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Background The relationship between allergy and autoimmune disorders is complex and poorly understood. Objective We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. Methods We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. Results Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy ( P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. Conclusion We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between pubertal timing and cardiometabolic markers among adolescents.Study Design: We used data from Dutch adolescents participating in a birth cohort study. The study population for the current study consisted of 799 adolescents of whom data were available for at least 1 of the exposure variables (pubertal timing and/or age at menarche) and any of the cardiometabolic markers (waist circumference, cholesterol, blood pressure [BP], glycated hemoglobin) measured at age 16 years. Adolescents self-reported pubertal development at ages 11, 14, and 16 years. We categorized participants with early (84 girls, 88 boys), intermediate (240 girls, 211 boys), or late pubertal timing (89 girls, 85 boys). We estimated differences in cardiometabolic markers using linear regression analysis.Results: Girls with early pubertal timing had 1.54 cm larger waist circumference (95% CI .05; 3.03) and 3.98 mm Hg higher systolic BP (95% CI 1.69; 6.27) at age 16 years than girls with intermediate pubertal timing. The association with systolic BP remained after adjusting for childhood body mass index (BMI) (age 8 years) but attenuated after adjusting for BMI in adolescence (age 16 years). Boys with early pubertal timing had 0.79 mmol/mol lower glycated hemoglobin (95%CI -1.38; -0.20) than boys with intermediate pubertal timing.Conclusions: Girls with early pubertal timing had unfavorable BP levels at age 16 years, independent of BMI in childhood. Girls and boys with late pubertal timing had a tendency for lower waist circumference, but no differences in other cardiometabolic markers. Late pubertal timing does not appear to be a risk factor for unfavorable cardiometabolic markers in adolescence. [ABSTRACT FROM AUTHOR]

Background Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively. Objective The aim of this study was to identify common genetic variants associated with FEV 1 and its ratio to forced vital capacity (FVC) in never-smokers. Methods Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results ( P < 10 −5 ) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses. Results We identified associations between the FEV 1 /FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein (HHIP) and family with sequence similarity 13 member A (FAM13A) were shown to have an additive effect on FEV 1 /FVC levels in the genetic risk score analysis; were associated with gene expression of HHIP and FAM13A in lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts ( P < 2.19 × 10 −7 ). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV 1 identification analysis were not replicated. Conclusion The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non–IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases. [ABSTRACT FROM AUTHOR]

Background Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthmatic patients are lacking. Objective We sought to investigate pollution effects in a longitudinal asthma study and effect modification by controller medications. Methods We examined associations of lung function and methacholine responsiveness (PC 20 ) with ozone, carbon monoxide (CO), nitrogen dioxide, and sulfur dioxide concentrations in 1003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to ZIP/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV 1 and forced vital capacity (FVC) percent predicted, FEV 1 /FVC ratio, and PC 20 , adjusting for seasonality and confounders. Results Same-day and 1-week average CO concentrations were negatively associated with postbronchodilator percent predicted FEV 1 (change per interquartile range, −0.33 [95% CI, −0.49 to −0.16] and −0.41 [95% CI, −0.62 to −0.21], respectively) and FVC (−0.19 [95% CI, −0.25 to −0.07] and −0.25 [95% CI, −0.43 to −0.07], respectively). Longer-term 4-month CO averages were negatively associated with prebronchodilator percent predicted FEV 1 and FVC (−0.36 [95% CI, −0.62 to −0.10] and −0.21 [95% CI, −0.42 to −0.01], respectively). Four-month averaged CO and ozone concentrations were negatively associated with FEV 1 /FVC ratio ( P < .05). Increased 4-month average nitrogen dioxide concentrations were associated with reduced postbronchodilator FEV 1 and FVC percent predicted. Long-term exposures to sulfur dioxide were associated with reduced PC 20 (percent change per interquartile range, −6% [95% CI, −11% to −1.5%]). Treatment augmented the negative short-term CO effect on PC 20 . Conclusions Air pollution adversely influences lung function and PC 20 in asthmatic children. Treatment with controller medications might not protect but rather worsens the effects of CO on PC 20 . This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication. [ABSTRACT FROM AUTHOR]

