Asthma in farm children is more determined by genetic polymorphisms and in non-farm children by environmental factors.

BACKGROUND: The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. METHODS: Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single-nucleotide polymorphisms (SNPs) were selected from a genome-wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. RESULTS: Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57-0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61-0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62-0.78]). CONCLUSIONS: Asthma in farm children is more likely predicted by other factors as compared to non-farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance.

Bacterial microbiota of the upper respiratory tract and childhood asthma.

BACKGROUND: Patients with asthma and healthy controls differ in bacterial colonization of the respiratory tract. The upper airways have been shown to reflect colonization of the lower airways, the actual site of inflammation in asthma, which is hardly accessible in population studies. OBJECTIVE: We sought to characterize the bacterial communities at 2 sites of the upper respiratory tract obtained from children from a rural area and to relate these to asthma. METHODS: The microbiota of 327 throat and 68 nasal samples from school-age farm and nonfarm children were analyzed by 454-pyrosequencing of the bacterial 16S ribosomal RNA gene. RESULTS: Alterations in nasal microbiota but not of throat microbiota were associated with asthma. Children with asthma had lower α- and ß-diversity of the nasal microbiota as compared with healthy control children. Furthermore, asthma presence was positively associated with a specific operational taxonomic unit from the genus Moraxella in children not exposed to farming, whereas in farm children Moraxella colonization was unrelated to asthma. In nonfarm children, Moraxella colonization explained the association between bacterial diversity and asthma to a large extent. CONCLUSIONS: Asthma was mainly associated with an altered nasal microbiota characterized by lower diversity and Moraxella abundance. Children living on farms might not be susceptible to the disadvantageous effect of Moraxella. Prospective studies may clarify whether Moraxella outgrowth is a cause or a consequence of loss in diversity.

Identification of fungal candidates for asthma protection in a large population-based study.

BACKGROUND: Exposure to molds has been related to asthma risk both positively and negatively, depending on the environmental setting. The pertinent results are based on generic markers or culturing methods although the majority of present fungi cannot be cultured under laboratory conditions. The aim of the present analysis was to assess environmental dust samples for asthma-protective fungal candidates with a comprehensive molecular technique covering also non-cultivable and non-viable fungi. METHODS: Mattress dust samples of 844 children from the GABRIELA study were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) of the fungus-specific internal transcribed spacer (ITS) region. Known asthma candidate species were tested for their associations with asthma, and further gel positions were sought to explain the above. As a second, data-driven, analysis, we tested the association of each individual gel position with asthma. RESULTS: In the hypothesis-driven approach, Penicillium chrysogenum emerged with an odds ratio of 0.80 (95% confidence interval 0.66-0.96; p = 0.020). The effect size was changed by 39% toward the null when adjusting for the two bands 683 (DNA of Metschnikowia sp., Aureobasidium spp.) and 978 (DNA of Epicoccum spp., Galactomyces spp., uncultured Penicillium). The data-driven approach yielded an additional band (containing DNA of Pseudotaeniolina globosa) with reduced risk of asthma (OR = 0.80 [0.66-0.96], p = 0.012). CONCLUSIONS: A large population-based study revealed several fungal taxa with inverse associations with childhood asthma. Molds produce a variety of bioactive compounds with detrimental but also beneficial immunoregulatory capacities, which renders them promising targets for further asthma research.

The combined effects of family size and farm exposure on childhood hay fever and atopy.

BACKGROUND: Exposure to farming environments and siblings is associated with reduced risks of childhood hay fever and atopy. We explored the independence and interaction of these protective effects in the GABRIELA study. METHODS: Questionnaire surveys on farming, asthma, and allergies were conducted in four central European areas among 79,888 6-12-yr-old children. Aeroallergen-specific serum IgE was measured in a stratified sample of 8,023 children. Multiple logistic regression was used to compare gradients in allergy prevalence by sibship size across three categories of exposure to farming environments. RESULTS: The prevalence of hay fever ranged from 2% (95% confidence interval 1.6%; 2.7%) among farmers' children with more than two siblings to 12% (11.2%; 13.0%) among children with no farm exposure and no siblings. Farming families were larger on average. More siblings and exposure to farming environments independently conferred protection from hay fever and atopy. There was no substantial effect modification between family size and exposure to farming environments. The odds ratios for hay fever per additional sibling were 0.79 among unexposed non-farm children, 0.77 among farm-exposed non-farm children, and 0.72 among children from farming families (2df interaction test: p = 0.41). CONCLUSION: The inverse association of exposure to farming environments with hay fever is found in all sizes of family, with no substantial tendency to saturation or synergism. This suggests that different biological mechanisms may underlie these two protective factors. Combinations of a large family and exposure to farming environments markedly reduce the prevalence of hay fever and indicate the strength of its environmental determinants.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide.

