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The ongoing COhort for Childhood Origin of Asthma and allergic diseases (COCOA) study is a prospective birth cohort investigating the origin and natural courses of childhood allergic diseases, including atopic dermatitis, food allergy, allergic rhinitis and asthma, with long-term prognosis. Initiated under the premise that allergic diseases result from a complex interplay of immune development alterations, environmental exposures, and host susceptibility, the COCOA study explores these dynamic interactions during prenatal and postnatal periods, framed within the hygiene and microbial hypotheses alongside the developmental origins of health and disease (DOHaD) hypothesis. The scope of the COCOA study extends to genetic predispositions, indoor and outdoor environmental variables affecting mothers and their offsprings such as outdoor and indoor air pollution, psychological factors, diets, and the microbiomes of skin, gut, and airway. We have embarked on in-depth investigations of diverse risk factors and the pathophysiological underpinnings of allergic diseases. By employing multi-omics approaches-proteomics, transcriptomics, and metabolomics-we gain deeper insights into the distinct pathophysiological processes across various endotypes of childhood allergic diseases, incorporating the exposome using extensive resources within the COCOA study. Integration with large-scale datasets, such as national health insurance records, enhances robustness and mitigates potential limitations inherent to birth cohort studies. As part of global networks focused on childhood allergic diseases, the COCOA study fosters collaborative research across multiple cohorts. The findings from the COCOA study are instrumental in informing precision medicine strategies for childhood allergic diseases, underpinning the establishment of disease trajectories., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objective: The identification of allergic rhinitis (AR) in early life is important for the target of intervention. AR is caused by various environmental factors, including house dust mites. We investigated the relationship between the Dermatophagoides farinae (Der f)-IgE and eosinophil in mothers with AR at delivery and the eosinophil levels and AR incidence in children., Methods: The study participants were 983 mother-child pairs from the COhort for Childhood Origin of Asthma and Allergic Diseases. AR was diagnosed by a doctor at delivery in mother and at 3 years of age in offspring. The association between eosinophil level and AR was assessed using logistic regression analysis., Results: The Der f-IgE level in mother having AR at delivery was associated with the mother's eosinophil level, and the mother's eosinophil level was associated with the child's eosinophil level both at age 1 and 3. The risk of AR at age 3 in children was increased according to increased eosinophil levels in mothers at delivery and in children both aged 1 and 3 years (adjusted odds ratio [aOR] and 95% confidence interval [CI]: 2.57 [1.14-5.78], 2.28 [1.02-5.13], respectively). The risk of childhood AR at the age of 3 is increased when both mothers and children have high eosiniophils (aOR and 95% CI: 2.62 [1.01-6.79], 1.37 [0.98-1.91])., Conclusions: Der f-IgE in mothers at delivery was related to eosinophil levels in mothers with AR and higher level of eosinophils in both mother and children was associated with the increased risk of AR incidence at the first 3 years of life of children., (© 2023. The Author(s).)

