The protective role of country living on skin prick tests, immunoglobulin E and asthma in adults from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy.

BACKGROUND: Farming environment and traditional lifestyle seem to protect from childhood allergy. OBJECTIVE: The aim is to analyse the relationships of living in the country to asthma, positive skin prick tests and IgE among adults considering various windows of exposure over the life-span. METHODS: The study concerns 805 adults drawn from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy (EGEA) (asthmatic cases, non-asthmatic controls, and parents of cases with and without asthma). Ever living in the country concerned 55% of the subjects. Early (beginning < 1 years), childhood (beginning < or = 16 years), prolonged (duration > or = 10 years) and current life in the country were studied. RESULTS: The results based on the case control and family components of the study show that IgE levels were significantly lower in those who ever lived in the country and in particular in those who lived for > or = 10 years. Positive skin prick tests (SPT) were significantly less prevalent in those who ever lived in the country and in particular in those with childhood (< or = 16 years) exposure. These associations remained independent of age, sex, smoking or asthma with IgE levels of 64 vs. 88 IU/mL; P = 0.004 for those ever living in the country vs. others and odds ratio for SPT positivity of 0.72 (95% CI [0.53-0.98]). In the more specific group with traditional mode of heating in childhood (use of wood) associations were stronger. The association with asthma, studied in parents of asthmatic probands showed that fathers, but not mothers, of asthmatics were significantly less often asthmatic themselves in relation to country living. CONCLUSION: Country life protects from asthma and adulthood allergy. The protective effect is not restricted to exposure in early childhood.     

Association of a lymphotoxin alpha gene polymorphism and atopy in Italian families

Tumour necrosis factor (TNF) is a proinflammatory cytokine that increases human airway tissue responsiveness and is considered a candidate gene for asthma. Two common polymorphisms (LTalphaNcoI and TNFalpha-308) in the TNF gene complex were studied in 600 subjects from 131 Italian families with atopic asthmatic children. Skin prick test (SPT), total IgE levels, atopy (defined as increased IgE levels or SPT positivity or both), bronchial hyperresponsiveness, and clinical asthma were investigated. The observed distribution of the identical by descent alleles at the LTalphaNcoI locus was different from expected for SPT and atopy (p=0.015). The LTalphaNcoI genotype distribution for increased IgE levels was different between males and females (p=0.0011), and an association of the 2.2 genotype with increased IgE levels was observed in females (p=0.0032). The results indicate that the LTalpha gene, or a closely linked locus, is associated with atopy, and suggest a sex difference in the effect of the gene.     

Relationships of allergic sensitization, total immunoglobulin E and blood eosinophils to asthma severity in children of the EGEA Study

BACKGROUND: Although allergy is highly associated with childhood asthma, it is not well known if there is a relationship between the intensity of allergic sensitization and asthma severity. OBJECTIVE: The objectives of the study were to examine the relationships between several markers of allergy and asthma severity in asthmatic children included in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness and atopy (EGEA). METHODS: The population comprised 216 asthmatic children below 16 years of age. Total IgE and blood eosinophil counts were measured and skin prick tests to 11 aeroallergens were performed. The intensity of the allergic sensitization was assessed by the number of positive skin prick tests and by skin weal sizes. Asthma severity was measured with four criteria: a clinical severity score, history of hospitalization for asthma, FEV1% predicted and inhaled steroid use in the last 12 months. RESULTS: Most of the children were sensitized to at least one aeroallergen (88.2%). Atopy was not related to the severity of asthma, except for a tendency for a more severe clinical score in non-atopic children. The type and intensity of the allergic sensitization were not associated with any criteria of asthma severity. Total IgE was significantly increased in children treated with inhaled corticosteroids and in children ever hospitalized for asthma (P-values 0.009 and 0.04, respectively). Eosinophil counts were not related to asthma severity. CONCLUSION: Our results suggest that severe childhood asthma may be related to a high level of total IgE but not to blood eosinophil counts. The lack of positive relationships between both atopy and the intensity of allergic sensitization with asthma severity supports the hypothesis of different risk factors being associated with asthma and with the severity of asthma.     

