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Skin fibrotic remodeling is a major feature in human atopic dermatitis (AD). Inflammation and tissue fibrosis are common consequences of Th2 responses. Elevated IL-13 and thymic stromal lymphopoietin (TSLP) have been found in the AD skin lesions. Fibrocytes can be recruited to inflamed tissues to promote wound healing and fibrosis. Dermal transgenic expression of IL-13 causes an AD-like phenotype with fibrosis and increased TSLP. However, the role of TSLP in fibrotic remodeling is unknown. In this study, we investigated the role of TSLP and fibrocytes in the generation of IL-13–induced skin fibrosis. In AD lesion, cessation of IL-13 transgene expression resulted in reduced skin inflammation but with no effect on further progression of fibrosis. This was accompanied by markedly increased CD34+/procollagen 1+ fibrocytes. Furthermore, fibrocytes express TSLP receptor (TSLPR), and TSLP directly promotes PBMC-derived fibrocytes to produce collagen. Neutralization of TSLP or genetic deletion of TSLPR in IL-13 transgenic mice resulted in a significant reduction in fibrocytes and in skin fibrosis. Furthermore, reduction of fibrosis by depletion of TSLP was independent of IL-13. Interestingly, the number of fibrocytes was highly increased in the skin samples of AD patients. These data indicate that the progression of skin fibrosis in IL-13–induced AD occurs via TSLP/TSLPR-dependent but IL-13–independent novel mechanisms by promoting fibrocyte functions.

Activation of the prostaglandin D2 receptor (PTGDR) may contribute to pulmonary vasodilation, bronchoconstriction, recruitment of eosinophils, basophils and T-lymphocytes, and enhanced synthesis of leukotriene C4. We investigated whether polymorphisms of the leukotriene C4 synthase (LTC4S) -444A/C and PTGDR -441T/C were associated with clinical phenotypes and responsiveness to leukotriene receptor antagonist (LTRA) in Korean asthmatic children. We enrolled 270 normal and 870 asthmatic children. We prescribed montelukast (5 mg per day) to 100 of asthmatic children, and analyzed the responsiveness to LTRA by exercise challenge tests. Polymorphisms were genotyped by PCR-restriction fragment length polymorphism. As the number of minor alleles of the PTGDR -441T/C and LTC4S -444A/C polymorphisms increased, the log total eosinophil counts increased in atopic asthmatic children (P-value=0.03). We found a significant association between responsiveness to montelukast and the PTGDR polymorphism (P-value=0.038). However, the LTC4S -444A/C and PTGDR -441T/C were not associated with the susceptibility for asthma (LTC4S, AA versus AC+CC, adjusted odds ratio of 0.98 (95% confidence interval, 0.73-1.31); PTGDR, TT versus TC+CC, adjusted odds ratio of 0.90 (95% confidence interval, 0.68-1.19)) or clinical phenotypes (P-value>0.05). The effects of the PTGDR and LTC4S polymorphisms on the enhancement of eosinophil counts were additive in the Korean children with asthma. In addition, the PTGDR polymorphism seems to be associated with the responsiveness to LTRA. Therefore, therapies that target the PTGDR may be useful for modulating the responsiveness to LTRA.

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).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.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.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.

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions. The pathogenesis of AD may include disrupted epidermal barrier function, immunodysregulation, and IgE-mediated sensitization to food and environmental allergens. AD is also part of a process called the atopic march, a progression from AD to allergic rhinitis and asthma. This has been supported by multiple cross-sectional and longitudinal studies and experimental data. Research on the mechanisms of AD has been centered on the adaptive immune system with an emphasis on the T-helper 1 (Th1)-Th2 paradigm. Recently, the conceptual focus has largely shifted to include a primary defect in the epithelial barrier as an initial event in AD providing a significant insight into the disease initiation and pointing to a complex secondary interplay of environmental and immunological sequelae with barrier disruption. Further understanding of AD will help the development of more effective treatment for AD and ultimately, preventative algorithms for the atopic march. In this review we highlight recent advances in our understanding of the pathogenesis of AD and the atopic march.

Background: The results of recent studies suggest that factors in rural environments may protect against the development of allergic diseases, but the underlying mechanisms are not well understood. The aim of this study was to investigate the prevalence of allergic diseases, to establish if this prevalence is influenced by migration from rural to urban areas and to identify environmental risk factors associated with these diseases. Methods: A cross-sectional study of children aged 9–12 years from a rural village, a rural town and an urban city in Korea was conducted. Demographic and disease-related information was obtained via a detailed questionnaire, and skin prick tests were performed. Results: There were significant differences in lifestyle and environmental factors between children from the rural village, the rural town and the urban children. The prevalence of allergic diseases and atopy was higher in urban children. A lower prevalence of allergic diseases and atopy was associated with farming parents, contact with farm animals during pregnancy, owning pets or a stable, breast-feeding and having older siblings. A comparison of rural village and rural town children revealed no evidence of an association of allergic diseases and atopy with farming parents, contact with farm animals during pregnancy or owning a stable. On the other hand, having older siblings and antibiotic use during infancy were significantly associated with allergic diseases and atopy in these children. Conclusions: Protective factors associated with a farming environment and/or rural lifestyle may influence the prevalence of allergic diseases and atopy in Korean children.

