TY - JOUR AU - Klaut, G.M.* AU - Frei-Stuber, L.* AU - Karrasch, S. AU - Kutzora, S.* AU - Huss, J.* AU - Gerstner, D.* AU - Nowak, D.* AU - Quartucci, C.* C1 - 74546 C2 - 57503 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Longitudinal study of fractional exhaled nitric oxide (FeNO) and spirometric indices in trainee bakers and confectioners. JO - Clin. Exp. Allergy PB - Wiley PY - 2025 SN - 0954-7894 ER - TY - JOUR AU - Suhrkamp, I.* AU - Fonfara, M.* AU - Magdalena, M.* AU - Hartmann, J.N.* AU - Rodriguez, E. AU - Harder, J.* AU - Emmert, H.* AU - Weidinger, S.* C1 - 73430 C2 - 57060 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 443-445 TI - Th2-polarised CD4+ T cells enhance Staphylococcus aureus growth in a 3D skin model. JO - Clin. Exp. Allergy VL - 55 IS - 5 PB - Wiley PY - 2025 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers. AU - Böck, A.* AU - Urner, K.* AU - Eckert, J.K.* AU - Salvermoser, M.* AU - Laubhahn, K.* AU - Kunze, S. AU - Kumbrink, J.* AU - Hoeppner, M.P.* AU - Kalkbrenner, K.* AU - Kreimeier, S.* AU - Beyer, K.* AU - Hamelmann, E.* AU - Kabesch, M.* AU - Depner, M. AU - Hansen, G.* AU - Riedler, J.* AU - Roponen, M.* AU - Schmaußer-Hechfellner, E. AU - Barnig, C.* AU - Divaret-Chauveau, A.* AU - Karvonen, A.M.* AU - Pekkanen, J.* AU - Frei, R.* AU - Roduit, C.* AU - Lauener, R.* AU - Schaub, B.* AU - PASTURE Study Group (Illi, S. AU - Pechlivanis, S. AU - Pagani, G. AU - Ege, M.J.) C1 - 70367 C2 - 55534 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 314-328 TI - An integrated molecular risk score early in life for subsequent childhood asthma risk. JO - Clin. Exp. Allergy VL - 54 IS - 5 PB - Wiley PY - 2024 SN - 0954-7894 ER - TY - JOUR AU - Schrumpf, J.A.* AU - Ninaber, D.K.* AU - Müller, C.* AU - Rankl, B. AU - Tham, M.* AU - von Mutius, E. AU - Smits, H.H.* AU - Hiemstra, P.S.* C1 - 71046 C2 - 55873 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Farm dust exposure reduces cytokine- and rhinovirus-induced IL-33 expression in bronchial epithelial cells. JO - Clin. Exp. Allergy PB - Wiley PY - 2024 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Although children can frequently experience a cough that affects their quality of life, few epidemiological studies have explored cough without a cold during childhood. OBJECTIVES: The objective of the study was to describe the latent class trajectories of cough from one to 10 years old and analyse their association with wheezing, atopy and allergic diseases. METHODS: Questions about cough, wheeze and allergic diseases were asked at 1, 1.5, 2, 3, 4, 5, 6 and 10 years of age in the European prospective cohort of Protection against Allergy: STUdy in Rural Environment (PASTURE). Specific IgE assays were performed at 10 years of age. Questions regarding a cough without a cold were used to build a latent class model of cough over time. RESULTS: Among the 961 children included in the study, apart from the never/infrequent trajectory (59.9%), eight trajectories of cough without a cold were identified: five grouped acute transient classes (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. For asthma, the strongest association was with the early persistent trajectory (ORa  = 31.00 [14.03-68.51]), which was inversely associated with farm environment (ORa  = 0.39 [0.19-0.77]) and had a high prevalence of cough triggers and unremitting wheeze. Late and early persistent trajectories were also associated with food allergy. Atopic sensitization was only associated with the late persistent trajectory. CONCLUSION: Late and early persistent coughs without a cold are positively associated with atopic respiratory diseases and food allergy. Children having recurrent cough without a cold with night cough and triggers would benefit from an asthma and allergy assessment. Growing up on a farm is associated with reduced early persistent cough. AU - Divaret-Chauveau, A.* AU - Mauny, F.* AU - Hose, A.* AU - Depner, M. AU - Dalphin, M.L.* AU - Kaulek, V.* AU - Barnig, C.* AU - Schaub, B.* AU - Schmaußer-Hechfellner, E. AU - Renz, H.* AU - Riedler, J.* AU - Pekkanen, J.* AU - Karvonen, A.M.* AU - Täubel, M.* AU - Lauener, R.* AU - Roduit, C.* AU - Vuitton, D.A.* AU - von Mutius, E. AU - Demoulin-Alexikova, S.* C1 - 66844 C2 - 53316 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 429-442 TI - Trajectories of cough without a cold in early childhood and associations with atopic diseases. JO - Clin. Exp. Allergy VL - 53 IS - 4 PB - Wiley PY - 2022 SN - 0954-7894 ER - TY - JOUR AB - Background: The progression of chronic destructive lung disease in patients with humoral immunodeficiency (ID) and concomitant development of bronchiectasis is difficult to prevent. Lung function tests in these patients typically show bronchial obstruction of the small airways in combination with increased air trapping in the distal airways, which is consistent with small airway dysfunction. Objective: The objective was to assess the grade of chronic lower airway inflammation and small airway dysfunction from induced sputum and the corresponding local pro-inflammatory mediator pattern to discriminate patients affected by bronchiectasis-related Small Airway Dysfunction (SAD). Methods: In a prospective design, 22 patients with ID (14 CVID, 3 XLA, 3 hyper-IgM syndrome, 1 hyper-IgE syndrome and low IgG levels due to treatment with rituximab and 1 SCID after BMT and persistent humoral defect) and 21 healthy controls were examined. Lung function, Fraction Expiratory Nitric Oxide (FeNO) and pro-inflammatory cytokine levels were compared in subsets of patients with (ID + BE) and without bronchiectasis (ID) pre-stratified using high-resolution computed tomography (HRCT) scans and control subjects. Results: Analysis of induced sputum showed significantly increased total cell counts and severe neutrophilic inflammation in ID. The concomitant SAD revealed higher total cell numbers compared to ID. Bronchial inflammation in ID is clearly mirrored by pro-inflammatory mediators IL-1β, IL-6 and CXCL-8, whilst TNF-α revealed a correlation with lung function parameters altered in the context of bronchiectasis-related Small Airway Dysfunction. Conclusions: In spite of immunoglobulin substitution, bronchial inflammation was dominated by neutrophils and was highly increased in patients with ID + BE. Notably, the pro-inflammatory cytokines in patients with ID were significantly increased in induced sputum. The context-dependent cytokine pattern in relation to the presence of concomitant bronchiectasis associated with SAD in ID patients could be helpful in delimiting ID patient subgroups and individualizing therapeutic approaches. AU - Zissler, U.M. AU - Thron, A.* AU - Eckrich, J.* AU - Bakhtiar, S.* AU - Schubert, R.* AU - Zielen, S.* C1 - 64779 C2 - 52453 SP - 760-773 TI - Bronchial inflammation biomarker patterns link humoral immunodeficiency with bronchiectasis-related small airway dysfunction. JO - Clin. Exp. Allergy VL - 52 IS - 6 PY - 2022 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without of allergen-specific immunotherapy (AIT). METHODS: Induced sputum samples of healthy controls (HC), AIT-treated and -untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR-microarray and transcriptome-microarray analysis of the same samples. miR-targets were predicted in silico and used to identify inverse regulation. Local PGE2 levels were measured using ELISA. RESULTS: 259 miRs were upregulated in the sputum of AA patients compared to HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR-3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared to untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL-13 levels, inflammatory cell load, sputum eosinophils and symptom burden. CONCLUSIONS: While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR-3935 and its predicted target gene, the prostaglandin E3 receptor, which might mediate AIT effects through suppression of the PGE2 -PTGER3 axis. AU - Jakwerth, C.A. AU - Chaker, A. AU - Guerth, F. AU - Oelsner, M. AU - Pechtold, L. AU - zur Bonsen, L.S. AU - Ullmann, J.T. AU - Krauss-Etschmann, S.* AU - Erb, A. AU - Kau, J. AU - Plaschke, M. AU - Winkler, M. AU - Kurz, A. AU - Kloss, A. AU - Esser-von Bieren, J. AU - Schmidt-Weber, C.B. AU - Zissler, U.M. C1 - 63063 C2 - 51252 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy. JO - Clin. Exp. Allergy PB - Wiley PY - 2021 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Current in vitro allergen-specific IgE (sIgE) detection assays measure IgE against allergen extracts or molecules in a single- or multiplex approach. Direct comparisons of the performance of such assays among young children with common presentations of allergic diseases regardless of sensitization status are largely missing. OBJECTIVES: The aim of this study was a comparison of the analytical and diagnostic performance for common clinical questions of three commonly used technologies which rely upon different laboratory methodologies among children of the All Age Asthma (ALLIANCE) cohort (clinicaltrials.gov: NCT02496468). METHODS: Sera from 106 pediatric study participants (mean age 4 years) were assessed for the presence of sIgE by means of the ImmunoCAP™ sx1 and fx5 mixes, the ImmunoCAP ISAC™ 112 microarray, and a Euroline™ panel. RESULTS: Total and negative concordance were high (>82% - >89%), while positive concordance varied considerably (0-100%) but was also >50% for the most common sensitizations analyzed (house dust mite and birch). All three test systems showed good sensitivity and specificity (AUC consistently > 0.7). However, no significant differences with regards to identifying sIgE sensitizations associated with symptoms in children with suspected pollen- or dust-triggered wheeze or presenting with symptoms of allergic rhinoconjunctivitis or food allergy were detected. Extending the number of allergens did not change the similar performance of the three assay systems. CONCLUSION AND CLINICAL RELEVANCE: Among young children, the three sIgE assays showed good analytical and diagnostic concordance. Our results caution that the identification of larger numbers of sensitizations by more comprehensive multiplex approaches may not improve clinical utility of sIgE testing in this age group. AU - Skevaki, C.