BACKGROUND: Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes. OBJECTIVE: We sought to study the farm effect on wheeze phenotypes and objective markers, such as lung function and exhaled nitric oxide, and their interrelation with atopy in children. METHODS: The GABRIEL Advanced Studies are cross-sectional, multiphase, population-based surveys of the farm effect on asthma and allergic disease in children aged 6 to 12 years. Detailed data on wheeze, farming exposure, and IgE levels were collected from a random sample of 8023 children stratified for farm exposure. Of those, another random subsample of 858 children was invited for spirometry, including bronchodilator tests and exhaled nitric oxide measurements. RESULTS: We found effects of exposure to farming environments on the prevalence and degree of atopy, on the prevalence of transient wheeze (adjusted odds ratio, 0.78; 95% CI, 0.64-0.96), and on the prevalence of current wheeze among nonatopic subjects (adjusted odds ratio, 0.45; 95% CI, 0.32-0.63). There was no farm effect on lung function and exhaled nitric oxide levels in the general study population. CONCLUSIONS: Children living on farms are protected against wheeze independently of atopy. This farm effect is not attributable to improved airway size and lung mechanics. These findings imply as yet unknown protective mechanisms. They might include alterations of immune response and susceptibility to triggers of wheeze, such as viral infections.

Protection from childhood asthma and allergy in Alpine farm environments-the GABRIEL Advanced Studies.

BACKGROUND: Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining this protective farm effect has consistently been identified. OBJECTIVE: We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy. METHODS: In rural regions of Austria, Germany, and Switzerland, 79,888 school-aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever. RESULTS: Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio [aOR], 0.68; 95% CI, 0.59-0.78; P< .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P< .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P= .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P< .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity. CONCLUSION: A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy.

Health-related quality of life does not explain the protective effect of farming on allergies.

BACKGROUND: Numerous studies report a protective effect of farming against allergic diseases. Some specific underlying exposures contributing to this effect have recently been described in the GABRIEL survey. So far, psycho-social factors have not been included in these analyses. METHODS: In order to assess the potential influence of health-related quality of life (HRQOL) on the protective effect of farming, 8259 school aged children from the European GABRIEL study answered questions concerning farming and allergic diseases, as well as validated questions about HRQOL. RESULTS: Farm children reported higher HRQOL than non farm children. However, HRQOL did not modify the protective effect of farming against allergies. Children with allergic diseases reported significantly lower HRQOL scores suggesting that the higher HRQOL of farm children was in part explained by the lower prevalence of these diseases among farm children. CONCLUSION: Although farm children reported higher HRQOL scores than did non-farm children, HRQOL did not explain the protective effect of farming against allergic diseases. The relationship between allergic diseases and HRQOL is likely bidirectional and needs to be assessed prospectively.

The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study.