Association of FcεR1-β polymorphisms with asthma and associated traits in Australian asthmatic families

BACKGROUND: Asthma is a genetically complex disease, and is characterized by elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts and increased airway responsiveness. Polymorphisms in the beta subunit of the high affinity receptor for IgE (FcepsilonR1-beta) have been previously associated with these phenotypes and with an increased risk of asthma. OBJECTIVE: To investigate the association of all known bi-allelic polymorphisms in FcepsilonR1-beta to asthma and quantitative traits associated with asthma in a selected sample of Australian asthmatic children and their nuclear families. METHODS: Australian Caucasian nuclear families (n = 134 subjects) were recruited on the basis of a child proband with current, severe, symptomatic asthma. The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts and the dose-response slope of the forced expiratory volume in 1 s to histamine provocation. RESULTS: Neither the Leu181 nor the E237G mutations were detected in this population. Allele B of RsaI intron 2 (RsaI_in2*B) was significantly associated with physician-diagnosed asthma (ever) (P = 0.002). Alleles of both the RsaI_in2 and RsaI exon 7 (RsaI_ex7) polymorphisms were significantly associated with loge total serum IgE levels and the combined RAST index. RsaI_ex7 was also associated with loge blood eosinophil counts. These associations were independent of age, sex and familial correlations. CONCLUSION: This study supports a role for the FcepsilonR1-beta gene or a nearby gene in the pathogenesis of asthma.     

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE

BACKGROUND: Although most children and young adults with asthma are atopic, exacerbations of asthma are frequently associated with viral respiratory tract infections, especially those caused by rhinovirus (HRV). OBJECTIVE: Young atopic adults with mild asthma were evaluated before and during an experimental HRV infection to test the hypothesis that airway inflammation before virus inoculation may be a risk factor for an adverse response to HRV. METHODS: Experimental HRV infections were evaluated in 16 allergic volunteers with mild asthma and 9 nonatopic control patients (age, 18 to 30 years). Before virus inoculation, each participant was screened with tests for lung function, prick skin tests for sensitization to common aeroallergens, measurements of total serum IgE, and serum neutralizing antibody to rhinovirus-16 (the serotype used for inoculation). The response to infection was monitored for 21 days by using symptom diary cards, tests for lung function, and markers of airway inflammation in nasal washes, blood, and expired air. RESULTS: During the infection, asthmatic patients had cumulative upper and lower respiratory tract symptom scores that were significantly greater over the course of 21 days than scores from the control patients. At baseline, the asthmatic patients also had increased sensitivity to methacholine and significantly lower values for FEV(1) (percent predicted) than the control patients (geometric mean and intraquartile values: 87% [79% to 91%] for the asthmatic patients and 101% [90% to 104%] for the control patients, P <.03). Among the patients with mild asthma, 6 had levels of total serum IgE that were substantially elevated (range, 371 to 820 IU/mL) compared with 10 who had lower levels (range, 29 to 124 IU/mL). Those with high levels of IgE had significantly greater lower respiratory tract symptom scores during the initial 4 days of the infection than the low IgE group. They also had higher total blood eosinophil counts at baseline, increased eosinophil cationic protein in their nasal washes (>200 ng/mL), and augmented levels of expired nitric oxide at baseline and during peak cold symptoms. In contrast, levels of soluble intracellular adhesion molecule-1 in nasal wash supernatants from the asthmatic patients with high IgE were diminished, both at baseline and during the infection. CONCLUSIONS: The reduced lung function and increased markers of inflammation observed before virus inoculation in the asthmatic patients who had high levels of total serum IgE may be risk factors for an adverse response to infections with HRV.     