* AU - Tafo, P.* AU - Eiringhaus, K.* AU - Timmesfeld, N.* AU - Weckmann, M.* AU - Happle, C.* AU - Nelson, P.P.* AU - Maison, N. AU - Schaub, B.* AU - Ricklefs, I.* AU - Fuchs, O.* AU - von Mutius, E. AU - Kopp, M.V.* AU - Renz, H.* AU - Hansen, G.* AU - Dittrich, A.M.* C1 - 62338 C2 - 50797 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1331-1345 TI - Allergen extract- and component-based diagnostics in children of the ALLIANCE asthma cohort. JO - Clin. Exp. Allergy VL - 51 IS - 10 PB - Wiley PY - 2021 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: The SQ tree SLIT-tablet (containing birch extract) proved clinically significant effects during the pollen season for birch as well as alder/hazel. Immune outcomes of this treatment for allergens from multiple birch homologous trees needs further investigation. We hypothesize that birch pollen extract AIT modulate a highly cross-reactive immune response and that this may be the basis for the observed clinical cross-protection. METHODS: Blood samples were collected from 397 birch allergic patients during SQ tree SLIT-tablet or placebo treatment (1:1) for up to 40 weeks. Serum-IgE and IgG4 specific to birch, and birch homologous tree pollens from alder, hazel, hornbeam, beech, and chestnut were measured by ImmunoCAP. IgE-Blocking Factor (IgE-BF) for alder, birch, and hazel during treatment were measured by Advia Centaur and blocking effects for birch and all these birch homologous tree pollens were further investigated by basophil activation (BAT). Antibody readouts were investigated in patient subsets. T-cell responses (proliferation) to allergen extracts and peptide pools (group 1 allergens) were investigated in T-cell lines from 29 untreated birch pollen allergic individuals. RESULTS: Significant Pearson correlations between serum-IgE toward birch, alder, hazel, hornbeam, and beech were observed (r-values>0.86). T-cell reactivity was observed throughout the birch homologous group. Almost identical kinetics for changes in IgE towards birch, alder, and hazel were observed during treatment and similar species-specific changes were seen for serum-IgG4 . IgG4 reactivity toward birch and alder, hazel, hornbeam, and beech, correlated significantly at end-of-treatment (r-values>0.72). Treatment resulted in similar IgE-BF kinetics for alder, birch, and hazel and blocking of BAT for multiple trees in most actively treated patients investigated. CONCLUSIONS: Systematic analyses of T-cell and antibody cross-reactivities before and during birch pollen extract AIT provides the immunological basis for the observed clinical effect of SQ tree SLIT-tablet treatment of tree pollen allergy induced by multiple trees in the birch homologous group. AU - Würtzen, P.A.* AU - Grønager, P.M.* AU - Lund, G.* AU - Gupta, S.* AU - Andersen, P.S.* AU - Biedermann, T. AU - Ipsen, H.* C1 - 60645 C2 - 49557 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 284-295 TI - Simplified AIT for allergy to several tree pollens - Arguments from the immune outcome analyses following treatment with SQ tree SLIT-tablet. JO - Clin. Exp. Allergy VL - 51 IS - 2 PB - Wiley PY - 2021 SN - 0954-7894 ER - TY - JOUR AB - Rationale: The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH-2-driven asthma-like disease.Objectives: Lung function parameters in mild CF patients may be different in patients with and without A fumigatus sensitization. We aimed to ascertain whether allergen exposure to A fumigatus by bronchial allergen provocation (BAP) induces TH-2 inflammation comparable to an asthma-like disease.Methods: A total of 35 patients, aged 14.8 +/- 8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n = 18): specific (s)IgE negative, and group 2 (n = 17): sIgE positive (>= 0.7 KU/L) for A fumigatus. Lung function, exhaled NO, and induced sputum were analysed. All sensitized patients with an FEV1 > 75% (n = 13) underwent BAP with A fumigatus, and cell counts, and the expression of IL-5, IL-13, INF-gamma, and IL-8 as well as transcription factors T-bet, GATA-3, and FoxP3, were measured.Results: Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH-2-mediated inflammation involving eosinophils, IL-5, IL-13, and FoxP3 became apparent in induced sputum cells.Conclusion: Our study demonstrated the clinical relevance of A fumigatus for the majority of sensitized CF patients. A distinct IgE/TH-2-dominated inflammation was found in induced sputum after A fumigatus exposure. AU - Eickmeier, O.* AU - Zissler, U.M. AU - Wittschorek, J.* AU - Unger, F.* AU - Schmitt-Grohé, S.* AU - Schubert, R.* AU - Herrmann, E.* AU - Zielen, S.* C1 - 58014 C2 - 48022 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Clinical relevance of Aspergillus fumigatus sensitization in cystic fibrosis. JO - Clin. Exp. Allergy PB - Wiley PY - 2020 SN - 0954-7894 ER - TY - JOUR AB - Background: Maternal asthma during pregnancy is considered an environmental risk factor for asthma development in children. Immunoglobulin G (IgG) antibodies that are transferred from the mother to the fetus are known to act in a pro- or anti-inflammatory manner depending on their glycosylation status. Objective: Using a mouse model, we examined how maternal allergic airway inflammation during pregnancy influenced offspring experimental asthma severity, as well as maternal and offspring serum IgG antibody glycosylation patterns. Additionally, the effects of maternal and offspring exposure to the same or different allergens were investigated. Methods: Female mice were either sham sensitized or sensitized to casein (CAS) or ovalbumin (OVA) before mating. Subsequently, allergic lung inflammation was induced in pregnant dams via aerosol allergen challenge (sham, CAS or OVA). After weaning, pups were subjected to an experimental asthma protocol using OVA. Asn-297 IgG glycosylation was analysed in maternal and offspring serum. Results: When mothers and offspring were sensitized to the same allergen (OVA-OVA), offspring had more severe experimental asthma. This was evidenced by altered antibody concentrations, increased bronchoalveolar lavage inflammatory cell influx and decreased lung tissue and lung draining lymph node regulatory T cell percentages. When mothers and offspring were sensitized to different allergens (CAS-OVA), this phenotype was no longer observed. Additionally, maternal serum from allergic mothers had significantly higher levels of pro-inflammatory IgG1, shown by decreased galactosylation and sialylation at the Asn-297 glycosylation site. Similar glycosylation patterns were observed in the serum of adult allergic offspring from allergic mothers. Conclusions and Clinical Relevance: We observed a strong association between maternal experimental asthma during pregnancy, increased offspring airway inflammation and pro-inflammatory IgG glycosylation patterns in mothers and offspring. IgG glycosylation is not a standard measurement in the clinical setting, and we argue that it may be an important parameter to include in future clinical studies. AU - Sodemann, E.B.* AU - Dähling, S.* AU - Klopfleisch, R.* AU - Boiarina, E.* AU - Cataldo, D.* AU - Alhasan, M.M.* AU - Yildirim, A.Ö. AU - Witzenrath, M.* AU - Tabeling, C.* AU - Conrad, M.L.* C1 - 58792 C2 - 48328 SP - 520-531 TI - Maternal asthma is associated with persistent changes in allergic offspring antibody glycosylation. JO - Clin. Exp. Allergy VL - 50 IS - 4 PY - 2020 SN - 0954-7894 ER - TY - JOUR AB - BackgroundMarkers of microbial exposure are thought to be associated with risk of allergic sensitization; however, the associations are inconsistent and may be related to gene-environment interactions.ObjectiveTo examine the relationship between polymorphisms in the CD14 gene and allergic sensitization and whether sibling exposure, as a marker of microbial exposure, modified this relationship.MethodsWe used data from the Tasmanian Longitudinal Health Study and the Melbourne Atopy Cohort Study. Two CD14 polymorphisms were genotyped. Allergic sensitization was defined by a positive response to a skin prick test. Sibling exposure was measured as cumulative exposure to siblings before age 6months, 2 and 4years. Logistic regression and multi-level mixed-effects logistic regression were used to examine the associations. Effect estimates across the cohorts were pooled using random-effects meta-analysis.ResultsCD14 SNPs were not individually associated with allergic sensitization in either cohort. In TAHS, cumulative sibling exposure before age 6months, 2 and 4years was each associated with a reduced risk of allergic sensitization at age 45years. A similar effect was observed in MACS. Meta-analysis across the two cohorts showed consistent evidence of an interaction between cumulative sibling exposure before 6months and the rs5744455-SNP (P=0.001) but not with the rs2569190-SNP (P=0.60). The pooled meta-analysis showed that the odds of sensitization with increasing cumulative exposure to sibling before 6months of age was 20.9% smaller in those with the rs5744455-C-allele than the T-allele (OR=0.83 vs 1.05, respectively).Conclusion and Clinical RelevanceCumulative sibling exposure reduced the risk of sensitization from childhood to middle age in genetically susceptible individuals. AU - Lau, M.Y.Z.* AU - Dharmage, S.C.* AU - Burgess, J.A.* AU - Win, A.K.* AU - Lowe, A.J.* AU - Lodge, C.J.* AU - Perret, J.* AU - Hui, J.* AU - Thomas, P.S.* AU - Giles, G.* AU - Thompson, B.R.* AU - Abramson, M.J.* AU - Walters, E.H.* AU - Matheson, M.C.* AU - Collaboration (Wjst, M.) C1 - 54803 C2 - 45833 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 331-340 TI - Early-life exposure to sibling modifies the relationship between CD14 polymorphisms and allergic sensitization. JO - Clin. Exp. Allergy VL - 49 IS - 3 PB - Wiley PY - 2019 SN - 0954-7894 ER - TY - JOUR AB - Background: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries.Objectives: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App.Methods: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach.Results: A total of 12143 users were registered. A total of 6949 users reported at least one VAS data recording. Among them, 1887 users reported >= 7 VAS data. About 1195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR >= 70% and PDC <= 1.25), 51 (4.23%) were partly adherent (MPR >= 70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR <70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users.Conclusion and clinical relevance: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting. AU - Menditto, E.