Background: The aims of this study were to determine (1) the prevalence of atopic dermatitis (AD) in Seoul, Korea, and (2) the influence of environmental and genetic factors on disease risk. Methods: A questionnaire survey was conducted in 5,036 primary school children and 4,607 middle school children in 2008. For each child, a modified version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and a questionnaire assessing exposure to environmental variables were completed. Results: In primary school children, the lifetime prevalence of itchy eczema was 24.3%, the 12-month prevalence of itchy flexural eczema was 18.0%, the lifetime prevalence of AD diagnosis was 31.3%, and the 12-month prevalence of AD treatment was 14.5%. In middle school children, the corresponding rates were 16.0, 10.8, 22.1, and 8.3%, respectively. These rates are significantly higher than those reported in similar studies conducted in 1995 and 2000. In both primary and middle school children, a parental history of allergic disease and a history of having moved into a newly built house before 1 year of age were independently associated with a risk for current AD. For current AD, the prevalence odds ratio was higher in the subgroup with both a genetic and a specific environmental risk factor than in the subgroup with no risk factor or subgroups with only one risk factor. Conclusions: The prevalence of AD in primary and middle school children in Seoul has increased. Its development may be influenced by gene-environment interactions, particularly before 1 year of age.

The gasdermin A (GSDMA) and gasdermin B (GSDMB) genes are located at 17q21.2. The GSDM family genes have been studied in the gastrointestinal tract but recent reports suggest that GSDMB is associated with childhood asthma in several populations. We investigated the association of the GSDMA and GSDMB variants with asthma in Korean children, and to assess the effect of these variants on intermediate phenotypes of asthma. Asthmatic (n = 778) and normal (n = 522) children were enrolled and genotypes were determined using PCR-RFLP. Asthma susceptibility was associated with GG of the GSDMA (rs7212938) and TT of GSDMB (rs7216389). And a combination of risk alleles of two polymorphisms was associated with asthma susceptibility and a frequency of those was higher in asthmatic children with increased levels of total IgE (aOR 1.77, 95% CI 1.15-2.72) and BHR (aOR 1.54, 95% CI 0.99-2.40) compared to normal. Also, we observed a significant association between haplotype of two polymorphisms and asthma susceptibility. The region including the GSDMA and GSDMB polymorphisms may be associated with asthma susceptibility and intermediate phenotypes of asthma, such as elevated IgE and BHR, in Korean children with asthma. These results strongly support an important role for the GSDMA and GSDMB in the development of childhood asthma.

PURPOSE 4-1BB (CD 137) is a costimulatory molecule expressed on activated T-cells. Repression by 4-1BB is thought to attenuate Th2-mediated allergic reactions. The aim of this study was to investigate the effect of 4-1BB on allergic airway inflammation in a murine asthma model. METHODS BALB/c mice were sensitized to and challenged with ovalbumin (OVA). Hu.4-1BB-Fc was administered 1 day before the first OVA sensitization or 1 day after the second OVA sensitization. Following antigen challenge, airway responsiveness to methacholine was assessed and bronchoalveolar lavage (BAL) fluid was analyzed. Total immunoglobulin (Ig) E, OVA-specific IgE, IgG(1), and IgG(2a) levels in sera were measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. RESULTS In mice treated with Hu.4-1BB-Fc before the first OVA sensitization, there was a marked decrease in airway hyperresponsiveness, total cell count, and eosinophil count in the BAL fluid. In addition, Hu.4-1BB-Fc treatment decreased serum OVA-specific IgG(1) levels and increased serum IgG(2a) level significantly compared with the corresponding levels in mice sensitized to and challenged with OVA. Hu.4-1BB-Fc-treated mice also showed suppressed peribronchial and perivascular inflammatory cell infiltration. In contrast, treatment with Hu.4-1BB-Fc 1 day after sensitization had no effect on airway hyperresponsiveness and showed less suppression of inflammation in lung tissue. CONCLUSION Administration of Hu.4-1BB-Fc can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. In addition, administration before sensitization may be more effective. These findings suggest that 4-1BB may be a useful therapeutic molecule against asthma.

Background The hygiene hypothesis suggests that infectious diseases in early life reduce the risk of allergic diseases. Objective To investigate the association between measles infection during early childhood and the prevalence of allergic diseases, lung function, bronchial hyperresponsiveness (BHR), and sensitization in later childhood. Methods A survey was conducted 5 years after a nationwide measles outbreak in Korea. From September 1 through November 30, 2006, we obtained information on history of measles and allergic diseases but not of measles vaccination through a questionnaire completed by 1,004 schoolchildren aged 6 to 7 years. Furthermore, we measured measles antibody titers and performed skin prick tests, pulmonary function tests, and methacholine challenge tests. Children were divided into groups based on their history of measles infection and antibody titers. Results Prevalence of measles infection was 8.2%. Children with both a positive measles history and a positive antimeasles antibody had significantly higher antimeasles antibody levels than those without a measles history. The prevalence of current rhinitis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.02-3.40), rhinitis ever (aOR, 2.17; 95% CI, 1.19-3.94), and current BHR (aOR, 1.98; 95% CI, 1.04-3.78) was significantly higher in the group with a positive measles history compared with the group with a negative measles antibody. No differences were found among groups in the prevalence of asthma, lung function, provocation concentration that caused a decrease in forced expiratory volume of 1 second of 20%, or sensitization. Conclusion Early measles infection was associated with increased prevalence of rhinitis and BHR at the age of 7 years but has no effect on the development of asthma and allergy at the age of 7 years. This study indicates that common childhood infections such as measles in early age do not protect against later development of allergic diseases.