Role of gender and hormone-related events on IgE, atopy, and eosinophils in the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy

BACKGROUND: The pattern of asthma over the lifespan is different in male and female patients, but etiologic differences according to gender are only partially understood. In women, information regarding factors explaining perimenstrual asthma and the role of hormone-related aspects on asthma-related phenotypes is scanty. OBJECTIVE: To assess the relationships of eosinophils, IgE, and atopy with (1) asthma according to gender and age of onset and (2) hormone-related events. METHODS: Using data from the Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness and Atopy, adults and children with asthma recruited in chest clinics (n=313) and first-degree relatives of patients with asthma (n=214) were compared with nonasthmatic controls (n=334) and first-degree relatives without asthma (n=595). RESULTS: Among asthmatic women, eosinophilia was significantly associated with perimenstrual asthma independently from age, smoking, and asthma severity (eosinophils/mm(3) 330 vs 194; P=.01). In nonasthmatic women, IgE level was significantly decreased (by half) and atopy decreased with menopause, and IgE increased with oral contraceptive use, independently from age and smoking. Considering both genders, the increase of eosinophil counts with asthma was significantly greater in women with childhood-onset asthma than in women with adulthood-onset or in men in general. No interaction between gender and asthma was observed for eosinophils in children and for IgE level and atopy in children and adults. CONCLUSION: Results suggest a role of hormone-related events on asthma-related traits and support the hypothesis of the role of eosinophils in the persistence and severity of asthma.     

Allergy markers in adults in relation to the timing of pet exposure: the EGEA study

BACKGROUND: Studies suggest that early childhood exposure to pets may protect from the development of atopy, but limited information is available on adults. The association of allergy markers in adulthood with current and childhood exposure to pets was studied considering retrospectively the window of exposure. METHODS: Immunoglobulin E (IgE), skin prick tests (SPT), eosinophils were related to exposure to pets in 187 adult asthmatic cases and 243 controls from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) study. Analyses were redone after exclusion of subjects who removed pets or experienced symptoms to animals to take into account selection in that retrospective study. RESULTS: In asthmatic cases, current exposure to pets was unrelated to SPT positivity (+), whereas childhood exposure was significantly related to less SPT+ to any allergen, and to cat in particular, with an association restricted to those exposed before 2 years of age [OR = 0.30 (CI 0.12-0.76)]. Considering the relative timing of exposure in relation to asthma onset showed that the protective effect of exposure to pets occurs for pet exposure starting before asthma onset [OR for SPT+ = 0.19 (CI 0.08-0.48)]. CONCLUSION: Results support the hypothesis that exposure to pets in early life, and in particular before asthma onset, may protect against allergen sensitization in adulthood.     

In childhood asthma the degree of allergen-induced T-lymphocyte proliferation is related to serum IgE levels and to blood eosinophilia.

OBJECTIVE: To investigate whether the state of activation of circulating T-cells in childhood asthma could be related to serum IgE levels and/or to blood eosinophilia. METHODS: Seventeen atopic asthmatic children, sensitized to Dermatophagoides pteronyssinus (Der p), in stable condition at the time of the study and 15 sex-matched and age-matched controls were studied. The expression of activation surface markers (HLA-DR and CD25) on peripheral blood mononuclear cells (PBMCs) was tested by monoclonal antibodies and FACS analysis, while the PBMC proliferative response to Der p antigens was measured by tritiated thymidine (3HTdR) incorporation. RESULTS: As compared to controls, atopic children showed higher eosinophil counts (P < .01), similar lymphocyte counts (P > .1, each comparison) but higher proportion of HLA-DR+ and CD25+ T-lymphocytes (P < .05, each comparison). A significant Der p allergen-induced PBMC proliferation was observed in atopic children (P < .01) but not in controls (P > .1). Both in controls and in atopic children, no correlations were found between lymphocyte counts and eosinophil counts or total or allergen-specific IgE levels (P > .1, each comparison). In contrast, weak correlations were detected between the degree of allergen-induced PBMC proliferation and: a) allergen-specific IgE levels in serum (P < .05) and b) eosinophil counts (P < .05). CONCLUSION: These data support the concept that the degree of activation of allergen-specific T-lymphocytes in blood may reflect the intensity of allergic sensitization in childhood asthma.     