Background: Prenatal antibiotic exposure and delivery mode may affect the gut microbiome in early life and influence the development of childhood asthma, but the combined effect of these 2 factors is unknown., Objective: To identify the individual and combined effects of prenatal antibiotic exposure and delivery mode on the development of asthma in children and the potential mechanisms underlying these associations., Methods: A total of 789 children from the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study were enrolled. Asthma was defined as a physician-confirmed diagnosis with asthma symptoms in the previous 12 months at age 7 years. Information on prenatal antibiotic exposure was obtained by mothers using a questionnaire. Logistic regression analysis was used. Gut microbiota analysis using 16S rRNA gene sequencing of fecal specimens obtained at 6 months was undertaken for 207 infants., Results: Prenatal antibiotic exposure and cesarean section delivery (adjusted odds ratio [aOR], 95% confidence interval [CI], 5.70 [1.25-22.81] and 1.57 [1.36-6.14], respectively) were associated with childhood asthma, especially synergistically when compared with the vaginal delivery-prenatal antibiotic exposure reference group (aOR, 7.35; 95% CI, 3.46-39.61; Interaction P = .03). Prenatal antibiotic exposure was associated with childhood asthma with aORs 21.79 and 27.03 for 1 and 2 or more exposures, respectively. Considerable small-airway dysfunction (R5-R20 in impulse oscillometry) was observed with prenatal antibiotic exposure and cesarean section delivery, compared with those with spontaneous delivery without prenatal antibiotic exposure. There was no significant difference in the diversity of gut microbiota among the 4 groups. However, the relative abundance of Clostridium was significantly increased in infants with prenatal antibiotic exposure and delivered by means of cesarean section., Conclusion: Prenatal antibiotic exposure and delivery mode might modulate asthma development in children and small-airway dysfunction, potentially through early-life gut microbiota alterations., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Spirometry is an unrivalled tool for determining asthma and asthma severity. The ratio of forced expiratory volume (FEV) in 1 second (FEV 1 ) to forced vital capacity (FVC) and the forced expiratory flow between 25% and 75% of FVC (FEF 25-75 ) are well-known markers of airway obstruction, but they are limited by low reproducibility, particularly in children. In this study, we defined terminal expiration volume (TEV) as FEV in 3 seconds forced expiratory volume in 3 seconds (FEV₃) minus forced expiratory volume in 1 seconds (FEV 1 ) and investigate whether TEV/FEV₃ can function as a coherent marker to compensate for existing markers. Methods: This retrospective study comprised 980 children ages ≤ 18 years who underwent spirometry and the bronchial provocation testing. TEV/FEV₃ was compared with regard to asthma presence and severity. The findings were verified with an external validation group (n = 105). Results: FEV₃ was obtained in 837 children (85.4%). TEV/FEV₃ was significantly higher in patients with asthma than in patients who did not have asthma (17.1 ± 5.5 versus 12.0 ± 4.4, p < 0.001). External validation with 73 patients showed similar results (18.0 ± 5.9 in asthma versus 10.2 ± 5.1 in non-asthma, p < 0.001). The discriminatory power of TEV/FEV₃ for asthma was comparable with that of FEF 25-75 (p = 0.804). TEV/FEV₃ significantly increased with asthma severity (mild, 16.1 ± 5.4; moderate, 17.7 ± 5.4; severe, 22.0 ± 5.3; p < 0.001). For patients who could not achieve FEV₃, FEF 25-75 demonstrated no significant difference between mild and moderate asthma, and could not discriminate asthma or asthma severity. Conclusion: TEV/FEV₃ is a new metric that may help diagnose and determine asthma severity by using conventional spirometry by assessing small airway dysfunction. TEV/FEV₃ promotes a reassessment of the reliability of other spirometric parameters, particularly in young children. Caution is needed in interpreting the result of spirometry in children who cannot achieve FEV₃.

Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers., (© 2022. The Author(s).)

Objective: Evaluation of airway inflammation and dysfunction is important in management of allergic rhinitis (AR) since AR is a risk factor for developing asthma. Theoretical nonlinear modeling of exhaled nitric oxide (NO) has revealed extended flow-independent NO parameters that could explain where or how NO metabolism was altered. We aimed to evaluate the association between extended NO parameters and bronchial hyperresponsiveness (BHR) in children with AR., Methods: Exhaled NO was measured in 74 children with AR on the same day they underwent the provocholine challenge test (PCT). Extended NO was measured in three different exhaled flow rates (30, 100, 200 mL/s) and calculated using the Högman-Meriläinen model. We compared the extended NO parameters including bronchial NO (JawNO), airway tissue NO (CawNO), alveolar tissue NO (CaNO), and diffusing capacity of NO (DawNO) between AR with and without BHR groups, and analyzed the correlation between extended NO parameters and the response-dose ratio (RDR) of the PCT. We additionally evaluated 49 respiratory healthy controls., Results: Among the 74 children with AR, nine showed BHR. JawNO increased more in children with AR than the control group. In children with AR, JawNO was higher in the AR with BHR than without BHR group, and was correlated positively with log RDR ( r  = 0.373, p  = .001)., Conclusions: Extended NO analysis including JawNO can be a useful tool for assessing BHR in AR.