* AU - Costa, E.* AU - Midao, L.* AU - Bosnic-Anticevich, S.* AU - Novellino, E.* AU - Bialek, S.* AU - Briedis, V.* AU - Mair, A.* AU - Rajabian-Soderlund, R.* AU - Arnavielhe, S.* AU - Bedbrook, A.* AU - Czarlewski, W.* AU - Annesi-Maesano, I.* AU - Antò, J.M.* AU - Devillier, P.* AU - De Vries, G.* AU - Keil, T.* AU - Sheikh, A.* AU - Orlando, V.* AU - Larenas-Linnemann, D.* AU - Cecchi, L.* AU - De Feo, G.* AU - Illario, M.* AU - Stellato, C.* AU - Fonseca, J.* AU - Malva, J.* AU - Morais-Almeida, M.* AU - Pereira, A.M.* AU - Todo-Bom, A.M.* AU - Kvedariene, V.* AU - Valiulis, A.* AU - Bergmann, K.C.* AU - Klimek, L.* AU - Moesges, R.* AU - Pfaar, O.* AU - Zuberbier, T.* AU - Cardona, V.* AU - Mullol, J.* AU - Papadopoulos, N.G.* AU - Prokopakis, E.P.* AU - Bewick, M.* AU - Ryan, D.* AU - Roller-Wirnsberger, R.E.* AU - Tomazic, P.V.* AU - Cruz, A.A.* AU - Kuna, P.* AU - Samolinski, B.* AU - Fokkens, W.J.* AU - Reitsma, S.* AU - Bosse, I.* AU - Fontaine, J.-F.* AU - Laune, D.* AU - Haahtela, T.* AU - Toppila-Salmi, S.* AU - Bachert, C.* AU - Hellings, P.W.* AU - Melén, E.* AU - Wickman, M.* AU - Bindslev-Jensen, C.* AU - Eller, E.* AU - O'Hehir, R.E.* AU - Cingi, C.* AU - Gemicioğlu, B.* AU - Kalayci, O.* AU - Ivancevich, J.C.* AU - Bousquet, J.* AU - MASK Study Group (Darsow, U.) C1 - 55880 C2 - 46643 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 442-460 TI - Adherence to treatment in allergic rhinitis using mobile technology. The MASK Study. JO - Clin. Exp. Allergy VL - 49 IS - 4 PB - Wiley PY - 2019 SN - 0954-7894 ER - TY - JOUR AB - In childhood, the most common type of eczema/dermatitis is atopic dermatitis, which occurs in up to 25% of children world-wide. However, the diagnosis may sometimes be challenging and atopic dermatitis may resemble other types of dermatitis as well as other skin diseases such as psoriasis, infections, infestations and malignancies as well as metabolic, genetic and autoimmune disorders. This review will focus on how to recognize the most common types of dermatitis in children and adolescents and how to separate them from the most common differential diagnoses clinically and histologically. AU - Mortz, C.G.* AU - Brockow, K. AU - Bindslev-Jensen, C.* AU - Broesby-Olsen, S.* C1 - 55637 C2 - 46498 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 744-753 TI - It looks like childhood eczema but is it? JO - Clin. Exp. Allergy VL - 49 IS - 6 PB - Wiley PY - 2019 SN - 0954-7894 ER - TY - JOUR AB - Introduction The fractional exhaled nitric oxide (FENO) is a marker for type 2 inflammation used in diagnostics and management of asthma. In order to use FENO as a reliable biomarker, it is important to investigate factors that influence FENO in healthy individuals. Men have higher levels of FENO than women, but it is unclear whether determinants of FENO differ by sex. Objective To identify determinants of FENO in men and women without lung diseases. Method Fractional exhaled nitric oxide was validly measured in 3881 healthy subjects that had answered the main questionnaire of the European Community Respiratory Health Survey III without airways or lung disease. Results Exhaled NO levels were 21.3% higher in men compared with women P < 0.001. Being in the upper age quartile (60.3-67.6 years), men had 19.2 ppb (95% CI: 18.3, 20.2) higher FENO than subjects in the lowest age quartile (39.7-48.3 years) P = 0.02. Women in the two highest age quartiles (54.6-60.2 and 60.3-67.6 years) had 15.4 ppb (14.7, 16.2), P = 0.03 and 16.4 ppb (15.6, 17.1), P = FENO, compared with the lowest age quartile. Height was related to 8% higher FENO level in men (P < 0.001) and 5% higher FENO levels in women (P = 0.008). Men who smoked had 37% lower FENO levels and women had 30% lower levels compared with never-smokers (P < 0.001 for both). Men and women sensitized to both grass and perennial allergens had higher FENO levels compared with non-sensitized subjects 26% and 29%, P Fractional exhaled nitric oxide levels were higher in men than women. Similar effects of current smoking, height, and IgE sensitization were found in both sexes. FENO started increasing at lower age in women than in men, suggesting that interpretation of FENO levels in adults aged over 50 years should take into account age and sex. AU - Nerpin, E.* AU - Olivieri, M.* AU - Gislason, T.* AU - Olin, A.C.* AU - Nielsen, R.* AU - Johannessen, A.* AU - Ferreira, D.S.* AU - Marcon, A.* AU - Cazzoletti, L.* AU - Accordini, S.* AU - Pin, I.* AU - Corsico, A.* AU - Demoly, P.* AU - Weyler, J.* AU - Nowak, D.* AU - Jõgi, R.* AU - Forsberg, B.* AU - Zock, J.P.* AU - Sigsgaard, T.* AU - Heinrich, J. AU - Bono, R.* AU - Leynaert, B.* AU - Jarvis, D.* AU - Janson, C.* AU - Malinovschi, A.* AU - on behalf of the European Community Respiratory Health Survey (ECRHS) study group* C1 - 55919 C2 - 46671 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 969-979 TI - Determinants of fractional exhaled nitric oxide in healthy men and women from the European Community Respiratory Health Survey III. JO - Clin. Exp. Allergy VL - 49 IS - 7 PB - Wiley PY - 2019 SN - 0954-7894 ER - TY - JOUR AB - Background Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. Objective Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. Methods We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed. Results The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 x 10(-8) for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 x 10(-6)) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 x 10(-7)), 14q22 (rs7493885 near NIN; P = 2.9 x 10(-6)) and 2p22 (rs232542 near CYP1B1; P = 4.1 x 10(-6)). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. Conclusions and Clinical Relevance We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms. AU - Sugier, P.E.* AU - Sarnowski, C.* AU - Granell, R.* AU - Laprise, C.* AU - Ege, M.J.* AU - Margaritte-Jeannin, P.* AU - Dizier, M.H.* AU - Minelli, C.* AU - Moffatt, M.F.* AU - Lathrop, M.* AU - Cookson, W.O.C.M.* AU - Henderson, A.J.* AU - von Mutius, E. AU - Kogevinas, M.* AU - Demenais, F.* AU - Bouzigon, E.* C1 - 56710 C2 - 47251 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 1342-1351 TI - Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood. JO - Clin. Exp. Allergy VL - 49 IS - 10 PB - Wiley PY - 2019 SN - 0954-7894 ER - TY - JOUR AB - Stings of Hymenoptera can induce IgE-mediated systemic and even fatal allergic reactions. Venom-specific immunotherapy (VIT) is the only disease-modifying and curative treatment of venom allergy. However, choosing the correct venom for VIT represents a necessary prerequisite for efficient protection against further anaphylactic sting reactions after VIT. In the past, therapeutic decisions based on the measurement of specific IgE (sIgE) levels to whole venom extracts were not always straightforward, especially when the patient was not able to identify the culprit insect. In the last years, the increasing knowledge about the molecular structure and relevance of important venom allergens and their availability as recombinant allergens, devoid of cross-reactive carbohydrate determinants, resulted in the development of an advanced component-resolved diagnostics (CRD) approach in venom allergy. Already to date, CRD has increased the sensitivity of sIgE detection and enabled the discrimination between primary sensitization and cross-reactivity, particularly in patients with sensitization to both honeybee and vespid venom. Hence, CRD in many patients improves the selection of the appropriate immunotherapeutic intervention. Moreover, the detailed knowledge about sensitization profiles on a molecular level might open new options to identify patients who are at increased risk of side-effects or not to respond to immunotherapy. Therefore, increasing potential of CRD becomes evident, to direct therapeutic decisions in a personalized and patient-tailored manner. Reviewed here are the state of the art options, recent developments and future perspectives of CRD of Hymenoptera venom allergy. AU - Blank, S. AU - Bilò, M.B.* AU - Ollert, M.* C1 - 52725 C2 - 44350 CY - Hoboken SP - 354-364 TI - Component-resolved diagnostics to direct in venom immunotherapy: Important steps towards precision medicine. JO - Clin. Exp. Allergy VL - 48 IS - 4 PB - Wiley PY - 2018 SN - 0954-7894 ER - TY - JOUR AB - Background: Mice models suggest epigenetic inheritance induced by parental allergic disease activity. However, we know little of how parental disease activity before conception influences offspring's asthma and allergy in humans. Objective: We aimed to assess the associations of parental asthma severity, bronchial hyperresponsiveness (BHR), and total and specific IgEs, measured before conception vs. after birth, with offspring asthma and hayfever. Methods: The study included 4293 participants (mean age 34, 47% men) from the European Community Respiratory Health Survey (ECRHS) with information on asthma symptom severity, BHR, total and specific IgEs from 1991 to 1993, and data on 9100 offspring born 1972-2012. Adjusted relative risk ratios (aRRR) for associations of parental clinical outcome with offspring allergic disease were estimated with multinomial logistic regressions. Results: Offspring asthma with hayfever was more strongly associated with parental BHR and specific IgE measured before conception than after birth [BHR: aRRR = 2.96 (95% CI: 1.92, 4.57) and 1.40 (1.03, 1.91), respectively; specific IgEs: 3.08 (2.13, 4.45) and 1.83 (1.45, 2.31), respectively]. This was confirmed in a sensitivity analysis of a subgroup of offspring aged 11-22 years with information on parental disease activity both before and after birth. Conclusion & Clinical Relevance: Parental BHR and specific IgE were associated with offspring asthma and hayfever, with the strongest associations observed with clinical assessment before conception as compared to after birth of the child. If the hypothesis is confirmed in other studies, parental disease activity assessed before conception may prove useful for identifying children at risk for developing asthma with hayfever. AU - Bertelsen, R.J.