Double-blind, randomized, placebo-controlled trial of effect of nedocromil sodium on clinical and inflammatory parameters of asthma in children allergic to dust mite

BACKGROUND: The purpose of this study was to determine the clinical effect of nedocromil sodium and its relationship with serum levels of inflammatory mediators by monitoring lung function and noninvasive markers of airway inflammation, such as eosinophil blood counts; serum ECP, sIL-2R, IL-4 and sICAM; and total IgE. Anti-inflammatory medications cause a reduction in the markers of airway inflammation, decrease the intensity of airway hyperresponsiveness, and improve clinical symptoms of asthma. Among the available choices is nedocromil sodium, which is favored in the treatment of asthmatic children due to its very mild side-effects. It has been previously shown to improve the clinical parameters of asthma, but there are limited data on its effect on inflammatory mediators in the serum of asthmatic children. METHODS: In this double-blind, randomized, placebo-controlled 8-week trial, 39 children, aged 9-16 years, with moderate atopic asthma were randomly allocated to receive either nedocromil sodium, two puffs twice daily, 0.002 g/puff, or placebo, two puffs twice daily. The primary end points were the clinical parameters of asthma measured by asthma symptom score, FEV1, and PC20H. Other end points included the serum levels of various inflammatory markers - ECP, sIL-2R, IL-4, sICAM, and IgE. RESULTS: Clinical and inflammatory parameters improved with the use of nedocromil sodium, compared with placebo. Nedocromil significantly decreased serum levels of inflammatory markers, as shown in the following table. No correlation was found between any of the measured parameters. CONCLUSION: Nedocromil sodium provided effective anti-inflammatory treatment for children with moderate atopic asthma.     

维生素D水平与成人哮喘及非哮喘的相关性研究

目的 评估哮喘及非哮喘者的血清维生素D水平及其与肺功能、嗜酸性粒细胞计数的相关性。方法 选取我院2015年9月1日~2016年1月20日收治的85例哮喘患者以及73例健康体检者作为研究对象。根据皮肤过敏试验结果将哮喘患者分为过敏哮喘组56例和非过敏性哮喘组29例,对比两亚组间维生素D水平的差异性;采外周血测量嗜酸性粒细胞计数,用肺功能仪测量肺功能,包括肺活量（FVC）、第1秒最大呼气量（FEV1）、第1秒最大呼气率（FEV1/FVC）,分析过敏哮喘组和非过敏性哮喘组维生素D水平与肺功能、嗜酸性粒细胞计数的相关性。结果 哮喘患者的维生素D水平为（14.36±0.57）ng/ml,低于健康体检组的（22.13±0.84）ng/ml,统计学意义显著（P＜0.01）。过敏哮喘组和非过敏哮喘组的维生素D水平比较,差异无统计学意义（P＞0.05）。低水平维生素D患哮喘的风险增加1.2倍（优势比:1.194,95%可信区间:1.194~1.286,P＜0.01）。维生素D水平与肺功能和嗜酸性粒细胞计数水平无显著相关性。结论 哮喘患者的维生素D水平低于正常人群,维生素D的缺乏与哮喘的发生密切相关;维生素D水平与肺功能、嗜酸性粒细胞计数没有相关性。     

Eosinophil cationic protein in peripheral blood of pediatric patients with allergic diseases