BACKGROUND: Farm milk consumption has been identified as an exposure that might contribute to the protective effect of farm life on childhood asthma and allergies. The mechanism of action and the role of particular constituents of farm milk, however, are not yet clear. OBJECTIVE: We sought to investigate the farm milk effect and determine responsible milk constituents. METHODS: In rural regions of Germany, Austria, and Switzerland, a comprehensive questionnaire about farm milk consumption and other farm-related exposures was completed by parents of 8334 school-aged children, and 7606 of them provided serum samples to assess specific IgE levels. In 800 cow's milk samples collected at the participants' homes, viable bacterial counts, whey protein levels, and total fat content were analyzed. Asthma, atopy, and hay fever were associated to reported milk consumption and for the first time to objectively measured milk constituents by using multiple regression analyses. RESULTS: Reported raw milk consumption was inversely associated to asthma (adjusted odds ratio [aOR], 0.59; 95% CI, 0.46-0.74), atopy (aOR, 0.74; 95% CI, 0.61-0.90), and hay fever (aOR, 0.51; 95% CI, 0.37-0.69) independent of other farm exposures. Boiled farm milk did not show a protective effect. Total viable bacterial counts and total fat content of milk were not significantly related to asthma or atopy. Increased levels of the whey proteins BSA (aOR for highest vs lowest levels and asthma, 0.53; 95% CI, 0.30-0.97), α-lactalbumin (aOR for interquartile range and asthma, 0.71; 95% CI, 0.52-0.97), and ß-lactoglobulin (aOR for interquartile range and asthma, 0.62; 95% CI, 0.39-0.97), however, were inversely associated with asthma but not with atopy. CONCLUSIONS: The findings suggest that the protective effect of raw milk consumption on asthma might be associated with the whey protein fraction of milk.

Gene-environment interaction for childhood asthma and exposure to farming in Central Europe.

BACKGROUND: Asthma is a disease in which both genetic and environmental factors play important roles. The farming environment has consistently been associated with protection from childhood asthma and atopy, and interactions have been reported with polymorphisms in innate immunity genes. OBJECTIVE: To detect gene-environment interactions for asthma and atopy in the farming environment. METHODS: We performed a genome-wide interaction analysis for asthma and atopy by using 500,000 genotyped single nucleotide polymorphisms (SNPs) and farm-related exposures in 1708 children from 4 rural regions of Central Europe. We also tested selectively for interactions between farm exposures and 7 SNPs that emerged as genome-wide significant in a large meta-analysis of childhood asthma and 5 SNPs that had been reported previously as interacting with farm exposures for asthma or atopy. RESULTS: Neither the asthma-associated SNPs nor the SNPs previously published for interactions with asthma showed significant interactions. The genome-wide interaction study did not reveal any significant interactions with SNPs within genes in the range of interacting allele frequencies from 30% to 70%, for which our study was well powered. Among rarer SNPs, we identified 15 genes with strong interactions for asthma or atopy in relation to farming, contact with cows and straw, or consumption of raw farm milk. CONCLUSION: Common genetic polymorphisms are unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy, but rarer variants, particularly of the glutamate receptor, metabotropic 1 gene, may do so. Given the limited statistical power of our study, these findings should be interpreted with caution before being replicated in independent farm populations.

The GABRIEL Advanced Surveys: study design, participation and evaluation of bias.

Exposure to farming environments has been shown to protect substantially against asthma and atopic disease across Europe and in other parts of the world. The GABRIEL Advanced Surveys (GABRIELA) were conducted to determine factors in farming environments which are fundamental to protecting against asthma and atopic disease. The GABRIEL Advanced Surveys have a multi-phase stratified design. In a first-screening phase, a comprehensive population-based survey was conducted to assess the prevalence of exposure to farming environments and of asthma and atopic diseases (n = 103,219). The second phase was designed to ascertain detailed exposure to farming environments and to collect biomaterial and environmental samples in a stratified random sample of phase 1 participants (n = 15,255). A third phase was carried out in a further stratified sample only in Bavaria, southern Germany, aiming at in-depth respiratory disease and exposure assessment including extensive environmental sampling (n = 895). Participation rates in phase 1 were around 60% but only about half of the participating study population consented to further study modules in phase 2. We found that consenting behaviour was related to familial allergies, high parental education, wheeze, doctor diagnosed asthma and rhinoconjunctivitis, and to a lesser extent to exposure to farming environments. The association of exposure to farm environments with asthma or rhinoconjunctivitis was not biased by participation or consenting behaviour. The GABRIEL Advanced Surveys are one of the largest studies to shed light on the protective 'farm effect' on asthma and atopic disease. Bias with regard to the main study question was able to be ruled out by representativeness and high participation rates in phases 2 and 3. The GABRIEL Advanced Surveys have created extensive collections of questionnaire data, biomaterial and environmental samples promising new insights into this area of research.