Background: Genome-wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European-ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma., Methods: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS. We validated our GWAS findings using UK Biobank data. We then used the Genotype-Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma., Results: Variants at the 17q12-21 locus and SNPs in CYBRD1 and TNFSF15 genes were associated with persistent childhood asthma at genome-wide thresholds of significance. Four SNPs in the TNFSF15 gene were also associated with childhood-onset asthma in British white participants in the UK Biobank data. The asthma-associated rs7856856-C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries. Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856-CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children., Conclusions: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, and replicated associations at the 17q12-21 childhood-onset asthma locus. This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Abstract: Asthma is a heterogeneous disease characterized by chronic airway inflammation with a genetic predisposition. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily that plays an important role in regulating T cell activation and immune homeostasis. Here, we aimed to investigate the association of the genetic variants of BTNL2 with childhood asthma and asthma-related traits by utilizing extreme asthma phenotypes and employing a genome-wide association study. Our study included 243 children with well-defined moderate to severe atopic asthma and 134 healthy children with no history of allergic diseases and allergic sensitization. DNA from these subjects was genotyped using AxiomTM Genome-Wide Array Plates. Although no single nucleotide polymorphisms (SNPs) reached a genome-wide threshold of significance, 3 SNPs, rs3817971, rs41355746, and rs41441651, at BTNL2 were significantly associated with moderate to severe atopic asthma after performing Bonferroni correction. These SNPs were also associated with the risk of allergic sensitization toward house dust mites and the presence and degree of bronchial hyperresponsiveness. Thus, we identified that BTNL2 was associated with atopic moderate to severe persistent asthma in Korean children, and this may play an important role in disease development and susceptibility., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: It is still debatable whether dog ownership during early childhood is a risk factor for the development of allergic diseases., Objective: We investigated the association of dog ownership in early life with sensitization and asthma in childhood., Methods: Data from the Cohort for Childhood Origin of Asthma and Allergic diseases were used to investigate the association between dog ownership at any time from pregnancy to 1 year of age and sensitization to aeroallergens at 3 and 7 years old, bronchial hyperresponsiveness (BHR), and asthma at 7 years old. We analyzed the cytokine levels in cord blood (CB) and indoor environmental measurement concentrations in the mother's residence obtained at 36 weeks of pregnancy., Results: Sensitization to dogs at age 3 and 7 did not differ between dog ownership and nonownership, but dog ownership during early life decreased the risk of sensitization to aeroallergens at age 7 (aOR = 0.44, 95% CI 0.21-0.90). Dog ownership significantly increased the risk of nonatopic BHR (aOR = 2.86; 95% CI 1.32-6.21). In addition, dog ownership was associated with asthma, especially nonatopic asthma at 7 years old (aOR = 2.73, 95% CI 1.02-7.32; aOR = 7.05, 95% CI 1.85-26.90, respectively). There were no significant differences in the concentrations of IL-13 or interferon-γ in CB or indoor environmental measurements according to dog ownership during pregnancy., Conclusion: Early-life dog exposure in this birth cohort has been shown to reduce atopy but increase the risk of nonatopic BHR and nonatopic asthma at 7 years old., (© 2021 S. Karger AG, Basel.)

