Bronchodilation and bronchoconstriction: predictors of future lung function in childhood asthma

BACKGROUND: Persistently low levels of lung function are associated with subsequent symptoms in patients with asthma as children. OBJECTIVES: We hypothesized that objective measures of baseline pulmonary function would be independently associated with future lung function in the Childhood Asthma Management Program and that these associations might vary with treatment. METHODS: We evaluated the association of FEV1, airway responsiveness, and bronchodilator response at randomization as predictors of longitudinal growth in FEV1 at the 48-month follow-up visit in the 1041 Childhood Asthma Management Program participants. RESULTS: Baseline levels of airway responsiveness and bronchodilator response were significantly associated with baseline level of lung function. In multivariate models, higher bronchodilator response (beta = 0.22; P < .0001), log PC20 (beta = 1.82; P < .0001), and FEV1 (beta = 0.58; P < .0001) at randomization were each associated with higher levels of prebronchodilator FEV1, as a percent of predicted, after 4 years. Similar associations were noted for prebronchodilator forced vital capacity and FEV1/forced vital capacity ratio. Baseline bronchodilator response was a particularly powerful predictor of lung function improvements while on inhaled corticosteroids, whereas airway responsiveness was a better predictor in subjects not randomized to any controller medications. CONCLUSION: We conclude that baseline bronchodilator response, airway responsiveness, and level of FEV1 are independent predictors of subsequent level of FEV1 in childhood asthma and may have treatment-specific prognostic significance for persistence of symptoms into early adulthood. CLINICAL IMPLICATIONS: In asthma, bronchodilator and bronchoconstrictor responses are independent predictors of future lung function and should not be used interchangeably; bronchodilator response may indicate good response to inhaled corticosteroids.     

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma.

BACKGROUND: Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE: To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS: The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION: In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.     

Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program

BACKGROUND: Severe asthma causes the majority of asthma morbidity. Understanding mechanisms that contribute to the development of severe disease is important. OBJECTIVE: The goal of the Severe Asthma Research Program is to identify and characterize subjects with severe asthma to understand pathophysiologic mechanisms in severe asthma. METHODS: We performed a comprehensive phenotypic characterization (questionnaires, atopy and pulmonary function testing, phlebotomy, exhaled nitric oxide) in subjects with severe and not severe asthma. RESULTS: A total of 438 subjects with asthma were studied (204 severe, 70 moderate, 164 mild). Severe subjects with asthma were older with longer disease duration (P < .0001), more daily symptoms, intense urgent health care utilization, sinusitis, and pneumonia (P < or = .0001). Lung function was lower in severe asthma with marked bronchodilator reversibility (P < .001). The severe group had less atopy by skin tests (P = .0007), but blood eosinophils, IgE, and exhaled nitric oxide levels did not differentiate disease severity. A reduced FEV(1), history of pneumonia, and fewer positive skin tests were risk factors for severe disease. Early disease onset (age < 12 years) in severe asthma was associated with longer disease duration (P < .0001) and more urgent health care, especially intensive care (P = .002). Later disease onset (age > or = 12 years) was associated with lower lung function and sinopulmonary infections (P < or = .02). CONCLUSION: Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization. CLINICAL IMPLICATIONS: Lung function abnormalities in severe asthma are reversible in most patients, and pneumonia is a risk factor for the development of severe disease.     

Sensitization to Ascaris lumbricoides and severity of childhood asthma in Costa Rica