We have studied the levels of eosinophil cationic protein (ECP) and tumour necrosis factor (TNF) in peripheral blood obtained from 68 children with bronchial asthma and 11 children with atopic dermatitis. The ECP mean concentrations of the patients were 23.7 +/- 21.4 micrograms/l and 21.2 +/- 18.7 micrograms/l for bronchial asthma and atopic dermatitis respectively, which were significantly higher than the control value, 5.8 +/- 2.3 micrograms/l (P less than 0.005). TNF was unmeasurable in almost all the samples and no significant difference was observed between normal controls and asthmatic children. A significant correlation was observed between serum levels of ECP and blood eosinophil counts in both diseases (r = 0.873; P less than 0.01 and r = 0.740; P less than 0.01, respectively). However, no obvious correlation was observed between serum levels of ECP and IgE levels. ECP levels were significantly reduced by treatment and normalized in parallel with blood eosinophil counts in the patients with total IgE levels less than 800 U/ml. Irrespective of the total IgE levels, the reduction of serum ECP levels was correlated with a decrease in the number of asthmatic attacks and/or improvement of pulmonary function. These results suggest that the ECP levels in peripheral blood indicate an increased activity of eosinophil and would be a more useful marker than eosinophil counts for making clinical analyses and estimating treatment efficacy in paediatric patients with allergic diseases.     

A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation

BACKGROUND: Exhaled nitric oxide (ENO) has been proposed as a noninvasive marker of airway inflammation in asthma. OBJECTIVE: We investigated the relationships among ENO, eosinophilic airway inflammation as measured by induced sputum, and physiologic parameters of disease severity (spirometry and methacholine PC(20)). We also examined the effect of corticosteroid treatment and atopy on ENO levels and eosinophil counts in induced sputum. METHODS: Measurements were taken on one day in 22 healthy nonatopic subjects, 28 healthy atopic subjects, 38 asthmatic subjects not taking inhaled steroids, 35 asthmatic subjects taking inhaled steroids, and 8 subjects with eosinophilic bronchitis without asthma. RESULTS: ENO levels showed significant but weak correlations with eosinophil differential counts in the steroid-naive asthmatic and healthy atopic groups (r (s) < 0.05). ENO levels were significantly lower in the asthmatic subjects taking steroids compared with the asthmatic subjects not taking steroids, despite there being no difference in the sputum cell counts, and a tendency to increased airflow limitation. ENO levels and sputum eosinophil counts were equally good at differentiating from steroid-naive asthmatic subjects. ENO levels were consistently raised in subjects with eosinophilic bronchitis without asthma. Atopy had no effect on ENO levels in the healthy subjects. CONCLUSION: We conclude that ENO is likely to have limited utility as a surrogate clinical measurement for either the presence or severity of eosinophilic airway inflammation, except in steroid-naive subjects.     

Risk factors and characteristics of early-onset asthma in Taiwanese children.

BACKGROUND AND PURPOSE: Early-onset asthma has been reported to be associated with a family history of allergy and exposure to environmental factors. This study was designed to evaluate the relationship between age of onset of asthma and genetic and environmental factors with asthma severity in Taiwanese children. METHODS: A group of 352 children with asthma (220 males and 132 females), ranging in age from 5 to 15 years, were enrolled in this study. The subjects were divided into 2 groups: early-onset asthma (up to and including age 3) and late-onset asthma. General characteristics including family history of allergies and exposure to domestic pets and tobacco smoke were recorded. The subjects underwent pulmonary function testing and analysis of serum immunoglobulin E (IgE), eosinophil counts, and specific IgE for common allergens. RESULTS: Early-onset asthma was present in 149 subjects and late-onset asthma in 203. Family history of allergies included a sibling with asthma or urticaria predisposed to early-onset asthma (asthma, p=0.034; urticaria, p=0.024). Food and milk allergen sensitization were more common in early-onset asthma (food allergens, p=0.025; milk, p=0.034). Children with early-onset asthma had higher eosinophil counts (p=0.041). However, there was no correlation between age at onset and pulmonary function testing, the levels of total IgE and IgE specific for Dermatophagoides pteronyssinus or Dermatophagoides farinae. CONCLUSIONS: A history of asthma or urticaria in a sibling is a risk factor for early-onset asthma. A greater prevalence of food allergen sensitization and high eosinophil counts are characteristic of early-onset disease.     

