respectively). Significant correlations were found between EDN and PC(20) (gamma = -0.281; p < 0.001), between ECP and PC(20) (gamma = -0.274; p < 0.005), and between EDN and ECP (gamma = 0.443; p < 0.001). In conclusion, serum EDN, as another marker of eosinophilic inflammation together with ECP, may aid in the diagnosis of asthma, especially atopic asthma, and in the evaluation of the severity and bronchial hyperresponsiveness in childhood asthma.

Monosensitization differs both immunologically and clinically from polysensitization, and specific immunotherapy is more effective in patients sensitized only to a single pollen than in multiple-pollen sensitized patients. To further examine the differences between monosensitized and polysensitized allergies, allergic indices were examined in 68 monosensitized and 62 polysensitized patients with childhood asthma. Measurements included symptom scores, eosinophil counts, skin prick tests, serum total and specific IgE levels, and IL-10 levels, and were used to compare allergic indices between the two groups. Patients were followed for 18 months following immunotherapy to examine the effectiveness of the treatment. Symptom scores and total IgE levels were significantly higher in the polysensitized group than those in the monosensitized group (p<0.05). The levels of skin test response decreased significantly in both groups following immunotherapy. In the monosensitized group, symptom scores and specific IgE levels were significantly reduced after immunotherapy (p<0.05). In the polysensitized group, symptom scores were reduced after immunotherapy (p<0.05), but the degree of reduction was less than that of the monosensitized group (p<0.05). Moreover, in the polysensitized group, specific IgE levels after immunotherapy did not differ from that before immunotherapy. Serum IL-10 levels were not significantly increased after immunotherapy in either group. In conclusion, polysensitized patients tend to show higher allergic indices and immunotherapy might be less effective for these patients.

The increasing prevalence of asthma has coincided with an increase of body mass index (BMI) in both children and adults. We investigated the relationship between BMI and the symptom prevalence of asthma and the possible influences of dietary pattern. This was a community-based, cross-sectional study of 24,260 school children aged 6-12 years. Prevalences of asthma and potential confounding factors were assessed using a Korean version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire which was completed by parents. We analyzed the relationship between BMI and symptoms of asthma and the possible influences of dietary pattern. A significant positive association between high BMI and previous 12-month prevalence of wheeze remained in boys (adjusted odds ratio, 1.610; 95% confidence interval, 1.274-2.033) but not in girls. In addition, there were significant associations between high BMI and lifetime prevalence of wheeze, previous 12-month wheeze, exercise-induced wheeze, diagnosis, and treatment of asthma. There were significant associations between high BMI and previous 12-month wheeze regardless of breast-milk feeding or whole-milk feeding. Frequent intake of fresh seafood, fresh fruits, and vegetables was associated with reduced prevalence of current asthma symptoms and was also associated with decreased BMI. These results indicate that BMI may be an independent risk factor for the development of asthma symptoms in boys. Intake of fresh seafood, fresh fruit, and vegetables, which may be associated with decreased BMI, may contribute to protect against the development of asthma symptoms in Korean elementary schoolchildren.

Pulmonary function testing plays a key role in the diagnosis and management of asthma in children. However, the literature does not clearly show whether children with clinically stable asthma have significantly reduced lung function when compared with normal children. We compared the lung function of 242 clinically stable asthmatic children who were initially diagnosed with mild intermittent or mild persistent asthma with the lung function of 100 nonasthmatic controls. The lung function was assessed using FEV1, FEV1/FVC, FEF25-75 and PEF. In addition, we measured bronchial hyperresponsiveness (BHR) using the provocation concentration of methacholine needed to produce a 20% fall in FEV1. All measures of pulmonary function were significantly decreased in the children with asthma. Pulmonary function was not influenced by atopy, serum IgE, or total eosinophil count (TEC). However, the likelihood ratio for trends revealed a significant association between our pulmonary parameters and the degree of BHR. Children with mild-to-severe BHR had greatly decreased lung function compared with those with normal BHR, the control group. In addition, a direct correlation was found between PC20 and our pulmonary parameters in asthmatic children. However, only atopic children with asthma had a significant correlation between PC20 and TEC. We found children with clinically stable asthma to have pulmonary obstruction, which associated strongly with their degree of BHR.