The Dutch hypothesis was first articulated in 1961, when many novel and advanced scientific techniques were not available, such as genomics techniques for pinpointing genes, gene expression, lipid and protein profiles, and the microbiome. In addition, computed tomographic scans and advanced analysis techniques to dissect (small) airways disease and emphysema were not available. At that time, the group of researchers under the visionary guidance of Professor N. G. M. Orie put forward that both genetic and environmental factors can determine whether one would have airway obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Moreover, they stipulated that the phenotype of obstructive airway disease could be affected by sex and changes with aging. Orie and colleagues' call to carefully phenotype patients with obstructive airways diseases has been adopted by many current researchers in an attempt to determine the heterogeneity of both asthma and COPD to better define these diseases and optimize their treatment. The founders of the Dutch hypothesis were far ahead of their time, and we can learn from their insights. We should fully characterize all patients in our clinical practice and not just state that they have asthma, COPD, or asthma and COPD overlap syndrome. This detailed phenotyping can help in understanding these obstructive airway diseases and provide guidance for disease management. [ABSTRACT FROM AUTHOR]

Background Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity. Methods 202 mild-to-very-severe COPD patients and 83 old (40-75 years) and 110 young (18-40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co-morbidities and lung function values were obtained. Results COPD patients (FEV1 = 55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p < 0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV1/FVC, MEF50/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p < 0.05). Conclusions SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD. [ABSTRACT FROM AUTHOR]

Background: The clinical and demographic variables defining the heterogeneity of chronic obstructive pulmonary disease (COPD) are unclear. A post-hoc analysis of five randomised studies in patients with a history of previous exacerbations examined the clinical and demographic characteristics describing moderate-to-very-severe COPD. Methods: Factor analysis was performed on all continuous baseline demographic and clinical data, without variable selection. Analyses were based on the full cohort and on stratifications by pack-years smoked, smoking status, gender, and comorbidities; patient exacerbation history was analysed in two of the five studies. Findings: 6162 COPD patients were evaluated (70% male; 40% current smokers; mean pre- bronchodilator forced expiratory volume in 1 s [FEV1] 35.2% predicted). Baseline clinical and demographic variables loaded differentially on six factors with minimal overlap, explaining 60.4% of the heterogeneity: 1) symptoms (cough, dyspnoea, sleep disturbance), health status, reliever use; 2) pre-bronchodilator FEV11, FEV1/forced vital capacity, morning peak expiratory flow (PEF), body mass index (BMI); 3) blood pressure; 4) age, months since first COPD symptoms; 5) PEF variability; 6) pulse, FEV1 reversibility. Most factors loaded similarly in stratified and exacerbation analyses. BMI loaded with reversibility in females, and with age and months since first COPD symptoms in ex-smokers. Exacerbations loaded to factor 6. Interpretation: Readily available data can explain ~ 60% of COPD heterogeneity in a large dataset of predominantly severe COPD patients. Factors were robust over determinants of disease outcome; gender, smoking status, pack-years smoked, and comorbidities. The main factors were largely unchanged by adding exacerbations. Only BMI loaded to other factors. [ABSTRACT FROM AUTHOR]

Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice. [Copyright &y& Elsevier]

Abstract: Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV1) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV1 level and inflammatory markers in COPD patients.We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV1 decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting β2-agonists. Additionally we investigate the association of MRP1 variants with FEV1 decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV1 decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV1 decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV1 decline than in those with a weak staining. None of the variants was associated with FEV1 decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV1 decline occurring selectively in COPD patients with long-term (30-month) ICS therapy. [Copyright &y& Elsevier]

Summary: Background: Inhaled glucocorticosteroids reduce airway inflammation in asthma patients, thereby improving lung function and reducing airway hyperresponsiveness and symptoms. The response to glucocorticosteroids can be measured with the glucocorticosteroid skin-blanching test. We investigated if asthmatics have a lower skin-blanching response to glucocorticosteroids than non-asthmatic subjects and if asthmatics with airway obstruction have lower skin-blanching response than those without obstruction. Finally, we assessed which clinical and inflammatory parameters influence the variability in skin-blanching response. Methods: We evaluated the skin-blanching response to topical budesonide in a large group of 315 well-characterized asthmatics and their relatives (asthma n = 114, healthy n = 140, other = 61) Results: The skin-blanching scores of the asthma probands and their healthy spouses were not significantly different. The skin-blanching score of patients with FEV1 < 80% predicted was lower than of patients without obstruction. Lower skin-blanching score was significantly associated with lower FEV1 %predicted, higher age, female gender, absence of allergy and summer season, but not with use of inhaled or oral glucocorticosteroids or packyears smoking. Conclusions: Asthmatics do not have lower skin-blanching response to glucocorticosteroids than healthy subjects. Furthermore, lower skin-blanching response to glucocorticosteroids is associated with lower FEV1, female gender, higher age and the absence of allergy. [ABSTRACT FROM AUTHOR]