* AU - Rava, M.* AU - Carsin, A.E.* AU - Accordini, S.* AU - Benediktsdóttir, B.* AU - Dratva, J.* AU - Franklin, K.A.* AU - Heinrich, J. AU - Holm, M.* AU - Janson, C.* AU - Johannessen, A.* AU - Jarvis, D.L.* AU - Jõgi, R.* AU - Leynaert, B.* AU - Norbäck, D.* AU - Omenaas, E.R.* AU - Raherison, C.* AU - Sánchez-Ramos, J.L.* AU - Schlünssen, V.* AU - Sigsgaard, T.* AU - Dharmage, S.C.* AU - Svanes, C.* C1 - 50932 C2 - 42692 CY - Hoboken SP - 627-638 TI - Clinical markers of asthma and IgE assessed in parents before conception predict asthma and hayfever in the offspring. JO - Clin. Exp. Allergy VL - 47 IS - 5 PB - Wiley PY - 2017 SN - 0954-7894 ER - TY - JOUR AB - Background: Westernized lifestyle has been blamed for allergy epidemics. One of its characteristics is increased distances and frequency of travelling from early life onwards. Early life travelling to places which substantially differ from home environment in terms of climate, vegetation and food could increase the exposure to further unknown allergens and hence promote the development of allergies, but no epidemiological study has investigated this speculation. Methods: Detailed data on travelling during the first 2 years of life as well as a range of atopic outcomes along with potential confounders up to age 15 years were collected prospectively within two large population-based multicentre German birth cohorts - GINIplus and LISAplus. Farthest travelling destination (within Germany; middle/northern/eastern Europe; southern Europe; outside Europe), total number of trips and their combination were considered as exposures. Six atopic outcomes were used: (1) doctor-diagnosed asthma, (2) doctor-diagnosed allergic rhinitis, (3) nose and eye symptoms, (4) sensitization to food allergens, (5) sensitization to indoor and (6) outdoor inhalant allergens. Longitudinal associations between each exposure and health outcome pair were analysed using generalized estimation equations (GEEs). Results: The results of our longitudinal analyses of 5674 subjects do not support the research hypothesis that travelling abroad to different regions in Europe or beyond Europe and frequency of travelling increase prevalence of doctor-diagnosed asthma and allergic rhinitis, nose and eye symptoms and allergic sensitization up to 15 years of age. Furthermore, there was no indication of age-varying effects. Conclusions: Early life travelling does not seem to increase risk of atopic outcomes. Nevertheless, as we could not account for the type of visited environment or length of stay, these first findings should be interpreted with caution. AU - Markevych, I. AU - Baumbach, C. AU - Standl, M. AU - Koletzko, S.* AU - Lehmann, I.* AU - Bauer, C.P.* AU - Hoffmann, B.* AU - von Berg, A.* AU - Berdel, D.* AU - Heinrich, J. C1 - 50524 C2 - 42466 SP - 395-400 TI - Early life travelling does not increase risk of atopic outcomes until 15 years: Results from GINIplus and LISAplus. JO - Clin. Exp. Allergy VL - 47 IS - 3 PY - 2017 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Besides allergens, pollen release bioactive, low molecular weight compounds that modulate and stimulate allergic reactions. Clinical relevance of these substances hasn't been investigated to date. OBJECTIVE: To elucidate the effect of a non-allergenic, low molecular weight factors from aqueous birch pollen extracts (Bet-APE<3kDa) on the human allergic immune response in vivo. METHODS: Birch and grass pollen allergic individuals underwent skin prick testing with allergen alone, allergen plus Bet-APE<3kDa, or allergen plus pre-identified candidate substances from low molecular pollen fraction. Nasal allergen challenges were performed in non-atopic and pollen allergic individuals using a 3 day repeated threshold challenge battery. Subjects were either exposed to allergen alone or to allergen plus Bet-APE<3kDa. Local cytokine levels, nasal secretion weights, nasal congestion and symptom scores were determined. RESULTS: Skin prick test reactions to pollen elicited larger wheals when allergens were tested together with the low molecular weight compounds from pollen. Similar results were obtained with candidate pollen-associated lipid mediators. In nasal lining fluids of allergic patients challenged with allergen plus Bet-APE<3kDa, IL-8 and IgE was significantly increased as compared to allergen-only challenged patients. These patients also produced increased amounts of total nasal secretion and reported more severe rhinorrhea than the allergen-only challenged group. CONCLUSIONS: Low molecular compounds from pollen enhance the allergen specific immune response in the skin and nose. They are therefore of potential clinical relevance in allergic patients. AU - Gilles-Stein, S. AU - Beck, I. AU - Chaker, A. AU - Bas, M.* AU - McIntyre, M.* AU - Cifuentes, L.* AU - Petersen, A.* AU - Gutermuth, J. AU - Schmidt-Weber, C.B. AU - Behrendt, H. AU - Traidl-Hoffmann, C. C1 - 48381 C2 - 39992 CY - Hoboken SP - 1355-1365 TI - Pollen derived low molecular compounds enhance the human allergen specific immune response in vivo. JO - Clin. Exp. Allergy VL - 46 IS - 10 PB - Wiley-blackwell PY - 2016 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Increased mucus production is a critical factor impairing lung function in patients suffering from bronchial asthma, the most common chronic inflammatory lung disease worldwide. OBJECTIVE: This study aimed at investigating whether goblet cell (GC) metaplasia and mucus production are differentially regulated in proximal and distal airways. METHODS: Female Balb/c mice were sensitized to ovalbumin (OVA) and challenged with an OVA-aerosol on two consecutive days for one week (acute) or twelve weeks (chronic). Real-time RT-PCR analysis was applied on microdissected airways. RESULTS: In acutely and chronically OVA-challenged mice GC metaplasia and mucus production was observed in proximal but not in distal airways. In contrast, inflammation reflected by the infiltration of eosinophils and expression of the TH2-type cytokines IL-4 and IL-13 was increased in both, proximal and distal airways. Abundance of IL-13Rα1 was lower in distal airways of healthy control mice. Under acute and chronic OVA-exposure, activation of IL-13Rα1-dependent signaling cascade, reflected by Spdef and Foxo3A transcription factors, was attenuated in distal compared to proximal airways. CONCLUSION & CLINICAL RELEVANCE: These data indicate that distal airways might be less sensitive to IL-13 induced GC metaplasia and mucus production through lower expression of IL-13Rα1 and attenuated activation of downstream signaling. This might represent a protective strategy in order to prevent mucus plugging of distal airways and thus, impaired ventilation of attached alveoli. AU - Vock, C.* AU - Yildirim, A.Ö. AU - Wagner, C.* AU - Schlick, S.* AU - Lunding, L.P.* AU - Lee, C.G.* AU - Elias, J.A.* AU - Fehrenbach, H.* AU - Wegmann, M.* C1 - 44446 C2 - 36845 CY - Hoboken SP - 1447-1458 TI - Distal airways are protected from goblet cell metaplasia by diminished expression of IL-13 signaling components. JO - Clin. Exp. Allergy VL - 45 IS - 9 PB - Wiley-blackwell PY - 2015 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Data on molecular allergy diagnostics in adults with grass pollen allergy with regard to conjunctival and nasal provocation test outcome and specific immunotherapy is lacking to date. OBJECTIVE: To assess whether molecular allergy diagnostics for grass pollen allergens could help with predicting provocation test outcomes and serve as a basis for future component resolved specific immunotherapy. METHODS: Sera of 101 adults with grass pollen allergy was analysed for IgE against timothy grass pollen (Phleum pratense), rPhl p 1, rPhl p 2, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11 and rPhl p12 and correlated to the individuals' outcome in the nasal and conjunctival provocation tests and investigated in regard to a potential component resolved specific immunotherapy. RESULTS: An increasing number of sensitizations to timothy grass allergens was correlated to a positive reaction in the conjunctival (4.9 vs. 3.6, p=0.003) and nasal provocation tests (4.5 vs. 2.2, p=0.0175). In molecular sensitization profiles a substantial heterogeneity was detected, with none of the patients exactly matching the allergen composition of a previously published component resolved specific immunotherapy containing Phl p 1, Phl p 2, Phl p 5a/b and Phl p 6. The results indicate that in 95% of the patients a proportion of 50% of timothy-IgE would be targeted with such a specific immunotherapy, while in 50% and 10% of patients 80% and 90% of timothy-IgE would be targeted respectively. CONCLUSION AND CLINICAL RELEVANCE: Molecular allergy diagnostics is a prerequisite for future component-resolved specific immunotherapy due to the high heterogeneity of sensitization profiles. However, of current clinical relevance is the observed correlation between the number of sensitizations and provocation test outcome. AU - Darsow, U. AU - Brockow, K. AU - Pfab, F. AU - Jakob, T.* AU - Petersson, C.J.* AU - Borres, M.P.* AU - Ring, J.* AU - Behrendt, H. AU - Huss-Marp, J.