PURPOSE: Lactobacilli are probiotic bacteria that are effective in the management of allergic diseases or gastroenteritis. It is hypothesized that such probiotics have immunoregulatory properties and promote mucosal tolerance. Our goal was to investigate whether Lactobacillus casei rhamnosus Lcr35 could inhibit airway inflammation in an ovalbumin (OVA)-induced murine model of asthma. METHODS: BALB/c mice aged 6 weeks were used in the present study. Lactobacillus casei rhamnosus Lcr35 was administered daily, starting 1 week prior to the first OVA sensitization (group 1) and 2 days before the first 1% OVA airway challenge (group 2). Mice that received only saline at both sensitization and airway challenge time points were used as negative controls (group 3), and those that had OVA-induced asthma were used as positive controls (group 4). Airway responsiveness to methacholine was assessed, and bronchoalveolar lavage (BAL) was performed. At the endpoint of the study, total IgE as well as OVA-specific IgE, IgG(1) and IgG(2a) in serum was measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. RESULTS: Airway hyperresponsiveness, total cell counts and the proportion of eosinophils in BAL fluid were significantly decreased in group 1 compared with group 4 (P

Purpose T cells play a central role in cell-mediated immunity, atopic disease, and asthma. The balance of CD28/cytotoxic T-lymphocyte antigen 4 (CTLA4)-derived signal transduction plays an important role in the activation of T cells and an increased immunoglobulin E (IgE) response. The aim of the current study was to investigate the association between polymorphisms in the genes encoding both CTLA4 and the high-affinity IgE receptor 1B (FCER1B) and serum IgE levels in Korean children with asthma. Methods We enrolled 238 controls and 742 children with asthma. The CTLA4 +49A/G and FCER1B -654C/T polymorphisms were genotyped by PCR-restriction fragment length polymorphism analysis. Results We observed no difference in the distribution of CTLA4 +49A/G among controls, children with asthma, and those with atopic asthma. In contrast, the GA genotype of CTLA4 +49A/G in children with atopic asthma was significantly higher compared to that in those with non-atopic asthma. Moreover, significantly higher log Dp/Df-specific IgE levels were found in children with asthma and those with atopic asthma carrying one or two copies of the CTLA4 +49A versus those homozygous for +49G. Gene-gene interactions between CTLA4 and FCER1B with the heterozygote and homozygote of variant genotypes were associated with the log Dp/Df-specific IgE levels, but not asthma development. In addition, children with Dp/Df (+) asthma carried an elevated combined genotype of risk allele compared to those with Dp/Df (-) asthma. Conclusions The CTLA4 +49A/G polymorphism may contribute to the production of IgE in Korean children with asthma, especially in Dp/Df-specific IgE levels, but not in the direct development of asthma. In addition, Dp/Df-specific IgE levels with a FCER1B -654C/T polymorphism may involve additive effects.

Xenon ventilation CT using dual-source and dual-energy technique is a recently introduced, promising functional lung imaging method. To expand its clinical applications evidence of additional diagnostic value of xenon ventilation CT over conventional chest CT is required.To evaluate the usefulness of xenon ventilation CT using dual-source and dual-energy technique in children with bronchiolitis obliterans (BO).Seventeen children (age 7-18 years; 11 boys) with BO underwent xenon ventilation CT using dual-source and dual-energy technique. Xenon and CT density values were measured in normal and hyperlucent lung regions on CT and were compared between the two regions. Volumes of hyperlucent regions and ventilation defects were calculated with thresholds determined by visual and histogram-based analysis. Indexed volumes of hyperlucent lung regions and ventilation defects were correlated with pulmonary function test results. Effective doses of xenon CT were calculated.Xenon (14.6 +/- 6.4 HU vs 26.1 +/- 6.5 HU; P0.001) and CT density (-892.8 +/- 25.4 HU vs -812.3 +/- 38.7 HU; P0.001) values were significantly lower in hyperlucent regions than in normal lung regions. Xenon and CT density values showed significant positive correlation for the entire lung in 16 children (gamma = 0.55 +/- 0.17, P0.001 or =0.017) and for hyperlucent regions in 13 children (gamma = 0.44 +/- 0.16, P0.001 or =0.001-0.019). Indexed volumes and volume percentages of hyperlucent lung regions and ventilation defects showed strong negative correlations with forced expiratory volume [FEV1, (gamma = -0.64--0.85, Por= 0.006)], FEV1/forced vital capacity [FVC, (gamma = -0.63--0.84, Por= 0.008), and forced midexpiratory flow rate [FEF(25-75), (gamma = -0.68--0.88, Por= 0.002). Volume percentages of xenon ventilation defects (35.0 +/- 16.4%) were not significantly different from those of hyperlucent lung regions (38.2 +/- 18.6%). However, mismatches between the volume percentages were variable up to 21.4-33.3%. Mean effective dose of xenon CT was 1.9 +/- 0.5 mSv.In addition to high-resolution anatomic information, xenon ventilation CT using dual-source and dual-energy technique demonstrates impaired regional ventilation and its heterogeneity accurately in children with BO without additional radiation exposure.

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.

IL-13 is a pivotal cytokine in allergic inflammation and bronchial hyperresponsiveness, and is known to influence leukotriene levels.We investigated whether IL-13 polymorphisms may be associated with clinical phenotypes and drug responsiveness to the leukotriene receptor antagonist (LTRA) in Korean asthmatic children with exercise-induced bronchoconstriction (EIB).We enrolled 242 normal controls and 374 patients with asthma. Of the asthmatic patients, 100 performed exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks and included 80 subjects in drug responsiveness analysis. We assessed IL-13 polymorphisms (-1512A/C, -1112C/T, +2044G/A) through PCR-restriction fragment length polymorphism analysis.Significantly higher total IgE levels and maximum percent fall in forced expiratory volume in 1 s (FEV1) (%) after exercise challenge test were found in asthmatic patients carrying one or two copies of the IL-13 +2044A versus those homozygous for +2044G (P=0.011 and 0.040, respectively). We further noted a correlation of total IgE with maximum percent fall in FEV1 (%) in asthmatic patients, as well as a reverse correlation with improvement of maximum percent fall in FEV1 (%) after exercise challenge tests. Finally, we observed a significant association between responsiveness to montelukast and IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms.The IL-13 +2044G/A polymorphism may be associated with atopy and EIB severity in Korean children with EIB, and thus could potentially be considered as a disease-modifying gene. Moreover, the IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms seem to be associated with LTRA drug responsiveness, and thus might prove useful as a target for modulation of LTRA drug responsiveness.