Objective: Mold exposure in early life may be associated with development of atopic dermatitis; however, studies of this link are inconclusive and evidence for the underlying mechanism(s) is lacking. This study identified the association between the time of mold exposure and development of atopic dermatitis and investigated the underlying mechanisms., Method: The association between atopic dermatitis and mold exposure was examined in the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study (n=1446). Atopic dermatitis was diagnosed at 1 year of age by pediatric allergists. Exposure to mold was assessed by questionnaire. The Illumina MiSeq platform was used to examine the environmental mycobiome in 20 randomly selected healthy infants and 20 infants with atopic dermatitis at 36 weeks of gestation., Results: Prenatal, but not postnatal, mold exposure was significantly associated with atopic dermatitis (adjusted odds ratio, 1.36; 95% confidence interval, 1.01-1.83). Levels of total serum IgE at 1 year of age were higher in infants with atopic dermatitis exposed to mold during pregnancy than in healthy infants not exposed to mold during pregnancy (p=0.021). The relative abundance of uncultured Ascomycota was higher in infants with atopic dermatitis than in healthy infants. The relative abundance of uncultured Ascomycota correlated with total serum IgE levels at 1 year of age (r=0.613, p<0.001)., Conclusion: Indoor mold exposure during the fetal period is associated with development of atopic dermatitis via IgE-mediated allergic inflammation. Avoidance of mold exposure during this critical period might prevent the development of atopic dermatitis., (Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) infection., Methods: We measured YKL-40 levels in human nasopharyngeal aspirate (NPA) from hospitalized children presenting with acute respiratory symptoms. Wild-type (WT) and BRP-39 knockout (KO) C57BL/6 mice were inoculated with live RSV (A2 strain). Bronchoalveolar lavage fluid and lung tissue samples were obtained on day 7 after inoculation to assess lung inflammation, airway reactivity, and expression of cytokines and BRP-39., Results: In human subjects, YKL-40 and IL-13 levels in NPA were higher in children with RSV infection than in control subjects. Expression of BRP-39 and Th2 cytokines, IL-13 in particular, was increased following RSV infection in mice. Airway inflammation caused by RSV infection was reduced in BRP-39 KO mice as compared to WT mice. Th2 cytokine levels were not increased in the lungs of RSV-infected BRP-39 KO mice. BRP-39 regulated M2 macrophage activation in RSV-infected mice. Additionally, treatment with anti-CHI3L1 antibody attenuated airway inflammation and Th2 cytokine production in RSV-infected WT mice., Conclusion: These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection. CHI3L1 could be a potential therapeutic candidate for attenuating Th2-associated immunopathology during RSV infection., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Exhaled breath temperature (EBT) has been suggested as a non-invasive marker of airway inflammation in asthma. There have been no studies examining longitudinal changes in EBT following asthma attacks., Objective: To investigate changes in EBT during and after an asthma attack and to relate these changes to changes in respiratory physiological measurements., Methods: We evaluated 38 hospitalized children aged 5-18 years diagnosed with an asthma attack. Spirometry was performed upon hospitalization. During hospitalization, EBT, peak expiratory flow rate (PEFR), and asthma score were measured daily. These tests were repeated 1 week and 1 month after discharge. The overall PEFR change, temporal changes in plateau values at the end of expiration, and time-dynamic associations were evaluated using linear mixed models., Results: FEV 1 was lower at admission than at discharge (63.3 ± 24 vs 99.5 ± 14 percent of predicted, P < 0.001). The EBT was higher at admission than at 1 week after discharge (34.1°C [range: 33.9-34.8°C] vs 33.6°C [range: 33.0-34.2°C], P = 0.007); overall, EBTs decreased over time (P = 0.007). Among individual subjects, decreased EBT was correlated with increased PEFR over time. Furthermore, plateau values at the end of expiration had a time-dependent, dynamic association with the PEFR during hospitalization (P = 0.005) and between asthma attack onset and asthma status stabilization (P = 0.032)., Conclusions: The EBT was elevated during asthma attacks and gradually decreased until asthma was well controlled. The EBT may be a useful, non-invasive tool for monitoring asthma control in children., (© 2019 Wiley Periodicals, Inc.)

Background: Impulse oscillometry (IOS) measures respiratory resistance and reactance during tidal breaths and is a convenient tool for evaluation of lung function. Respiratory resistance and reactance can be measured separately during inspiration and expiration (inspiratory-expiratory analysis)., Objective: We investigated the differences in inspiratory-expiratory measurements obtained using IOS between children with and without asthma., Methods: We analyzed 819 subjects aged 4-18 years, including asthmatic children (n = 600) and controls (n = 219). Asthma was diagnosed in accordance with the American Thoracic Society/European Respiratory Society guideline. Spirometry and IOS were performed in all subjects., Results: In whole-breath analysis, the asthma group had higher resistance at 5 Hz (R5) and reactance area (AX) and lower reactance at 5 Hz (X5) than the control groups. In inspiratory-expiratory analysis, the asthma group showed increased expiratory R5 and AX and decreased expiratory X5 when compared with the control group. The absolute changes in R5, X5, and AX values between inspiration and expiration were greater in children with asthma than those in controls (0.138 ± 0.195 vs 0.102 ± 0.162, P = 0.014; -0.106 ± 0.200 vs -0.086 ± 0.434, P < 0.001 and 0.460 ± 11.63 vs 0.398 ± 2.88, P = 0.002, respectively)., Conclusions: Inspiratory-expiratory IOS analysis differentiated asthmatic children from control subjects, reflecting airway narrowing on expiration in pediatric asthma. The changes in R5, X5, and AX between inspiration and expiration can be a useful index for diagnosis of asthma in children without assessment of the response to a bronchodilator., (© 2018 Wiley Periodicals, Inc.)