BACKGROUND: Little is known about sensitization (defined as a positive IgE) to helminths and disease severity in patients with asthma. OBJECTIVES: To examine the relationship between sensitization (defined as a positive IgE) to Ascaris lumbricoides and measures of asthma morbidity and severity in a Costa Rican population with low prevalence of parasitic infection but high prevalence of parasitic exposure. METHODS: Cross-sectional study of 439 children (ages 6 to 14 years) with asthma. Linear regression and logistic regression were used for the multivariate statistical analysis. RESULTS: After adjustment for parental education and other covariates, sensitization to Ascaris lumbricoides was associated with having at least 1 positive skin test to allergens (odds ratio, 5.15; 95% CI, 2.36-11.21; P < .001), increased total serum IgE and eosinophils in peripheral blood, reductions in FEV(1) and FEV(1)/forced vital capacity, increased airway responsiveness and bronchodilator responsiveness, and hospitalizations for asthma in the previous year (odds ratio, 3.08; 95% CI, 1.23-7.68; P = .02). CONCLUSION: Sensitization to Ascaris lumbricoides is associated with increased severity and morbidity of asthma among children in Costa Rica. This association is likely mediated by an increased degree of atopy among children with asthma who are sensitized to Ascaris. CLINICAL IMPLICATIONS: In areas with a low prevalence of helminthiasis such as Costa Rica, Ascaris sensitization may be an important marker of severe atopy and disease morbidity in children with asthma.     

IgE expression pattern in lung: relation to systemic IgE and asthma phenotypes

BACKGROUND: IgE-mediated responses contribute to allergy and asthma. Little is understood regarding the relationship of tissue IgE to systemic IgE, inflammation or clinical outcomes. OBJECTIVES: To evaluate local IgE expression and cellular inflammation in the proximal and distal lung of normal subjects and subjects with asthma of varying severity and relate those tissue parameters to systemic IgE levels, atopy, lung function, and history of severe exacerbations of asthma. METHODS: Tissue from more than 90 subjects with eosinophilic (SAeo(+)) and noneosinophilic (SAeo(-)) severe asthma, mild asthma and normal subjects were immunostained for IgE, signal-amplifying isoform of IgE receptor (FcepsilonRIbeta) and markers of mast cells, eosinophils, and lymphocytes. Tissue expression of IgE, FcepsilonRIbeta, cellular inflammation, serum IgE, and atopy were compared. Regression models were used to determine the relationship of local and systemic IgE to lung function and severe exacerbations of asthma. RESULTS: Mast cell-bound IgE was present along airways but absent in lung parenchyma. Although the groups were similar in systemic/serum IgE and atopy, local/tissue IgE was highest in SAeo(+) and correlated with eosinophils and lymphocytes (r(s) = 0.52, P < .0001; and r(s) = 0.23, P = .03, respectively). Higher local IgE was associated with better lung function, but also with more severe exacerbations of asthma. CONCLUSION: Local IgE appears to be primarily a component of responses within the mucosal immune compartment and is related to cellular inflammation, lung function, and clinical outcomes in asthma. CLINICAL IMPLICATIONS: Local/airway IgE-related processes rather than systemic markers of atopy may be relevant in determining clinical outcomes in asthma.     

支气管哮喘患者FeNO的表达及临床意义

目的:探讨不同呼出气一氧化氮(Fractional exhaled nitric oxide,FeNO)水平下支气管哮喘患者痰液、血液、肺功能检测等多个观察指标的表达特点,并分析在气道高反应性中的预测价值。方法:选取2017年1月至2019年5月于我院就诊的120例疑似支气管哮喘患者作为研究对象进行前瞻性分析,根据FeNO水平不同,将FeNO>49 ppb的42例患者列为高水平组,FeNO为26~49 ppb的33例患者为低水平组,FeNO≤25 ppb的45例患者为正常组。比较三组患者的基本临床资料、痰嗜酸性粒细胞、痰中性粒细胞、血嗜酸性粒细胞阳离子蛋白(Eosinophilic cationic protein,ECP)和免疫球蛋白E(Immunoglobulin E,IgE)以及第1s用力呼气容积(Forced expiratory volume at 1s,FEV1)、FEV1占预测值百分比(FEV1%Pred)、用力肺活量(Forced vital capacity,FVC)以及FEV1与FVC比值(FEV1/FVC)等肺功能检测结果进行统计分析。结果:经Spearman相关性分析显示,血IgE、ECP水平与FeNO水平呈正相关(r=0.615/0.629,P>0.01),FEV1%pred、FEV1/FVC与FeNO水平呈负相关(r=-0.494/0.789,P>0.01)。其中血IgE、ECP、FEV1%pred、FEV1/FVC对于预测支气管哮喘有一定的价值,而联合上述指标对于预测支气管哮喘的准确性最佳(AUC=0.920,P>0.01)。结论:不同FeNO水平支气管哮喘患者在临床表现中具有显著差异,在血IgE、ECP和肺功能FEV1%pred、FEV1/FVC指标检测的基础上增加FeNO可大大增加预测支气管哮喘的准确性。     

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.     

Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma.

BACKGROUND: In the Collaborative Study on the Genetics of Asthma, 314 families with 2584 subjects were characterized for asthma and allergy. OBJECTIVE: The purpose of this investigation was to examine clinical heterogeneity observed in asthma and allergic characteristics among 3 ethnic groups (African American, white, and Hispanic family members). METHODS: Pulmonary function parameters and asthma associated phenotypes were compared among the ethnic groups. RESULTS: In comparison with the other groups, African American sibling pairs had a significantly lower baseline FEV(1) percent of predicted (P =.0001) and a higher rate of skin test reactivity to cockroach allergen (P =.0001); Hispanic sibling pairs had significantly more skin reactivity overall (P =.001); and white sibling pairs had significantly lower total serum IgE (P <.05). In addition, there were significantly more relatives with asthma among the African American families than among the white and the Hispanic families (P =.001). CONCLUSION: Although different environmental backgrounds should be considered, these clinical differences could be due to differences in genetic susceptibility among the ethnic groups, such as those suggested by our previous genome screen.     

Inhaled steroids are associated with reduced lung function decline in subjects with asthma with elevated total IgE

BACKGROUND: Few studies have investigated the long-term association between inhaled corticosteroids (ICSs) and lung function decline in asthma. OBJECTIVE: To evaluate whether prolonged treatment with ICSs is associated with FEV(1) decline in adults with asthma. METHODS: An international cohort of 667 subjects with asthma (20-44 years old) was identified in the European Community Respiratory Health Survey (1991-1993) and followed up from 1999 to 2002. Spirometry was performed on both occasions. FEV(1) decline was analyzed according to age, sex, height, body mass index, total IgE, time of ICS use, and smoking, while adjusting for potential confounders. RESULTS: As ICS use increased, the decline in FEV(1) was lower (P trend = .025): on average, decline passed from 34 mL/y in nonusers (half of the sample) to 20 mL/y in subjects treated for 48 months or more (18%). When adjusting for all covariates, there was an interaction (P = .02) between ICS use and total IgE: in subjects with high (>100 kU/L) IgE, ICS use for 4 years or more was associated with a lower FEV(1) decline (23 mL/y; 95% CI, 8-38 compared with nonusers). This association was not seen in those with lower IgE. CONCLUSION: Although confirming a beneficial long-term association between ICSs and lung function in asthma, our study suggests that subjects with high IgE could maximally benefit from a prolonged ICS treatment. CLINICAL IMPLICATIONS: This study adds further evidence to the beneficial effect of inhaled steroids on lung function in asthma; future studies will clarify whether calibrating the corticosteroid dose according to the level of total IgE is a feasible approach in asthma management.     

Prognostic factors of asthma severity: a 9-year international prospective cohort study

BACKGROUND: The natural history of asthma severity is poorly known. OBJECTIVE: To investigate prognostic factors of asthma severity. METHODS: All current patients with asthma identified in 1991 to 1993 in the European Community Respiratory Health Survey were followed up, and their severity was assessed in 2002 by using the Global Initiative for Asthma categorization (n = 856). Asthma severity (remittent, intermittent, mild, moderate, severe) was related to potential determinants evaluated at baseline and during the follow-up by a multinomial logistic model, using the intermittent group as the reference category for relative risk ratios (RRRs). RESULTS: Asthma severity measured at baseline was a determinant of a patient's severity at the end of the follow-up. At baseline, severe persistent had a poorer FEV1% predicted, a poorer symptom control, higher IgE levels (RRR, 2.06; 95% CI, 1.38-3.06), and a higher prevalence of chronic cough/mucus hypersecretion (RRR, 4.90; 95% CI, 2.18-11.02) than patients with intermittent asthma. Moderate persistent showed the same prognostic factors as severe persistent, even if the associations were weaker. Mild persistent had a distribution of prognostic factors that was similar to patients with intermittent asthma, although the former showed a poorer symptom control than the latter. Remission mainly occurred in patients with less severe asthma and was negatively associated with a change in body mass index (RRR, 0.86; 95% CI, 0.75-0.97). Allergic rhinitis, smoking, and respiratory infections in childhood were not associated with asthma severity. CONCLUSION: Patients with moderate and severe persistent asthma are characterized by early deterioration of lung function. High IgE levels and persistent cough/mucus hypersecretion are strong markers of moderate/severe asthma, which seems to be a different phenotype from mild persistent or intermittent asthma. CLINICAL IMPLICATIONS: Our results suggest that the evolution of asthma severity is to a large extent predictable.     

