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Asthma is a chronic inflammatory disease around the world. Extracellular adenosine triphosphate works as a dangerous signal in responding to cellular stress, irritation, or inflammation. It has also been reported its association with the pathogenicity in asthma, with increased level in lungs of asthmatics. Pannexin-1 is one of the routes that contributes to the release of adenosine triphosphate form intracellular to extracellular. The aim of this study was to apply pannexin-1 peptide antagonist 10 Panx1 into adeno-associated viral (AAV) vectors on ovalbumin (OVA)-induced asthmatic mouse model. The results demonstrated that this treatment was able to reduce the adenosine triphosphate level in bronchoalveolar lavage fluid and downregulate the major relevant to the symptom of asthma attack, airway hyperresponsiveness to methacholine. The histological data also gave a positive support with decreased tissue remodeling and mucus deposition. Other asthmatic related features, including eosinophilic inflammation and OVA-specific T helper type 2 responses, were also decreased by the treatment. Beyond the index of inflammation, the proportion of effector and regulatory T cells was examined to survey the potential mechanism behind. The data provided a slightly downregulated pattern in lung GATA3 + CD4 T cells. However, an upregulated population of CD25 + FoxP3 + CD4 T cells was seen in spleens. These data suggested that exogeneous expression of 10 Panx1 peptide was potential to alleviated asthmatic airway inflammation, and this therapeutic effect might be from 10 Panx1-mediated disruption of T cell activation or differentiation. Collectively, AAV vector-mediated 10 Panx1 expression could be a naval therapy option to develop.

High levels of allergen exposure increase the prevalence of asthma in developed countries. The asthmatic type 2 T-helper (Th2) response is characterized with high eosinophil infiltration, elevated Th2 cytokines, and immunoglobulin (Ig) E secretion resulting in local or systemic inflammation. However, the treatment with palliative Th2 inhibitor drugs cannot completely control asthma and that is why the development of novel approaches is still important. Based on type 1 T-helper (Th1) and Th2 immune homeostasis, the enhanced Th1 immune response has high potential to alleviate Th2 immune response. Thus, we aimed to overexpress single chain IL-12 (scIL-12) through recombinant adeno-associated virus (rAAV) vector (as rAAV-IL-12) and test the efficacy in an ovalbumin (OVA)-induced asthmatic murine model. We firstly demonstrated the bioactivity of exogenous scIL-12. The expression of exogenous scIL-12 was also detected in the lungs of rAAV-IL-12 transduced mice. The data demonstrated that overexpression of exogenous scIL-12 significantly suppressed total number of cells and eosinophil infiltration, as well as the mucus secretion in rAAV-IL-12-treated mice. The decreased OVA-specific IgE in bronchoalveolar lavage fluid and gene expression of Th2-cytokines or C-C motif ligand (CCL) 11 (also eotaxin-1) in lung were observed. In addition, the production of cytokines in the supernatants of OVA-stimulated splenocytes were suppressed with rAAV-IL-12 treatment. Thus, scIL-12 expression by rAAV vector was able to modulate Th2 activity and has the potential to be developed as a feasible strategy in modulating allergic diseases.

Sophoraflavanone G (SG), isolated from Sophora flavescens , has anti-inflammatory and anti-tumor bioactive properties. We previously showed that SG promotes apoptosis in human breast cancer cells and leukemia cells and reduces the inflammatory response in lipopolysaccharide-stimulated macrophages. We investigated whether SG attenuates airway hyper-responsiveness (AHR) and airway inflammation in asthmatic mice. We also assessed its effects on the anti-inflammatory response in human tracheal epithelial cells. Female BALB/c mice were sensitized with ovalbumin, and asthmatic mice were treated with SG by intraperitoneal injection. We also exposed human bronchial epithelial BEAS-2B cells to different concentrations of SG to evaluate its effects on inflammatory cytokine levels. SG treatment significantly reduced AHR, eosinophil infiltration, goblet cell hyperplasia, and airway inflammation in the lungs of asthmatic mice. In the lungs of ovalbumin-sensitized mice, SG significantly promoted superoxide dismutase and glutathione expression and attenuated malondialdehyde levels. SG also suppressed levels of Th2 cytokines and chemokines in lung and bronchoalveolar lavage samples. In addition, we confirmed that SG decreased pro-inflammatory cytokine, chemokine, and eotaxin expression in inflammatory BEAS-2B cells. Taken together, our data demonstrate that SG shows potential as an immunomodulator that can improve asthma symptoms by decreasing airway-inflammation-related oxidative stress.

Background: Several studies have reported the relevance between serum vitamin D and allergic immunoglobulin E (IgE) responses and atopic diseases. However, a metabolomics-based approach to the impacts of vitamin D on allergic reactions remains unclear., Methods: A total of 111 children completed a 3-year follow-up were enrolled and classified based on longitudinal vitamin D status (≥ 30 ng/ml, n = 54; 20-29.9 ng/ml, n = 41; <20 ng/ml, n = 16). Urinary metabolomic profiling was performed using 1 H-Nuclear magnetic resonance (NMR) spectroscopy at age 3. Integrative analyses of their associations related to vitamin D levels, atopic indices, and allergies were performed, and their roles in functional metabolic pathways were also assessed., Results: Six and five metabolites were identified to be significantly associated with vitamin D status and atopic diseases, respectively (FDR-adjusted p-value <.05). A further correlation analysis revealed that vitamin D-associated 3-hydroxyisobutyric acid and glutamine were positively correlated with atopic disease-associated succinic acid and alanine, respectively. Furthermore, hippuric acid was negatively correlated with atopic disease-associated formic acid, which was positively correlated with vitamin D level (p < .01). Absolute eosinophil count (AEC) was positively correlated with serum D. pteronyssinus- and D. farinae-specific IgE level (p < .01) but negatively correlated with vitamin D level (p < .05). Amino acid metabolisms were significantly associated with vitamin D related to childhood allergies., Conclusion: Integrative metabolomic analysis provides the link of vitamin D-associated metabolites with the gut microbiome and immunoallergic reactions related to childhood allergies., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Asthma is an important cause of subacute cough. The concentration of alveolar nitric oxide (CANO) is a sensitive inflammatory indicator in peripheral airways, and it has received much less attention than the fraction of exhaled nitric oxide (FeNO 50 ). The main objective of this study was to explore the correlation between CANO and clinical parameters in asthmatic and non-asthmatic subacute cough, which might promote understanding of the clinical utility of CANO in these special patient populations. 155 patients with subacute cough were included consecutively, of which 25 were diagnosed as asthmatic. Data for demographic characteristics, FeNO 50 , CANO, baseline spirometry, bronchial provocation test (or bronchodilation test) and response dose ratio (RDR) were collected. Differences between the asthmatic and non-asthmatic groups were analyzed. Spearman's correlation coefficient ( ρ ) was used to evaluate the correlation between FeNO 50 , CANO and other clinical parameters. In patients with subacute cough, baseline CANO values did not differ between asthmatic and non-asthmatic patients (4.4(1.3, 11.4) versus 4.0(2.1, 6.8) ppb, P > 0.05). Besides, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO 50 . For asthmatic subacute cough, CANO was inversely correlated with FEV 1 /FVC ( ρ = -0.69, P < 0.01) and small airway parameters including MEF25 ( ρ = -0.47, P < 0.05) and MMEF ( ρ = -0.45, P < 0.05). For non-asthmatic subacute cough, CANO was inversely correlated with MEF25 ( ρ = -0.19, P < 0.05) and RDR ( ρ = -0.21, P < 0.05). In subacute cough, asthmatic and non-asthmatic patients had similar values of baseline CANO. In both asthmatic and non-asthmatic subacute cough, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO 50 . A low CANO value in non-asthmatic subacute cough corresponded to a higher value of RDR, which implied a stronger tendency towards airway responsiveness., (© 2021 IOP Publishing Ltd.)