Kawasaki disease (KD) is an acute vasculitis syndrome of unknown etiology that frequently affects small to medium size arteries. C-C chemokine receptor 5 (CCR5) is a chemokine receptor that binds C-C chemokines. This study investigated the association of the CCR5 (-2135C/T) polymorphism with KD in Korean children.The study population consisted 189 Korean children with KD and 194 Korean children with congenital heart disease (CHD). CCR5 (-2135C/T) polymorphism genotypes were determined using the single-base extension method.The allele frequencies of the CCR5 (-2135C/T) polymorphism differed significantly between CHD children and KD children (-2135T/T, 16.75% vs. 30.05%, aOR 2.14, 95% CI 1.31-3.51). The tested laboratory parameters differed significantly between the KD and CHD groups. The development of coronary artery aneurysm in KD patients was not associated with the CCR5 polymorphism.Our findings suggest that the T allele at the CCR5 (-2135C/T) polymorphism might be associated with the development of KD in Korean children but does not appear to be associated with the development of coronary artery aneurysm.

Aim: Tracheal and chest auscultation for wheeze and transcutaneous oximetry have both been suggested as outcome measures of bronchial provocation tests in young children. The aims of this study were to compare the sensitivity of these two techniques as endpoints for methacholine challenge in young children with cough-variant asthma (CVA) and with classic asthma (CA), and to investigate whether oxygen saturation levels at the presence of wheezing differ in these two groups. Methods: We performed a retrospective analysis of methacholine challenge test data from 4- to 6-year-old children with CVA (n = 41) and from those with CA (n = 53). The challenges used a modified auscultation method that set wheeze detection and/or oxygen desaturation for determining the endpoint. Results: The frequency of wheeze detection at the endpoint was significantly lower than that of oxygen desaturation (46.3% vs. 78.0%) in the CVA group, which contrasted with findings (75.5% vs. 50.9%) in the CA group. Oxygen saturation levels at the presence of wheezing were significantly lower in the CVA group than in the CA group (94.5 ± 1.5% vs. 95.9 ± 1.8%, p = 0.006). Conclusion: Wheeze detection is a less sensitive outcome measure than oxygen desaturation and is associated with a lower oxygen saturation level in young children with CVA, compared to those with CA.

Background: Bronchial hyperresponsiveness is a characteristic feature of asthma, and is usually measured by bronchial challenges using direct or indirect stimuli. Blood eosinophil numbers and serum levels of eosinophil cationic protein (ECP) are considered as indirect measures of airway inflammation in asthma. The aim of this study was to investigate whether bronchial responsiveness to adenosine 5′-monophosphate (AMP) is more closely associated with blood eosinophil markers, compared with that to methacholine, in young children with asthma. Methods: Methacholine and AMP bronchial challenges were performed in 4- to 6-year-old children with asthma (n = 77) and in healthy controls (n = 32), using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. The peripheral blood eosinophil counts and serum ECP concentrations were determined in each subject. Results: A positive response to methacholine (end-point concentration ≤8 mg/ml) and to AMP (end-point concentration ≤200 mg/ml) was observed in 74 (96.1%) and 66 asthmatic children (85.7%), respectively. A majority of controls was unresponsive to both challenges. In the asthma group, there was no significant correlation between methacholine end-point concentration and the eosinophil counts (r = −0.111, P = 0.337) or serum ECP levels (r = −0.126, P = 0.274). In contrast, AMP end-point concentration correlated significantly with the eosinophil counts (r = −0.372, P = 0.001) and with serum ECP levels (r = −0.371, P = 0.001). Conclusions: Our results suggest that bronchial responsiveness to AMP is more closely related to airway inflammation, compared with that to methacholine, and support the potential usefulness of AMP challenges in detecting inflammatory changes in young children with asthma.

In asthmatic individuals, airway sensitivity and maximal airway response are increased. Airway sensitivity is usually evaluated by measuring the provocation concentration of inhaled methacholine or histamine that causes a decrease in forced expiratory volume in 1 second of 20% (PC20). The percentage decrease in forced vital capacity at the PC20 (deltaFVC) has been proposed as a surrogate marker for maximal airway response. Individuals with allergic rhinitis and no clinical evidence of asthma frequently exhibit airway hypersensitivity.To compare the deltaFVC between patients with allergic rhinitis and mild asthmatic patients with a similar degree of airway hypersensitivity.A retrospective analysis of methacholine challenge test data from 72 children with allergic rhinitis and airway hypersensitivity (methacholine PC2016 mg/mL) (rhinitis group) and from 72 children with mild atopic asthma matched to the rhinitis group regarding the methacholine PC20 (asthma group). The deltaFVC was calculated on the concentration-response curve to methacholine.The mean +/- SD deltaFVC was significantly lower in the rhinitis group (15.0% +/- 3.6%) vs the asthma group (17.4% +/- 5.3%) (P = .002). There was no significant correlation between the deltaFVC and PC20 in the rhinitis (r = -0.101; P = .41) and asthma (r = -0.023; P = .85) groups when 2 patients with PC20 less than 1 mg/mL were excluded from each group.Patients with allergic rhinitis and airway hypersensitivity had a significantly lower deltaFVC than methacholine PC20-matched mild asthmatic patients, suggesting that the level of maximal airway response in patients with allergic rhinitis is lower than that in mild asthmatic patients with a similar degree of airway hypersensitivity.

