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BACKGROUND: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma.OBJECTIVE: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life.METHODS: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (n [ 769). Fecal samples at ages 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parent -reported symptoms and/or physician's diagnosis of hay fever in the last 12 months using questionnaires at 10.5 years.RESULTS: Farm children had half the risk of hay fever at 10.5 years (adjusted odds ratio [aOR] 0.50; 95% CI 0.31-0.79) than that of nonfarm children. Whereas early life events such as gut microbiome richness at 12 months (aOR 0.66; 95% CI 0.46-0.96) and exposure to animal sheds in the first 3 years of life (aOR 0.26; 95% CI 0.06-1.15) were determinants of hay fever, the continuous consumption of farm milk from infancy up to school age was necessary to exert the protective effect (aOR 0.35; 95% CI 0.17-0.72).CONCLUSIONS: While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories. (c) 2022 The Authors. Published by Elsevier Inc

Introduction: Environmental exposure to mites and fungi has been proposed to critically contribute to the development of IgE-mediated asthma. A common denominator of such organisms is chitin. Human chitinases have been reported to be upregulated by interleukin-13 secreted in the context of Th2-type immune responses and to induce asthma. We assessed whether chitin-containing components induced chitinases in an innate immune-dependent way and whether this results in bronchial hyperresponsiveness. Materials and Methods: Monocyte/macrophage cell lines were stimulated with chitin-containing or bacterial components in vitro. Chitinase activity in the supernatant and the expression of the chitotriosidase gene were measured by enzyme assay and quantitative PCR, respectively. Non-sensitized mice were stimulated with chitin-containing components intranasally, and a chitinase inhibitor was administered intraperitoneally. As markers for inflammation leukocytes were counted in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness was assessed via methacholine challenge. Results: We found both whole chitin-containing dust mites as well as the fungal cell wall component zymosan A but not endotoxin-induced chitinase activity and chitotriosidase gene expression in vitro. The intranasal application of zymosan A into mice led to the induction of chitinase activity in the BAL fluid and to bronchial hyperresponsiveness, which could be reduced by applying the chitinase inhibitor allosamidin. Discussion: We propose that environmental exposure to mites and fungi leads to the induction of chitinase, which in turn favors the development of bronchial hyperreactivity in an IgE-independent manner.

Importance Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and is driven by a complex pathophysiology underlying highly heterogeneous phenotypes. Current advances in precision medicine emphasize the need for stratification. Objective To perform deep phenotyping and identification of severity-associated factors in adolescent and adult patients with AD. Design, setting, and participants Cross-sectional data from the baseline visit of a prospective longitudinal study investigating the phenotype among inpatients and outpatients with AD from the Department of Dermatology and Allergy of the University Hospital Bonn enrolled between November 2016 and February 2020. Main outcomes and measures Patients were stratified by severity groups using the Eczema Area and Severity Index (EASI). The associations of 130 factors with AD severity were analyzed applying a machine learning-gradient boosting approach with cross-validation-based tuning as well as multinomial logistic regression. Results A total of 367 patients (157 male [42.8%]; mean [SD] age, 39 [17] years; 94% adults) were analyzed. Among the participants, 177 (48.2%) had mild disease (EASI ≤7), 120 (32.7%) had moderate disease (EASI >7 and ≤ 21), and 70 (19.1%) had severe disease (EASI >21). Atopic stigmata (cheilitis: odds ratio [OR], 8.10; 95% CI, 3.35-10.59; white dermographism: OR, 4.42; 95% CI, 1.68-11.64; Hertoghe sign: OR, 2.75; 95% CI, 1.27-5.93; nipple eczema: OR, 4.97; 95% CI, 1.56-15.78) was associated with increased probability of severe AD, while female sex was associated with reduced probability (OR, 0.30; 95% CI, 0.13-0.66). The probability of severe AD was associated with total serum immunoglobulin E levels greater than 1708 IU/mL and eosinophil values greater than 6.8%. Patients aged 12 to 21 years or older than 52 years had an elevated probability of severe AD; patients aged 22 to 51 years had an elevated probability of mild AD. Age at AD onset older than 12 years was associated with increased probability of severe AD up to a peak at 30 years; age at onset older than 33 years was associated with moderate to severe AD; and childhood onset was associated with mild AD (peak, 7 years). Lifestyle factors associated with severe AD were physical activity less than once per week and (former) smoking. Alopecia areata was associated with moderate (OR, 5.23; 95% CI, 1.53-17.88) and severe (OR, 4.67; 95% CI, 1.01-21.56) AD. Predictive performance of machine learning-gradient boosting vs multinomial logistic regression differed only slightly (mean multiclass area under the curve value: 0.71 [95% CI, 0.69-0.72] vs 0.68 [0.66-0.70], respectively). Conclusions and relevance The associations found in this cross-sectional study among patients with AD might contribute to a deeper disease understanding, closer monitoring of predisposed patients, and personalized prevention and therapy.