Background: Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled leukotriene B 4 (LTB 4 ), characterizes childhood asthma. While fractional exhaled nitric oxide (FeNO) has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment., Methods: Levels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA., Results: In addition to those previously reported, including LTB 4 , the levels of exhaled 15-hydroxyeicosatetraenoic acid (15-HETE), but not thromboxane B 2 (TXB 2 ), showed significant difference between asthmatics (N = 318) and healthy controls (N = 97), particularly the severe group showed the lowest levels of exhaled 15-HETE. Receiver operating characteristic (ROC) curve analyses revealed similar distinguishing power for the levels of 15-HETE, FEV 1 (forced expiratory volume in the first second), and FeNO, while the 15-HETE/LTB 4 ratio was significantly lower in subjects with asthma as compared to that of healthy controls (p < 0.0001). Analysis of asthmatics (N = 75) during exacerbation and convalescence showed significant improvement in lung function (FEV 1 , p < .001), but not FeNO, concomitant with significantly increased levels of 15-HETE (p < .001) and reduced levels of TXB 2 (p < .05) at convalescence, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB 4 and lipoxin A 4 (LXA 4 ) at convalescence were noted only in those at the top 30 percentile during exacerbation., Conclusion: The exhaled 15-HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB 2 and increased levels of 15-HETE were prominent at convalescence., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Objective: Air pollution is associated with the prevalence of respiratory diseases. This study aimed to evaluate the impacts of outdoor air pollutants and indoor Dermatophagoides pteronyssinus 1 ( Der p 1) exposure on levels of fractional exhaled nitric oxide (FeNO), exhaled breath condensate (EBC) pH, and pulmonary function in atopic children., Methods: This study recruited 59 atopic mild-to-moderate asthmatic children and 23 atopic non-asthmatic children. Data on personal characteristics, FeNO, EBC pH, and pulmonary function were collected. Group 1 allergens of Der p 1 were measured on the tops of mattresses and on bedroom floors in the children's homes, and outdoor air pollutant concentrations were estimated from air quality monitoring stations, using the ordinary kriging method., Results: Exposure levels of outdoor air pollutants, except for particulate matter (PM) 2.5 , for the recruited children met outdoor air quality standards set by the Taiwan Environmental Protection Agency. The lag effect of outdoor PM 10 exposure was negatively associated with the forced expiratory volume in one second (FEV 1 ) [(Lag 1: β =-0.771, p  = 0.028), and O 3 (Lag 1-7: β =-2.02, p  = 0.04, Lag 1-28: β =-3.213, p  = 0.029)]. Median pulmonary function parameters differed significantly in forced vital capacity (FVC) ( p  = 0.004) and FEV 1 ( p  = 0.024) values between atopic asthmatic and non-asthmatic children. No association was found between the FeNO/EBC pH level and exposure to Der p 1 allergen and air pollutants in the recruited children., Conclusions: Outdoor PM 10 and O 3 exposure was associated with reduction in FEV 1 in atopic asthmatic and non-asthmatic children.

Asthma is a T helper 2 (Th2) cell-associated chronic inflammatory diseases characterized with airway obstruction, increased mucus production, and eosinophil infiltration. Conventional medications for asthma treatment cannot fully control the symptoms, and potential side effects are also the concerns. Thus, complement or alternative medicine (CAM) became a new option for asthma management. Ding Chuan Tang (DCT) is a traditional Chinese herbal decoction applied mainly for patients with coughing, wheezing, chest tightness, and asthma. Previously, DCT has been proved to improve children airway hyperresponsiveness (AHR) in a randomized and double-blind clinical trial. However, the mechanisms of how DCT alleviates AHR remain unclear. Since asthmatic features such as eosinophil infiltration, IgE production, and mucus accumulation are relative with Th2 responses, we hypothesized that DCT may attenuate asthma symptoms through regulating Th2 cells. Ovalbumin (OVA) was used as a stimulant to sensitize BALB/c mice to establish an asthmatic model. AHR was detected one day before sacrifice. BALF and serum were collected for immune cell counting and antibody analysis. Splenocytes were cultured with OVA in order to determine Th2 cytokine production. Lung tissues were collected for histological and gene expression analyses. Our data reveal that DCT can attenuate AHR and eosinophil accumulation in the 30-day sensitization asthmatic model. Histological results demonstrated that DCT can reduce cell infiltration and mucus production in peribronchial and perivascular site. In OVA-stimulated splenocyte cultures, a significant reduction of IL-5 and IL-13 in DCT-treated mice suggests that DCT may alleviate Th2 responses. In conclusion, the current study demonstrates that DCT has the potential to suppress allergic responses through the reduction of mucus production, eosinophil infiltration, and Th2 activity in asthma., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 Jason Ma et al.)

The proportion of allergic diseases attributable to atopy remains a subject of controversy. This study aimed to estimate the population risk of physician-diagnosed asthma, rhinitis and eczema attributed to atopy among a population sample of Asian school-age children. Asian children aged 5-18 years (n = 1321) in the Prediction of Allergies in Taiwanese CHildren (PATCH) study were tested for serum allergen-specific immunoglobulin E. Physician-diagnosed asthma, rhinitis and eczema were assessed by a modified International Study of Asthma and Allergies in Childhood questionnaire. Atopy was defined as the presence of serum allergen-specific immunoglobulin E. In this population-based study, 50.4% of the subjects with asthma, 46.3% with rhinitis, and 46.7% with eczema were attributable to atopy. The population attributable risk (PAR) of atopy for three allergic diseases was higher in adolescents (asthma, 54.4%; rhinitis, 59.6%; eczema, 49.5%) than younger children aged less than 10 years (asthma, 46.9%; rhinitis, 39.5%; eczema, 41.9%). Among the seven allergen categories, sensitization to mites had the highest PARs for all three allergic diseases (51.3 to 64.1%), followed by sensitization to foods (asthma, 7.1%; rhinitis, 10.4%; eczema 27.7%). In conclusion, approximately half (46.3 to 50.4%) of Asian children in Taiwan with allergic diseases are attributable to atopy., (© 2021. The Author(s).)