Intranasal air sampling in homes: relationships among reservoir allergen concentrations and asthma severity

BACKGROUND: The relationship among inhaled allergen exposure, sensitization, and asthma severity is unknown. OBJECTIVES: To investigate the relationship among personal allergen exposure, reservoir dust allergen concentrations, and physiological measures of asthma severity; to examine the numbers of particles inspired that react with autologous IgE and IgG4. METHODS: A total of 117 patients with asthma wore 5 nasal air samplers (NASs) at home: 1 each for exposure to mite, cat and dog allergens, NAS-IgE, and NAS-IgG4. NASs were processed by HALOgen assay for allergen measurement and incubated with autologous serum for detection of NAS-IgE and NAS-IgG4. Reservoir allergen concentrations were measured by ELISA. Subjects' asthma severity was ascertained by measurement of lung function, exhaled nitric oxide, and nonspecific bronchial reactivity to histamine. RESULTS: Nasal air sampler counts correlated with reservoir concentrations for cat (r=0.31; P=.001) and dog (r=0.20; P=.03) but not mite allergen (r=0.001; P=1.0). There was no significant relationship between sensitization with exposure measured by NAS to any allergen and PD20FEV1 (F[3,60]=1.60; P=.20); however, sensitization with exposure in dust reservoirs had significant effects on PD20FEV1 for any allergen (F[3,59]=3.12; P=.03), cat (F[3,59]=3.77; P=.01), and mite (F[3,59]=2.78; P=.05), but not dog (F[3,59]=1.06; P=.37). We repeated the analysis with separate variables for sensitization and exposure, controlling for the confounders; sensitization but not exposure conferred lower PD20FEV1 values. However, increasing cat allergen exposure was associated with improving bronchial reactivity in not cat-sensitized patients. NAS-IgE and NAS-IgG4 counts bore no relationship to any measure of asthma severity. CONCLUSION: Nasal air samplers confer no advantage over reservoir dust analysis for studies of asthma severity. CLINICAL IMPLICATIONS: In common with other measures of exposure, single nasal air samples do not provide a useful measure of home allergen exposure for the individual patient with allergic asthma.     

Eotaxin polymorphisms and serum total IgE levels in children with asthma

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.     

Contribution of dust mite and cat specific IgE to total IgE: relevance to asthma prevalence

BACKGROUND: The prevalence of asthma is strikingly different in some Westernized countries: approximately 20% in New Zealand and approximately 8% in northern Sweden. OBJECTIVE: We investigated differences in total IgE and in the prevalence of wheezing related to the observation that high exposure to dust mite allergens induces high titers of IgE antibodies. METHODS: Two age-matched, population-based cohorts-1155 children in New Zealand (224 sera) and 3431 children (797 sera) in the Norrbotten area of Sweden-were studied. Sera were assayed for total IgE and specific IgE antibodies to relevant allergens. RESULTS: The mean total IgE among wheezing children was higher in New Zealand than Sweden (218 IU/mL vs 65.2 IU/mL; P < .001). In addition, the prevalence of high titer specific IgE antibody (> or =50 IU/mL) was greater among the wheezing children in New Zealand compared with Sweden (35.7% vs 13.0%; P < .001). Specific IgE antibody to mite in New Zealand was significantly related to high total IgE (> or =200 IU/mL; r = 0.47; P < .001), whereas the IgE antibody response to cat allergens did not make a significant contribution to high total IgE in either country. CONCLUSION: The quantity of IgE antibody produced to dust mite provides a possible explanation for the higher total IgE levels found in children in New Zealand and may help to explain the differences in prevalence and severity of asthma between these 2 countries. CLINICAL IMPLICATIONS: Specific IgE antibody responses to dust mite and cat allergens may contribute differently to total serum IgE and to the prevalence of allergic disease.     