BackgroundImprovement of paediatric healthcare is hampered by inefficient processes of generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardized between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality.AimsSwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based common data model (CDM) that covers all processes of routine paediatric care in hospitals.MethodsA taskforce of paediatricians from large Swiss children’s hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalization. We then used a modified Delphi method to reach a broad consensus on a national EHR-based CDM.ResultsAll Swiss children’s hospitals use EHR to document some or all aspects of care. 119 paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national CDM that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 common data elements (CDEs): 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional.ConclusionSwissPedData is a CDM for information to be collected in EHR of Swiss children’s hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials.

BACKGROUND: Allergies are a serious public health issue, and prevalences are rising worldwide. The role of antibiotics in the development of allergies has repeatedly been discussed, as results remain inconsistent. The aim of this study was to investigate the association between pre- and post-natal antibiotic exposure and subsequent development of allergies (atopic dermatitis, food allergy, asthma, atopic sensitization and allergic rhinitis). METHODS: A total of 1080 children who participated in a European birth cohort study (PASTURE) were included in this analysis. Data on antibiotic exposure during pregnancy and/or first year of life and allergic diseases were collected by questionnaires from pregnancy up to 6 years of age and analysed by performing logistic regressions. To take into account reverse causation, we included models, where children with diagnosis or symptoms of the respective disease in the first year of life were excluded. RESULTS: Antibiotic exposure in utero was significantly and positively associated with atopic dermatitis and food allergy. The strongest effect was on diseases with onset within the first year of life (for atopic dermatitis: aOR 1.66, 95% CI 1.11-2.48 and for food allergy: aOR 3.01, 95% CI 1.22-7.47). Antibiotics in the first year of life were positively associated with atopic dermatitis up to 4 years (aOR 2.73, 95% CI 1.66-4.49) and also suggested a dose-response relationship. A tendency was observed with asthma between 3 and 6 years (aOR 1.65, 95% CI 0.95-2.86). CONCLUSIONS: Our findings show positive associations between exposure to antibiotics and allergies, mainly atopic dermatitis and food allergy within the first year of life, after prenatal exposure, and atopic dermatitis and asthma after post-natal exposure to antibiotics in children born in rural settings.

The acquisition of the infant gut microbiota is key to establishing a host-microbiota symbiosis. Microbially produced metabolites tightly interact with the immune system, and the fermentation-derived short-chain fatty acid butyrate is considered an important mediator linked to chronic diseases later in life. The intestinal butyrate-forming bacterial population is taxonomically and functionally diverse and includes endospore formers with high transmission potential. Succession, and contribution of butyrate-producing taxa during infant gut microbiota development have been little investigated. We determined the abundance of major butyrate-forming groups and fermentation metabolites in faeces, isolated, cultivated and characterized the heat-resistant cell population, which included endospores, and compared butyrate formation efficiency of representative taxa in batch cultures. The endospore community contributed about 0.001% to total cells, and was mainly composed of the pioneer butyrate-producing Clostridium sensu stricto. We observed an increase in abundance of Faecalibacterium prausnitzii, butyrate-producing Lachnospiraceae and faecal butyrate levels with age that is likely explained by higher butyrate production capacity of contributing taxa compared with Clostridium sensu stricto. Our data suggest that a successional arrangement and an overall increase in abundance of butyrate forming populations occur during the first year of life, which is associated with an increase of intestinal butyrate formation capacity.

International audience; Background The effect of exposure to micro-organisms on allergic diseases has been well studied. The protective effect of early food diversity against allergic diseases was previously shown in the PASTURE cohort study. The consumption of cheese, a food potentially rich in microbial diversity, deserves further examination. We aimed to evaluate whether cheese consumption is associated with allergic diseases. Methods In the PASTURE study (birth cohort in 5 European countries), data on feeding practices, environmental factors and allergic diseases were collected by questionnaires from birth to 6 years (N=931). Cheese consumption at 18 months of age was quantified in terms of frequency and diversity (i.e., number of consumed types among 6 types: hard pressed, semi-pressed, soft, blue, fresh cheese, from the farm). Multiple logistic regressions were performed to evaluate the effect of cheese consumption on atopic dermatitis (AD), food allergy (FA), allergic rhinitis, asthma and atopic sensitization at 6 years after adjustment for confounders of atopy. Results Cheese consumption (vs. non-consumption) had a significant protective effect on AD (OR=0.51 [0.29-0.90], p=0.02) and FA (OR=0.32, [0.15-0.71], p=0.004), but no effect on atopic sensitization, allergic rhinitis and asthma at 6 years. This effect on AD and FA may be related to the diversity of consumed cheeses (OR=0.64 [0.48-0.85] per cheese type, p=0.002; OR=0.55 [0.33-0.92], p=0.02, respectively). Conclusions Although reverse causality cannot totally be ruled out, cheese diversity at 18 months had a protective effect against AD and FA at 6 years in addition to the protective effect of diversity of other foods.