Background: The association between oxidative stress and atopic diseases is uncertain. Several risk factors for atopic diseases have been identified, however, a comprehensive investigation of the relationship between oxidative stress markers and atopic indices related to atopic diseases is currently lacking., Methods: We investigated 132 children who completed a 7-years follow-up in a birth cohort. Oxidative stress markers including plasma glutathione peroxidase (GPx), myeloperoxidase (MPO), total anti-oxidant capacity (TAC), and urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were measured. Allergen-specific IgE levels, FeNO levels, and pulmonary function tests were also obtained., Results: The activity of GPx and levels of MPO were inversely correlated to food (shrimp and crab) and house dust mite sensitization respectively. The 8-OHdG levels were strongly negatively correlated with FeNO levels (p < 0.01). A significant positive correlation was found between TAC levels and pre-and post-bronchodilator FVC % and FEV1% predicted (p < 0.05). All oxidative stress markers were not associated with the risk of atopic diseases. However, GPx-related crab sensitization and 8-OHdG related FeNO levels were significantly associated with increased risk of allergic rhinitis, while MPO-related mite sensitization and TAC-related pulmonary function parameters were strongly associated with risk of asthma (p < 0.01)., Conclusion: Oxidative stress is strongly correlated with allergic indices, potentially playing a role in the modulation of allergic responses contributing to atopic diseases., Competing Interests: Declaration of Competing Interest All the authors declare no conflicts of interest in relation to the present study., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To evaluate the diagnostic value of fractional exhaled nitric oxide (FeNO) and maximum mid-expiratory flow (MMEF) for differentiating cough variant asthma (CVA) from chronic cough in patients with or without allergic rhinitis., Methods: In total, 328 patients with chronic cough who underwent spirometry and FeNO testing were consecutively included in the retrospective analysis. Patients were divided into the CVA ( n  = 125) or NCVA ( n  = 203) groups according to the diagnostic criteria of CVA. Receiver operating characteristic (ROC) curves were established to assess the diagnostic efficiency and optimal cutoff points of FeNO and MMEF for the prediction of CVA., Results: The optimal cutoff values of FeNO and MMEF to discriminate CVA from chronic cough were 24.5 ppb (AUC, 0.765; sensitivity, 69.60%; specificity 72.91%; PPV, 61.27%; NPV, 79.57%) and 66.2% (AUC, 0.771; sensitivity, 67.20%; specificity 78.33%; PPV, 65.63%; NPV, 79.50%). The optimal cutoff values of combining FeNO with MMEF to discriminate CVA from chronic cough were >22 ppb for FeNO and <62.6% for MMEF (AUC, 0.877). In patients with and without allergic rhinitis, the optimal cutoff point of FeNO to discriminate CVA from chronic cough was 24.5 ppb (AUC, 0.820) and 33.5 ppb (AUC, 0.707), respectively., Conclusions: FeNO and MMEF might have greater value as negative parameters for differentiating CVA from chronic cough. Combining FeNO and MMEF provided a significantly better prediction than either alone. The diagnostic accuracy of FeNO for predicting CVA in chronic cough patients with allergic rhinitis was higher than in chronic cough patients without allergic rhinitis.

Helminthostachys zeylanica is a traditional folk herb used to improve inflammation and fever in Taiwan. Previous studies showed that H. zeylanica extract could ameliorate lipopolysaccharide-induced acute lung injury in mice. The aim of this study was to investigate whether H. zeylanica water (HZW) and ethyl acetate (HZE) extracts suppressed eosinophil infiltration and airway hyperresponsiveness (AHR) in asthmatic mice, and decreased the inflammatory response and oxidative stress in tracheal epithelial cells. Human tracheal epithelial cells (BEAS-2B cells) were pretreated with various doses of HZW or HZE (1  μ g/ml-10  μ g/ml), and cell inflammatory responses were induced with IL-4/TNF- α . In addition, female BALB/c mice sensitized with ovalbumin (OVA), to induce asthma, were orally administered with HZW or HZE. The result demonstrated that HZW significantly inhibited the levels of proinflammatory cytokines, chemokines, and reactive oxygen species in activated BEAS-2B cells. HZW also decreased ICAM-1 expression and blocked monocytic cells from adhering to inflammatory BEAS-2B cells in vitro . Surprisingly, HZW was more effective than HZE in suppressing the inflammatory response in BEAS-2B cells. Our results demonstrated that HZW significantly decreased AHR and eosinophil infiltration, and reduced goblet cell hyperplasia in the lungs of asthmatic mice. HZW also inhibited oxidative stress and reduced the levels of Th2 cytokines in bronchoalveolar lavage fluid. Our findings suggest that HZW attenuated the pathological changes and inflammatory response of asthma by suppressing Th2 cytokine production in OVA-sensitized asthmatic mice., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Wen-Chung Huang et al.)

Background: Atopic eczema and food allergy most commonly occur in the early childhood. However, the relationships between eczema onset and their relevance to the occurrence of atopic diseases relating to allergen sensitization remain unclear., Methods: We investigated 186 children who were followed up regularly at the clinic for 4 years in a birth cohort study. The children were classified into three groups: early-onset eczema (<2 years old, n = 55), late-onset eczema (≥2 years old, n = 40), and never eczema groups (n = 91). The associations between the different onsets of eczema and total immunoglobulin E levels, absolute eosinophil count, sensitization to food and inhalant allergens, and allergic outcomes were assessed., Results: A significantly higher prevalence of sensitization to food, especially milk was observed in children with early-onset eczema compared with those without eczema at age 1, 1.5, 2, 3, and 4 years. Furthermore, a significantly higher number of eosinophils was detected in children with early or late-onset eczema at the age of 1.5 years. Both the early- and late-onset eczema were significantly associated with a higher prevalence of allergic rhinitis at age 2, 3, and 4 years, and asthma at age 2. Moreover, the early-onset eczema group showed a significantly increased risk of allergic rhinitis (P = 0.010) and asthma (P = 0.032) at age 4., Conclusion: The children with early-onset eczema (<2 years old) appear to be associated with an increased prevalence of milk sensitization and risk of rhinitis and asthma in early childhood., (Copyright © 2019. Published by Elsevier B.V.)

Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma.

In Chinese medicine, Descurainia sophia is used to treat cough by removing the phlegm in asthma and inflammatory airway disease, but the mechanism is not clear. In this study, we evaluated whether D. sophia water extract (DSWE) can alleviate airway inflammation and airway hyperresponsiveness (AHR) in the lungs of a murine asthma model. Female BALB/c mice were divided into five groups: normal controls, ovalbumin (OVA)-sensitized asthmatic mice, and OVA-sensitized mice treated with DSWE (2, 4, 8 g/day) by intraperitoneal injection. After sacrificing the mice, serum was collected to detect OVA-specific antibodies by ELISA, as well as bronchoalveolar lavage fluid (BALF) to detect cytokine levels. We also detected gene expression and histopathologically evaluated the lungs of asthmatic mice. DSWE reduced AHR, goblet cell hyperplasia, eosinophil infiltration, and collagen aggregation in the lungs of asthmatic mice. DSWE also suppressed the gene expression of Th2-associated cytokines and chemokines in lung tissue and inhibited serum OVA-IgE and Th2-associated cytokine levels in the BALF of OVA-sensitized mice. Our findings suggest that DSWE is a powerful immunomodulator for ameliorated allergic reactions by suppressing Th2 cytokine expression in asthmatic mice.

Background: Airway hyperresponsiveness (AHR) is a key feature of asthma and can be detected using various bronchoprovocation tests. In pediatric populations, the percentage of a positive methacholine challenge test (MCCTs) in children with asthma varies among studies, and some have reported seasonal variability. However, these studies have mostly been conducted in temperate regions. This study evaluated the prevalence of AHR to methacholine and its seasonal variation in asthmatic children in Taiwan, a subtropical country., Methods: A total of 276 children with asthma and their MCCT results were retrospectively reviewed. All were diagnosed with asthma and received asthma controllers regularly. They were assigned to four season groups depending in which season MCCTs were administered, with seasons categorized by the Central Weather Bureau of Taiwan. Subgroup analyses, including for sex, age, and atopy level, were compared for seasonal difference., Results: The prevalence of methacholine hyperresponsiveness was 70.7% (n = 195), and the children who were younger and had higher total serum IgE were more sensitive to methacholine (p = 0.019 and p < 0.005, respectively). No significant difference in AHR prevalence among seasons was observed (p = 0.480). The percentage of borderline, mild, and moderate severity of MCCT results was almost equally distributed among the seasons. In subgroup analysis, the children with a higher IgE level (≥75th percentile of all data) had a higher proportion of positive MCCTs in summer (88.6%, p = 0.016)., Conclusion: In total, 70% of the children with asthma in Taiwan had AHR to methacholine, which varied among seasons. Children with a higher total serum IgE level may be more seasonally dependent, particularly in summer., (Copyright © 2018. Published by Elsevier B.V.)