It is difficult to distinguish at preschool age whether a wheezing child will or will not have asthma at school age. A prediction rule for asthma in preschool children might help to determine a prognosis and to study improvements in treatment and prevention. This review discusses (1) the development and use of clinical prediction rules, (2) the European Respiratory Society Task Force classification of wheeze at preschool age, (3) published prediction rules developed to identify preschool children who will have asthma at school age, and (4) recommendations to improve asthma prediction. Prediction rules are currently created more frequently, yet their clinical use remains low. The classification of episodic wheeze and multiple-trigger wheeze in preschool children shows conflicting results as to whether episodic wheeze and multiple-trigger wheeze differ in clinical features and has limited value in predicting asthma at school age. Clearly, more studies are needed to confirm this. Currently available prediction rules aiming to identify preschool children having asthma at school age are of modest clinical value. Prediction can be improved by more precise definitions and measures and, ultimately, by more knowledge of pathophysiologic mechanisms. In the future, biomarkers and genomic risk profiles to develop personalized medicine might further improve asthma prediction, treatment, and prevention. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The GOLD guidelines advocate not to institute inhaled corticosteroids (ICS) in patients with mild-to-moderate COPD. However, many patients do use ICS and in some patients, withdrawal is associated with deteriorating lung function and increased exacerbation rates. Unfortunately, physicians do not know in which patients they can stop ICS treatment safely. Aim: To identify predictors of COPD exacerbations after ICS withdrawal. Methods: During ICS treatment, post-bronchodilator spirometry, body plethysmography, and health status assessment were performed in 68 COPD patients using ICS. Additionally, sputum cell differentials, supernatant leukotriene B4, eosinophilic cationic protein, and myeloperoxidase, serum C-reactive protein and soluble intracellular adhesion molecule, and urinary desmosine were assessed. Sputum was also analysed for mRNA levels of haemoxygenase-1, tumour necrosis factor-α, RANTES, interleukin 5(IL-5), IL-10, IL-12, IL-13, transforming growth factor-β, and interferon-γ. Statistics: Cox regression analyses were performed using time to exacerbation as outcome variable to identify significant hazards for a COPD exacerbation after ICS withdrawal. Results: Higher sputum % eosinophils, higher sputum MPO/neutrophil level, longer duration of COPD symptoms, <40 packyears smoking, and ICS withdrawal in November, December or January were significant hazards (all p <0.05) for experiencing a COPD exacerbation after ICS withdrawal in a monovariate model. In a multivariate model, all factors proved independent predictors except for sputum MPO/neutrophil level. Conclusions: Decisions on whether or not inhaled corticosteroids can be safely withdrawn in mild-to-moderate COPD can be facilitated by assessment of sputum inflammation, particularly eosinophil numbers, next to packyears smoking, season, and duration of COPD symptoms. [ABSTRACT FROM AUTHOR]

Summary: Rationale: Patient-reported outcomes provide new insights into the dynamics of asthma management. Further to asthma control and quality of life, self-reported side effects of treatment can be assessed with the validated Inhaled Corticosteroid Questionnaire (ICQ). Objectives: To compare patient-reported side effects between the inhaled corticosteroids ciclesonide and fluticasone propionate. Methods: Patients with moderate or moderate-to-severe asthma, pre-treated with a constant dose and type of medication, were randomized in three separate studies: 1) once daily ciclesonide 320 μg (n = 234) or twice daily fluticasone propionate 200 μg (n = 240); 2) twice daily ciclesonide 320 μg (n = 255) or twice daily fluticasone propionate 375 μg (n = 273); and 3) twice daily ciclesonide 320 μg (n = 259) or twice daily fluticasone propionate 500 μg (n = 244). Patients rated the side effect questions of the 15 domain ICQ on a 7-point Likert scale (0 = not at all, 6 = a very great deal) during scheduled visits. Results: The majority of side effect scores remained similar with ciclesonide but worsened statistically significantly with fluticasone propionate from baseline to the end of the study in within-treatment analyses. In between-treatment analyses of studies 1 and 3 ciclesonide significantly improved total side effect scores (p < 0.025) and 14 out of 30 individual local and systemic domain scores (p < 0.025) compared with fluticasone propionate. In Study 2, although ciclesonide improved the majority of scores compared with fluticasone propionate only ‘oropharyngeal itching’ reached statistical significance (p < 0.025, one-sided). Conclusion: Patient-perceived side effects differ depending on the type of inhaled corticosteroids used. Patients with moderate-to-severe asthma report less intense side effects assessed with ICQ with ciclesonide than with fluticasone propionate. Clinical trial registration: The reported trials were completed before July 1 2005 and, therefore, are not registered. [Copyright &y& Elsevier]