Objective.Infliximab (IFX) is a monoclonal tumor necrosis factor-α–inhibiting antibody used in children with refractory arthritis and uveitis. Immunogenicity is associated with a lack of clinical response and infusion reactions in adults; data on immunogenicity in children treated with IFX for rheumatic diseases are scarce. We aimed to describe the prevalence of anti-IFX antibodies and determine co-factors associated with anti-IFX antibodies in children with inflammatory rheumatic and ocular diseases.Methods.Consecutive children treated between August 2009 and August 2012 with IFX at our department were included. Blood samples were collected every 6 months before IFX infusion and tested for anti-IFX antibodies by radioimmunoassay. Patients’ charts were retrospectively reviewed for clinical features and analyzed for associations with anti-IFX antibodies.Results.Anti-IFX antibodies occurred in 14/62 children (23%) and 32/253 blood samples (12.6%) after a mean treatment time of 1084 days (range 73–3498). Infusion reactions occurred in 10/62 (16%) children during the treatment period. With continuation of IFX, anti-IFX antibodies disappeared in 7/14 children. In the bivariate analysis, the occurrence of anti-IFX antibodies was associated with younger age at IFX treatment start (mean age 7.01 vs 9.88 yrs, p = 0.003) and infusion reactions (OR 15.0), while uveitis as treatment indication was protective against development of anti-IFX antibodies (OR 0.17), likely because of higher IFX doses. In the multivariate logistic regression, all 3 covariates remained highly significant.Conclusion.Anti-IFX antibodies occurred commonly at any time during IFX treatment. Anti-IFX antibodies were associated with younger age at IFX start, infusion reactions, and arthritis as treatment indication.

Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments (PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (beta = 0.27 (0.12-0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56-0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case-control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09-0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17-0.84), P = 0.017) and the relative abundance of the gene encoding butyryl-coenzyme A (CoA):acetate-CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19-0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.Growing up in the rich microbial environment of a farm strongly influences the maturation of the gut microbiome in the first year of life, which helps protect against the development of asthma in children.

OBJECTIVES: Lack of microbiota accessible carbohydrates (MAC) can drive gut commensal extinctions. Infant formula lacks the MAC found in breastmilk, human milk oligosaccharides (HMOs). As a result, a switch from breastmilk feeding (high MAC) to formula (low MAC) may drive extinctions of infant gut commensals. METHODS: The prevalence of Bifidobacterium longum subsp. infantis, a bacterium that efficiently consumes HMOs, was compared in cohorts from Austria, Bangladesh, Finland, Gambia, Germany, Switzerland, and United States. Scientific literature reports that both Bangladesh and Gambia have long duration breastfeeding without a history of prevalent formula use; Bangladesh has a mean duration of breastfeeding of 31.9 months and Gambia has a median duration of breastfeeding >18 months. This contrasts with European countries and the US, who all have median duration of breastfeeding 50% relative abundance Bifidobacterium) despite the low frequency of colonization with B. infantis. The R0 of B. infantis transmission varied by country. CONCLUSIONS: The prevalence of infant colonization with B. infantis may be sensitive to breastfeeding duration in populations. Our data supports the concept that lack of MAC drives commensal extinctions, and suggests that deliberate intervention may be needed to restore B. infantis, a bacteria that benefits infant health. More studies are needed, particularly to determine whether species of Bifidobacterium other than B. infantis are sensitive to breastfeeding duration, and to understand the impact of different types of Bifidobacterium on infant health. FUNDING SOURCES: NIH awards F32HD093185 (DHT), AT007079 (DAM), and AT008759 (DAM).

Background: Childhood asthma is often preceded by early wheeze. Usually, wheezing episodes are recorded retrospectively, which may induce recall bias. Aims and objectives: The aim of this study was to investigate true-positive recall of parent-reported wheeze at 1year of age, its determinants, and its implications for asthma and lung function at 6years of age. Methods: The PASTURE (Protection Against Allergy—Study in Rural Environments) study followed 880 children from rural areas in 5 European countries from birth to age 6years. Wheeze symptoms in the first year were asked weekly. At age 6, parent-reported asthma diagnosis was ascertained and lung function measurements were conducted. Correct parental recall of wheeze episodes at the end of the first year was assessed for associations with lung function, asthma, and the asthma risk locus on chromosome 17q21. Results: Parents correctly recalled wheeze after the first year in 54% of wheezers. This true-positive recall was determined by number of episodes, timing of the last wheeze episode, and parental asthma. Independently from these determinants, true-positive recall predicted asthma at age 6years (odds ratio 4.54, 95% confidence interval (CI) [1.75-14.16]) and impaired lung function (β=−0.62, 95% CI [−1.12; −0.13], P-value=.02). Associations were stronger in children with asthma risk SNPs on chromosome 17q21. Conclusion: Correct parental recall of wheezing episodes may reflect clinical relevance of early wheeze and its impact on subsequent asthma and lung function impairment. Questions tailored to parental perception of wheezing episodes may further enhance asthma prediction.