Enhanced type 2 helper T (Th2) cell responses to inhaled harmless allergens are strongly associated with the development of allergic diseases. Antigen formulated with an appropriate adjuvant can elicit suitable systemic immunity to protect individuals from disease. Although much has been learned about Th1-favored immunomodulation of OK-432, a streptococcal preparation with antineoplastic activity, little is known about its adjuvant effect for allergic diseases. Herein, we demonstrate that OK-432 acts as an adjuvant to favor a systemic Th1 polarization with an elevation in interferon- (IFN-) γ and ovalbumin- (OVA-) immunoglobulin (Ig) G2a. Prior vaccination with OK-432 formulated against OVA attenuated lung eosinophilic inflammation and Th2 cytokine responses that were caused by challenging with OVA through the airway. This vaccination with OK-432 augmented the ratios of IFN- γ /interleukin- (IL-) 4 cytokine and IgG2a/IgG1 antibody compared to the formulation with Th2 adjuvant aluminum hydroxide (Alum) or antigen only. The results obtained in this study lead us to propose a potential novel adjuvant for clinical use such as prophylactic vaccination for pathogens and immunotherapy in atopic diseases.

Few studies have addressed the mother-to-child transmission of Th2 immunity and the impact on the development of atopic diseases in early childhood. We investigated 186 children who were followed-up regularly for 4 years in a birth cohort study. The levels of Th2 related chemokine (C-C motif) ligand 17 (CCL17) and CCL22 were quantified in cord blood and at 1.5 years-of-age using multiplex Luminex kits. The levels of 125 pairs of CCL17 and CCL22 chemokines from birth to 1.5 years were recorded in this study. Using K-means clustering, only the declining trend of CCL22 levels was separately clustered (cluster A, n = 51; cluster B, n = 46; cluster C, n = 28). Mothers of children with higher CCL22 chemokine levels at birth were significantly more likely to display Dermatophagoides pteronyssinus sensitization. A lower CCL22 level at birth with a slight rise during infancy was associated with higher prevalence of mite sensitization and a higher risk of asthma at 3 years-of-age (P = 0.014). In conclusion, low mother-to-child Th2-associated chemokine CCL22 levels appear to be inversely related to mite sensitization and the risk of asthma development in early childhood.

Background: Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma., Methods: Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases., Results: Exhaled LTB 4 , LTE 4 , PGE 2, and LXA 4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB 4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB 4 , LXA 4 , together with FeNO and FEV 1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively., Conclusions: In a pediatric study population in Taiwan, the levels of exhaled LTB 4 , LTE 4 , LXA 4, and PGE 2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB 4 and LXA 4 , together with FeNO and FEV 1 , best characterized childhood asthma., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

This study's aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFα, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.

Ethnopharmacological Relevance: Selaginella uncinata (Desv.) Spring, known as "Cuiyuncao", is a perennial herb widely distributed in the Southeast Asian countries. In the folk medicine, the local minority commonly use it to treat cough and asthma for centuries., Aim of the Study: This study was carried out to investigate the protective mechanisms of total flavonoids from S. uncinata (SUF) on airway hyperresponsiveness, cytokine release and bitter taste receptors (T2Rs) signaling with emphasis on inflammatory responses in a rat model of ovalbumin (OVA)-induced asthma., Materials and Methods: Rats were sensitized and challenged with OVA to induce typical asthmatic reactions. Pathological changes of lung tissue were examined by HE staining. The serum levels of T cell-associated cytokines (IFN-γ, IL-4, IL-5 and IL-13), total IgE and OVA-specific IgE were determined by enzyme-linked immunosorbent assay (ELISA). Gene expressions of T2R10, IP3R1 and Orai1 in lung tissue were assayed by fluorescence quantitative real-time polymerase chain reaction (FQ-PCR) while protein expressions of NFAT1 and c-Myc were assayed by western blot analysis. The activation of SUF was investigated on tansgentic T2R10-GFP HEK293 cells., Results: SUF treatment attenuated airway hyperresponsiveness and goblet cell hyperplasia compared with OVA-challenged asthmatic rats. The serum levels of IL-4, IL-5 and IL-13 as well as total and OVA-specific IgE were decreased while serum IFN-γ was increased in SUF-treated rats. SUF treatment significantly up-regulated T2R10 gene expression, down-regulated IP3R1 and Orai1 gene expression. SUF further suppressed eotaxin, NFAT1 and c-Myc protein expression in lung tissues of OVA-challenged rats., Conclusions: These results imply that SUF exerts anti-inflammatory function through the T2R10/IP3R1/NFAT1 dependent signaling pathway, and may warrant further evaluation as a possible agent for the treatment of asthma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Tomatidine is isolated from the fruits of tomato plants and found to have anti-inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR) and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro , tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice.

Background: Epidemiological studies have revealed that intrauterine growth retardation (IUGR) or low birth weight is linked to the later development of asthma. Epigenetic regulatory mechanisms play an important role in the fetal origins of adult disease. However, little is known regarding the correlation between epigenetic regulation and the development of asthma following IUGR., Methods: An IUGR and ovalbumin (OVA)-sensitization/challenge rat model was used to study whether epigenetic mechanisms play a role in the development of asthma following IUGR., Results: Maternal nutrient restriction increased histone acetylation levels of the endothelin-1 (ET-1) gene promoter in lung tissue of offspring, but did not cause significant alterations of DNA methylation. The effect was maintained until 10 weeks after birth. Furthermore, these epigenetic changes may have induced IUGR individuals to be highly sensitive to OVA challenge later in life, resulting in more significant changes related to asthma., Conclusions: These findings suggest that epigenetic mechanisms might be closely associated with the development of asthma following IUGR, providing further insight for improved prevention of asthma induced by environmental factors.

Background: Poor adherence to inhaled corticosteroids (ICS) is known as the main cause for therapeutic failure in asthma treatment and associated morbidity. To improve adherence, targetted and effective interventions need to be developed ideally based on using longitudinal follow-up of a large study cohort to establish patterns and influences on adherence., Objective: To develop an annual measure of asthma patients' adherence to ICS using primary care prescribing data over consecutive annual intervals, and to statistically model ICS adherence controlling for a range of patient factors., Setting: A retrospective cohort study between 1997 and 2010 using United Kingdom general practice prescribing data on asthma patients aged between 12 and 65 years, without a diagnosis of chronic obstructive pulmonary disease., Method: Patient's ICS prescriptions are used to calculate the 'number of days prescribed during calendar year' divided by 'number of days in the interval' to form an annual prescription possession ratio (PPR) for each patient. Several definitions of PPR are considered and compared when calculating numerator and denominator. Adherence, measured by the preferred PPR, is then modelled to estimate the effect of asthma exacerbation, severity, control and other patient factors on adherence., Main Outcome Measure: PPR, being a proxy measure for adherence., Results: Annual PPR by all strategies gave a similar frequency profile. ICS were either over- or under-prescribed for over half of the follow-up time. Adherence was lower in younger patients, those newer to the study timeframe, those with less severe asthma, those with good control, with lower previous adherence, and who had not previously experienced an exacerbation., Conclusion: The chosen PPR simulated clinical use of ICS most closely; including overlapping days, excess days passed to the next interval, considering gaps in the denominator, with censoring at 100 %. The PPR is a useful measure for signalling or measuring adherence changes over time. The modelling results identified many characteristics which would indicate which asthma patients and at what points in their treatment cycle they would be at increased risk of low adherence.

