Frequency of exacerbation and degree of required asthma medication can characterize childhood longitudinal asthma trajectories.

BACKGROUND: To the best of our knowledge, there have been no investigations of longitudinal asthma trajectories based on asthma exacerbation frequency and medications required for asthma control in children. OBJECTIVE: To investigate longitudinal asthma trajectories based on the exacerbation frequency throughout childhood and asthma medication ranks. METHODS: A total of 531 children aged 7 to 10 years were enrolled from the Korean childhood Asthma Study. Required asthma medications for control of asthma from 6 to 12 years of age and asthma exacerbation frequency from birth to 12 years of age were obtained from the Korean National Health Insurance System database. Longitudinal asthma trajectories were identified on the basis of asthma exacerbation frequency and asthma medication ranks. RESULTS: Four asthma clusters were identified: lesser exacerbation with low-step treatment (8.1%), lesser exacerbations with middle-step treatment (30.7%), highly frequent exacerbations in early childhood with small-airway dysfunction (5.7%), and frequent exacerbations with high-step treatment (55.6%). The frequent exacerbations with high-step treatment cluster were characterized by a high prevalence of male sex, increased blood eosinophil (counts) with fractional exhaled nitric oxide, and high prevalence of comorbidities. The highly frequent exacerbation in early childhood with small-airway dysfunction cluster was characterized by recurrent wheeze in preschool age, with high prevalence of acute bronchiolitis in infancy and a greater number of family members with small-airway dysfunction at school age. CONCLUSION: The present study identified 4 longitudinal asthma trajectories on the basis of the frequency of asthma exacerbation and asthma medication ranks. These results would help clarify the heterogeneities and pathophysiologies of childhood asthma.

Fetal growth rather than prematurity determines lung function in children with asthma.

BACKGROUND AND OBJECTIVE: Preterm birth or fetal growth has been associated with reduced lung function and asthma during childhood in the general population. We aimed to elucidate whether prematurity or fetal growth has a significant influence on lung function or symptoms in children with stable asthma. METHODS: We included children with stable asthma who participated in the Korean childhood Asthma Study cohort. Asthma symptoms were determined by asthma control test (ACT). Percent predicted values of pre- and post-bronchodilator (BD) lung function including forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), and forced expiratory flow at 25%-75% of FVC (FEF25%-75% ) were measured. Lung function and symptoms were compared according to the history of preterm birth and birth weight (BW) for gestational age (GA). RESULTS: The study population consisted of 566 children (age range: 5-18 years). There were no significant differences in lung function and ACT between preterm and term subjects. We observed no significant difference in ACT but significant differences were observed in pre- and post-BD FEV1 , pre- and post-BD FVC, and post-BD FEF25%-75% according to BW for GA in total subjects. Two-way ANOVA revealed that BW for GA rather than prematurity was a significant determining factor for pre- and post-BD lung function. After regression analysis, BW for GA was still a significant determining factor of pre- and post-BD FEV1 and pre- and post-BD FEF25%-75% . CONCLUSION: Fetal growth rather than prematurity appears to have a significant effect on lung function in children with stable asthma.

Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function.

The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.

Leukotriene receptor antagonists and risk of neuropsychiatric events in children, adolescents and young adults: a self-controlled case series.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are widely used for asthma and allergic rhinitis (AR), but concerns about the risk of neuropsychiatric events (NPEs) have been raised since the first Drug Safety Communication by the US Food and Drug Administration in 2008. This study evaluates the association between LTRA use and NPEs in children, adolescents and young adults with asthma or AR. METHODS: A self-controlled case series study was conducted using the Korean National Health Insurance Service claims database from two 3-year observation periods (observation period 1 (Obs1): 2005-2007; observation period 2 (Obs2): 2016-2018). Asthma or AR patients aged 3-30 years who were prescribed LTRAs and diagnosed with NPEs were included. The incidence rate ratios (IRRs) for the exposed period and risk periods (1-3, 4-7, 8-14, 15-30, 31-90 and >90 days from initiation of LTRA) compared with unexposed periods were calculated using conditional Poisson regression. Subgroup analysis according to age group, type of NPEs and indication of LTRA was performed. RESULTS: Among 17 001 included patients, the risk of NPEs increased in Obs2 (IRR 1.11, 95% CI 1.00-1.22), but did not increase in Obs1. Risk was increased during risk periods 4-7 days (IRR 2.36, 95% CI 1.99-2.76) and 8-14 days (IRR 1.78, 95% CI 1.46-2.15) after initiation of LTRA, particularly in adolescents (IRR 1.28, 95% CI 1.05-1.55) and young adults (IRR 1.14, 95% CI 1.02-1.28), while risk was decreased in children (3-11 years). Risk was not increased for any single type of NPE. AR patients were at increased risk (IRR 1.19, 95% CI 1.01-1.39), but not those with asthma. CONCLUSIONS: Overall, risk of NPEs with LTRA use differed between risk periods and subgroups. Physicians should prescribe LTRAs according to indications and inform patients about possible NPEs.