Streszczenie • Odwrotna zaleznośc pomiedzy spozyciem nieprzetworzonego mleka krowiego a zakazeniami ukladu oddechowego u niemowląt wskazuje na obecnośc przeciwzakaźnych i immunomodulujących cząsteczek związanych z tego typu zakazeniami u ludzi. • Zapobieganie zakazeniom ukladu oddechowego we wczesnym okresie zycia moze nie tylko ogolnie poprawiac stan tego ukladu, ale moze takze korzystnie wplywac na poźniejszy rozwoj ciezkich chorob ukladu oddechowego, jak np. astmy. Bezpieczne mikrobiologicznie, choc minimalnie przetworzone mleko moze miec istotny wplyw na zdrowie spoleczne w odniesieniu do czestych zakazen ukladu oddechowego. Wprowadzenie Karmienie piersią zapobiega zakazeniom ukladu oddechowego w pierwszych miesiącach zycia. Biorąc pod uwage wspolne ewolucyjne procesy adaptacyjne ludzi i bydla, mozliwe, ze mleko krowie wywiera podobny efekt ochronny u niemowląt u ludzi. Cel pracy Analiza wplywu spozywania surowego i przetworzonego mleka krowiego na najczestsze zakazenia ukladu oddechowego u niemowląt. Metody W ramach kohorty urodzeniowej w badaniu PASTURE obserwowano 983 niemowleta z terenow wiejskich z Austrii, Finlandii, Francji, Niemiec i Szwajcarii przez pierwszy rok zycia, obejmując lącznie 37 306 osobo-tygodni. Na podstawie cotygodniowych wpisow w dzienniczku stanu zdrowia analizowano spozycie roznych rodzajow mleka krowiego oraz wystepowanie niezytu blony śluzowej nosa, zakazenia ukladu oddechowego, zapalenia ucha i gorączki. Po 12 miesiącach pobierano probki krwi i oznaczano stezenie bialka C-reaktywnego. Wyniki W porownaniu z mlekiem UHT ( ultra-heat treatment ) spozywanie surowego mleka wykazywalo odwrotną zaleznośc z wystepowaniem niezytu blony śluzowej nosa (skorygowany iloraz szans z modeli longitudinalnych [95% CI]: 0,71 [0,54–0,94]), zakazen ukladu oddechowego (0,77 [0,59–0,99]), zapalenia ucha (0,14 [0,05–0,42]) i gorączki (0,69 [0,47–1,01]). Gotowane mleko wiejskie wykazalo podobną, choc nieco slabszą zaleznośc. Fabrycznie przetworzone mleko pasteryzowane wykazalo odwrotną zaleznośc z wystepowaniem gorączki. Spozywanie surowego mleka wiejskiego wiązalo sie odwrotnie zaleznie ze stezeniami bialka C-reaktywnego po 12 miesiącach (stosunek średnich geometrycznych [95% CI]: 0,66 [0,45–0,98]). Wnioski Spozywanie surowego mleka krowiego we wczesnym okresie zycia zmniejsza ryzyko wystepowania zakazen ukladu oddechowego i gorączki o okolo 30%. Biorąc pod uwage bardzo czeste wystepowanie zakazen ukladu oddechowego w pierwszym roku zycia oraz związane z tym koszty pośrednie i bezpośrednie wydaje sie, ze eliminacja zagrozen zdrowotnych związanych ze spozywaniem surowego mleka moglaby umozliwic ogromny wplyw minimalnie przetworzonego, ale pozbawionego patogenow mleka na zdrowie publiczne.

BACKGROUND Multiple breath washout (MBW) is an attractive test to assess ventilation inhomogeneity, a marker of peripheral lung disease. Systematic research on MBW feasibility in preschool children is scanty. OBJECTIVES We assessed feasibility of nitrogen MBW in children aged 3-7 years in a clinical setting applying current ERS/ATS consensus. METHODS Sixty-two children with asthma were enrolled in the Swiss rehabilitation center Hochgebirgsklinik Davos without MBW experience and prior to consensus release. Age range was 3.1-6.7 years. All children were naive to MBW, received training, and then aimed for triplicate nitrogen MBW within 20 min. We afterward assessed the number of MBW attempts and successful tests according to consensus asking for three technically acceptable trials with functional residual capacity (FRC) measurements within 25% of median FRC. Secondly, factors related to success rate and FRC variability were assessed. RESULTS Out of 205 MBW attempts in 62 children, 103 trials (50%) in 51 children were successful. Only 15 children (24%) achieved three valid trials as suggested by consensus. At least two valid trials were obtained in 37 children (60%). Age was positively correlated with success rate. FRC variability was inversely correlated with variability of tidal volume. CONCLUSIONS MBW was only feasible in one quarter of inexperienced children

Background: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-alpha-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, mediates environmentally induced asthma protection. Objective: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. Methods: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective'' farms or LPS. NF-kappa B signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. Results: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P