Ethnopharmacological Relevance: Matrine has been isolated from Sophora flavescens, and found to show anti-inflammatory effects in macrophages and anti-cachectic effects in hepatomas. The present study investigated whether matrine suppressed eosinophil infiltration and airway hyperresponsiveness (AHR) in mice, and decreased the inflammatory response of tracheal epithelial cells., Materials and Methods: BALB/c mice were sensitized and challenged with ovalbumin to induce allergic asthma in mice. These asthmatic mice were given various doses of matrine by intraperitoneal injection. Additionally, activated human tracheal epithelial cells (BEAS-2B cells) were treated with matrine, and evaluated for levels of proinflammatory cytokines and chemokines., Results: We found that matrine significantly decreased AHR, and suppressed goblet cell hyperplasia, eosinophil infiltration, and inflammatory response in the lung tissue of asthmatic mice. Matrine also reduced the levels of Th2 cytokines and chemokines in bronchoalveolar lavage fluid, and suppressed OVA-IgE production in serum. Furthermore, matrine treatment of activated BEAS-2B cells decreased production of proinflammatory cytokines and eotaxins, as well as suppressed ICAM-1 expression and thus adhesion of eosinophils to inflammatory BEAS-2B cells in vitro., Conclusions: Our findings suggest that matrine can improve allergic asthma in mice, and therefore has potential therapeutic potential in humans., (© 2013 Published by Elsevier Ireland Ltd.)

Objective: Asthma is a chronic respiratory disorder characterized by airway hyperreactivity, eosinophilic infiltration, high titer of allergen-specific IgE, and overproduction of T helper 2 (Th2) cytokines. Antigen combined with an appropriate adjuvant and administrated through the proper route can elicit suitable immunological responses to protect humans and animals from diseases. Antigen formulated with monophosphoryl lipid A (MPLA) can produce priming of Th1-mediated immune responses. The purpose of this study was to examine the utility of MPLA as an adjuvant to prevent asthma., Methods: BALB/c mice were immunized with ovalbumin (OVA) formulated with or without MPLA by intraperitoneal, footpad, or subcutaneous injection. Vaccinated mice were challenged with OVA aerosol to estimate the protective efficacy of MPLA in comparison to Th2-adjuvant aluminum hydroxide (Alum). Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid (BALF), circulating titers of OVA-specific antibodies, and stimulating levels of IFN-γ and IL-4 cytokines from splenocytes were evaluated., Results: Mice immunized by all injection routes with OVA formulated with MPLA increased the ratio of Th1/Th2 responses compared to mice receiving antigen alone. For prophylactic vaccination purpose, MPLA reduced airway responsiveness and eosinophilic inflammation in the lung, decreased serum OVA-specific IgE level, and increased the serum ratio of OVA-specific IgG2a/IgG1 and the ratio of IFN-γ/IL4 from OVA-activated splenocytes compared with mice vaccinated with Alum., Conclusion: MPLA may be clinically useful in the vaccination of individuals predisposed to asthma.

Toll-like receptors (TLR) initiate innate and often affect adaptive immune response. This study aimed to determine if TLR response and T regulatory cell (Treg) function in peripheral blood mononuclear cells (PBMC) correlate with clinical severity in non-infectious asthma. TLR1-9 expression and representative response cytokine TNF-α, IL-6, and IFN-β secretions were analyzed after stimulation by TLR1-9 ligands from 17 non-infectious asthmatic children. TNF-α production was higher in TLR1/2 (median 385.4 vs. 250.3 pg/ml in 1 μg/ml Pam3CSK4, p=0.0078), TLR4 (2392.4 vs. 1355.9 in 1 μg/ml LPS; p=0.0005), and TLR7/8 (10,776.2 vs. 4237.0 pg/ml in 1 μg/ml R848, p=0.0079) of patients in exacerbation than those in convalescence and healthy controls despite equal TLR expression. TNF-α production stimulated by TLR9 agonist was significantly lower in exacerbation (17.7 vs. 34.9 pg/ml in 1 μg/ml ODN2216, p=0.0175), while IL-6 production had similar patterns but was significantly lower in TLR3 signaling (119.7 vs. 245.0 pg/ml in 0.1 μg/ml poly(I:C), p=0.0033). IFN-β production by TLR3 agonist also decreased in exacerbation but not statistically significant. Six older children showed decreased FOXP3 percentage in CD4+CD25(high) and decreased suppression capability in exacerbation but restored in stabilization (82.8% vs. 90.0%, p=0.0061 and 60.9% vs. 81.7%, p=0.0071; respectively). In conclusion, normalizing imbalanced TLR signaling and enhancing Treg cell capability may guide possible therapeutic strategies for non-infectious asthma in exacerbation., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Background: Asthma is characterized as a chronic inflammatory disorder of the airways associated with an enhanced TH2 response to inhaled allergens. CD4+ T regulatory (Treg) cells are controlled by the master transcription factor FoxP3 and strictly maintain peripheral immunotolerance. Epigenetic regulation of FoxP3 by DNA methyltransferase inhibitors, such as 5-azacytidine (Aza), can generate a steady supply of functional Treg cells. Therefore, we propose that Aza can augment Treg cells in vivo to prevent the pathogenesis of asthma., Methods: BALB/c mice were sensitized with chicken ovalbumin (OVA) and treated with different doses of Aza. Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid, circulating titers of OVA-specific IgG1 and IgE, and stimulating levels of TH2 cytokines from splenocytes were then determined. Cellular populations were examined by flow cytometry. PC61 antibody, which depletes CD25+ cells, was used to verify the role of CD25+ cells in Aza-induced tolerance., Results: Administration of Aza to OVA-sensitized mice diminished airway hyperreactivity, pulmonary eosinophilia, levels of OVA-specific IgG1 and IgE in serum, and secretion of TH2 cytokines from OVA-stimulated splenocytes in a dose-dependent manner. Percentages of CD25+ and FoxP3+ cells in the CD4+ cell population were notably increased in Aza-treated mice compared to sensitized control mice. Furthermore, the major symptoms of asthma were exacerbated by depleting CD25+ cells in Aza-treated mice., Conclusions: Aza may have applications as a novel clinical strategy to increase the production of Treg cells in order to modulate the airway inflammation associated with asthma., (Copyright © 2012 S. Karger AG, Basel.)

Asthma is a chronic airway inflammatory disease characterized by eosinophilic infiltration and airway hyperresponsiveness. The over-activated Th2 and lung epithelium cells express many different cytokines, and chemokines mainly contribute to the severity of lung inflammation. Clara cell 10 kD protein (CC10) is highly expressed in airway epithelium cells and exhibits anti-inflammatory and immunomodulatory effects. Adeno-associated virus (AAV) 2/9 vector, composed of AAV2 rep and AAV9 cap genes, can efficiently and specifically target lung epithelium cells. Thus, AAV2/9 vector might carry therapeutic potential gene sequences for the treatment of asthma. This study tested whether AAV2/9 vector carrying CC10 could reduce inflammatory and asthmatic responses in OVA-induced asthmatic mouse model. The results showed that AAV2/9-CC10 vector virus significantly reduced airway hyperresponsiveness, CCL11, interleukin (IL)-4, IL-5, IL-6, IL-13, and eosinophilia in the lungs of sensitized mice. CC10 level in OVA-sensitized mice was rescued with the administration of AAV2/9-CC10 vector virus. Lung tissue remodeling, including collagen deposition and goblet cell hyperplasia, was also alleviated. However, serum levels of OVA-specific IgG1 and IgE as well as Th2 cytokine levels in OVA-stimulated splenocyte culture supernatants were at the comparable levels to the sensitized control group. The results demonstrate that AAV2/9-CC10 vector virus relieved local inflammatory and asthmatic responses in lung. Therefore, we propose that AAV2/9-CC10 vector virus guaranteed sufficient CC10 expression and had an anti-inflammatory effect in asthmatic mice. It might be applied as a novel therapeutic approach for asthma.