* C1 - 30880 C2 - 33979 CY - Hoboken SP - 778-786 TI - Heterogeneity of molecular sensitization profiles in grass pollen allergy - implications for immunotherapy? JO - Clin. Exp. Allergy VL - 44 IS - 5 PB - Wiley-Blackwell PY - 2014 SN - 0954-7894 ER - TY - JOUR AB - The increase of allergies in East Germany - reaching West German prevalence shortly after the reunification - is considered a model for the allergy epidemic in the western world. Whether such a pattern was observed in all comparison studies and for all allergic manifestations is not known because a complete overview is missing. Hints about possible causal factors for the allergy epidemic could be gained by identifying known risk factors, which explain the observed pattern of allergy development in Germany. Again, an overview about these efforts is missing. We identified 14 cross-sectional studies conducted after 1989 and calculated prevalence ratios (West/East) for asthma, hayfever, eczema and allergic sensitization. Additionally, a tabular overview about the explanatory power of risk factors hypothesized in the nineties and covering outdoor exposure, indoor factors, early childhood influences, nutrition as well as awareness is given. At the time of the German reunification, the prevalence ratio West/East was largest for hayfever and sensitization to birch pollen, less pronounced for the other phenotypes and even less than one for atopic eczema. Hayfever and sensitization to birch pollen also showed the steepest increase in East Germany afterwards. Single-room heating with fossil fuels and living as only child in a family were identified as explaining up to 23.5% of the excess trend in East compared to the trend in West. Hayfever as most typical atopic disease showed the difference in allergy pattern between East and West Germany clearest. Risk factors identified for these phenotypes are completely different (single child) or even act in the opposite direction (single-room heating) from classical risk factors for airway diseases. This might be the most important lesson from the West/East German experience. It already stimulated many other studies focussing on protective factors such as microbial stimulation. AU - Krämer, U.* AU - Schmitz, R.* AU - Ring, J.* AU - Behrendt, H. C1 - 43020 C2 - 35944 SP - 94-107 TI - What can reunification of East and West Germany tell us about the cause of the allergy epidemic? JO - Clin. Exp. Allergy VL - 45 IS - 1 PY - 2014 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Serum levels of IL-16, IL-33 and the decoy receptor of IL-33, soluble ST2, are elevated in allergic rhinitis. Recent studies show that IL-16, soluble ST2 or anti-IL-33 reduce type 2 cytokines (such as IL-5) and eosinophilia in murine models of allergic asthma or allergic rhinitis respectively. OBJECTIVE: In this study, we studied the release of IL-5, IL-16, IL-33 and soluble ST2 in allergic rhinitis patients after nasal allergen challenge and natural pollen exposure. METHODS: The nasal lavages of 15 allergic and 14 non-allergic volunteers were collected during the pollen allergy season. In addition, six allergic volunteers underwent unilateral nasal allergen and control challenge out of season and nasal secretions and sera were collected. IL-5, IL-16, IL-33 and soluble ST2 in nasal secretions and sera were measured by electrochemiluminescent assay or ELISA, respectively. RESULTS: Nasal IL-5, IL-16 and soluble ST2 levels were significantly increased in seasonally pollen exposed allergic volunteers compared to control subjects (P < 0.001, P = 0.018 and P = 0.002 respectively), whereas IL-33 remained undetectable. Nasal IL-16 showed a weak inverse correlation trend with nasal symptoms (r = -0.48, P = 0.07). Nasal soluble ST2 concentrations were inversely correlated with nasal symptoms (r = -0.61, P = 0.02) and positively correlated with IL-16 (r = 0.56, P = 0.03). Significant increases of nasal IL-5, IL-16 and ST2 but not IL-33 were observed after nasal allergen challenge. At 24 h after allergen challenge, local ST2 and IL-5 concentrations showed an inverse correlation trend (r = -0.83, P = 0.04). Serum levels of IL-5, IL-16 and soluble ST2 rose in at least five of six volunteers tested at 5 or 24 h post-challenge. CONCLUSIONS AND CLINICAL RELEVANCE: The observed upregulation of soluble ST2 and IL-16 after nasal allergen challenge and during peak pollination season suggests potential regulatory roles of these cytokines in the inflammatory reaction in allergic rhinitis. AU - Baumann, R.* AU - Rabaszowski, M.* AU - Stenin, I.* AU - Tilgner, L.* AU - Gaertner-Akerboom, M.* AU - Scheckenbach, K.* AU - Wiltfang, J.* AU - Chaker, A. AU - Schipper, J.* AU - Wagenmann, M.* C1 - 27831 C2 - 32832 SP - 1134-1143 TI - Nasal levels of soluble IL-33R ST2 and IL-16 in allergic rhinitis: Inverse correlation trends with disease severity. JO - Clin. Exp. Allergy VL - 43 IS - 10 PB - Wiley-Blackwell PY - 2013 SN - 0954-7894 ER - TY - JOUR AU - Brockow, K. C1 - 28155 C2 - 32970 SP - 1200-1201 TI - Advances in our understanding of drug hypersensitivity. JO - Clin. Exp. Allergy VL - 43 IS - 11 PB - Wiley-Blackwell PY - 2013 SN - 0954-7894 ER - TY - JOUR AU - Brockow, K. C1 - 22406 C2 - 30893 SP - 5-7 TI - Time for more clinical research on non-steroidal anti-inflammatory drug-induced urticaria/angioedema and anaphylaxis. JO - Clin. Exp. Allergy VL - 43 IS - 1 PB - Wiley-Blackwell PY - 2013 SN - 0954-7894 ER - TY - JOUR AB - Background Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. Objective To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. Methods In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23000 individuals with predominantly European descent, of whom 8165 are asthmatics. Results We report associations between several DENND1B variants (P=2.2x107 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P<0.05) in two of the seven studies and of borderline significance in one (P=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30kg/m2 (P=0.01 for combined screening and replication data sets, N=4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. Conclusions and Clinical Relevance DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study. AU - Melén, E.* AU - Granell, R.* AU - Kogevinas, M.* AU - Strachan, D.* AU - Gonzalez, J.R.* AU - Wjst, M. AU - Jarvis, D.* AU - Ege, M.* AU - Braun-Fahrländer, C.* AU - Genuneit, J.* AU - Horak, E.* AU - Bouzigon, E.* AU - Demenais, F.* AU - Kauffmann, F.* AU - Siroux, V.* AU - Michel, S.* AU - von Berg, A.* AU - Heinzmann, A.* AU - Kabesch, M.* AU - Probst-Hensch, N.M.* AU - Curjuric, I.* AU - Imboden, M.* AU - Rochat, T.* AU - Henderson, J.* AU - Sterne, J.A.C.* AU - McArdle, W.L.* AU - Hui, J.* AU - James, A.L.* AU - Musk, A.W.* AU - Palmer, L.J.* AU - Becker, A.* AU - Kozyrskyj, A.L.* AU - Chan-Young, M.* AU - Park, J.E.* AU - Leung, A.* AU - Daley, D.* AU - Freidin, M.B.* AU - Deev, I.A.* AU - Ogorodova, L.M.* AU - Puzyrev, V.P.* AU - Celedón, J.C.* AU - Brehm, J.M.* AU - Cloutier, M.M.* AU - Canino, G.* AU - Acosta-Perez, E.* AU - Soto-Quiros, M.* AU - Avila, L.* AU - Bergström, A.* AU - Magnusson, J.* AU - Söderhäll, C.* AU - Kull, I.* AU - Scholtens, S.* AU - Boezen, H.M.* AU - Koppelman, G.H.* AU - Wijga, A.H.* AU - Marenholz, I.* AU - Esparza-Gordillo, J.* AU - Lau, S.* AU - Lee, Y.A.* AU - Standl, M. AU - Tiesler, C.M. AU - Flexeder, C. AU - Heinrich, J. AU - Myers, R.A.* AU - Ober, C.* AU - Nicolae, D.L.* AU - Farrall, M.* AU - Kumar, A.* AU - Moffatt, M.F.* AU - Cookson, W.O.C.M.* AU - Lasky-Su, J.* C1 - 24103 C2 - 31330 SP - 463-474 TI - Genome-wide association study of body mass index in 23000 individuals with and without asthma. JO - Clin. Exp. Allergy VL - 43 IS - 4 PB - Wiley-Blackwell PY - 2013 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Interferon-regulatory factors (IRFs) play a crucial role in immunity, not only influencing interferon expression but also T cell differentiation. IRF-4 was only recently recognized as a further major player in T cell differentiation. OBJECTIVE: As IRF-1 polymorphisms were shown to be associated with atopy and allergy, we comprehensively investigated effects of IRF-4 variants on allergy, asthma and related phenotypes in German children. METHODS: Fifteen tagging single nucleotide polymorphisms (SNPs) in the IRF-4 gene were genotyped by MALDI-TOF MS in the cross-sectional ISAAC phase II study population from Munich and Dresden (age 9-11; N = 3099). Replication was performed in our previously established genome-wide association study (GWAS) data set (N = 1303) consisting of asthma cases from the Multicenter Asthma Genetic in Childhood (MAGIC) study and reference children from the ISAAC II study. RESULTS: SNPs were not significantly associated with asthma but with bronchial hyperresponsiveness, atopy and, most interestingly, with recurrent bronchitis in the first data set. The IRF-4 variant rs9378805 was associated with recurrent bronchitis in the ISAAC population and replicated in the GWAS data set where further SNPs showed associations with recurrent bronchitis and asthma. CONCLUSIONS: We found genetic associations in IRF-4 to be associated with recurrent bronchitis in our two study populations. Associated polymorphisms are localized in a putative regulatory element in the 3'UTR region of IRF-4. These findings suggest a putative role of IRF-4 in the development of bronchitis. AU - Pinto, L.A.* AU - Michel, S.* AU - Klopp, N. AU - Vogelberg, C.* AU - von Berg, A.* AU - Bufe, A.* AU - Heinzmann, A.* AU - Laub, O.* AU - Simma, B.* AU - Frischer, T.* AU - Genuneit, J.* AU - Gorski, M.* AU - Illig, T. AU - Kabesch, M.* C1 - 27833 C2 - 32833 SP - 1152-1159 TI - Polymorphisms in the IRF-4 gene, asthma and recurrent bronchitis in children. JO - Clin. Exp. Allergy VL - 43 IS - 10 PB - Wiley-Blackwell PY - 2013 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: There is minimal data available concerning the dose-response relationship between allergen exposure and clinical reactivity for outdoor aeroallergens, such as timothy grass pollen. Timothy pollen-specific IgE (sIgE) determinations might assist in predicting the clinical reactivity in patients with allergic rhinoconjunctivitis (ARC). METHODS: Allergen-sIgE antibody levels of timothy grass pollen were correlated with individual threshold doses eliciting allergic reactions in skin prick test (SPT), conjunctival (CPT) and nasal (NPT) provocation tests in patients suffering from pollen-induced rhinoconjunctivitis and healthy controls. RESULTS: One hundred and four patients with ARC (median age: 27 years; range: 18-64; females: 58%) and 36 controls (25 years (22-77); females: 70%) were included in the study. Ninety-six percent of the patients showed a positive reaction in the nasal and 57% showed a positive reaction in the conjunctival provocation. With regarding to titrated SPT, 98% of the patients showed a positive skin test reaction; correlating with the level of sIgE for timothy (P < 0.001). For both provocation protocols, there was no correlation between the provocation concentration at the reaction and the level of sIgE for timothy. The ratio of sIgE/total IgE correlated with the dilution level of SPT (P < 0.002) and CPT (P < 0.01), respectively. CONCLUSION AND CLINICAL RELEVANCE: A dose-response relationship between the levels of sIgE and clinical outcome of timothy allergen exposure could not be established. Although IgE-determination remains an important key element in allergy diagnosis, provocation tests are procedures of choice if the clinical relevance of an allergen has to be confirmed. AU - Huss-Marp, J. AU - Darsow, U. AU - Brockow, K. AU - Pfab, F. AU - Weichenmeier, I. AU - Schober, W. AU - Petersson, C.J.