Objective: The hygiene hypothesis postulates that infections early in life might influence the development of asthma later in childhood. However, this hypothesis is controversial. The objective of this study was to determine whether there is a relationship between infection-related risk factors during infancy and development of asthma later in childhood., Methods: Data were obtained by a nationwide, population-based, cross-sectional study of 26,400 children, 7 to 12 years of age. Parents completed a questionnaire on symptoms of and risk factors for asthma, including the number of fever episodes, acute gastroenteritis, use of antibiotics, and immunization during infancy. The presence of asthma was defined by parental report of "wheeze in the last 12 months" or "asthma ever." Data were analyzed by logistic regression analysis., Results: The occurrence of fever during infancy was weakly associated with the development of asthma (P < 0.05). A higher frequency of episodes of fever was associated with a higher risk of development of asthma. The relationship between antibiotic use during infancy and development of asthma was also significant (P < 0.0001). The adjusted odds ratios of childhood asthma increased in proportion to the number of antibiotic courses during infancy. A history of acute gastroenteritis during infancy increased the risk of developing asthma in later life (P < 0.001). In contrast, immunization in infancy was not related to development of asthma in childhood (P > 0.05)., Conclusions: These data suggest that the development of childhood asthma is associated with episodes of fever, antibiotic use, and acute gastroenteritis during infancy.

Asthma is commonly described as an atopic disease in childhood, but some cases of this disorder do not fit this description. The aim of this study was to evaluate the frequency of atopy, asthma, and sensitization to house dust mites in children with allergic symptoms. This study was performed at the Severance Hospital of Yonsei University with patients who visited the allergy clinic for evaluation of nonspecific upper respiratory symptoms, typical symptoms of asthma, or a general health workup. The patients were divided into three age groups: 0-3 years (group 1), 4-7 years (group 2), and 8-12 years (group 3). Of the 1,244 children examined, 844 (67.8%) were atopic and 400 (32.2%) were non-atopic. The frequency of atopy and asthma increased with age. Asthma was diagnosed in the same proportion (64%) of atopic and non-atopic children. As risk factors for asthma symptoms, the positive values of house dust mite (HDM) sensitivity were significantly increased in groups 1, 2, and 3 to 53.5%, 68.9%, and 80.2%, respectively. A significant difference between the percentage of asthmatics sensitized to HDM and that of asthmatics not sensitized to HDM was found only in group 3. In conclusion, asthma is related to atopy with increasing age, and house dust mite sensitization seems to be an important determinant of asthma in older children in Korea.

Sensitization to aeroallergens is associated with diminished lung function in adults. Little has been studied on the relationship between the inhalant allergen-specific IgE and pulmonary function in asthmatic children. This study was focused on four major inhalant allergens found in Korea, including Dermatophagoides pteronyssinus (Der p.), Dermatophagoides farinae (Der f.), and Alternaria- and German cockroach-specific IgEs, with evaluation of pulmonary function in relation to the amount of allergens. The parents or legal guardians of participants enrolled in this study gave informed consent. Fifty-five asthmatic patients and 48 nonasthmatic children were included. The amounts of specific IgE for the four specified inhalant allergens were determined by employing the CAP system FEIA. Forced expiratory volume in 1 sec (FEV(1))/forced vital capacity (FVC), FEV(1), and forced expiratory flow between 25% and 75% of FVC (FEF(25-75)) of subjects were evaluated through pulmonary function tests. In the asthmatic group, FEV(1), FEV(1)/FVC, and FEF(25-75) were significantly reduced (P < 0.05): reduction in FEV(1) (r = -0.44) and FEF(25-75) (r = -0.33) in association with the Der f.-specific allergen, and reduction in FEV(1) (r = -0.37) and FEF(25-75) (r = -0.34) in association with the Der p.-specific allergen, were observed. However, there was no significant correlation with German cockroach and Alternaria allergen. In the control group, no significant correlation was detectable between the allergen-specific IgE titers and the results of pulmonary function tests. In asthmatic patients, Der p.- and Der f.-specific IgEs, and not German cockroach and Alternaria, seem to play a considerable role in reduced pulmonary function among asthmatic children.