Background Dietary changes are suggested to play a role in the increasing prevalence of allergic diseases and asthma. Short-chain fatty acids (SCFAs) are metabolites present in certain foods and are produced by microbes in the gut following fermentation of fibers. SCFAs have been shown to have anti-inflammatory properties in animal models. Our objective was to investigate the potential role of SCFAs in the prevention of allergy and asthma. Methods We analyzed SCFA levels by high-performance liquid chromatography (HPLC) in fecal samples from 301 one-year-old children from a birth cohort and examined their association with early life exposures, especially diet, and allergy and asthma later in life. Data on exposures and allergic diseases were collected by questionnaires. In addition, we treated mice with SCFAs to examine their effect on allergic airway inflammation. Results Significant associations between the levels of SCFAs and the infant's diet were identified. Children with the highest levels of butyrate and propionate (≥95th percentile) in feces at the age of one year had significantly less atopic sensitization and were less likely to have asthma between 3 and 6 years. Children with the highest levels of butyrate were also less likely to have a reported diagnosis of food allergy or allergic rhinitis. Oral administration of SCFAs to mice significantly reduced the severity of allergic airway inflammation. Conclusion Our results suggest that strategies to increase SCFA levels could be a new dietary preventive option for allergic diseases in children.

Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today

Allergies are usually referred to as type I hypersensitivity reactions against innocuous environmental antigens, characterized by a Th2/IgE-dominated inflammation. They can manifest themselves in various organs, such as skin, gastrointestinal and respiratory tract, and comprise diseases as diverse as allergic rhinitis and conjunctivitis, bronchial asthma, oral allergy syndrome, food allergy, urticaria and atopic eczema, but also anaphylactic shock. Within the last decades, there was a significant global increase in allergy prevalence, which has been mostly attributed to changes in environment and lifestyle. But which, among all factors discussed, are the most relevant, and what are the mechanisms by which these factors promote or prevent the development of allergic diseases? To answer this, it is necessary to go back to the two key questions that have occupied allergy researchers for the last decades: Firstly, what makes an allergen an allergen? Secondly, why are more and more individuals affected? Within the last decade, we have made considerable progress in answering these questions. This review gives an overview over scientific progress in the field, summarizes latest findings and points out future prospective and research needs.

RationaleAsthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting β-agonists.ObjectivesIn search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements.MethodsForced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy – Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns.Measurements and main resultsIn the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the17q21locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma.ConclusionsOur method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the17q21locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach.

Background: Rehabilitational programs at moderate altitude (1500-2500m) showed improvement of lung function and reduction in airways inflammation in asthmatic adults. Allergen avoidance was postulated as the major cause of these improvements. Methods: Spirometries of 344 and fractional exhaled nitric oxide measurements (FeNO) of 124 asthmatic children and adolescents, staying in a rehabilitation hospital in Davos (1590m) with at least 14days between admission and discharge, were analyzed in association with atopic sensitization (skin-prick testing and/or specific IgE), level of asthma control, and inhalative corticosteroid (ICS) dose. Results: Pulmonary conditions improved significantly on average during the sojourn. Uncontrolled asthmatics benefited most with an absolute increase in predicted FEV 1 , MEF 25 , and MEF 75 of 7.7%, 9.9%, and 12.7%, respectively (P < .001). FeNO decreased by 36.9ppb for uncontrolled, by 26.9ppb for partly controlled, and by 11.8ppb for controlled asthmatics. In uncontrolled subjects, pulmonary improvement was comparable between patients with and without house dust mites (HDM) sensitization. Pulmonary improvements of pollen-sensitized patients were not dependent on the season of the sojourn. For the group with constant ICS level, the absolute increase in FEV 1 was 4.9% (P < .001) with a FeNO decreased by 32.7ppb (P < .001). When the ICS dose was elevated by one GINA level, the absolute increase in FEV 1 was slightly higher (6.6%, P < .001), with a FeNO decrease of 31.4ppb (P < .001). Conclusion: Inpatient rehabilitation at moderate altitude improved pulmonary conditions in asthmatic children and adolescents independent of sensitization status to HDM or pollen. A positive effect was also observed in patients without change in medication.

The prognosis of pediatric low-grade gliomas is relatively favorable, but unresectable progressive tumors remain a challenge. Chemotherapy including carboplatin-containing regimens can delay the need for radiation therapy in young children. However, hypersensitivity reactions to carboplatin can at times be a severe complication. We have retrospectively evaluated and characterized the hypersensitivity reactions associated with carboplatin administration in pediatric low-grade glioma patients treated on an outpatient basis according to the SIOP/GPOH (International Society of Pediatric Oncology/ Gesellschaft fur Padiatrische Onkologie und Hamatologie) low-grade glioma 1996 protocol, and also reviewed the literature. Of nine patients consecutively treated with carboplatin, seven (78%) developed carboplatin hypersensitivity reactions. The first hypersensitivity reactions (always grade 2) occurred after a median of nine courses (range, 7-12). Although desensitization has been used successfully, there have been reports of severe cases of allergic reaction to carboplatin despite desensitization, including anaphylaxis and death. Since carboplatin hypersensitivity reactions are common and desensitization has not been proven to be safe, efforts should be made to design future therapy protocols for low-grade gliomas with clear guidelines on how to substitute carboplatin when hypersensitivity reactions occur. (J Pediatr Neurol 2004; 2(3): 151-155).