Abstract: Background: Inhalation of adenosine-5′-monophosphate (AMP) causes bronchoconstriction in asthma but not in healthy subjects. Bronchoconstriction upon AMP inhalation is thought to occur by histamine release and subsequent binding to receptors on airway smooth muscle cells. Methods: To explain enhanced sensitivity to AMP in asthma, mast cell expression of the adenosine A2A and A2B receptors and histamine release were measured after incubation of human mast cell line 1 (HMC-1) cells with AMP and the non-specific adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) for 1.5 and 6 h. To establish a Thelper-2 environment resembling the asthma phenotype, HMC-1 cells were additionally cultured with IL-4 and IL-13 alone or stimulated with the combination of both cytokines and AMP and NECA. To study effects of prolonged presence of the inflammatory environment, the cells were pre-incubated overnight (18 h) with IL-4 and IL-13 and additionally stimulated with AMP and NECA for 1.5 or 6 h. Results: AMP and NECA hardly affected adenosine receptor expression but increased IL-8 secretion. Incubation with IL-4 and IL-13 for 6 h increased adenosine A2A receptor expression and histamine secretion, but decreased IL-8 secretion. The combination of IL-4, IL-13, and AMP/NECA for 6 h increased A2B receptor expression and IL-8 secretion. Overnight stimulation with IL-4, IL-13 and subsequent stimulation with AMP/NECA for 1.5 h decreased A2AR expression which was accompanied by increased histamine secretion. Conclusion: These results suggest a role for decreased A2AR expression in enhanced adenosine responsiveness as observed in asthma. [Copyright &y& Elsevier]

Summary: The range and extent of inhaled corticosteroid (ICS) side effects experienced by patients in the general community are likely to be underestimated. Aims: To identify the side effects of ICS perceived by patients in the community and, through the use of a self-report questionnaire, measure their intensity, prevalence and relationship with daily medication dose. Methods: Focus groups and in-depth interviews were conducted to identify side effects that patients associated with their use of ICS. In an international multicentre cross-sectional survey, 395 inhaler users from community pharmacy (mean age 50, 53% female), divided into 4 daily dosage groups (β 2-agonist without ICS , beclometasone dipropionate (BDP) equivalent ICS low dose ⩽400μg, ; mid dose 401–800μg, ; and high dose >800μg, ) reported how much they were affected by these side effects on a 7-point Likert scale. Results: Focus groups and interviews revealed 57 side effects that were associated with ICS use. Cross-sectional survey results showed significant differences in side effect perception between the four dosage groups for 31 items (all ) and a rising intensity with increasing ICS dose for total side effect score (). For ICS users reporting the most bothersome side effects (scoring ⩾3 on 0–6 scale) there was a rising prevalence as ICS dose increased for 34 items. A multivariate model confirmed that mid and high ICS dosages were statistically significantly associated with side effect perception after controlling for the other factors and covariates. Conclusions: Higher daily ICS doses were associated with a higher intensity and a higher prevalence of many patient perceived side effects, lending support to the call for dose titration in clinical practice. Results indicate the usefulness of patient self-report scales for understanding the burden of side effects of ICS in the community. [Copyright &y& Elsevier]