Rationale: The activated leukocyte cell adhesion molecule (ALCAM) is a cluster of differentiation 6 ligand that is important for stabilizing the immunological synapse and inducing T-cell activation and proliferation., Objectives: In this study, we investigated the role of ALCAM in the development of inflammation in allergic asthma., Methods: An ovalbumin (OVA)-induced allergic asthma model was established in wild-type (WT) and ALCAM-deficient (ALCAM -/- ) mice. T-cell proliferation was evaluated in cocultures with dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) from WT and ALCAM -/- mice were cultured and adoptively transferred to OT-II mice for either OVA sensitization or challenge. An anti-ALCAM antibody was administered to assess its therapeutic potential. ALCAM concentrations in the sputum and serum of children with asthma were quantified by ELISA., Measurements and Main Results: Inflammatory responses were lower in ALCAM -/- mice than in WT mice, and T cells cocultured with DCs from ALCAM -/- mice showed reduced proliferation relative to those cocultured with DCs from WT mice. A decreased inflammatory response was observed upon adoptive transfer of BMDCs from ALCAM -/- mice as compared with that observed after transfer of BMDCs from WT mice. In addition, anti-ALCAM antibody-treated mice showed a reduced inflammatory response, and sputum and serum ALCAM concentrations were higher in children with asthma than in control subjects., Conclusions: ALCAM contributes to OVA-induced allergic asthma by stimulating T-cell activation and proliferation, suggesting it as a potential therapeutic target for allergic asthma.

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to play a role in the pathogenesis of various inflammatory diseases. However, no study has been performed on childhood asthma., Methods: Ninety-five children with asthma and 78 controls aged 5-18 years were included. Sputum induction, pulmonary function test (PFT), and methacholine challenge test were performed. The subjects were divided into the eosinophilic airway (EA) and non-EA (NEA) groups based on sputum analysis and into the high and low TWEAK groups according to the TWEAK cutoff level (263.0 pg/mL). TWEAK in induced sputum supernatant was measured through enzyme-linked immunosorbent assay., Results: Children with asthma had higher TWEAK levels than healthy controls (493.0 [157.1-904.3] vs 118.2 (67.5-345.5) pg/mL, P < .001). Sputum TWEAK levels were significantly correlated with PFT parameters reflecting airway obstruction. This association was particularly prominent in subjects with NEA inflammation. Significant differences in FEF 25-75 (maximum mid-expiratory flow, % predicted; P = .017), AX (reactance area; P < .001), R5-R20 (difference between resistance at 5 and 20 Hz; P = .025), and X5 (reactance at 5 Hz, % predicted; P < .001) were noted between the high and low TWEAK groups within the NEA group. Sputum TWEAK level also showed significant positive correlations with asthma severity (r = .358, P = .001) and control status (r = .470, P < .001), distinctively in subjects with NEA inflammation., Conclusions: Airway TWEAK may play a role in small airway inflammation especially in children with non-eosinophilic asthma., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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.

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.)