International audience; To date, only few studies have assessed oral immunotherapy (OIT) for wheat allergy and often describe severe adverse reactions during therapy. We developed partially hydrolyzed wheat-based cereals (pHC), which were used in a multicenter, open-label, OIT pilot study, in immunoglobulin E-mediated wheat allergy children (NCT01332084). The primary objective of the study was to test whether wheat allergic patients tolerate pHC and primary end point was the presence or not of immediate adverse reactions to pHC during the 1-day initial escalation phase (stepwise increased doses of pHC), with evaluation of the maximum dose tolerated. Of the 9 patients enrolled in the trial, 4 discontinued OIT because of mild to severe reactions at the initial escalation phase. The 5 patients who passed the escalation phase consumed pHC daily for 1 to 6 months. One of these patients withdrew due to noncompliance, whereas the 4 others completed the study and successfully passed the wheat challenge test at the end of the study. About 60% of the adverse events were unrelated to the study product. Our study provides preliminary evidence that pHC is tolerated by a subset of wheat allergic patients. Further studies are warranted to test its efficacy as a potential therapeutic option for wheat allergic patients.

Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of heterogeneity, AD is still considered a single disease and usually treated according to the "one-size-fits-all" approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype [panel of biomarkers]) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio.

Background The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine. Objective We sought to identify the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling. Methods Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H 2 R)–deficient mice, histamine receptors, and their signaling pathways were investigated. Results Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and T H 1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H 2 R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus , which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H 2 R-deficient animals. Conclusion Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H 2 R.

Background: IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Methods: Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4(+) CD25(high)FOXP3(+) Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. Results: rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95% CI = 1.02-3.08;OR = 1.79, 95% CI = 1.04-3.11) and CD4(+) CD25(high)FOXP3(+) Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004;p(LPS) = 0.005;p(U) = 0.001;p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p (rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. Conclusions: IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.

Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.

Over the past decades, an increase of the prevalence of allergic diseases has been observed in Western countries. The hygiene hypothesis proposes that viral, bacterial, or helminth infections; environments with high levels of microbial components, such as farms; and the nutrition are preventive against the development of allergies despite the same genetic predisposition. The timing of these exposures is crucial. The critical window of time starts already in utero and ends in school age depending on the kind of exposure. The underlying immunological mechanism of such exposures seems rather to include the induction of regulatory processes to control the allergic reaction than to prevent the production of IgE.

To cite this article: Mustonen K, Keski-Nisula L, Vaarala O, Pfefferle PI, Renz H, Riedler J, Dalphin J-C, Buechele G, Lauener R, Braun-Fahrlander C, von Mutius E, Pekkanen J and the PASTURE Study Group. Few associations between high-sensitivity C-reactive protein and environmental factors in 4.5-year-old children. Pediatr Allergy Immunol 2012: 00. ABSTRACT: Background: Low-grade inflammation in early childhood might protect from allergic diseases later in life. Our aim was to examine the effects of different environmental factors on low-grade inflammation measured with serum high-sensitivity C-reactive protein (hsCRP) at the age of 4.5 years. Methods: The high-sensitivity CRP values (n = 653) and serum-specific IgE concentrations were measured from 4.5-year-old children in rural areas in five European countries (Austria, Finland, France, Germany, and Switzerland). Children belonged to the prospective multi-center PASTURE birth cohort. Data on early and current farming environment and domestic animal exposure were collected by questionnaires. Results: Females as well as obese or very obese children at age of 4.5 years had higher hsCRP values than males (aOR 1.84 95% CI 1.27-2.66) and healthy weight children (aOR 4.47 95% CI 1.94-10.31), respectively. Levels were lowest in the summer. Few associations were detected between hsCRP values and farm environmental factors or atopic sensitization. However, there was evidence of children with low levels of hsCRP (below the detection limit) who had increased prevalence of sensitization to inhaled and seasonal allergens. Among non-sensitized children, spending time in stables was associated with reduced hsCRP (15 min-10 h aOR 0.40 95% CI 0.16-0.96 and