Summary Background It is well known that atopy is a major determinant of bronchial hyper-responsiveness (BHR) in both asymptomatic and asthmatic children. However, the relationship between atopy and BHR has not been well studied in preschool children with wheezing. BHR is usually measured by bronchial challenges using direct and indirect stimuli. Objective The aim of this study was to investigate whether atopic and non-atopic preschool wheezers display similar or different BHR profiles for direct and indirect stimuli. Methods Methacholine and adenosine 5′-monophosphate (AMP) bronchial challenges were performed in 4 to 6-year-old children with recurrent wheezing, using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. Atopy was determined to be present when a child had at least one positive reaction to a panel of 13 common airborne allergens in the presence of positive and negative controls. Results A positive response to methacholine (an end-point concentration 8 mg/mL) was observed in 89.3% (50/56) of atopic wheezers and in 83.8% (31/37) of non-atopic wheezers (P=0.44) for the difference. By contrast, the frequency of a positive response to AMP (an end-point concentration 200 mg/mL) was significantly higher in the atopic group (47/56, 83.9%) compared with the non-atopic group (12/37, 32.4%; P

Purpose To investigate whether prenatal exposure to indoor fine particulate matter (PM₂.₅) and environmental tobacco smoke (ETS) affects susceptibility to respiratory tract infections (RTIs) in infancy, to compare their effects between prenatal and postnatal exposure, and to determine whether genetic factors modify these environmental effects. Methods The study population consisted of 307 birth cohort infants. A diagnosis of RTIs was based on parental report of a physician's diagnosis. Indoor PM₂.₅ and ETS levels were measured during pregnancy and infancy. TaqMan was used for genotyping of nuclear factor erythroid 2-related factor (Nrf2) (rs6726395), glutathione-S-transferase-pi (GSTP) 1 (rs1695), and glutathione-S-transferase-mu (GSTM) 1. Microarrays were used for genome-wide methylation analysis. Results Prenatal exposure to indoor PM₂.₅ increased the susceptibility of lower RTIs (LRTIs) in infancy (adjusted odds ratio [aOR]=2.11). In terms of combined exposure to both indoor PM₂.₅ and ETS, prenatal exposure to both pollutants increased susceptibility to LRTIs (aOR=6.56); however, this association was not found for postnatal exposure. The Nrf2 GG (aOR=23.69), GSTM1 null (aOR=8.18), and GSTP1 AG or GG (aOR=7.37) genotypes increased the combined LRTIs-promoting effects of prenatal exposure to the 2 indoor pollutants. Such effects of prenatal indoor PM₂.₅ and ETS exposure were not found for upper RTIs. Conclusions Prenatal exposure to both indoor PM₂.₅ and ETS may increase susceptibility to LRTIs. This effect can be modified by polymorphisms in reactive oxygen species-related genes.

difference in FEV 1 %predicted, FEF25%–75% %predicted, methacholine DRS, and AMP DRS between asthmatic children with and without AR. In total asthmatics, methacholine DRS and AMP DRS significantly correlated with eNO levels ( r = 0.338, P < 0.001; r = 0.365, P < 0.001), but not with total IgE levels. However, eNO significantly correlated with total IgE levels ( r = 0.479, P < 0.001). Conclusion: These results suggest that AR may enhance airway inflammation but may not lead to enhanced BHR in children with asthma. (Allergy Asthma Respir Dis 2015;3:425-431)

Purpose Adherence to treatment with inhaled corticosteroids (ICS) is a critical determinant of asthma control. The objective of this study was to assess factors that determine adherence to ICS therapy in children with asthma. Methods Fifty-eight children with asthma, aged 5 to 16 years, used ICS with or without a spacer for 3 months. Adherence rates as measured from questionnaires and canisters, asthma symptom scores, and inhalation technique scores were assessed every 30 days. The degree of supervision by caregivers was assessed at day 30. Results Adherence rates measured using canisters were lower at day 60 than at day 30 (P=0.044) and did not change thereafter (74.4%±17.4% at day 30, 66.5%±18.4% at day 60, and 67.4%±22.2% at day 90). Adherence rates at days 60 and 90 and during the total study period were significantly different when measured by using questionnaires versus canisters (P

There has been growing concern regarding the effects of ambient air pollution on asthma. Particulate matter (PM) is one of the major air pollutants affecting both general population and the patients with asthma. This paper reviews the recent evidence of the adverse effects of PM on the inception and morbidity of asthma. Epidemiological studies confirmed that short-term exposure to PM aggravated respiratory symptoms and lung function in asthma patients. Furthermore, PM induces acute exacerbations of asthma with increased risk of hospitalization and death. Long-term exposure to PM is responsible for new onset of asthma and lung function decline in both children and adults. Various mechanisms are involved in the effects of PM on airway including oxidative stress, augmentation of inflammation, promotion of allergen sensitization, induction of airway hyperresponsiveness, aggravation of rhinitis and DNA methylation. Special attention and care is needed for the patients with asthma to prevent the detrimental effects of PM. (Allergy Asthma Respir Dis 2015;3:313-319)

Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in approximately one half of these subjects. BHR is usually assessed by measuring the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20). The percentage fall in FVC at the PC20 (deltaFVC) has been suggested to be a more useful index of disease severity in asthma than PC20.The aim of this study was to determine whether deltaFVC is higher in adolescents with symptomatic asthma than in those with clinical remission.Forty adolescents with symptomatic asthma and 80 adolescents with asthma remission underwent methacholine challenge testing. DeltaFVC and PC20 were measured on the methacholine dose-response curve.The mean (95% confidence interval [CI]) deltaFVC (15.5% [95% CI, 14.1 to 16.9%]) in the symptomatic group (n = 40) was significantly higher (p = 0.017) than that (12.8% [95% CI, 11.5 to 14.1%]) in the BHR-positive (PC2016 mg/mL) remission group (n = 44) or that (11.5% [95% CI, 10.2 to 12.8%]) of the BHR-negative remission group (n = 36), with no difference between the two latter groups (p = 0.581). No significant correlation was found between deltaFVC and PC20 in the symptomatic group (r = -0.156, p = 0.336) or in the whole remission group (r = -0.187, p = 0.097).Adolescents with symptomatic asthma had a higher deltaFVC than those with clinical remission, irrespective of the presence of BHR in the latter group. This finding suggests that deltaFVC may serve as an adjunct marker for differentiating between asthma persistence and remission during adolescence.

Airway hypersensitivity is routinely evaluated by measuring the concentration (PC20) of inhaled methacholine or histamine that causes a 20% fall in forced expiratory volume in 1 second (FEV1). It has been suggested that a percentage fall in forced vital capacity (FVC) measured at the PC20 dose of inhaled agonist (deltaFVC) is a potentially useful clinical measure in patients who have asthma because it provides indirect information about gas trapping and therefore the maximal airway response. The relationships between serum eosinophil cationic protein (ECP) levels and the maximal airway response or deltaFVC are largely unknown. The aims of this study were to determine whether deltaFVC is correlated with the degree of maximal airway response and to examine the relationships between serum ECP and deltaFVC or maximal airway response in patients who have mild asthma. Fifty-eight patients with mild asthma underwent high-dose methacholine challenge testing. The PC20, maximal airway response, and deltaFVC were measured on the methacholine dose-response curves. Serum ECP levels also were determined. Subjects without a maximal response plateau (n = 33) had a significantly higher level of deltaFVC (17.9 +/- 4.1%) than subjects with a plateau (n = 25; 14.9 +/- 4.8%). A significant correlation was found between deltaFVC and the level of maximal response plateau (r = 0.446; p = 0.026). Not only methacholine PC20 but also maximal airway response or deltaFVC had no relationships with serum ECP levels. Our results suggest that deltaFVC can be used as a surrogate marker of maximal airway response in patients who have mild asthma and that neither maximal airway response nor deltaFVC reflects blood eosinophil activation any more than methacholine PC20.

In asthmatic subjects, not only airway sensitivity but maximal airway response are increased on the dose-response curve to methacholine, and peak expiratory flow (PEF) variability is closely related to airway hypersensitivity and maximal airway response.The aims of this study were to compare the prevalence and the level of maximal response plateau between patients with cough-variant asthma (CVA) and those with classic asthma (CA), and to examine the relationship between airway hypersensitivity or maximal airway response and PEF variability in patients with CVA.A high-dose methacholine inhalation test was performed on 83 patients with CVA and on 83 patients with CA matched for provocative concentration of methacholine causing a 20% fall in FEV1 (PC20). PEF was recorded in the morning and evening for 14 consecutive days in 78 CVA patients, and the amplitude percentage mean was used to express the diurnal PEF variation.Fifty-two CVA subjects (62.7%) but only 33 CA subjects (39.8%) showed a maximal response plateau. This difference was significant after correction by the Bonferroni method (corrected p = 0.024). Subjects in the CVA and CA groups showing a plateau had significantly different plateau levels (38.0 +/- 5.9% vs 42.9 +/- 3.9%, corrected p = 1.0 x 10(-4)). In patients with CVA, no significant relationship was found between PC20 and PEF variability. However, the absence of a maximal response plateau and a higher plateau level were associated with increased PEF variability.Maximal airway response may be an important confounder in the relationship between airway hypersensitivity and the clinical expression of asthma. The identification of a maximal response plateau and the level of this plateau in patients with CVA provide information relevant to PEF variability.

Background Bronchial hyperresponsiveness is a universally recognized phenomenon of asthma, and increased levels of eosinophil cationic protein (ECP) have been identified in the serum of patients with asthma. Objectives To investigate whether enhanced bronchial responsiveness and elevated serum ECP levels are associated with recurrent wheezing in preschool children and to examine the possible relationship between these 2 variables. Methods We recruited 130 children aged 4 to 6 years: 59 with at least 3 episodes of wheezing in the previous year (current wheezers), 38 with a documented history of wheezing before 3 years of age but no subsequent wheezing episodes (past wheezers), and 33 who had never experienced wheezing (nonwheezers). The children underwent methacholine bronchial provocation tests using a modified auscultation method and blood sampling for the measurement of ECP levels. Results Current wheezers showed greater bronchial responsiveness than past wheezers and nonwheezers, as demonstrated by lower provocation concentrations that caused audible wheeze and lower provocation concentrations that caused a decline in oxygen saturation of at least 5% from baseline. Likewise, current wheezers had higher serum ECP levels than the other 2 groups. Among current wheezers, ECP levels showed a significant negative correlation with provocation concentrations that caused oxygen desaturation and a marginally significant correlation with provocation concentrations that caused audible wheeze. Conclusions Enhanced bronchial responsiveness and elevated serum ECP levels are associated with recurrent wheezing in 4- to 6-year-old children. These results suggest that wheezing during preschool years may be phenotypically similar to wheezing in older children.