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.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background: The upper‐airway microbiota may be associated with the pathogenesis of asthma and useful for predicting acute exacerbation. However, the relationship between the lower‐airway microbiota and acute exacerbation in children with asthma is not well understood. We evaluated the characteristics of the airway microbiome using induced sputum from children with asthma exacerbation and compared the microbiota‐related differences of inflammatory cytokines with those in children with asthma. Methods: We analysed the microbiome using induced sputum during acute exacerbation of asthma in children. We identified microbial candidates that were prominent in children with asthma exacerbation and compared them with those in children with stable asthma using various analytical methods. The microbial candidates were analysed to determine their association with inflammatory cytokines. We also developed a predictive functional profile using PICRUSt. Results: A total of 95 children with allergic sensitisation including 22 with asthma exacerbation, 67 with stable asthma, and 6 controls were evaluated. We selected 26 microbial candidates whose abundances were significantly increased, decreased, or correlated during acute exacerbation in children with asthma. Among the microbial candidates, Campylobacter, Capnocytophaga, Haemophilus, and Porphyromonas were associated with inflammatory cytokines including macrophage inflammatory protein (MIP)‐1β, programmed death‐ligand 1, and granzyme B. Both Campylobacter and MIP‐1β levels were correlated with sputum eosinophils. Increased lipopolysaccharide biosynthesis and decreased glycan degradation were observed in children with asthma exacerbation. Conclusion: Gram‐negative microbes in the lower airway were related to acute exacerbation in children with asthma. These microbes and associated cytokines may play a role in exacerbating asthma in children. [ABSTRACT FROM AUTHOR]

Rationale: The activated leukocyte cell adhesion molecule (ALCAM) is a cluster of differentiation 6 ligand that is important for stabilizing the immunological synapse and inducing T-cell activation and proliferation.Objectives: In this study, we investigated the role of ALCAM in the development of inflammation in allergic asthma.Methods: An ovalbumin (OVA)-induced allergic asthma model was established in wild-type (WT) and ALCAM-deficient (ALCAM-/-) mice. T-cell proliferation was evaluated in cocultures with dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) from WT and ALCAM-/- mice were cultured and adoptively transferred to OT-II mice for either OVA sensitization or challenge. An anti-ALCAM antibody was administered to assess its therapeutic potential. ALCAM concentrations in the sputum and serum of children with asthma were quantified by ELISA.Measurements and Main Results: Inflammatory responses were lower in ALCAM-/- mice than in WT mice, and T cells cocultured with DCs from ALCAM-/- mice showed reduced proliferation relative to those cocultured with DCs from WT mice. A decreased inflammatory response was observed upon adoptive transfer of BMDCs from ALCAM-/- mice as compared with that observed after transfer of BMDCs from WT mice. In addition, anti-ALCAM antibody-treated mice showed a reduced inflammatory response, and sputum and serum ALCAM concentrations were higher in children with asthma than in control subjects.Conclusions: ALCAM contributes to OVA-induced allergic asthma by stimulating T-cell activation and proliferation, suggesting it as a potential therapeutic target for allergic asthma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To explore psychological distress in Korean adolescents having allergic disease comorbid with obesity.Study Design: A total of 703 869 adolescents who completed the Korean Youth Risk Behavior Web-based Survey between 2007 and 2016 were analyzed. Participants were divided into 4 groups-healthy control, allergic disease only, obesity only, and comorbidity of allergic disease and obesity-and compared them to determine whether they showed differences in mental health.Results: Adolescents with both atopic dermatitis and obesity had significantly greater odds of experiencing unhappiness (OR, 1.17), stress (OR, 1.32), and suicidal ideation (OR, 1.25) than those without both conditions. The same was true of adolescents with obesity and allergic rhinitis (OR, 1.21, 1.37, and 1.27, respectively) or bronchial asthma (OR, 1.37, 1.39, and 1.37). The comorbidity groups also showed significantly greater odds of stress and suicidal ideation than the allergic disease-only (atopic dermatitis with obesity, 1.21 and 1.15, respectively; allergic rhinitis with obesity, 1.11 and 1.09; bronchial asthma with obesity, 1.17 and 1.14) and obesity-only groups (atopic dermatitis with obesity, 1.13 and 1.09; allergic rhinitis with obesity, 1.18 and 1.10; bronchial asthma with obesity, 1.18 and 1.21).Conclusions: Allergic disease and obesity negatively and additively influence mental health in adolescents. [ABSTRACT FROM AUTHOR]