Objective: The gene (SCGB1A1) encoding Clara cell 10-kDa protein (CC10), a steroid-inducible immune modulator, is a candidate gene for asthma, but the evidence is equivocal. The potential influence of a common variant on asthma severity and serum CC10 levels during acute exacerbation and after corticosteroid treatment in Chinese case-control children and its functional relevance was investigated., Methods: Genotyping of a non-coding variant G+38A was performed in 489 children, of whom 277 had asthma with varying severity, and 212 healthy controls. Associations were tested for asthma, asthma severity, and responsiveness to steroid treatment. The transcriptional activity of this variant was examined in a Clara-like cell line (H358) using transient transfection assays., Results: Significant association was observed for the combined GA and AA genotypes of the CC10 G+38A variant and an increased risk of asthma [odds ratio (OR), 2.62, p < .001]. This association was correlated with asthma severity (moderate: OR, 2.85, p < .001; near-fatal: OR, 4.81, p < .001). Also, patients with the GA and AA genotypes showed significantly lower serum CC10 (p < .01) and provocation concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1)) (p < .0001) when compared with those with the GG. After glucocorticoid treatment, the CC10 levels were significantly increased in asthmatic patients with GG (p < .0001), but not those with the GA and AA genotypes. Moreover, a lower dexamethasone-induced reporter (luciferase) activity was observed for H358 cells transiently transfected with the G38A risk allele (A) compared with wild-type allele (G)., Conclusions: These findings suggest that the CC10 G+38A variant may contribute to the severity of asthma and lower level of steroid responsiveness.

Background: Little is known about the prevalence of allergic diseases in children of different ages. This study aimed to investigate the prevalence of allergic diseases and allergic sensitization in children over a wide age range, with emphasis on the influence of age, gender, and body mass index (BMI)., Methods: In a cross-sectional study, we assessed 5351 Taiwanese children aged 4-18 years using an International Study of Asthma and Allergies in Childhood questionnaire, BMI, and total and specific serum immunoglobulin E., Results: Forty-eight percent were currently symptomatic for at least one of three allergic diseases. Prevalence of wheeze ever, current wheeze, and diagnosed asthma were 17.0%, 7.5%, and 9.8%, respectively; analogous features for rhinitis were 47.8%, 44.2%, and 39.8%. Allergic sensitization was very common (57.3%). Half of the children (50.6%) with current wheeze had not been diagnosed with asthma by physicians, whereas undiagnosed rates were 32.3% for rhinitis and 25.3% for eczema. The male-to-female prevalence ratios of current wheeze increased with age from <1 at 4-5 years, peaked at 10-11 years (2.24), then reversed to 0.57 at 16-18 years. Childhood wheezing tended to remit with age, but rhinitis and eczema were more persistent. Total immunoglobulin E levels increased with age until 14-15 years, and declined thereafter. Elevated BMI was associated with greater prevalence of wheezing and eczema, with no evidence of significant effect modification by either gender or age. Multivariate analyses revealed that younger age, boys, and obesity were significantly and independently associated with current wheezing in children (all p < .01)., Conclusions: The burden and co-morbidity of childhood allergies are substantial. There are striking age-dependent gender differences in asthma prevalence, exhibiting an inverted U-shaped curve for male-to-female prevalence ratios by age. Obesity is associated with a greater prevalence of asthma in children with no evidence of a significant modulation by either gender or age.

Background: Traditional asthma prevalence surveys were based on the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, which focuses on children aged 6-7 and 13-14. However, asthma-like symptoms usually commence in preschool aged children, in whom it is difficult to make a definite diagnosis of asthma. It is worth determining the prevalence rate of asthma or asthma-like symptoms and analyzing the risk factors for this phenomenon among preschool aged children., Methods: Children aged 3-6 years were recruited from kindergartens in Keelung City, northern Taiwan. The questionnaire used was based on the ISAAC phase III core and environmental questionnaires and included questions on asthma, rhino-conjunctivitis, and eczema, along with questions to elicit common and early presentations of asthma, as well as other demographic and environmental data. The questionnaires were delivered and completed by parents., Results: 2395 questionnaires were delivered to parents with children at 50 kindergartens, of which 2170 questionnaires were returned (return rate 90.6%). 9.9% of these preschool children had physician-diagnosed asthma. However, 20.4% of them experienced asthma like symptoms while attending kindergarten. Both the physician-diagnosed asthma and asthma-like symptoms groups had more clinical symptoms in all seasons except summer, compared to children without asthma. It was significant that the asthma-like symptoms commenced after joining a kindergarten (p < 0.001), and 66.5% of the children started to experience the symptoms within one month of beginning kindergarten. Using antibiotics or antipyretics in young infancy and mothers having asthma were the risk factors for developing asthma and asthma-like symptoms (p < 0.001), but parental smoking was not contributory to asthma development in preschool children. More frequent use of antipyretics in a year had a higher risk for the development of asthma and asthma-like symptoms., Conclusions: Asthma and asthma-like symptoms were common in preschool children. Early infection of the respiratory tract and use of antibiotics were associated with presentation of symptoms. Attending a kindergarten is also a risk factor for early presentation of asthma among preschool children.

Background: Previous studies have reported relationships between adverse respiratory health outcomes and residential proximity to traffic pollution, but have not shown this at a personal exposure level., Objective: We compared, among inner-city children with asthma, the associations of adverse asthma outcome incidences with increased personal exposure to particulate matter mass ≤ 2.5 μm in aerodynamic diameter (PM(2.5)) air pollution versus the diesel-related carbonaceous fraction of PM2.5., Methods: Daily 24-hr personal samples of PM(2.5), including the elemental carbon (EC) fraction, were collected for 40 fifth-grade children with asthma at four South Bronx schools (10 children per school) during approximately 1 month each. Spirometry and symptom scores were recorded several times daily during weekdays., Results: We found elevated same-day relative risks of wheeze [1.45; 95% confidence interval (CI), 1.03-2.04)], shortness of breath (1.41; 95% CI, 1.01-1.99), and total symptoms (1.30; 95% CI, 1.04-1.62) with an increase in personal EC, but not with personal PM(2.5) mass. We found increased risk of cough, wheeze, and total symptoms with increased 1-day lag and 2-day average personal and school-site EC. We found no significant associations with school-site PM(2.5) mass or sulfur. The EC effect estimate was robust to addition of gaseous pollutants., Conclusion: Adverse health associations were strongest with personal measures of EC exposure, suggesting that the diesel "soot" fraction of PM(2.5) is most responsible for pollution-related asthma exacerbations among children living near roadways. Studies that rely on exposure to PM mass may underestimate PM health impacts.

Personal exposures to fine particulate matter air pollution (PM(2.5)), and to its traffic-related fraction, were investigated in a group of urban children with asthma. The relationships of personal and outdoor school-site measurements of PM(2.5) and elemental carbon (EC) were characterized for a total of 40 fifth-grade children. These students, from four South Bronx, NY schools, each carried air pollution monitoring equipment with them for 24 h per day for approximately 1 month. Daily EC concentrations were estimated using locally calibrated reflectance of the PM(2.5) samples. Personal EC concentration was more closely related to outdoor school-site EC (median subject-specific: r=0.64) than was personal PM(2.5) to school-site PM(2.5) concentration (median subject-specific: r=0.33). Regression models also showed a stronger, more robust association of school site with personal measurements for EC than those for PM(2.5). High traffic pollution exposure was found to coincide with the weekday early morning rush hour, with higher personal exposures for participants living closer to a highway (<500 ft). A significant linear relationship of home distance from a highway with personal EC pollution exposure was also found (up to 1000 ft). This supports the assumptions by previous epidemiological studies using distance from a highway as an index of traffic PM exposure. These results are also consistent with the assumption that traffic, and especially smoke emitted from diesel vehicles, is a significant contributor to personal PM exposure levels in children living in urban areas such as the South Bronx, NY.