The investigation of asthmatic children by multiple factor analysis. II. The influence of 17 allergic factors on atopic dermatitis and allergic rhinitis in asthmatic children

We investigated possible influence of 17 allergy-associated factors on atopic dermatitis and allergic rhinitis using Multiple factor analysis in 150 asthmatic children. Atopic dermatitis was complicated in ninety-seven cases and allergic rhinitis in ninety-seven cases. 17 allergy-associated factors were as follows: 1) sex, 2) age, 3) onset age of asthma, 4) family history of allergy, 5) peripheral eosinophil counts, 6) IgE RIST, 7) IgE RAST score to egg white, 8) IgE RAST score to milk, 9) IgE RAST score to soybean, 10) IgG4 antibody titers to egg white, 11) IgG4 antibody titers to milk, 12) IgG4 antibody titers to soybean, 13) IgE RAST score to house dust, 14) IgE RAST score to Dermatophagoides farinae, 15) severity of asthma, 16) exercise-induced asthma, 17) atopic dermatitis or allergic rhinitis. We concluded as follows: 1) Factors which more strongly influenced both atopic dermatitis and allergic rhinitis were IgE RAST score to D.f., positive family history of allergy, IgE RIST and eosinophil counts. 2) Combination with high levels of IgG4 antibody to 3 food allergens such as egg-white, milk and soybean and IgE RAST to egg-white has a strong influence on atopic dermatitis, but high levels of IgG4 antibody to 3 food allergens except high level of IgG4 antibody to soybean have a weak influence on allergic rhinitis.     

Characterization of within-subject responses to fluticasone and montelukast in childhood asthma

BACKGROUND: Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. OBJECTIVE: We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. METHODS: Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 microg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. RESULTS: Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC(20) and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC(20) and pulmonary function values. CONCLUSIONS: Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.     

Basement membrane thickening and clinical features of children with asthma

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

The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma

BACKGROUND: Endotoxin, with its potential to enhance type 1 immunity, is a significant player in the hygiene hypothesis. The combined effects of the genetic variants of various molecules in the endotoxin response pathway on asthma related phenotypes are largely unknown. OBJECTIVE: To investigate the effects of the genetic variants of CD14 and TLR4 genes on asthma phenotypes in a large number of asthmatic children. METHODS: 613 asthmatic children were genotyped at the CD14-C159T, TLR4-A896G and TLR4-C1196T loci. IgE, eosinophil numbers and FEV1 were compared in 327 children who were not on any controller medications and were symptom free. Multivariate logistic regression was used to determine the factors associated with total IgE. RESULTS: Among children with atopic asthma, total IgE levels were significantly different among the three genotypes in the co-dominant model [CC: 435 kU/l (interquartile range: 146-820); CT: 361 (140-710); TT 204 (98-435), P = 0.035]. TT genotype was significantly and independently associated with lower IgE levels (OR: 0.5 95%; CI = 0.28-0.90, P = 0.021). Both TLR4-A896G and TLR4-C1196T polymorphisms were more frequent in the mild asthma group with atopy (P = 0.032, 0.018, respectively). The combined effects of the genetic variants in CD14 and TLR4 genes did not improve the observed associations. CONCLUSION: Our study demonstrates that the CD14-C159T promoter variant influences total IgE levels and also indicates that the T allele has a more profound effect on total IgE in children with atopic asthma. Polymorphisms in the TLR4 gene may be associated with milder forms of disease in atopic asthmatics in the population studied.     