Background: Results from epidemiologic studies have shown that childhood atopy is probably a hereditary disorder, because the offspring of affected parents have a higher risk of developing atopy. Among the atopic population, some subjects are sensitized to only one class of allergens (monosensitized), while other subjects are sensitized to more than one class of allergens (polysensitized). The aim of this study was to investigate whether atopy profile (monosensitization/polysensitization) in children is linked to the same conditions in their parents. Methods: We evaluated sensitization to five classes of aeroallergens (house dust mites, animal danders, pollens, molds, and cockroach) by skin prick testing in a group of 494 children with suspicious allergic symptoms and in their parents. Results: The frequency of parental atopy was highest (51.6%) in polysensitized children (n = 189), intermediate (37.1%) in monosensitized children (n = 178), and was lowest (22.4%) in nonsensitized children (n = 127). The proportion of polysensitized subjects among atopic parents was significantly higher for polysensitized children (45.6%) than for monosensitized children (31.1%). Polysensitized children were found to more frequently have one or both parents polysensitized (32.3%, 7.4%) than monosensitized children (18.5%, 2.2%) with odds ratios of 2.09 (95% CI: 1.29–3.40) and 3.48 (1.12–10.78), respectively, whereas the likelihood of having one or two monosensitized parents was not increased for polysensitized children. Conclusion: Our data suggest a familial coincidence of atopy profile in terms of monosensitization and polysensitization, although the relative importance of genetic or environmental influence should be studied further.

Background: The aims of this study were to compare the degree of airway inflammation in cough-variant asthma (CVA) with that in classic asthma (CA), and to examine the relationship between airway inflammation and airway hypersensitivity or maximal airway response to methacholine in both conditions. Methods: Sputum was induced in 41 CVA patients, in 41 methacholine PC20-matched CA patients, and in 20 healthy children. The sputum samples were analyzed for total and differential cell counts, and for eosinophilic cationic protein (ECP). A high-dose methacholine challenge test was performed in CVA and CA patients to determine PC20 and maximal airway response. Results: Sputum eosinophil percentages and ECP levels were significantly elevated in CVA and CA vs the control, but no significant differences were found between the two asthma groups. In the two asthma groups, neither sputum parameters correlated significantly with methacholine PC20. However, the absence of a maximal response plateau or its higher level, when present, was associated with increased eosinophil percentages and ECP levels in the CVA group. Conclusions: The degree of eosinophilic inflammation may not be causally related to differences in presented asthma manifestations. The identification of a maximal response plateau and the level of this plateau in patients with CVA may provide information pertinent to airway eosinophilic inflammation.

Results: The sensitization rates to Tree pollen mixture I and II were increased as 5.0%, 6.8% in 2000, 8.5%, 9.8% in 2005, and 14.8%, 17.3% in 2010, respectively (trend P < 0.001, P < 0.001, respectively). And the sensitization rates to D. pteronyssinus cat dander and dog dander were changed as 55%, 4.8%, 4.8% in 2000, 62.2%, 11.9%, 28% in 2005, and 63.1%, 12.7%, 16.7% in 2010, respectively. The distribution of sensitized pollens was oak (12.8%), beech (12.4%), pine (10.3%), birch (10%), hazel (9.6%), alder (8%), elder (6.9%), elm (5.4%) in the study of 2010. When allergen/histamine ratio was compared, rates of strong sensitization over 4+ to tree pollen were increased. Conclusion: The sensitization rates to inhalant allergens were increased in children with asthma or allergic rhinitis from a tertiary re- ferral hospital in Seoul over last 10 years. Especially, an increase in the degree of skin reactivity was observed in cat dander, dog dan- der, and tree pollens. The studies to investigate the etiology of this increase and prevention will be needed. (Allergy Asthma Respir Dis 2014;2:97-102)

Although it is difficult to find a cause of chronic urticaria in children, previous studies have been identified some triggers, such as autoimmunity, physical stimuli, food and its additives, and infection. History taking and physical examination remain the best tool for identifying an underlying cause of urticaria. First investigations include a complete blood count with differential, erythrocyte sedimentation rate, and C-reactive protein in children with chronic urticaria. If physical stimuli are suspected as triggers of chronic urticaria, appropriate provocation tests can be performed. Although the frequency of autoimmune urticaria was relatively high compared to the other causes in children with chronic urticaria, it is not easy to apply routine use of autologous serum skin tests to clinical practice. Additional extensive laboratory investigations are not required in the majority of cases. Second-generation H1-antihistamines are the mainstay of treatment from current guidelines in children with chronic urticaria, and dosage can be increased if the standard dose is not effective. Data on chronic urticaria in children are scarce, and causes have been considered to be similar to those in adults. Therefore, diagnostic approaches and treatment principles of chronic urticaria in children have been derived from extrapolating data in adults. In the future, comparative studies for the causes of chronic urticaria between children and adults, and therapeutic modalities for refractory cases will be needed. (Allergy Asthma Respir Dis 2014;2:236-242)

Purpose: Bronchial hyperresponsiveness is considered as a hallmark of asthma. The duration of asthma was demonstrated to be associated with bronchial responsiveness, expressed as methacholine PC20. We investigated the relationship between duration of asthma and percentage fall in forced vital capacity (FVC) at PC20 (ΔFVC), another index of bronchial responsiveness, which reflects excessive bronchoconstriction. Methods: Six- to 8-year-old children with asthma underwent methacholine inhalation test. The PC20 and ΔFVC were calculated for each individual. The subjects were classified into those with wheezing onset in the first three years of life (early-onset asthma [EA], n=63) and those with wheezing onset from three years onwards (late-onset asthma [LA], n=99). Results: From the time of wheezing onset, duration of asthma ranged from 0.2 to 8.3 years. The mean duration of asthma in patients with EA was 5.6 years (standard deviation [SD], 1.2 years), compared with 2.2 years (SD, 1.3 years) in the patients with LA. Patients with EA had a significantly lower forced expiratory volume in 1 second/FVC than did those with LA (84.6%±5.9% vs. 86.8%±5.1%, P