Background: Monocyte chemotactic protein 1 (MCP-1) plays an important role in various immune and allergic disorders since it is a potent chemo-attractant for inflammatory cells, such as eosinophils, memory T cells, and monocytes., Objective: To investigate serum MCP-1 during asymptomatic state and acute attacks of bronchial asthma., Methods: In this longitudinal cohort design study, sequential serum levels of MCP-1 were measured by a sandwich enzyme-linked immunosorbent assay (ELISA). Twenty-four asthma patients' MCP-1 levels were examined at 5 time points: during the asymptomatic phase, in an acute wheezing episode, and at 1 week, 1 month, and 2 months after acute asthma attack. Fifteen children without asthma were enrolled as control., Results: During the asymptomatic phase of asthma, serum MCP-1 levels were significantly higher than that of normal controls (329.57 +/- 99.20 pg/ml vs. 213.63 +/- 77.29 pg/ml, p = 0.001). In comparison with the asymptomatic phase, the serum MCP-1 levels during the acute asthma attack were significantly higher (682.88 +/- 88.45 pg/ml vs. 329.57 +/- 99.20 pg/ml, p < 0.001). After treatment of acute asthma exacerbation, all of the serum MCP-1 levels declined within 1 week, but were still higher than control 2 months later., Conclusion: In asthma patients, the consistently elevated serum levels of MCP-1 suggest its role in the pathogenesis of bronchial asthma - not only in the chronic inflammatory processes, but also in acute asthma attack exacerbation. These findings suggest a possible role for MCP-1 in the pathogenesis of asthma and a potential role for its use in anti-asthma treatment in the future.

Changes in methylation of CpG sites at the interleukin (IL)-4 and interferon (IFN)-gamma promoters are associated with T helper (Th) 2 polarization in vitro. No previous studies have examined whether air pollution or allergen exposure alters methylation of these two genes in vivo. We hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFN-gamma promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to the fungus allergen Aspergillus fumigatus. We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. BALB/c mice were exposed to a 3-week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Sera IgE levels were compared with methylation levels at several CpG sites in the IL-4 and IFN-gamma promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG(-45), CpG(-53), CpG(-205) sites of the IFN-gamma promoter and hypomethylation at CpG(-408) of the IL-4 promoter. Altered methylation of promoters of both genes was correlated significantly with changes in IgE levels. This study is the first to demonstrate that inhaled environmental exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis.

One of the responsibilities of a public health nurse is to provide asthma education to local residents. However, there have been no comprehensive education programs for public health nurses on asthma care in the past. This study aimed to determine level of competence of public health nurses on asthma care in order to improve their capability through a one-day national asthma education course. In addition to lectures on updated asthma management information, data was obtained through demonstrations and practice on inhalation techniques of various kinds of inhaled devices, including the ability to use and interpret the data of a peak flow meter. Two written examinations with the same questions were given to participants before and right after the lectures. All of the 560 public health nurses in the 392 public health bureaus were invited to join the program and 522 (93.2%) participated. Five hundred and six completed both the pre- and post-tests. Before the national education program, only 10.9% of the participants knew the purpose of the peak flow meter, while 62.6% had never heard of it. Initially, they showed less confidence on teaching patients on the use of inhaled devices (2.36 and 2.59 in 5 scales). Comparing the two tests, there was a significant increase in the public nurses' knowledge as regards: 1) the general concept of asthma, 2) prevention of trigger factors and environmental control, 3) proper medication knowledge, 4) peak flow meter (PEF) monitoring, and 5) intervention after acute exacerbation of asthma (p < 0.001). A well-designed course on asthma management is an efficient scheme to improve public health nurses' knowledge and confidence on asthma care.

Cytokines produced by Th2 cells are responsible for the pathogenesis of asthma. Th1-biased immune responses caused by attenuated salmonella have the potential to relieve asthmatic symptoms. We evaluated whether oral administration of attenuated salmonella could modulate allergic responses in a chicken ovalbumin (OVA)-induced asthmatic murine model. Mice were fed with attenuated salmonella SL7207 one dose before and three doses during the induction of an allergic response. Lung histology, percentages of eosinophil in bronchoalveolar lavage fluid, serum levels of OVA-specific antibodies and cytokine production by OVA-activated splenocytes were evaluated in mice with or without the administration of SL7207. A significant reduction in pulmonary eosinophilic infiltration was observed in mice receiving attenuated salmonella. Lower levels of OVA-specific IgG1 but higher titres of OVA-IgG2a in serum were also detected in this group. Splenocytes from salmonella-fed mice produced lower levels of Th2 cytokines upon OVA stimulation. The administration of attenuated salmonella significantly suppressed immunopathological symptoms in OVA-sensitized mice. Inhibition of Th2 responses might explain the potential mechanisms. This study provides some evidence for the feasibility of attenuated salmonella as an effective vaccine for allergic diseases.

Background: Asthma is a common disease in Taiwan. The promotion of quality care for asthmatic patients should focus not only on new treatment remedies but also on patient adherence to treatment and a continuous education program integrated into treatment plans. One reason for patients' poor response to treatment is the lack of asthma knowledge on the part of physicians in terms of attitudes toward treatment., Objective: To investigate the current status of asthma treatment among asthma specialists and general practitioners and their relative acceptance of and adherence to treatment guidelines., Methods: One thousand questionnaires were distributed to physicians throughout Taiwan using a randomized sampling procedure. The questionnaire asked about the use of different kinds of medications, including inhaled corticosteroids, to treat asthma; adherence to asthma treatment guidelines; the use of a peak flow meter for monitoring asthma status; and self-efficacy in the treatment of asthma., Results: A total of 526 questionnaires were returned. Of these, 90.4% of specialists and 63.2% of general practitioners would follow the guidelines for patient care (P = .002). It was significant that 79.8% of specialists but only 41.9% of general practitioners would instruct patients to use a peak flow meter to monitor symptoms (P < .001). Asthma specialists also seemed to be significantly more competent than general practitioners regarding asthma knowledge, instruction of inhalation techniques, use of peak flow meters to monitor symptoms, and making an action plan., Conclusions: To minimize the knowledge gap between specialists and general practitioners regarding asthma treatment, recognized treatment guidelines need to be popularized or simplified. Furthermore, the continuing education of general practitioners in asthma knowledge and management skills is important.

The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.003) of SNP rs545659. Haplotype analysis yielded additional evidence of linkage disequilibrium for the 1544G-1651G haplotype (P < 0.001). Population-based case-control analyses were conducted in two independent populations, and demonstrated significant association of the 1544G-1651G haplotype with asthma in an African American population (P = 0.004), and in a population of Chinese children (P < 0.001). Moreover, in the Chinese children the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (P = 0.001) and normal controls (P < 0.001). The 1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027). Transcriptional pulsing experiments showed that the 1544G-1651G haplotype confers a significantly higher level of reporter mRNA stability, when compared with a non-transmitted haplotype (1544C-1651A), suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.

Although annual influenza vaccinations are recommended by many authorities, some doctors may be reluctant to vaccinate asthmatic children because of the risk of inducing bronchial reactivity and exacerbating the asthma. In this study, the effect of split influenza vaccine on clinical symptoms, airway responsiveness and its influence on T lymphocytes was evaluated. Twenty-one asthmatic children with stable asthma were recruited and divided into two groups. Eleven patients who received the influenza vaccine formed the vaccination group and 10 patients who received a placebo formed the placebo group. Forced expiratory volume in 1 s (FEV1), airway response (PC20 methacholine, PC20=provocation concentration causing a 20% fall in FEV1) and the T lymphocyte subset ratio (Th1/Th2) were recorded on day 1 pre-vaccination and day 14 post-vaccination. Patients were also asked to record their peak expiratory flow (PEF) every morning and evening and to complete daily symptom scores over the period of 2 weeks. There were no significant changes in PC20, FEV1, PEF variability, symptom scores and the Th1/Th2 ratio between the vaccination and placebo groups between day 1 pre-vaccination and day 14 post-vaccination. Similar results of PEF variability and asthma symptom score were obtained when the analysis was restricted to the day 1 pre-vaccination and day 3 post-vaccination. Immunization with split influenza vaccine does not exacerbate asthma in children either with a clinical or immunological effect. These results suggest that children with stable asthma can safely be immunized with a split influenza vaccine.