A randomized, double‐blind trial of the effect of glucocorticoid, antileukotriene and bβ‐agonist treatment on IL‐10 serum levels in children with asthma

BACKGROUND: Levels of an immunoregulatory and anti-inflammatory cytokine IL-10 are reduced in asthmatic airways, potentially contributing to more intense inflammation. Triamcinolone has anti-inflammatory properties and the anti-inflammatory effects of montelukast and formoterol have been discussed. OBJECTIVE: The purpose of this study was to define the effect of treatment with triamcinolone, montelukast and formoterol on the serum level of IL-10, eosinophil blood counts, eosinophil cationic response (ECP) and clinical parameters (symptom score, FEV1 and PC20H) in children with moderate asthma. METHODS: An 8-week, placebo-controlled and randomized, double-blind trial was carried out. The subjects were 91 children with moderate atopic asthma who were allergic to dust mite. Patients were randomly allocated to receive 400 microg triamcinolone (n = 19), 5 or 10 mg (according to age) montelukast (n = 18), 24 microg formoterol (n = 18) or placebo (n = 36). RESULTS: Seventy-nine children completed the study. After treatment with triamcinolone and montelukast the level of IL-10 in blood serum significantly increased, eosinophil blood counts and ECP levels significantly decreased and all clinical parameters improved; treatment with formoterol had no effect on IL-10 level, eosinophil blood counts in serum and bronchial hyper-reactivity; ECP level significantly decreased after treatment and asthma symptoms and FEV1 improved significantly. Mean IL-10 levels in serum before and after treatment with triamcinolone were 7.23 pg/mL with 95% CI, 6.74 -7.72% and 14.24 pg/mL with 95% CI, 11.6-16.88%, respectively (P < 0.001); with montelukast they were 6.59 pg/mL with 95% CI, 6.26-7.23% and 10.94 pg/mL with 95% CI, 8.24-12.65%, respectively (P < 0.002); with formoterol they were 7.06 pg/mL with 95% CI, 6.61-7.52% and 7.04 pg/mL with 95% CI, 6.15-7.93%. We found statistically significant correlations between serum level of IL-10 and serum level of ECP after treatment with triamcinolone and montelukast. CONCLUSION: This study demonstrates that one possible way by which triamcinolone and montelukast contribute to inhibition of inflammation is by increasing IL-10 levels.     

A randomized, double-blind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1) in children with asthma

BACKGROUND: Anti-inflammatory properties of leukotriene modifiers and their effect on bronchial hyperresponsiveness have not been studied in children with asthma. OBJECTIVE: The primary objective of this study was to determine the changes in serum levels of inflammatory mediators, clinical efficacy, and bronchial hyperresponsiveness after treatment with montelukast. METHODS: In this double-blind, randomized, placebo-controlled trial, 39 children with mild-to-moderate atopic asthma were randomly allocated to receive montelukast or placebo for 6 weeks. Main outcome measures were changes in serum concentrations of soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1); peripheral blood eosinophil count; and eosinophilic cationic protein (ECP). Asthma severity score, FEV(1), and bronchial hyperreactivity (BHR) for histamine were secondary end points. RESULTS: Compared to placebo, serum concentrations of IL-4, sICAM-1, and ECP and eosinophil blood counts significantly decreased after 6 weeks of treatment with montelukast. Montelukast significantly improved asthma control and FEV(1). Montelukast resulted in within-group significant decrease in levels of serum sIL-2R (611 vs. 483 pg/mL), IL-4 (0.123 vs 0.102 pg/mL), sICAM-1 (280 vs. 244 ng/mL), and ECP (74 vs. 59 microg/mL) and in eosinophil blood counts (349 vs. 310 cells/mm(3)). Mean FEV(1) value changed from 85% of predicted to 95% (P <.001) and for histamine (PC(20)H) from 2.8 mg/mL to 3.8 mg/mL (P <.001) after treatment with montelukast. There was no significant difference between montelukast and placebo recipients in the serum concentrations of sIL-2R and PC(20)H after treatment. CONCLUSION: Montelukast provides clinical benefit to patients with chronic asthma and decreases bronchial hyperresponsiveness. Montelukast caused a statistically significant decrease of serum concentrations in cytokine, ICAM-1, and ECP and peripheral blood eosinophil counts over the 6-week treatment period. This observation raises the possibility that leukotriene receptor antagonists, such as montelukast, may have effects on parameters of asthmatic inflammation.