A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.     

A polymorphism in the coding region of interleukin-13 gene is associated with atopy but not asthma in Chinese children

BACKGROUND: Interleukin (IL)-13 is an important cytokine secreted from type 2 helper T lymphocytes. It is essential for modulating IgE synthesis by human B cells. Previous studies showed that polymorphisms in the IL-13 gene were associated with serum total IgE or allergic asthma. The relationship of this marker with sensitization to individual aeroallergens has not been evaluated. OBJECTIVE: We tested whether a polymorphism in the coding region of the IL-13 gene is associated with asthma and atopy in asthmatic children in Hong Kong. METHODS: We used restriction fragment length polymorphism to detect R130Q genotype in Chinese children with asthma and control subjects. Serum total IgE was measured by microparticle immunoassay and specific IgE to common aeroallergens was measured using fluorescent enzyme immunoassay. Pulmonary function studies were performed using spirometry. RESULTS: One hundred and fifty-seven patients and 54 control children were recruited. Their mean serum total IgE concentrations were 994 kIU/L and 473 kIU/L, respectively (P < 0.0001). Atopy as defined by > or = 1 positive RAST was found in 141 patients and 32 control children. The GlnGln form of the R130Q polymorphism in the IL-13 gene was associated with serum total IgE (P = 0.005) as well as specific IgE to Der p 1 (P = 0.021), mixed cockroaches (P = 0.03) and dog (P = 0.003) but not with physician-diagnosed asthma (P = 0.621). In addition, the R130Q polymorphism did not correlate with subjective or objective indicators of asthma severity in our patients. CONCLUSION: Our results suggest that the R130Q polymorphism of the IL-13 gene is associated with elevated serum total and allergen-specific IgE but not asthma in Chinese children.     

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.     

Avoidance therapy in reactive dye-induced occupational asthma: long-term follow-up.

BACKGROUND: Previous studies reported that early diagnosis and avoidance therapy are the most important factors for prevention of permanent lung impairment; however, few studies have evaluated the long-term prognosis of reactive dye-induced occupational asthma (RD-OA). OBJECTIVE: To evaluate the long-term outcomes of RD-OA. METHODS: Methacholine airway hyperresponsiveness (AHR) and lung functions were evaluated and compared in 26 patients with RD-OA at the time of diagnosis and after complete avoidance of the causative agents. Patients with continued (n = 13) or remitted (n = 6) AHR were further monitored for up to a mean +/- SD of 8.7 +/- 1.8 years. RESULTS: The AHR resolved in 10 (38%) of 26 patients a mean +/- SD of 2.2 +/- 1.3 years after complete avoidance of RDs; however, prebronchodilator forced expiratory volume in 1 second (FEV1) values were not different. Levels of IgE specific to the RD-human serum albumin complex were markedly decreased at first follow-up in 5 RD-atopic patients from whom paired serum samples were compared (P = .02). The AHR disappeared in an additional 5 patients and improved in 4 by the second follow-up. The FEV1 values also improved compared with diagnosis and first follow-up levels. Favorable prognosis was associated with early diagnosis of RD-OA and complete avoidance of the causative agent. No association was found with smoking history, latent periods, the presence of RD specific IgE, baseline provocation concentration that caused a decrease in FEV1 of 20%, or FEV1. CONCLUSIONS: Early diagnosis and avoidance therapy are the most important prognostic factors in RD-OA. The AHR and lung function of patients with RD-OA can sometimes be recovered steadily and slowly through avoidance measures.     

Association between preference-based health-related quality of life and asthma severity.