Longitudinal asthma exacerbation phenotypes in the Korean childhood asthma study cohort.

BACKGROUND: Asthma exacerbation (AE) leads to social and economic costs and long-term adverse outcomes. We aimed to predict exacerbation-prone asthma (EPA) in children. METHODS: The Korean childhood Asthma Study (KAS) is a prospective nationwide pediatric asthma cohort of children aged 5-15 years followed every 6 months. Patients with AE during the 6 months prior to all three visits, with AE prior to one or two visits, and without AE prior to any visit were defined as having EPA, exacerbation-intermittent asthma (EIA), and exacerbation-resistant asthma (ERA), respectively. Risk factors and prediction models of EPA were explored. RESULTS: Of the 497 patients who completed three visits, 42%, 18%, and 15% had exacerbations prior to visits 1, 2, and 3 and 5%, 47%, and 48% had EPA, EIA, and ERA, respectively. Univariate and multivariable logistic regression revealed forced expiratory volume in 1 s (FEV1) z-score, forced vital capacity (FVC) z-score, white blood cell (WBC) count, and asthma control test (ACT) score as relevant EPA risk factors. The EPA prediction model comprised FVC z-score, WBC count, ACT score, sex, and parental education level (area under the receiver operating characteristic curve [AUROC] 0.841 [95% confidence interval (CI): 0.728-0.954]). CONCLUSION: With appropriate management, AE decreases over time, but persistent AEs may occur. Apart from asthma control level, baseline lung function and WBC count predicted EPA.

Sublingual immunotherapy may be effective in reducing house dust mite allergies in children with atopic dermatitis.

AIM: We evaluated the efficacy of sublingual immunotherapy for children aged 5-17 years with atopic dermatitis who were allergic to house dust mites. METHODS: This open-label, controlled, randomised trial from June 2015 to February 2018 comprised 60 subjects from a specialist allergy centre in South Korea. Half received sublingual immunotherapy for 12 months and the other half formed the control group. The subjects were evaluated using specialist scores and specific immunoglobulin and skin prick tests. RESULTS: Sublingual immunotherapy significantly decreased the mean Scoring Atopic Dermatitis measurements in the sublingual group from baseline (30.2 ± 10.7) to 3 months (20.7 ± 8.5) and the effects persisted at 12 months (21.5 ± 12.4). However, the control group only showed a significant difference between baseline (30.4 ± 11.9) and 12 months (24.3 ± 10.2). The levels of Dermatophagoides farina-specific immunoglobulin G4 significantly increased in the treatment group from baseline (0.6 ± 0.5) to 12 months (1.0 ± 0.7), with no significant changes in the control group. New sensitisations to two or more allergens between baseline and 12 months were significantly lower in the sublingual group (21.4%) than controls (54.2%). CONCLUSION: Sublingual immunotherapy improved disease severity and prevented new sensitisations in children with atopic dermatitis who were allergic to dust mites.

Innate Type 2 Response to Aspergillus fumigatus in a Murine Model of Atopic Dermatitis-like Skin Inflammation.

BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease mediated by T helper type 2 (Th2) cells in acute phase. Group 2 innate lymphoid cells (ILCs) play a role in the initiation of the Th2 response. Although mold exposure is associated with the development of AD, studies on the underlying mechanisms are lacking. This study investigated whether group 2 ILCs are involved in inflammation in AD-like skin induced by Aspergillus fumigatus (Af). METHODS: We investigated changes of group 2 ILCs population in Af-induced AD-like skin lesions. To induce AD-like skin lesions, Af extracts were applied to the dorsal skin of BALB/c and Rag1-/- mice five times per week, with repeat exposures at 2-week intervals. RESULTS: The clinical parameters were higher in the Af-treated group than in the control group. Histologic findings revealed epiderrmal and dermal thickening as well as eosinophil and mast cell infiltration into the skin of Af-treated mice. Populations of group 2 ILCs in the skin were also significantly higher in the Af-treated group. In addition, interleukin-33 mRNA expression was significantly higher in the skin lesions of the Af-treated mice. In the Rag1-/- mice lacking mature lymphocytes, AD-like skin lesions were still induced by Af and ILCs depletion using an anti-CD90.2 mAb lowered the Af-induced inflammatory response. CONCLUSIONS: Group 2 ILCs may play a role in a murine model of Af-induced AD-like skin lesions.

Annual and seasonal patterns in etiologies of pediatric community-acquired pneumonia due to respiratory viruses and Mycoplasma pneumoniae requiring hospitalization in South Korea.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. METHODS: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. RESULTS: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. CONCLUSIONS: The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.

Asthma control test reflects not only lung function but also airway inflammation in children with stable asthma.

Objective: Various numerical asthma control tools have been developed to distinguish different levels of symptom control. We aimed to examine whether the asthma control test (ACT) is reflective of objective findings such as lung function, fractional exhaled nitric oxide (FeNO) and laboratory data in patients with stable asthma.Methods: We included patients who were enrolled in the Korean Childhood Asthma Study. ACT, spirometry, blood tests and FeNO were performed in patients after stabilization of their asthma. We examined differences among spirometry parameters, blood tests and FeNO according to control status as determined by ACT and investigated for any significant correlations.Results: The study population consisted of 441 subjects. Spirometry showed that forced expiratory volume in one second (FEV1), forced expiratory flow between 25% and 75% of forced vital capacity and FEV1/forced vital capacity were all significantly higher in the controlled asthma group. Likewise, FeNO and percent-change in FEV1 were both significantly lower in the controlled asthma group. In blood tests, the eosinophil fraction was significantly lower in the controlled asthma group while white blood cell count was significantly higher in the controlled asthma group. Lastly, among the various factors analyzed, only provocative concentration of methacholine causing a 20% fall in FEV1 significantly correlated with ACT score.Conclusion: ACT is useful as part of the routine evaluation of asthmatic children and should be used as a complement to existing tools such as spirometry and FeNO measurement.

Korean childhood asthma study (KAS): a prospective, observational cohort of Korean asthmatic children.

BACKGROUND: Asthma is a syndrome composed of heterogeneous disease entities. Although it is agreed that proper asthma endo-typing and appropriate type-specific interventions are crucial in the management of asthma, little data are available regarding pediatric asthma. METHODS: We designed a cluster-based, prospective, observational cohort study of asthmatic children in Korea (Korean childhood Asthma Study [KAS]). A total of 1000 Korean asthmatic children, aged from 5 to 15 years, will be enrolled at the allergy clinics of the 19 regional tertiary hospitals from August 2016 to December 2018. Physicians will verify the relevant histories of asthma and comorbid diseases, as well as airway lability from the results of spirometry and bronchial provocation tests. Questionnaires regarding subjects' baseline characteristics and their environment, self-rating of asthma control, and laboratory tests for allergy and airway inflammation will be collected at the time of enrollment. Follow-up data regarding asthma control, lung function, and environmental questionnaires will be collected at least every 6 months to assess outcome and exacerbation-related aggravating factors. In a subgroup of subjects, peak expiratory flow rate will be monitored by communication through a mobile application during the overall study period. Cluster analysis of the initial data will be used to classify Korean pediatric asthma patients into several clusters; the exacerbation and progression of asthma will be assessed and compared among these clusters. In a subgroup of patients, big data-based deep learning analysis will be applied to predict asthma exacerbation. DISCUSSION: Based on the assumption that asthma is heterogeneous and each subject exhibits a different subset of risk factors for asthma exacerbation, as well as a different disease progression, the KAS aims to identify several asthma clusters and their essential determinants, which are more suitable for Korean asthmatic children. Thereafter we may suggest cluster-specific strategies by focusing on subjects' personalized aggravating factors during each exacerbation episode and by focusing on disease progression. The KAS will provide a good academic background with respect to each interventional strategy to achieve better asthma control and prognosis.