Recurrent upper or lower respiratory symptoms, possibly allergy-related, are very frequent in childhood. It is therefore important that physicians involved in the primary care of these children have an accurate initial diagnostic tool available. In this study, we investigated the value of an in vitro diagnostic device testing 10 common allergens, the ImmunoCAP Rapid Wheeze/Rhinitis Child, for the primary evaluation of allergy. Children with non-infectious upper or lower respiratory symptoms possibly related to allergy were recruited in the primary health care setting of private practices of physician trained in immunology/allergology. The investigators carried out their usual diagnostic work-up including IgE tests, and the ImmunoCAP Rapid test was performed with capillary whole blood in a blinded way to the investigator. The investigators' conclusions on major triggering allergens were compared to the ImmunoCAP Rapid test results. In the whole patient population (n = 185), the sensitivity of the ImmunoCAP Rapid test for unveiling allergic disease was 92% (95% CI: 86-96%) and the specificity 97% (95% CI: 86-100%). Current guidelines for allergy diagnosis suggest screening children with recurrent, moderate/severe diseases for allergies. For children with asthma falling into these categories, sensitivity was 100% (95% CI: 88-100%) and specificity 100% (95% CI: 69-100%); for children with moderate and severe rhinitis sensitivity was 93% (95% CI: 86-97%) and the specificity 100% (95% CI: 79-100%). The ImmunoCAP Rapid test is an accurate test, in particular with regard to high specificity, for diagnosing allergy in children with recurrent respiratory diseases in primary care settings.

Background Consumption of farm milk in early life is associated with less asthma and allergies. Objective We hypothesized that genetic variation in the innate immunity receptor CD14 might modify the association between farm milk consumption and asthma and atopy. Methods Questionnaire data, serum IgE levels, and genotypes for 4 single nucleotide polymorphisms in CD14 were assessed in farmers' and nonfarmers' children from 2 European populations (Allergy and Endotoxin study, n=576; Prevention of Allergy Risk factors for Sensitization in children related to Farming and Anthroposophic Lifestyle study, n=1539). In a subsample (n = 222) CD14 gene expression was measured in peripheral blood leukocytes. The effects of farm milk and CD14 genotypes on asthma, allergies, and CD14 expression and their interactions were investigated. Results We found a significant interaction between genetic variation in CD14/−1721 and farm milk consumption. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07-0.47); AG, 0.47 (95% CI, 0.26-0.86); and GG, 0.98 (95% CI, 0.46-2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/−1721 also modified the association between farm milk and CD14 gene expression (adjusted geometric means ratios: AA, 1.61 (95% CI, 0.98-2.66); AG, 1.11 (95% CI, 0.71-1.72); and GG, 0.76 (95% CI, 0.39-1.48). Conclusion The protective effect of farm milk consumption on allergic diseases is stronger in children carrying the A allele in CD14/−1721 than in children homozygous for the G allele. This might be mediated through farm milk–induced upregulated CD14 gene expression. Clinical implications Our results support the hypothesis that the inverse association between farm milk consumption and allergic diseases is mediated by CD14 -activated innate immune mechanisms.

Background In recent years, studies have shown a protective effect of being raised in a farm environment on the development of hay fever and atopic sensitization. Inconsistent data on the relation of farming to asthma and wheeze have raised some doubt about a true protective effect. Objective We sought to study the differential effects of farm-associated exposures on specific asthma-related health outcomes. Methods The cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle study included 8263 school-age children from rural areas in 5 European countries. Information on farm-related exposures and health outcomes was obtained by using questionnaires. In subsamples allergen-specific IgE and RNA expression of CD14 and Toll-like receptor genes were measured, and dust from children's mattresses was evaluated for microbial components. Results Inverse relations with a diagnosis of asthma were found for pig keeping (odds ratio [OR], 0.57; 95% CI, 0.38-0.86), farm milk consumption (OR, 0.77; 95% CI, 0.60-0.99), frequent stay in animal sheds (OR, 0.71; 95% CI, 0.54-0.95), child's involvement in haying (OR, 0.56; 95% CI, 0.38-0.81), and use of silage (OR, 0.55; 95% CI, 0.31-0.98; for nonatopic asthma) and in Germany for agriculture (OR, 0.34; 95% CI, 0.22-0.53). Protective factors were related with higher expression levels of genes of the innate immunity. Potential risk factors for asthma and wheeze were also identified in the farm milieu. Levels of endotoxin and extracellular polysaccharides were related to the health outcomes independently of the farm exposures. Conclusions The protective effect of being raised in a farm environment was ascribed to distinct exposures. Clinical implications The development of atopic sensitization and atopic and nonatopic asthma is most likely determined by different environmental factors, possibly reflecting distinct pathomechanisms.

Summary Background Dietary interventions as a means for atopy prevention attract great interest. Some studies in rural environments claimed an inverse association between consumption of farm-produced dairy products and the prevalence of allergic diseases, but current evidence is controversial. Objective To investigate whether consumption of farm-produced products is associated with a lower prevalence of asthma and allergy when compared with shop-purchased products. Methods Cross sectional multi-centre study (PARSIFAL) including 14 893 children aged 5–13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children). A detailed questionnaire including a dietary component was completed and allergen-specific IgE was measured in serum. Results Farm milk consumption ever in life showed a statistically significant inverse association with asthma: covariate adjusted odds ratio (aOR) 0.74 [95% confidence interval (CI) 0.61–0.88], rhinoconjunctivitis: aOR 0.56 (0.43–0.73) and sensitization to pollen and the food mix fx5 (cut-off level of 3.5 kU/L): aOR 0.67 (0.47–0.96) and aOR 0.42 (0.19–0.92), respectively, and sensitization to horse dander: aOR 0.50 (95% CI 0.28–0.87). The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome. Conclusion Our results indicate that consumption of farm milk may offer protection against asthma and allergy. A deepened understanding of the relevant protective components of farm milk and a better insight into the biological mechanisms underlying this association are warranted as a basis for the development of a safe product for prevention.

Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped.Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09-2.67]; and aOR, 0.48 [95% CI, 0.30-0.76], respectively).These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies.

Introduction: Clustering approaches to asthma phenotyping using clinical parameters have facilitated the identification of various asthma phenotypes. However, several challenges remain unresolved: 1) The characterizing parameters are only assessed at a single point in time, yielding only “snapshot” phenotypes. 2) Some of the biomarkers utilized in previous studies can be difficult to obtain in a clinical setting. 3) Available clinical and biomarker data are often incomplete. Objective: To develop a clustering approach to asthma phenotyping solely based on low-cost and readily obtainable biomarkers measured during a pre-established time window that systematically copes with incomplete data sets. Methods: The EFRAIM/PASTURE study is a cohort of asthmatic and healthy children. At age 6, N=604 children were subject to twice daily PEF and FEV1 measurements during 4 weeks. We compared the individual PEF and FEV1 distributions among all children using a metric assessing differences in the mean value, and in the magnitude and frequency of fluctuations around the mean. Using hierarchical clustering we identified clusters of children sharing similar distributions. We assessed the stability of the identified clusters upon random data removal. Results: Tolerable levels of missing data were found via cluster stability analysis. We clinically validated the method within the cohort by means of enrichment analysis of clinical characteristics. We found a good agreement between the most relevant features of some of the clusters identified and well-known clinical characteristics of asthma. Conclusion: Our method may be useful in the context of personalized asthma care.

Background: Growing up on a farm is inversely related to childhood asthma. The asthma risk locus 17q21 modifies the effects of smoking and early viral infections on subsequent asthma. Aims and objectives: To determine whether wheeze or farm exposure before age 1 year predict asthma at age 6 years; whether farm exposure affects wheezing during year 1; and whether these relationships are modified by the 17q21 locus. Methods: We followed 983 children in rural areas of Austria, Finland, France, Germany, and Switzerland from birth until age 6 years. Symptoms and exposures during year 1 were recorded with weekly diaries. Questionnaires were administered between pregnancy and 6 years. Wheezing during year 1 was stratified by a concomitant cold. Asthma at age 6 was defined as reported doctor9s diagnosis, or wheezy bronchitis more than once. SNPs in genes ORMDL3 and GSDMB at locus 17q21 were assessed in cord blood. Results: Asthma at age 6 was predicted by wheeze without a cold (aOR, 95%CI: 2.67, 1.47-4.85) and wheeze with a cold (2.24, 1.33-3.77). The association of wheeze with a cold was modified by SNPs at locus 17q21 (gene-environment interaction: P=0.001) . Animal shed exposure during year 1 was inversely related to asthma (0.55, 0.31-0.94). Siblings (carriers of allele A in rs8076131: 1.57, 1.20-2.06) and animal shed exposure (allele A: 0.45, 0.34-0.61) were associated with wheeze before age 1 among carriers of asthma risk alleles. Conclusions: Environmental exposures such as siblings or exposure to animal sheds affect wheezing largely in carriers of known asthma risk alleles. The 17q21 locus might be related both to environmental susceptibility and to progress from wheeze towards asthma.

Living on farms has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow9s milk directly obtained from a farm (Loss, G. et al. JACI 2011;128:766-773). In contrast to farm milk, industrially processed cow9s milk is subjected to heat-treatment and alteration of fat fraction and fat globule size. Aim of this analysis was to assess whether the composition of fatty acids (FA) differed between unprocessed farm milk and industrially processed milk and, if so, whether this contributed to the protective effect of farm milk on asthma. The PASTURE study followed 934 children living in rural areas in 5 European countries from birth to age 6 years. During this time, their milk consumption was assessed by questionnaires. Samples of the usually consumed milk were taken at the age of 4.5 years. Doctor-diagnosed asthma was parent-reported at age 6 years. In a random sample of 35 asthma cases and 49 controls, the content of 46 FA was quantified. Proportions of omega-3 FA were highest in raw farm milk and lowest in UHT milk. The risk of asthma was reduced when consuming raw farm milk as compared to shop milk (OR=0.31 [0.14-0.69]). Part of the effect was explained by the higher fat content of farm milk (OR high vs. low fat 0.59 [0.33-1.05]). Half of this effect was attributable to the contents of omega-3 FA (CIE=56%), which had significant inverse association with asthma after adjustment for milk fat content (OR=0.2 [0.04-0.91]). The asthma-protective effect of unprocessed farm milk is partially attributable to omega-3-FA, which counterbalance the synthesis of pro-inflammatory leukotriens and prostaglandins.