BACKGROUND: Preference-based measures of health-related quality of life (HRQL) focus on choice and strength of preference for health outcomes. If the value people attach to the health improvement they receive from medical treatments for asthma is known, preference-based measures can be used in cost-effectiveness analyses to aid resource allocation decisions. International guidelines have been developed to guide medical management according to asthma severity defined by lung function and symptom frequency. OBJECTIVE: To test the hypothesis that preferences correlate with asthma severity and that the relationships vary among the preference instruments used and the components of asthma severity studied. METHODS: Preferences for subjects' health states were measured using (1) a rating scale (RS), (2) standard gamble (SG), (3) time tradeoff (TTO), (4) Health Utilities Index 3 (HUI3), and (5) Asthma Symptom Utility Index (ASUI). We measured level of airways obstruction by forced expiratory volume in 1 second (FEV1) and symptom frequency of cough, wheeze, dyspnea, and nighttime awakening. Asthma severity was defined by either percentage of predicted FEV1 or symptom frequency. RESULTS: One hundred adults with asthma were studied. Preference scores were lowest for the HUI3 (mean, 0.57) and highest for the SG (mean, 0.91). Spearman correlations showed that the strength of the relationship between preference scores and percentage of predicted FEV1 was weak to moderate (r = 0.14-0.36). One-way analysis of variance showed that RS, TTO, and ASUI scores were significantly associated with the percentage of predicted FEV1 (P < or = .01). Both RS and HUI3 scores were significantly associated with frequency of all symptoms (P < .05). CONCLUSIONS: Preference-based measures of HRQL are correlated with asthma severity defined by lung function or symptoms. The RS was significantly associated with level of airways obstruction and all 4 symptoms evaluated, whereas the SG was not correlated with either marker of asthma severity.     

Allergen-induced bronchial inflammation in house dust mite-allergic patients with or without asthma

BACKGROUND: It is presently unknown which factors determine the occurrence and persistence of asthma in house dust mite-allergic individuals. The level of allergen-specific IgE antibodies does not seem to be decisive for asthmatic symptoms. Moreover, levels of exposure to mite allergens do not seem to differ significantly between asthmatic and non-asthmatics individuals. AIM: It was hypothesized that the presence or absence of asthmatic symptoms in house dust mite-allergic patients is associated with quantitative or qualitative differences in the cellular bronchial inflammatory response during the late phase of the allergic reaction. This hypothesis was tested in the bronchial allergen challenge model. MATERIAL AND METHODS: Whole lung challenges with house dust mite extract were performed in 52 house dust mite-allergic subjects, of whom 26 had asthma and 26 had perennial rhinitis without asthmatic symptoms. Primary outcomes were parameters for bronchial inflammation in serial samples of induced sputum (cell differentials, eosinophil cationic protein (ECP), interleukin-8 (IL-8), myeloperoxydase (MPO)). In addition, lung function, non-specific bronchial hyper-responsiveness and serial blood samples (eosinophils and IL-5) were analysed. RESULTS: At baseline sputum eosinophils and ECP were similar in both groups but neutrophils and IL-8 were higher in asthmatics. The early bronchoconstriction after allergen challenge was similar in asthma and non-asthmatic rhinitis (median decrease in FEV1: asthma -31.7% vs. non-asthmatics -29.1%, P > 0.1). The late phase bronchoconstriction was significantly greater in asthma (median decrease in FEV1: asthma -27.6% vs. non-asthmatics -18.9%, P = 0.02). Induction of bronchial hyper-responsiveness was similar in both groups. Bronchial allergen challenge elicited significant increases in sputum eosinophils and ECP, which were indistinguishable for both groups (P > 0.1 and P = 0.07, respectively). In contrast, higher numbers of neutrophils persisted in asthma 24h after challenge and were accompanied by significant increases in IL-8 and MPO, which were absent in non-asthmatics (difference between groups P = 0.007 and P = 0.05, respectively). CONCLUSION: Allergen challenge inducedvery similar increases in eosinophils and ECP in induced sputum in allergic asthmatics and in allergic non-asthmatic patients. The difference in bronchial inflammation between asthma and non-asthmatic rhinitis appeared to be more closely related to indices for neutrophilic inflammation.     

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma

BACKGROUND: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. OBJECTIVE: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. METHODS: Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. RESULTS: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. CONCLUSION: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. CLINICAL IMPLICATIONS: Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.