Respiratory reactance in children aged three to five years with postinfectious bronchiolitis obliterans is higher than in those with asthma.

AIM: We investigated airway function in preschoolers with postinfectious bronchiolitis obliterans (PIBO) using impulse oscillometry (IOS). METHODS: This study enrolled 182 children aged three to five years: 12 with PIBO, 135 with asthma and 35 nonatopic controls. Respiratory resistance and reactance were assessed using IOS. RESULTS: The percentage predicted (% predicted) of prebronchodilator respiratory resistance at 5 Hz was significantly higher in children with PIBO (177.9 ± 118.4%) than the asthma (126.1 ± 30.5%, p = 0.013) or control (121.1 ± 21.8%, p = 0.014) groups. After bronchodilator use, children with PIBO did not reach the values of Rrs5% predicted in the asthma and control groups. Respiratory reactance (Xrs5% predicted) in children with PIBO (337.1 ± 478.5%) was significantly higher than both asthma (130.0 ± 80.0%, p = 0.004) and control (105.1 ± 30.8%, p < 0.001) groups before bronchodilator use and significantly higher than the two groups after bronchodilator use (p = 0.010 and p = 0.004, respectively). The changes in Rrs5 and Xrs5 were not significantly different between the children with PIBO and asthma. CONCLUSION: Measuring Rrs5 and Xrs5 before and after bronchodilator use may help to discriminate PIBO from asthma in children aged three to five years with chronic or recurrent respiratory symptoms.

The First Successful Lung Transplantation in a Korean Child with Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive inherited multisystem disorder caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Respiratory failure remains the most frequent cause of morbidity and mortality. Lung transplantation is the only option to treat end-stage lung disease. Very few cases of CF occur in Koreans. We report the case of a 12-year-old girl with respiratory failure due to CF who underwent lung transplantation. She had been diagnosed with CF 8 years previously after being treated for recurrent Pseudomonas aeruginosa pneumonia and malnutrition based on sweat chloride concentrations and the CFTR protein gene mutation test. Progression to end-stage lung disease and respiratory failure led to registration with the Korean Network for Organ Sharing. She underwent successful double lung transplantation in 2014. Although she has diabetes mellitus and chronic kidney disease, she has a better quality of life and a prolonged life expectancy.

The Different Clinical Aspects of Pediatric Primary Airway Tumors in the Larynx, Trachea, and Bronchi.

Primary airway tumors are rare in children and no literature reviewed their characteristics each location. We evaluate the clinical characteristics and outcomes of Korean children with primary airway tumors, from the larynx to bronchi. A retrospective chart review of children with primary tumors of the larynx, trachea, and bronchi at Asan Medical Center from January 2000 to July 2016 was conducted. Nineteen children were diagnosed with primary airway tumors of the larynx (47.4%), trachea (10.5%), and bronchi (42.1%). Median follow-up duration was 2.8 years and there were recurrences in 21.1%. Laryngeal tumors were associated with a younger median age at onset (2 months) and diagnosis (4 months), and most were relatively small (median size = 5.3 mm) and symptomatic. Tracheal and bronchial tumors were found in older children (age at onset and diagnosis > 11 years) and large (> 15.0 mm). Most (75%) patients with bronchial tumors were asymptomatic and all the patients with tracheal tumors were symptomatic. This study suggests that we should consider different the locations in primary airway tumor based on the age at onset and diagnosis, initial symptoms or signs, and size of tumor.

The First Successful Heart-Lung Transplant in a Korean Child with Humidifier Disinfectant-Associated Interstitial Lung Disease.

From 2006 to 2011, an outbreak of a particular type of childhood interstitial lung disease occurred in Korea. The condition was intractable and progressed to severe respiratory failure, with a high mortality rate. Moreover, in several familial cases, the disease affected young women and children simultaneously. Epidemiologic, animal, and post-interventional studies identified the cause as inhalation of humidifier disinfectants. Here, we report a 4-year-old girl who suffered from severe progressive respiratory failure. She could survive by 100 days of extracorporeal membrane oxygenation support and finally, underwent heart-lung transplantation. This is the first successful pediatric heart-lung transplantation carried out in Korea.