To validate the prevalence rate of symptoms of asthma produced by the phase I ISAAC (International Study of Asthma and Allergies in Childhood) study, hypertonic saline challenge test was carried out during the phase II study at a year after the phase I study. For the phase II study, six middle schools from three cities in the phase I study were selected. Finally, 499 children who responded to both studies were analyzed. All subjects were asked to complete the written questionnaire (WQ) first, followed by a video questionnaire (AVQ 3.0) during the phase I study. Of the 499 children, only 19 (3.8%) were positive to the hypertonic saline bronchial challenge test. The degree of agreement between responses to the two corresponding questions "wheezing at rest" and "nocturnal wheeze" in the AVQ 3.0 and WQ were moderate and weak with a Kappa indices of 0.45 and 0.23, respectively. The question on "severe wheeze" in the AVQ 3.0 had the highest Youden's index among the five questions related to asthma symptoms in the previous 12 months, but its specificity was low whereas its sensitivity was 1.0. There was no consistency of priority between the two questionnaires in predicting bronchial hyperreactivity in a group of Korean schoolchildren. Therefore we need to develop more appropriate WQ or AVQ to compare the prevalences of asthma to other countries.

The purpose of this study was to estimate the national prevalence of childhood asthma and other allergic diseases in Korea, and to determine potential risk factors for the diseases. Stratified random samples of 42,886 were selected from 34 elementary (6-12 yr olds) and 34 middle schools (12-15 yr olds) nationwide, and 38,955 were in the final analysis. The Korean-translated modified version of the International Study of Asthma and Allergies in Childhood questionnaire was used in this cross-sectional survey. Twelve-month prevalences of the symptoms of asthma, rhinoconjunctivitis, and flexural eczema were 8.7%, 10.5%, 7.3% in 6-12 yr olds, and 8.2%, 10.0%, 3.9% in 12-15 yr olds, respectively. For allergic conjunctivitis, food allergy, and drug allergy, the prevalences in 6-12 yr olds were 11.2%, 6.5%, and 1.5%, respectively. Asthma and flexural eczema decreased significantly with age. Other significant risk factors were also noted. For 6-12 yr-old asthma, adjusted odds ratio (aOR) of body mass index was 1.21 with 95% confidence interval (CI) 1.0-1.48, aOR of passive smoking was 1.37 with 95%CI 1.24-1.51, aOR of carpet use was 1.28 with 95%CI 1.10-1.49. For 6-12 yr-old eczema, aOR of affluence was 1.22 with 95%CI 1.07-1.39. The control of obesity and passive smoking would be the most important preventive measures of allergic diseases.

It is widely known that the cockroach is an inhalant allergen in atopic asthma and allergic rhinitis. Even though Bla g I and Bla g II are considered as the major allergens, several relatively high-molecular weight (MW) cockroach allergens have also been recently identified by IgE-immunoblot in western countries. However, the environmental control and diagnostic tests mainly focussed on Bla g I and Bla g II. Furthermore there is no data about major IgE-binding cockroach antigens in Korea. We performed this study to identify the major German cockroach allergens in Korean atopic children. By the results of allergy skin tests, 14 children with atopic asthma (9 were cockroach-sensitive and 5 were cockroach-nonsensitive atopics) were enrolled in this study. We conducted IgE immunoblot and autoradiographic analysis using Yonsei-extract of German cockroach antigen produced in our laboratory, individual sera from 9 cockroach-sensitive children, and the pooled sera of 5 house-dust-mites-only-sensitive children. We performed an allergic skin test to cockroach mix, and a radioallergosorbent test (RAST) using German cockroach crude extract on all subjects. German cockroach-specific IgE was detected in 6 out of 9 subjects by RAST. We identified at least 15 IgE-binding protein bands, and among them, the components of MWs of 76, 64, 50, 38, and < 14 kilodaltons (kDa) were the major German cockroach allergens in study subjects. Therefore, Bla g I (25-30 kDa) and Bla g II (36 kDa) could not be the absolute indicators of German cockroach sensitization and parameters of environmental control.