* AU - Borres, M.P.* AU - Ring, J.* AU - Behrendt, H. C1 - 6617 C2 - 28970 CY - Malden, MA SP - 1116-1124 TI - Can Immunoglobulin E-measurement replace challenge tests in allergic rhinoconjunctivits to grass pollen? JO - Clin. Exp. Allergy VL - 41 IS - 8 PB - Wiley-Blackwell PY - 2011 SN - 0954-7894 ER - TY - JOUR AB - Chronic spontaneous urticaria is triggered by many direct and indirect aggravating factors including autoreactive/autoimmune mechanisms, infections, non-allergic and pseudoallergic intolerance reactions. However, the role of neuroimmune mechanisms in chronic spontaneous urticaria so far is unclear. Thus, we wanted to address the regulation of the neurotrophin brain-derived neurotrophic factor (BDNF) in serum and inflammatory skin of patients with chronic spontaneous urticaria in comparison to subjects with healthy skin. Fifty adult patients with chronic spontaneous urticaria and 23 skin-healthy subjects were studied. Chronic spontaneous urticaria was defined as recurrent weals for more than 6 weeks. Autologous serum skin test was performed in all patients with chronic spontaneous urticaria and BDNF serum levels were analysed by enzyme immunoassay in all subjects. Furthermore, skin biopsies were taken from weals of eight patients with chronic spontaneous urticaria as well as from healthy skin of eight controls to evaluate the expression of BDNF and its receptors including tyrosine kinase (trk) B and pan-neurotrophin receptor p75(NTR) by immunohistochemistry. RESULTS: BDNF serum levels were detectable in all subjects studied. However, BDNF levels were significantly higher in patients with chronic spontaneous urticaria compared to non-atopic skin-healthy controls (P<0.001). Furthermore, epidermal and dermal expression of BDNF and epidermal expression of p75(NTR) was significantly higher in patients with chronic spontaneous urticaria compared with controls (P<0.05-0.001). There was no difference with regard to the expression of trkB between chronic spontaneous urticaria and controls and no difference in BDNF serum levels between autologous serum skin test-positive (n=23) and -negative (n=27) patients with chronic spontaneous urticaria. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that BDNF is increased in serum and diseased skin of patients with chronic spontaneous urticaria, suggesting a role for neurotrophins in the pathophysiology of this chronic inflammatory skin disease. Further studies are needed to address the functional role of BDNF on key target effector cells in chronic spontaneous urticaria to establish new therapeutic implications AU - Rossing, K.* AU - Novak, N.* AU - Mommert, S.* AU - Pfab, F. AU - Gehring, M.* AU - Wedi, B.* AU - Kapp, A.* AU - Raap, U.* C1 - 4865 C2 - 29441 CY - Oxford, UK SP - 1392-1399 TI - Brain-derived neurotrophic factor is increased in serum and skin levels of patients with chronic spontaneous urticaria. JO - Clin. Exp. Allergy VL - 41 IS - 10 PB - Wiley-Blackwell PY - 2011 SN - 0954-7894 ER - TY - JOUR AB - Background The association between dietary fatty acid intake and the development of atopic diseases has been inconsistent. This could be due to inter-individual genetic differences in fatty acid metabolism. Objective The aim of the current study was to assess the influence of FADS1 FADS2 gene cluster polymorphisms on the association between dietary fatty acid intake and atopic diseases and allergic sensitization in 10-year-old children. Methods The analysis was based on data from two German prospective birth cohort studies. Data on margarine and fatty acid intake were collected using a food frequency questionnaire. Information on atopic diseases was collected using a questionnaire completed by the parents. Specific IgE against common food and inhalant allergens were measured. Six variants of the FADS1 FADS2 gene cluster (rs174545, rs174546, rs174556, rs174561, rs174575 and rs3834458) were tested. Logistic regression modelling, adjusted for gender, age, maternal education level and study centre, was used to analyse the association between fatty acid intake and atopic diseases stratified by genotype. Results No significant association was found between the six FADS single nucleotide polymorphisms (SNPs) and allergic diseases or atopic sensitization. The total n-3/total n-6 ratio was positive associated with an increased risk of hayfever in homozygous major allele carriers ranging from an adjusted odds ratios of 1.25 (95%-CI: 1.00-1.57) to 1.31 (95%-CI: 1.01-1.69) across the six tested SNPs although this association was not significant anymore after correcting for multiple testing. Daily margarine intake was significantly associated with asthma [1.17 (1.03-1.34) to 1.22 (1.06-1.40)] in individuals carrying the homozygous major allele. This association was also significant after correcting for multiple testing. Conclusions & Clinical Relevance The association between dietary intake of fatty acids and allergic diseases might be modulated by FADS gene variants in children. AU - Standl, M. AU - Sausenthaler, S. AU - Lattka, E. AU - Koletzko, S.* AU - Bauer, C.-P.* AU - Wichmann, H.-E. AU - von Berg, A.* AU - Berdel, D.* AU - Krämer, U.* AU - Schaaf, B.* AU - Roder, S.* AU - Herbarth, O.* AU - Klopp, N. AU - Koletzko, B.* AU - Heinrich, J. AU - GINIplus Study Group (Heinrich, J. AU - Wichmann, H.-E. AU - Schoetzau, A. AU - Popescu, M. AU - Mosetter, M. AU - Schindler, J. AU - Franke, K. AU - Laubereau, B. AU - Sausenthaler, S. AU - Thaqi, A. AU - Zirngibl, A. AU - Zutavern, A.) AU - LISAplus Study Group (Zutavern, A. AU - Chen, C.-M. AU - Schnappinger, M. AU - Rzehak, P. AU - Wichmann, H.-E. AU - Heinrich, J. AU - Bolte, G. AU - Belcredi, P. AU - Jacob, B. AU - Schoetzau, A. AU - Mosetter, M. AU - Schindler, J. AU - Höhnke, A. AU - Franke, K. AU - Laubereau, B. AU - Sausenthaler, S. AU - Thaqi, A. AU - Zirngibl, A.) C1 - 6811 C2 - 29295 SP - 1757-1766 TI - FADS gene variants modulate the effect of dietary fatty acid intake on allergic diseases in children. JO - Clin. Exp. Allergy VL - 41 IS - 12 PB - Wiley-Blackwell PY - 2011 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Asthma is a chronic inflammatory disorder in which Th2, Th1 and suppressive T cells (Tregs) play a role. The transcription factor FoxP3 plays a role in Treg differentiation while T-bet is important for Th1 and GATA-3 for Th2 differentiation from naïve T cells. Recent data show that age-related deregulation of Treg cells is a mechanism of senescence affecting several chronic diseases. It is crucial to understand the behaviour of these cell populations in asthma for elderly patients. OBJECTIVE: To evaluate FoxP3, GATA-3 and T-bet gene expression under basal conditions and after in vitro activation in a group of elderly asthmatic compared with age-matched healthy individuals. METHODS: Thirty-two elderly asthmatics and 17 healthy elderly individuals were selected. Serum total IgE was measured, and peripheral blood mononuclear cells (PBMCs) were isolated and stimulated in vitro with anti-CD3/anti-CD28, followed by mRNA isolation. After reverse transcription, real-time quantitative PCR was performed and relative quantification was determined 2(-ΔΔCt)(2(-ΔΔCt) method).RESULTS: The mean values and standard deviation of FoxP3, GATA-3 and T-bet relative expression for control vs. asthma were 10.2±6.8 vs. 4.8±3.8, 2.4±2.9 vs. 1.7±0.9 and 3.3±2.1 vs. 2.1±1.5, respectively. Healthy individuals showed significantly higher expression of FoxP3 and T-bet; asthmatics had a lower T-bet/GATA-3 ratio, higher serum IgE and a positive significant correlation between total IgE and GATA-3 expression. CONCLUSION AND CLINICAL RELEVANCE: Elderly asthmatic patients have lower FoxP3 mRNA expression in PBMC, which can be associated with the sustained inflammatory process and with the decreased immune tolerance by Treg cells. The T-bet deficiency and the correlation of GATA-3 expression with the increase of IgE are characteristics of long-lasting asthma. Changes related to the immunosenescence process could provide an explanation for the minor differences observed between the groups. It is important to clarify persistent modifications in long-lasting asthma in the elderly and adequate future therapeutic approaches. AU - Vale-Pereira, S.* AU - Todo-Bom, A.* AU - Geraldes, L.* AU - Schmidt-Weber, C.B. AU - Akdis, C.A.* AU - Mota-Pinto, A.* C1 - 6396 C2 - 28606 SP - 490-496 TI - FoxP3, GATA-3 and T-bet expression in elderly asthma. JO - Clin. Exp. Allergy VL - 41 IS - 4 PB - Wiley-Blackwell PY - 2011 SN - 0954-7894 ER - TY - JOUR AB - Flow cytometric basophil activation tests (BAT) have been developed as cellular tests for in vitro diagnosis of IgE-mediated reactions. Different markers and techniques have been used after stimulation with various allergens. It was the aim of the present study to compare an established BAT (Flow-CAST) with a newly developed basophil activation protocol using CD63 and CCR3 (Flow2 CAST) in patients with type-I allergy to antibiotics.Twenty-four patients with a history of type-I allergy to antibiotics were examined. A careful allergy history was taken, and skin tests and determination of specific IgE antibodies were performed. Two different BAT using CD63 expression but different protocols were carried out after stimulation with different concentrations of antibiotics. Fifteen healthy subjects without a history of antibiotic allergy were studied as controls. The Flow2 CAST showed a higher sensitivity than the Flow-CAST (55% vs. 53%) with regard to patients' history. Specificity was 80% both for the Flow2 CAST and for the Flow-CAST with regard to controls with negative history and negative RAST.These results show the value of two different BAT as cellular tests in the in vitro diagnosis of patients with antibiotic allergy with equal specificity and a slightly higher sensitivity for the Flow2 CAST. AU - Eberlein, B. AU - León Suárez, I.