Association of symptom control with changes in lung function, bronchial hyperresponsiveness, and exhaled nitric oxide after inhaled corticosteroid treatment in children with asthma.

BACKGROUND: A key therapeutic approach to asthma, which is characterized by chronic airway inflammation, is inhaled corticosteroid (ICS). This study evaluated the association of symptom control with changes in lung function, bronchial hyperresponsiveness (BHR), and exhaled nitric oxide (eNO) after ICS treatment in asthmatic children. METHODS: A total of 33 children aged between 5 and 12 years with mild to moderate persistent asthma were treated with 160 µg ciclesonide per day for 3 months. At days 0 and 90, the following parameters were assessed: asthma symptom scores; lung function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%); BHR to methacholine and adenosine 5-monophosphate (AMP); and eNO. RESULTS: Asthma symptom scores, lung function parameters, BHR to methacholine and AMP, and eNO levels at day 90 were significantly improved versus day 0 (all p < 0.001). Symptom scores at day 90 were not correlated with changes in lung function and BHR to methacholine during the follow-up period, whereas those at day 90 were more closely correlated with changes in BHR to AMP (r = 0.511, p = 0.003) than with eNO (r = -0.373, p = 0.035). Additionally, changes in PC20 AMP were correlated with changes in PC20 methacholine (r = 0.451, p = 0.011) and eNO (r = -0.474, p = 0.006). CONCLUSIONS: Changes in the BHR to AMP, and to a lesser extent eNO, correlate with asthma symptom control after ICS treatment. BHR to AMP may better reflect the relationship between improved airway inflammation due to ICS treatment and asthma symptoms.

Effects of Lactobacillus rhamnosus on allergic march model by suppressing Th2, Th17, and TSLP responses via CD4(+)CD25(+)Foxp3(+) Tregs.

Allergic march (AM) is characterized by the progression of clinical signs of atopic dermatitis (AD) to allergic asthma or rhinitis, but its pathogenesis is not completely understood. We developed mouse model of AM with three 1-week exposures (separated by 2-week interval) to an OVA or saline (control) followed by OVA challenge. The development of AM was confirmed by phenotypes of AD and allergic asthma. Increases in IL-4, IL-17, and thymic stromal lymphopoietin (TSLP) responses were associated with the progression of AM, and these responses were suppressed by treatment with Lcr35. Moreover, Lcr35 treatment led to an increase in the number of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells in the mesenteric lymph nodes (MLNs) of AM mice. In conclusion, the oral application of Lcr35 prevented the development of AM in this model by suppressing Th2, Th17, and TSLP responses via a mechanism that may involve CD4(+)CD25(+)Foxp3(+) Tregs in MLNs.

Feasibility of Home-Based Pulmonary Rehabilitation of Pediatric Patients with Chronic Respiratory Diseases.

BACKGROUND AND OBJECTIVE: Chronic respiratory diseases in children deteriorate their daily life due to dyspnea and reduced lung function. We aimed to evaluate the feasibility of home-based pulmonary rehabilitation in pediatric chronic respiratory diseases. METHODS: This prospective, single-arm, cohort study included children with chronic lung disease. They were instructed to perform home-based pulmonary rehabilitation 30 min/session, three sessions/week for three months. Pulmonary function test (PFT) using spirometry, respiratory muscle strength (RMT), cardiopulmonary exercise test (CPET), 6 min walk test (6MWT), dyspnea questionnaires, speech evaluation, and pediatric quality of life inventory (PedsQL) were assessed pre- and post-pulmonary rehabilitation. Compliance and satisfaction of the program were also evaluated. RESULTS: Twenty children (mean age: 11.2 ± 3.1 years) with chronic respiratory diseases without cardiopulmonary instability participated. The overall compliance was 71.1% with no related adverse events. After pulmonary rehabilitation, forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), RMT, 6MWT, dyspnea questionnaire, speech rate, and PedsQL (child) significantly improved (p < 0.05), particularly better in the FEV1 < 60% group than in the FEV1 ≥ 60% group and in the high-compliance group (compliance ≥ 50%) than in the low-compliance group (compliance < 50%). CONCLUSIONS: Home-based pulmonary rehabilitation for children with chronic lung disease was feasible with high compliance and effective in terms of objective functions, subjective dyspnea symptom, and quality of life.

Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes.

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.

IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin.

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.