Correction to: Prevalence of wheezing and atopic diseases in Austrian schoolchildren in conjunction with urban, rural or farm residence.

Correction: Wien Klin Wochenschr 2014 https://doi.org/10.1007/s00508-014-0571-z The disclosure needs to additionally mention the following:Erika von Mutius is listed as inventor on the following patents: Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis ….

Exhaled nitric oxide: interactions between asthma, hayfever, and atopic dermatitis in school children.

BACKGROUND: Clinicians frequently rely on reported symptoms and basic pulmonary function testing to assess asthma prevalence in the community. However, given that spirometry results are often normal for asthmatic children and the fact that there is no equivalent word for 'wheeze' in languages other than English, the assessment of asthma prevalence can be troublesome. OBJECTIVE: To evaluate in a population based setting, whether FeNO as a non-invasive marker, contributes to the detection of asthma. METHODS: This cross-sectional study was carried out on primary school children from Northern and Southern Tyrol. FeNO measurements were made using the online single breath technique prior to spirometry. Symptom status including asthma, hayfever and atopic dermatitis was determined by the ISAAC questionnaire. RESULTS: Six hundred and forty-four Tyrolean children aged 8-10 years participated. In terms of FEV1 % predicted, the asthma and hayfever group had significantly lower values compared to the asymptomatic group, the hayfever only, and the atopic dermatitis only groups. For FeNO, participants with asthma and hayfever, asthma and atopic dermatitis, and hayfever only recorded significantly greater FeNO values when compared to the asymptomatic group. Moreover, the asthma and atopic dermatitis group recorded significantly greater FeNO when compared to the asthma only group. Multivariate regression revealed that asthma had a small significant inverse association with FEV1 % predicted for the individual model and when combined with hayfever. For FeNO, each of the individual and combined model analyses achieved significance. CONCLUSION: Although FeNO appears to be influenced by asthma, the presence of other atopic conditions confounds the relationship. Elevated levels of FeNO do not distinguish between asthma and other atopic conditions. Therefore, FeNO does not contribute to the detection of asthma in the community. CLINICAL IMPLICATION: FeNO is not a valuable tool for the detection of asthma in the community as it is confounded by other atopic conditions.

Association between environmental tobacco smoke exposure and wheezing disorders in Austrian preschool children.

QUESTIONS: Passive smoking is a problem in children and adults, but recent studies found the impact to be strongest in the developing foetus and the first years of life. In this cross sectional study we investigated the effect of environmental tobacco smoke (ETS) on atopic and wheezing disorders in Austrian preschool children. METHODS: 1737 Austrian preschool children participated in a cross sectional questionnaire survey about passive smoking and the impact on wheezy bronchitis, asthma, hay fever and atopic dermatitis. RESULTS: Up to 46% of the participating children were exposed to ETS at some stage in their life. Children of lower socioeconomic status were at exceptionally risk.ETS exposure during pregnancy resulted in a significantly increased risk for wheezing in the first year of life (OR 1.6; 95% CI 1.0-2.6), wheezing in the past 12 months (OR 1.5; 95% CI1.0-2.4) and doctor diagnosed asthma (OR 2.1;95% CI 1.0-4.1). Furthermore, breastfeeding and consumption of fruits and vegetables were less common in smoking families. CONCLUSIONS: Our study confirms previous studies, that in particular prenatal ETS exposure is a risk factor for wheezing and asthma in preschool children. Despite this, children exposed to ETS also live a "less healthier life" in terms of breast feeding and antioxidant intake. In the light of recent studies reporting increased oxidative stress in children exposed to passive smoking, the low intake of fruits and vegetables is a further concern.

[Long-acting beta-2 agonists in pediatric asthma therapy--friend or foe]. / Langwirksame Beta-2-Sympathomimetika in der pädiatrischen Asthmatherapie--Freund oder Feind?

Recent publications suggest that long-acting beta-2 agonists (LABAs) increase the risk for death in asthma. The American Food and Drug Administration (FDA) published a relevant alert in 2005. In the currently valid Austrian consensus guidelines for drug therapy of bronchial asthma in children and adolescents, LABAs are only recommended as add-on therapy in those patients whose asthma is not sufficiently controlled by inhaled corticosteroids (ICS) alone. LABAs have no established role in earlier steps of the therapeutic algorithm; consequently, the prescription of ICS-LABA combinations for initial treatment of paediatric asthma is not supported by these consensus treatment guidelines.