Background: Exposure to microbial agents might inhibit the development of atopy and asthma. Objective: We measured the association between microbial exposure assessed at 3 months and the development of atopic sensitization and doctor-diagnosed (DD) asthma and wheeze in the first 4 years in a birth cohort study of children with atopic mothers. Methods: Endotoxin, fungal (1→3)-β-D-glucans, extracellular polysaccharides from the genera Penicillium and Aspergillus (EPS-Pen/Asp), and dust on living room floors were measured at 3 months of age. Serum IgE levels against common allergens were determined at 1 and 4 years, and questionnaire information about respiratory morbidity was collected yearly. Results: Microbial levels in mattresses were low and not associated with serum IgE levels, DD asthma, and wheeze. Floor levels of biocontaminants and dust, on the other hand, were inversely associated with DD asthma, being most pronounced for endotoxin (odds ratio [OR], 0.40; 95% CI, 0.21-0.77) and EPS-Pen/Asp (OR, 0.42; 95% CI, 0.18-0.99). Mutual adjustment for other exposures did not significantly alter the results for endotoxin and only moderately affected the results for EPS-Pen/Asp. Persistent wheeze was also consistently less common in the high-exposure group, being significant only for EPS-Pen/Asp (OR, 0.37; 95% CI, 0.15-0.96). Transient wheeze and wheeze in the past 12 months were also reduced, but effects were smaller and not significant. Relationships with serum-specific IgE levels, which could only be assessed in 41% at age 4 years, were less pronounced and statistically significant only for EPS-Pen/Asp. Conclusions: Early exposure to common microbial contaminants, including fungal agents, might protect against asthma. Clinical implications: Microbial exposure in early life might protect against asthma and might constitute a novel target for prevention. [Copyright &y& Elsevier]

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 α 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 α 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. [Copyright &y& Elsevier]

Background: Inhalation of allergens by sensitized patients with asthma induces reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. Attenuation of allergen-induced bronchoconstriction and inflammation has been used to examine the efficacy of therapeutic agents such as inhaled corticosteroids in asthma. Ciclesonide, a nonhalogenated inhaled corticosteroid being developed for the treatment of persistent asthma, remains inactive until cleaved by esterases in the lung. Objective: This study examined the effect of low doses of inhaled ciclesonide, 40 μg and 80 μg, on allergen-induced bronchoconstriction, serum eosinophil cationic protein, and eosinophilic airway inflammation. Methods: Twenty-one nonsmokers with mild atopic asthma completed a multicenter, randomized, 3-way crossover study comparing the effects of 7-day treatment of ciclesonide or placebo. Allergen-induced responses, including the early and late fall in FEV1, peripheral blood eosinophils, serum eosinophil cationic protein levels, and eosinophils in induced sputum were measured. Results: Ciclesonide 80 μg attenuated the early and late asthmatic responses, including the change in FEV1, serum eosinophil cationic protein, and sputum eosinophils measured at 24 hours postchallenge (P < .025). Ciclesonide 40 μg attenuated the late asthmatic responses and sputum eosinophils measured at 24 hours postchallenge (P < .025), with no effect on the early allergen-induced bronchoconstriction, 24-hour FEV1, or serum eosinophil cationic protein levels (P < .025). Conclusion: With the exception of 24-hour postchallenge peripheral blood eosinophils, a low dose of ciclesonide, 80 μg, was effective in blocking all allergen-induced responses measured. [Copyright &y& Elsevier]

Background: Asthma is a common respiratory disease caused by the interaction of genetic susceptibility and exposure to various environmental factors. Passive smoke exposure, characterized by parental smoking, has been shown to be a risk factor for the development of atopy and asthma. Objective: We sought to perform a genome-wide linkage screen for asthma and bronchial hyperresponsiveness (BHR) and to determine the influence of passive tobacco smoke exposure during childhood on the results of genetic linkage studies to investigate gene-environment interactions. Methods: A genome-wide linkage screen for asthma and BHR was performed in 200 families ascertained through a parent with asthma. Analyses were performed separately for the entire sample and for the smoking-exposed and nonexposed families. Results: For asthma and BHR, the strongest evidence for linkage was observed for chromosomes 3p and 5q. The families in which the children were exposed to passive smoking accounted for the evidence for linkage of BHR to 5q (P < .001), but evidence for linkage to 3p was found in both sets of families. Similar results were observed for asthma. However, there was no observed difference in the frequency of asthma or BHR in the offspring from the smoke-exposed compared with the nonexposed families. Conclusion: The results from this study demonstrate that the influence of susceptibility genes for a common disease such as asthma might not be apparent unless there is the appropriate exposure to environmental stimuli, such as passive exposure to cigarette smoke. This approach should be useful for identification of asthma susceptibility genes. [Copyright &y& Elsevier]