Purpose: Pulmonary function test (PFT) plays a key role in the diagnosis and management of asthma in adolescents.But, it is not clear whether adolescents with asthma have significantly reduced lung function when compared with adolescents without asthma. The purpose of this study was to determine the effect of atopy and allergic diseases on pulmonary function and bronchial hyperresponsiveness (BHR) in Korean adolescents. Methods: A questionnaire survey was conducted on 647 middle school students (male, 264; female, 383) from Seoul city to determine the prevalence of symptoms and diagnosed allergic diseases. We also performed the PFT, methacholine challenge test, skin prick tests and serum total immunoglobulin E. Current atopic dermatitis was diagnosed by doctor’s medical examination. Results: Female showed higher values of forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) and higher numbers of BHR (PC20 less than 25 mg/dL) compared to male (P

Lidocaine is a commonly used local anesthetic for dental treatment. Urticaria caused by lidocaine has seldom been reported. Generally, urticaria immediately develops after exposure to a causative agent and is considered a manifestation of IgE-mediated hypersensitivity. However, delayed urticaria caused by local anesthetics was reported to be related to cell mediated hypersenstivity. A 3-year old girl visited our allergy clinic due to delayed urticaria after local administration of lidocaine. Both skin prick and intradermal tests with lidocaine revealed negative reactions. However, the provocation test with subcutaneous injection of lidocaine showed urticaria 7 hours after test. In order to identify alternative local anesthetic for the subsequent dental procedure, we performed skin prick, intradermal and provocation tests with procaine, a local anesthetic of the other class, all of which showed negative results. Therefore, we recommended procaine as an alternative local anesthetic, and the patient was successfully treated with procaine. To the best of our knowledge, this is the first case of delayed urticaria caused by lidocaine in Korea. (Allergy Asthma Respir Dis 2014;2:298-301)

BACKGROUND: The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD. METHODS: This retrospective, 1∶3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire. RESULTS: The median age of the affected children (43.8% male) was 26 months (18.25-36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41-5.90, P = 0.00) were independently associated with an increased risk. CONCLUSIONS: This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.

Background Recent studies have identified an increase in the prevalence of asthma associated with paracetamol use. Objective To identify the relationship among asthma, biomarkers, genes, and paracetamol use in preschool children. Methods We undertook a population-based, cross-sectional survey of 933 preschool children. Asthma status was classified according to medical history and asthmatic symptoms. History of paracetamol use in infancy was recorded. Impulse oscillometry, blood tests for eosinophils and total IgE, and genotyping of NAT2 , Nrf2 , and GSTP1 polymorphisms by TaqMan assay were conducted. Result Paracetamol use in infancy was associated with an increased risk of treatment for asthma within the previous 12 months. Paracetamol use together with a family history of asthma increased the risk of asthma diagnosis ever, current asthma, and treatment for asthma within the previous 12 months. Gene polymorphisms in NAT2 (rs4271002), Nrf2 (rd6726395), and GSTP1 (rd1695) increased the risk of treatment for asthma within the last 12 months. Eosinophils were significantly elevated in the group with paracetamol use and a family history of asthma; however, the serum total IgE level and IOS did not show any significant difference. Conclusion Paracetamol use in infancy was significantly associated with increased risk of asthma. The association is more significant in genetically susceptible children, related to antioxidant genes, and the effect may be mediated by eosinophilic inflammation.

Purpose Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier. Recent studies showed that atopic dermatitis (AD) associates closely with loss-of-function mutations in the FLG gene. Asian and European populations differ in the frequencies of FLG mutations. Several FLG mutations, including 3321delA, E2422X, K4671X, S2554X, and R501X, occur frequently in Chinese and Japanese populations. The association between three FLG null mutations and AD in Korean children was investigated. Methods The FLG mutations in 1,430 children (aged 0-18 years) with AD and 862 control subjects were genotyped by using the TaqMan assay. Results The FLG null mutation E2422X was not detected in any patients with AD or control subjects. The R501X null mutation was detected in only one child with AD (0.1%). Children with AD had the 3321delA deletion significantly more frequently (2.4%) than the control subjects (0.0%, P

Purpose: The prevalence of allergic diseases has risen over the last few decades. Many factors, including environmental factors such as those related to diet, have been considered. Among dietary factors, intake of antioxidant-related nutrients has been associated with the risk of allergic disease. We investigated the association of antioxidant nutritional status with allergic rhinitis (AR) in Korean schoolchildren aged 6-12 years. Methods: Subjects were 4,554 children in Seoul, Korea. The risk of allergic disease was measured using the Korean version of the International Study of Asthma and Allergies in Childhood, and dietary intake was measured by a semi-quantitative food frequency questionnaire. Intake of vitamins A (including retinol and β-carotene), C, and E was used in the analysis. Results: Vitamin C intake was negatively associated with an increased risk of current symptoms (adjusted odds ratio, 0.886; 95% confidence interval, 0.806-0.973). There was no association between AR and intake of vitamin A, retinol, β-carotene, or vitamin E. Total serum IgE level and sensitization to allergen did not differ according to nutrient intake. Conclusions: The group of children with increased vitamin C consumption had fewer AR symptoms, despite the lack of a difference in total serum IgE level or allergen sensitization. These findings suggest that nutrient intake, especially that of vitamin C, influences AR symptoms.