Diagnosis and management of asthma - Statement on the 2015 GINA Guidelines.

This statement was written by a group of pulmonologists and pediatric pulmonologists belonging to the corresponding professional associations ÖGP (Austrian Society for Pulmonology) and ÖGKJ (Austrian Society for pediatric and adolescent medicine) to provide a concise overview of the latest updates in the 2015 GINA Guidelines and to include aspects that are specific to Austria.

Impact of disease severity on quality of life in adults with asthma.

Health-related quality of life is increasingly used as an outcome measure in asthma. The aim of this study was to define the relationship between asthma symptoms, lung function and health related quality of life in a community based sample of people with asthma ranging from no recent asthma to severe persistent asthma. We recruited subjects at the age of 42 years from a well-described community cohort, the Melbourne Epidemiological Study of Childhood Asthma, to define this association. 161 subjects completed a respiratory symptom survey, the Asthma Quality of Life Questionnaire and had lung function testing. According to the previous surveys and when applicable in agreement with GINA, subjects were classified into 4 groups: no recent asthma, sporadic asthma, intermittent asthma and persistent asthma, with the persistent asthma group further categorised by wheezing frequency and lung function. 55 had no recent asthma, 31 had sporadic asthma, 39 had intermittent asthma and 36 had persistent asthma. There was clear evidence of lower total scores with increased asthma severity, with median scores of 6.8 for the sporadic asthma group, 6.4 for the intermittent and 5.5 for the persistent asthma group compared to 6.9 in those with no recent asthma. All domain scores within the intermittent and persistent asthma groups were lower than scores for the no recent asthma group (p < 0.01). Those with persistent asthma and low FEV1% had the lowest quality of life scores (4.6). Analysis of this population cohort highlights that health related quality of life in patients with asthma strongly depends on symptom frequency and lung function and underlines the necessity of adequate treatment.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Lung function and symptom perception in children with asthma and their parents.

A large proportion of children with asthma are managed without recourse to specialized care, and treatment decisions are based solely on symptoms as reported by the children and their parents. We investigated 90 school-age children with the diagnosis of asthma and their accompanying parent to evaluate whether we can obtain better information by using three different means of asking for asthma symptoms: a questionnaire for children (QSR(children)), "smilies," and a visual analogue scale for children (VAS(children)). Furthermore, we analyzed the relationship between these symptom reports and lung function results. Finally, we attempted to determine whether performing a lung function test contributes relevant information toward improving asthma management. Multiple linear regression adjusted for age and gender showed a significant relationship between VAS for children and forced expiratory volume in 1 sec (FEV(1)) (P = 0.047) and maximal expiratory flow at 50% of forced vital capacity (MEF(50)) (P = 0.037). Neither age, gender, QSR for children, "smilies for children" nor all the parents' scores showed a significant association with lung function measurement in the regression model. Subgroup analysis with Spearman's rank correlation coefficients by age group revealed significant correlation in children <10 years between VAS for children, QSR for parents, smilies for parents, and the lung function parameters FEV(1), and MEF(50). Above age 10 years there was no correlation at all, with the accuracy correlation ranging from -0.04 to +0.21. Our data demonstrate that reported symptoms do not reliably correlate with lung function results in asthmatic children and the childrens' parents, and correlation is dependent on the instrument used for symptom evaluation. In children, the VAS, and in parents, the QSR were the most valuable means of obtaining best information on asthma symptoms. This underlines the importance of supplementing information on asthma symptoms with lung function measurements to more reliably assess the severity of asthma.

Multiple cavitating pulmonary nodules and clubbing in a 12-year-old girl.

We report on a 12-year-old girl with a prolonged history of cough and hemoptysis on three occasions. X-ray and computed tomography of the chest showed several cavitating lesions and mediastinal lymphadenopathy. Lung biopsy revealed nodular sclerosing Hodgkin's disease. Hodgkin's disease should be considered in the differential diagnosis of cavitating pulmonary lesions.