Gisela Büchele

Prenatal exposure to a farm environment modifies atopic sensitization at birth

BACKGROUND Previous cross-sectional surveys have suggested that maternal exposure to animal sheds during pregnancy exerted a protective effect on atopic sensitization in children lasting until school age. OBJECTIVE We sought to evaluate the effects of maternal exposure to animal sheds and other farm-related exposures during pregnancy on cord blood IgE levels in a prospective birth cohort. METHODS Pregnant women living in rural areas in Austria, Finland, France, Germany, and Switzerland were recruited in the third trimester of pregnancy. Information on maternal farm-related exposures, nutrition, and health during pregnancy was obtained by means of interviews. Specific IgE levels for food and common inhalant allergens were assessed in cord blood of 922 children and peripheral blood samples of their mothers. RESULTS Different sensitization patterns in cord blood of farm and nonfarm children were observed. In multivariable analysis consumption of boiled, but not unboiled, farm milk during pregnancy was positively associated with specific IgE to cows milk independently from maternal IgE. In contrast, there was an inverse relationship between maternal exposure to animal sheds and cord blood IgE levels against seasonal allergens (adjusted odds ratio, 0.38; 95% CI, 0.21-0.70). This association was not confounded by maternal IgE levels. Maternal contact with hay enhanced the protective effect of exposure to animal sheds on IgE levels to grass pollen in cord blood. CONCLUSIONS Maternal exposure during pregnancy influences atopic sensitization patterns in cord blood. The (microbial) context of allergen contact possibly modifies the risk of atopic sensitization.

Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE Study

BACKGROUND Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. OBJECTIVES To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. METHODS Supernatants from phorbol 12-myristate 13-acetate/ionomycin-stimulated CB mononuclear cells were assessed for the production of IFN-gamma, TNF-alpha, IL-5, IL-10, and IL-12. RESULTS Significantly higher levels of IFN-gamma and TNF-alpha in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-gamma and TNF-alpha in umbilical blood. CONCLUSION Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.

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.

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.

Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis

BACKGROUND Cross-sectional studies have suggested that prenatal farm exposures might protect against allergic disease and increase the expression of receptors of the innate immune system. However, epidemiologic evidence supporting the association with atopic dermatitis remains inconsistent. OBJECTIVE To study the association between prenatal farm-related exposures and atopic dermatitis in a prospective study. We further analyzed the association between the expression of innate immune genes at birth and atopic dermatitis. METHODS A total of 1063 children who participated in a birth cohort study, Protection against Allergy-Study in Rural Environments, were included in this study. Doctor diagnosis of atopic dermatitis was reported by the parents from 1 to 2 years of age by questionnaire. Gene expression of Toll-like receptors (TLRs) and CD14 was assessed in cord blood leukocytes by quantitative PCR. RESULTS Maternal contact with farm animals and cats during pregnancy had a significantly protective effect on atopic dermatitis in the first 2 years of life. The risk of atopic dermatitis was reduced by more than half among children with mothers having contact with 3 or more farm animal species during pregnancy compared with children with mothers without contact (adjusted odds ratio, 0.43; 95% CI, 0.19-0.97). Elevated expression of TLR5 and TLR9 in cord blood was associated with decreased doctor diagnosis of atopic dermatitis. A significant interaction between polymorphism in TLR2 and prenatal cat exposure was observed in atopic dermatitis. CONCLUSION Maternal contact with farm animals and cats during pregnancy has a protective effect on the development of atopic dermatitis in early life, which is associated with a lower expression of innate immune receptors at birth.

Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood

BACKGROUND European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. OBJECTIVE We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. METHODS From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctors diagnosis. RESULTS Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. CONCLUSIONS Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.

How well do questionnaires perform compared with physical examination in detecting flexural eczema? Findings from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two

Background  Questionnaires are widely used in epidemiological studies to measure eczema symptom prevalence, but there are concerns regarding their accuracy if used as a diagnostic tool.

Development of atopic dermatitis according to age of onset and association with early-life exposures

BACKGROUND Environmental factors can affect the development of atopic dermatitis, and this was described to be already effective during pregnancy and in early life. An important early postnatal exposure is nutrition, although its association with allergic disease remains unclear. OBJECTIVE We sought to determine prospectively whether early postnatal exposures, such as the introduction to complementary food in the first year of life, are associated with the development of atopic dermatitis, taking into account the reverse causality. METHODS One thousand forty-one children who participated in the Protection Against Allergy-Study in Rural Environments birth cohort study were included in the current study. Atopic dermatitis was defined by a doctors diagnosis reported by the parents of children up to 4 years of age, by questionnaires, and/or by positive SCORAD scores from 1 year of age and according to the age of onset within or after the first year of life. Feeding practices were reported by parents in monthly diaries between the 3rd and 12th months of life. RESULTS The diversity of introduction of complementary food in the first year of life was associated with a reduction in the risk of having atopic dermatitis with onset after the first year of life (adjusted odds ratio for atopic dermatitis with each additional major food item introduced, 0.76; 95% CI, 0.65-0.88). The introduction of yogurt in the first year of life also reduced the risk for atopic dermatitis (adjusted odds ratio, 0.41; 95% CI, 0.23-0.73). CONCLUSION As early-life exposure, the introduction of yogurt and the diversity of food introduced in the first year of life might have a protective effect against atopic dermatitis.

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.

CSF filtration is an effective treatment of Guillain–Barré syndrome: A randomized clinical trial

Objective To compare CSF filtration (CSFF) and plasma exchange (PE) in the treatment of patients with Guillain–Barré syndrome (GBS). MethodsIn a prospective controlled clinical trial, 37 patients with acute GBS were randomized to receive either CSFF or PE. Inclusion criteria were fulfillment of National Institute of Neurological and Communicative Disorders and Stroke criteria and disability to walk >5 m unassisted. ResultsWith similar baseline features in both groups (initial disability grades on the six-point grading scale of the GBS Study Group) the primary outcome variable (improvement within 28 days after randomization) was almost identical (test for equivalence p = 0.0014), the mean grade values being 0.82 in the CSFF group and 0.80 in the PE group. After 56 days, 56% (9 of 16 patients) of the CSFF group and 37% (7 of 19 patients) of the PE group had reached grade 2 (i.e., ability of unassisted walking >5 m). After 6 months, the probability to reach grade 2 was about 80% in both groups. In the CSFF group, transient pleocytosis occurred without apparent clinical complications. Clinically relevant complications were higher in the PE-treated group. ConclusionsAlthough the number of patients was small, the authors found that the treatment of GBS with CSFF is at least as effective as with PE. CSFF might work by removing from the CSF inflammatory mediators, autoantibodies, or other factors.