Background: RANTES promoter polymorphisms were found associated with asthma/atopy in some studies but not others, possibly reflecting the genetic heterogeneity among different ethnicities and different asthma severity., Objective: The purpose of this investigation was to test the genetic association between the RANTES -28C/G and -403G/A polymorphisms and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks., Methods: Forty-eight children with near-fatal asthma, 134 children with mild-to-moderate asthma, 69 children with allergic disorders but no asthma, and 107 nonasthmatic nonatopic control children were genotyped through use of a PCR-based assay., Results: No significant difference was demonstrated for frequency of the RANTES -28C/G polymorphism when the mild-to-moderate asthma, atopic/nonasthmatic, and normal control groups were compared. The RANTES -28G allele was present in a significantly higher proportion of the children with near-fatal asthma compared with the nonasthmatic nonatopic controls (odds ratio, 2.93 [1.41-6.06]; P =.006) and the children with mild-to-moderate asthma (odds ratio, 3.52 [1.73-7.16]; P =.001). The frequency of -28G allele carriage correlated with asthma severity. The RANTES -28G allele was also associated with an increased blood eosinophil count and a higher degree of bronchial hyperresponsiveness. The RANTES -403G/A polymorphism did not influence asthma/atopy susceptibility, blood eosinophil count, or bronchial hyperresponsiveness. Interestingly, a higher frequency of -403A allele carriage was observed in the moderate asthma subgroup compared with the mild asthma analog., Conclusions: We conclude that the RANTES -28C/G polymorphism exacerbates asthma severity, representing a genetic risk factor for life-threatening asthma attacks in Chinese children. In addition, the linkage disequilibrium between these 2 polymorphisms is a potential confounder that must be considered in the design and interpretation of RANTES gene association studies.

Allergen immunotherapy results in a number of changes in clinical and immunological parameters. To study the kinetic influence of immunotherapy on cytokine production, we evaluated the ratios of Th1/Th2 for patients receiving mite-extract immunotherapy with 3-month intervals. Changes in Th1/Th2 ratio were calculated based on the intracellular cytokine and surface CD4 staining of peripheral blood mononuclear cells (PBMC). No significantly different Th1/Th2 ratios were detected after immunotherapy, although ratios were lower for asthmatic children when compared with normal controls. Cytokine production was also determined on supernatants from mite- or mitogen-activated PBMC cells. A significantly increased production of all cytokines was detected from activated PBMC from patients after immunotherapy. Thus hyposensitization with mite extract for 1 year might improve the cytokine production capacity of asthma patients' PBMC.

Study Objective: Previous studies have suggested that aggressive treatment of sinusitis can decrease bronchial hyperresponsiveness (BHR). However, there is still too little evidence to draw this conclusion, and the concept remains controversial., Design: A prospective, open-label study., Setting: University children's hospital allergy and immunology center and radiologic department., Patients: Sixty-one children with mild asthma and allergic rhinitis participated in the study. Forty-one of these 61 children had sinusitis, and the remainder had no sinusitis. Ten matched, nonatopic, healthy children were used as a control group., Intervention: Children with chronic sinusitis were placed into two groups. One group was treated with amoxicillin-clavulanate for 6 weeks and then with nasal saline solution irrigation for 6 weeks. For the other group, the treatment order was reversed. Children without chronic sinusitis received nasal saline solution irrigation for 12 weeks., Measurements: Clinical symptoms and signs of sinusitis, FEV(1), and BHR were analyzed in the patients before and after treatment., Results: The clinical symptoms and signs of sinusitis, but not FEV(1), showed a significant improvement after antibiotic treatment. After aggressive treatment for sinusitis, it was found that the provocative concentration of methacholine causing a 20% fall in FEV(1) of children with mild asthma and sinusitis was significantly higher after treatment., Conclusion: The results suggest that every asthmatic patient needs to carefully evaluate to determine whether the patient has concomitant sinusitis. Respiratory infections that meet criteria for sinusitis, even if they do not exacerbate asthma, should be treated. It is suggested that sinusitis should always be kept in mind as a possible inducible factor for BHR, and that aggressive treatment of chronic sinusitis is indicated when dealing with an asthmatic patient who shows an unpredictable response to appropriate treatment. Moreover, the findings of this study provide more evidence for an association between sinusitis and asthma with respect to BHR.

T lymphocytes play a fundamental role in the initiation and regulation of chronic inflammatory responses in patients with asthma. CD69 is an early marker of T-cell activation. The levels of intercellular adhesion molecule-1 (ICAM-1, CD54) and L-selectin have been reported to increase in patients with allergic diseases and asthma. The present study was therefore undertaken to investigate the expression of CD69, CD54, and L-selectin by T lymphocytes of children with asthma, before and after immunotherapy. Eighteen children newly diagnosed with asthma, 11 good and nine poor responders to immunotherapy, and 16 normal subjects, were enrolled in this study. The percentages of CD69+, CD54+, and CD62L+ cells in T lymphocytes were measured by using flow cytometry. The levels of CD69, CD54, and CD62L in serum and culture supernatants were determined by using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD54 on CD3+ T lymphocytes was significantly higher in children with asthma than in control patients. All the patient groups expressed (spontaneously and following stimulation with phorbol myristate acetate and ionomycin together with mite-extract proteins) greater amounts of CD69 and CD54 than did control subjects. With long-term immunotherapy, the percentages of CD69+ and CD54+ T lymphocytes were significantly lower in patients with a good response to immunotherapy. Our results also showed significantly lower serum L-selectin levels following immunotherapy. In conclusion, successful immunotherapy resulted in decreased expression and production of CD69 and CD54. These results may explain, in part, the clinical efficacy of immunotherapy.

Paranasal sinus disease and bronchial asthma are frequently associated. Computed tomography imaging is currently the most reliable method for confirming the diagnosis of sinusitis. Due to the cost and amount of radiation during computed tomography, our aim was to analyze whether standard radiography, under computed tomography-control, had a reasonable degree of confidence in the diagnosis of sinusitis. Fifty-three asthmatic patients (42 males and 11 females) with a mean age of 9 years (range 4-14) were enrolled. We evaluated the maxillary sinuses, ethmoidal sinuses, frontal sinuses, and sphenoidal sinuses using standard radiography (Waters' view, Caldwell view, and lateral view) and compared with computed tomography (coronal views), the latter served as a standard. Computed tomography (CT) showed paranasal sinusitis in 58% (31/53) of the asthmatic children. Compared with the results of computed tomography, standard radiography revealed a sensitivity of 81.1% and a specificity of 72.7% for maxillary sinusitis. The sensitivity and specificity for ethmoidal, frontal, and sphenoidal sinusitis were 51.8%, 84.8%; 47.3%, 87.2%; and 40.8%, 93.3%, respectively. In 21 (40%) of the 53 patients, discrepancies were seen between the interpretations of standard radiography c and those of CT scans. In patients with maxillary sinusitis, the correlation between standard radiography and CT was good. However, ethmoidal, frontal, and sphenoidal sinusitis were poorly demonstrated using radiography. Standard radiography can be recommended as a screening method for maxillary sinusitis, but it is not recommended for the diagnosis of other paranasal sinusitis.