* AU - Darsow, U. AU - Rueff, F.* AU - Behrendt, H. AU - Ring, J. C1 - 5265 C2 - 27877 SP - 411-418 TI - A new basophil activation test using CD63 and CCR3 in allergy to antibiotics. JO - Clin. Exp. Allergy VL - 40 IS - 3 PB - Blackwell Scientific Publications PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - Evidence is accumulating that the pollen exsudate contains an array of non-allergenic, pro-inflammatory and immunomodulatory substances acting on the innate and adaptive immune system. In this context, pollen-associated E(1)-phytoprostanes (PPE(1)) were shown to licence human monocyte-derived dendritic cells for T-helper type 2 (Th2) polarization of naïve T cells. This study aims at analysing the impact of pollen-associated lipid mediators on cytokine secretion and maturation of 6-sulfo LacNAc(+) dendritic cells (slanDCs), the most abundant native dendritic cell (DC) in human peripheral blood, and further dissecting the biologically active substance(s) within aqueous pollen extracts. Aqueous birch pollen extracts dose-dependently inhibited the lipopolysaccharide (LPS)-induced IL-12 p70 production, while the levels of IL-6 remained unaffected. PPE(1) inhibited secretion of both IL-12 p70 and IL-6. Aqueous pollen extracts, but not PPE(1) or F(1)-phytoprostanes significantly reduced the LPS-induced surface expression of the maturation markers CD80, CD83, CD40 and CCR-7, an effect that was independent of proteins and that was still present in a 3 kDa cut-off fraction of the pollen extract. These effects were observed irrespective of the atopy status of the donors. Finally, slanDCs exposed to aqueous pollen extracts were impaired in eliciting an IFN-gamma response in naïve CD4(+) T cells. Our data show that slanDCs, a subset of human blood DCs with constitutively high potency to induce Th1 responses, are susceptible to the Th2 polarizing effect of low molecular weight, non-protein factors derived from pollen. AU - Gilles, S. AU - Jacoby, D.R. AU - Blume, C. AU - Mueller, M.J.* AU - Jakob, T.* AU - Behrendt, H. AU - Schaekel, K.* AU - Traidl-Hoffmann, C. C1 - 539 C2 - 27905 SP - 269-278 TI - Pollen-derived low-molecular weight factors inhibit 6-sulfo LacNAc⁺ dendritic cells' capacity to induce T-helper type 1 responses. JO - Clin. Exp. Allergy VL - 40 IS - 2 PB - Wiley-Blackwell Publishing PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - At the time of the German reunification in 1990, manifestations of most allergic diseases were less prevalent in East than in West Germany. It was hypothesized that these East-West differences would diminish with lifestyle and pollution changes in East Germany. To investigate whether changes in the prevalence of asthma, hayfever, eczema or allergic sensitization in East Germany approached the levels seen in West Germany and to identify possible lifestyle or environmental factors that may influence this. Between 1991 and 2000, 6-year-old children from four areas in East Germany participated in an annual survey. Every 3rd year, a parallel survey was performed in four areas of West Germany. In total, 31 903 children were included. Parents completed a questionnaire regarding lifestyle factors and diagnoses and symptoms of asthma, hayfever and eczema. In sub-areas, eczema was clinically assessed by a dermatologist. Specific IgE sensitization was determined for 6121 children. Logistic regression was used to analyse differences in time trends and the influence of lifestyle and pollution changes. Lifestyle and pollution changed significantly differently between East and West Germany. The trends in hayfever and in strong (specific IgE >3.5) sensitization against pollen, and particularly birch pollen, were steeper in East than in West Germany. The trend towards marked pollen sensitization was four times stronger (95% confidence interval 1.2-13.9) in East than in West Germany. Increasing numbers of only children, less single-room heating with fossil fuels and increasing importance of traffic-related pollution in East Germany partly explained these differences in time trends. Hayfever and sensitization against pollen were the most sensitive allergic manifestations to changes experienced specifically in East Germany. Influences of lifestyle (single-room heating, living as a single child) were important in explaining different trend developments. AU - Krämer, U. AU - Oppermann, H.* AU - Ranft, U.* AU - Schäfer, T. AU - Ring, J. AU - Behrendt, H. C1 - 715 C2 - 27885 SP - 289-298 TI - Differences in allergy trends between East and West Germany and possible explanations. JO - Clin. Exp. Allergy VL - 40 IS - 2 PB - Blackwell Scientific Publications PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - Background Recent studies indicate that prenatal vitamin D intake may protect against the development of atopic diseases in young children. Vitamin D has been shown to induce tolerogenic antigen-presenting cells such as dendritic cells. Whether the allergy-protective potential of prenatal vitamin D is mediated through such mechanisms is, however, unknown. Objective To evaluate the association between prenatal vitamin D supplementation and tolerogenic antigen-presenting cells in cord blood (CB) as determined by mRNA measurement of immunoglobulin-like transcripts (ILT)3 and ILT4. Methods A prospective multi-centre birth cohort was established in rural areas of five European countries. Information on maternal exposures including vitamin D intake was collected by questionnaires during pregnancy. The gene expression of ILT3 and ILT4 was analysed by real-time PCR in the CB of 927 children. Maternal vitamin D supplementation was assessed in Finland and France (n=349). Results Maternal vitamin D supplementation during pregnancy was associated with an increase in the gene expression of ILT3 (P=0.012) and ILT4 (P<0.001). This association remained significant for ILT4 (P=0.020) and showed a positive trend for the gene expression of ILT3 (P=0.059) after multivariate analysis controlling for various confounders. Conclusions Vitamin D supplementation during pregnancy may increase the mRNA levels of ILT3 and ILT4 in CB. This finding may point towards an early induction of tolerogenic immune responses by maternal vitamin D intake. AU - Rochat, M.K.* AU - Ege, M.J.* AU - Plabst, D.* AU - Steinle, J.* AU - Bitter, S.* AU - Braun-Fahrländer, C.* AU - Dalphin, J.-C.* AU - Riedler, J.* AU - Roponen, M.* AU - Hirvonen, M.R.* AU - Büchele, G.* AU - Renz, H.* AU - Lauener, R.* AU - Krauss-Etschmann, S. AU - von Mutius, E.* AU - PASTURE Study Group (*) C1 - 1460 C2 - 26983 SP - 786-794 TI - Maternal vitamin D intake during pregnancy increases gene expression of ILT3 and ILT4 in cord blood. JO - Clin. Exp. Allergy VL - 40 IS - 5 PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Food allergy is common, especially in childhood, where 6-8% of children are affected. Identification of early and efficient markers for later development of food allergy is very important. OBJECTIVE: We examined the ability of repeated measurements of food sensitization in early childhood to predict doctor-diagnosed food allergy (DDFA) at the age of 6 years. METHODS: The analysis was based on data from a prospective birth cohort study. Information was collected by parental questionnaires, and blood samples were obtained at 2 and 6 years of age. Children with repeated determination of sensitization to food allergens at 2 and 6 years of age were categorized into the sensitization phenotypes: no, early onset, late onset and persistent sensitization. The association between sensitization phenotypes and DDFA was prospectively investigated using multiple logistic regression analyses. RESULTS: Of 3097 children recruited at birth, a complete follow-up of IgE measurements and questionnaires at 1.5, 2 and 6 years were available for 1082 children. Early food allergen sensitization (fx5) was a strong risk for DDFA at 6 years [odds ratio (OR)=4.7; 95% confidence intervals (95% CI) 2.0-11.2] and for a new onset of DDFA at 6 years (OR=4.1; 95% CI 1.5-11.3). Additionally, persistent food allergen sensitization increased the risk of DDFA at 6 years (OR=6.1; 95% CI 2.7-13.7). Early sensitized children with a history of parental atopy showed the highest risk for DDFA at 6 years. CONCLUSION: Food-sensitized children during the first 2 years of life, especially with a family history of atopy, might be considered as a susceptible subgroup that requires specific attention concerning the development of food allergy-related symptoms. AU - Schnabel, E. AU - Sausenthaler, S. AU - Schaaf, B.* AU - Schäfer, T. AU - Lehmann, I.* AU - Behrendt, H. AU - Herbarth, O.* AU - Borte, M.* AU - Krämer, U.* AU - von Berg, A.* AU - Wichmann, H.-E. AU - Heinrich, J. AU - LISAplus Study Group (Wichmann, H.-E. AU - Heinrich, J. AU - Bolte, G. AU - Belcredi, P. AU - Jacob, B. AU - Schoetzau, A. AU - Mosetter, M. AU - Schindler, J. AU - Höhnke, A. AU - Franke, K. AU - Laubereau, B. AU - Sausenthaler, S. AU - Thaqi, A. AU - Zirngibl, A. AU - Zutavern, A.) C1 - 3229 C2 - 27294 SP - 450-457 TI - Prospective association between food sensitization and food allergy: Results of the LISA birth cohort study. JO - Clin. Exp. Allergy VL - 40 IS - 3 PB - Blackwell Publishing Ltd. PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - BACKGROUND: Nutritional intervention with hydrolysed infant formulas has been shown efficacious in preventing eczema in children predisposed to allergy. However, this preventive effect has never been related to the natural course of eczema in children with or without a family history of allergy. The aim of this study therefore was to compare the course of eczema in predisposed children after nutritional intervention to the natural course of eczema. METHOD: The prospective German birth cohort study GINIplus includes a total of 5991 children, subdivided into interventional and non-interventional groups. Children with a familial predisposition for allergy whose parents agreed to participate in the prospective, double-blind intervention trial (N=2252) were randomly assigned at birth to one of four formulas: partially or extensively hydrolysed whey, extensively hydrolysed casein (eHF-C) or standard cow's milk formula. Children with or without familial predisposition represented the non-interventional group (N=3739). Follow-up data were taken from yearly self-administered questionnaires from 1 up to 6 years. The outcome was physician-diagnosed eczema and its symptoms. The cumulative incidence of eczema in predisposed children with or without nutritional intervention was compared with that of non-predisposed children who did not receive intervention. Cox regression was used to adjust for confounding. RESULTS: Predisposed children without nutritional intervention had a 2.1 times higher risk for eczema [95% confidence interval (CI) 1.6-2.7] than children without a familial predisposition. The risk was smaller with nutritional intervention even levelling out to 1.3 (95% CI 0.9-1.9) in children fed eHF-C formula. CONCLUSION: Although direct comparability is somewhat restricted, the data demonstrate that early intervention with hydrolysed infant formulas can substantially compensate up until the age of 6 years for an enhanced risk of childhood eczema due to familial predisposition to allergy. AU - von Berg, A.* AU - Krämer, U.* AU - Link, E.* AU - Bollrath, C.* AU - Heinrich, J. AU - Brockow, I. AU - Koletzko, S.* AU - Grubl, A.* AU - Filipiak-Pittroff, B.* AU - Wichmann, H.-E. AU - Bauer, C.P.* AU - Reinhardt, D.* AU - Berdel, D.* C1 - 532 C2 - 27316 SP - 627-636 TI - Impact of early feeding on childhood eczema: Development after nutritional intervention compared with the natural course - the GINIplus study up to the age of 6 years. JO - Clin. Exp. Allergy VL - 40 IS - 4 PB - Blackwell Publishing Ltd PY - 2010 SN - 0954-7894 ER - TY - JOUR AB - Suppressors of cytokine signalling (SOCS) family members have been shown to play an important role in the balance of cytokines that determine the onset of T-helper type 1 (Th1)- and Th2-mediated immune responses. In particular, for cytokine-induced Src-homology 2 protein (CIS), SOCS1, SOCS3 and SOCS5, a role in the regulation of T cell differentiation has been discussed. However, only few data exist so far in the human system. OBJECTIVES: The aim of the present study was to analyse the relationship between these suppressors and Th1/Th2 regulation as well as allergic sensitizations within a population-based study. METHODS: Within the Lifestyle-Immune system-Allergy plus cohort study, mRNA was prepared from blood samples of 6-year-old children for the analysis of cytokines, transcription factors for T cell regulation and SOCS molecule expression by quantitative real-time polymerase chain reaction. In addition, total and specific IgE concentrations have been measured by the Pharmacia CAP System. A complete data set from 248 children was available. Results Among the SOCS molecules investigated, only SOCS1 showed a strong positive correlation to allergic sensitizations. In addition, an up-regulated SOCS1 expression correlated with down-regulated T-box expressed in T cells (Tbet) and higher expression levels of GATA-binding protein 3 (GATA-3) and IL-4. No association between SOCS1 and forkhead box P3 (FOXP3) was observed. For SOCS3, SOCS5 and CIS, a contradictory picture was found. The expression of these SOCS molecules was positively correlated with Tbet and FOXP3 and (with the exception of CIS) negatively with IL-4. CONCLUSIONS: Our data suggest that SOCS3, SOCS5 and CIS, which correlate with an up-regulated Th1 and regulatory T cell activity, are without relevance for the allergic status. In contrast, SOCS1 might be involved in the development of a Th2-skewed immune response and subsequent allergic sensitizations. AU - Daegelmann, C.* AU - Herberth, G.* AU - Roder, S.* AU - Herbarth, O.* AU - Giese, T.* AU - Krämer, U.* AU - Behrendt, H. AU - Borte, M.* AU - Heinrich, J. AU - Emmrich, F. AU - Lehmann, I.* C1 - 1411 C2 - 25274 SP - 438-448 TI - Association between suppressors of cytokine signalling, T-helper type 1/T-helper type 2 balance and allergic sensitization in children. JO - Clin. Exp. Allergy VL - 38 IS - 3 PB - Blackwell PY - 2008 SN - 0954-7894 ER - TY - JOUR AU - Traidl-Hoffmann, C. AU - Ring, J. C1 - 4293 C2 - 25588 SP - 1412-1415 TI - Is there an in vitro test for type IV allergy discriminating between sensitization and allergic disease? JO - Clin. Exp. Allergy VL - 38 IS - 9 PB - Blackwell PY - 2008 SN - 0954-7894 ER - TY - JOUR AB - A recent British-German study described ORMDL3 as a new asthma gene. Although the association with chromosome 17q 12 marker is plausible from earlier linkage data, it is far from being clear which gene caused the association signal, as it is derived from a large linkage disequilibrium (LD) block. Not only Aiolos and GSDML but also distant genes that are regulated by this site may be relevant. There may be even unidentified RNA transcripts requiring a much more detailed genetic and functional analysis before finding ORMDL3 guilty by association. AU - Wjst, M. C1 - 2603 C2 - 25834 SP - 1579-1581 TI - ORMDL3 - guilt by association? JO - Clin. Exp. Allergy VL - 38 IS - 10 PB - Blackwell PY - 2008 SN - 0954-7894 ER - TY - JOUR AB - There are few published studies on geographical variation in prevalence of eczema in adults or its association with recognised risk factors for allergic disease.To describe the geographical variation in prevalence of eczema in adults, assess the associations with sociodemographic risk factors, serum-specific IgE and IgG, and exposure to allergen.A community-based sample of 8206 adults aged 27-56 years, in 25 European centres and Portland, USA, provided questionnaire information on symptoms of eczema. Serum-specific IgE to house dust mite (HDM), cat, grass and Cladosporium, and IgG and IgG4 to HDM and cat were measured. Mattress levels of mite and cat allergen were assessed. Overall prevalence of eczema was 7.1% (range between countries of 2.2-17.6%). Eczema was associated with female gender [odds ratio (OR) 1.25; 95% confidence interval (CI) (1.01-1.55)], family history of atopic disease (OR 1.43; 95% CI 1.18-1.74), IgE sensitization to at least one allergen (OR 1.50; 95% CI 1.19-1.90), particularly Cladosporium (OR 3.65; 95% CI 1.81-7.37), and total IgE. Eczema was negatively associated with age and no clear associations were observed with sibship size, mattress mite and cat allergen levels or with cat and HDM-specific IgG or IgG4.There is geographical variation in the prevalence of eczema in adults both within and between countries. Although the disease is associated with IgE sensitization, in this study it was not related to mattress mite or cat allergen levels. AU - Harrop, J.* AU - Chinn, S.* AU - Verlato, G.* AU - Olivieri, M.* AU - Norbäck, D.* AU - Wjst, M. AU - Janson, C.* AU - Zock, J.P.* AU - Leynaert, B.* AU - Gislason, D.* AU - Ponzio, M.* AU - Villani, S.* AU - Carosso, A.* AU - Svanes, C.* AU - Heinrich, J. AU - Jarvis, D.* C1 - 1553 C2 - 24506 SP - 526-535 TI - Eczema, atopy and allergen exposure in adults: A population-based study. JO - Clin. Exp. Allergy VL - 37 IS - 4 PB - Blackwell PY - 2007 SN - 0954-7894 ER - TY - JOUR AB - Toll-like receptor (TLR) agonists are widely used as adjuvants in specific immune therapy protocols for patients with atopic disposition. Monocyte-derived dendritic cells (mDCs) are thought to be important target cells for these compounds. To compare surface markers, TLR expression, TLR functionality after ligand stimulation, and genetic polymorphisms in the TLR 2-, 3-, and 4-genes in mDCs from atopic vs. non-atopic patients. mDCs from highly atopic individuals (total serum IgE > 1000 IU/mL) and healthy control persons (total serum IgE < 75 IU/mL) were screened for TLR 1-10 expression by real-time PCR. Receptor function was analysed by IL-12 and TNF-alpha production after incubation with the respective ligands peptidoglycan (PGN) (TLR 2), polyriboinosinic-polyribocytidylic acid (poly IC) (TLR 3), lipopolysaccharide (LPS) (TLR 4), flagellin (TLR 5), and CpG-DNA/non-CpG-DNA (TLR 9). Haplotype-tagging single-nucleotide polymorphisms of the TLR 2-, 3-, and 4- genes were analysed for genetic associations. AU - Terhorst, D.* AU - Kalali, B.N.* AU - Weidinger, S.* AU - Illig, T. AU - Novak, N.* AU - Ring, J.* AU - Ollert, M. AU - Mempel, M.* C1 - 565 C2 - 24625 SP - 381-390 TI - Monocyte-derived dendritic cells from highly atopic individuals are not impaired in their pro-inflammatory response to toll-like receptor ligands. JO - Clin. Exp. Allergy VL - 37 IS - 3 PB - Blackwell PY - 2007 SN - 0954-7894 ER - TY - JOUR AU - Herberth, G.* AU - Daegelmann, C.* AU - Weber, A.* AU - Roder, S.* AU - Giese, T.* AU - Krämer, U.* AU - Schins, R.P.F.* AU - Behrendt, H. AU - Borte, M.* AU - Lehmann, I.* C1 - 1209 C2 - 24229 SP - 1408-1416 TI - Association of neuropeptides with Th1/Th2 balance and allergic sensitization in children. JO - Clin. Exp. Allergy VL - 36 PY - 2006 SN - 0954-7894 ER - TY - JOUR AU - Huss-Marp, J. AU - Eberlein-König, B. AU - Breuer, K.* AU - Mair, S.* AU - Ansel, A. AU - Darsow, U.* AU - Krämer, U. AU - Mayer, E.* AU - Ring, J.* AU - Behrendt, H. C1 - 5679 C2 - 23635 SP - 338-345 TI - Influence of short-term exposure to airborne Der p 1 and volatile organic compounds on skin barrier function and dermal blood flow in patients with atopic eczema and healthy individuals. JO - Clin. Exp. Allergy VL - 36 PY - 2006 SN - 0954-7894 ER - TY - JOUR AB - ackground Atopic women tend to have fewer children, although atopy may favour conception. Objective To assess whether atopy is associated with the number of new births and whether changes in parity are associated with a change in atopy in a cohort of young women. Methods Women had atopy (defined as the presence of serum-specific IgE against common aeroallergens) measured in the European Community Respiratory Health Study during the years 1991–92 (n=4580). About 9 years later, 2844 (62.1%) were recontacted and 2414 (52.7%) had atopy measured again. Results Atopic women had fewer children at baseline than non-atopic women but the association disappeared at the end of the follow-up. Atopy tended to increase parity during the follow-up, but in a non-statistically significant way (relative risk=1.08; 0.86–1.35, after adjusting for number of children at baseline, age, length of follow-up, education or social class). Prevalence of atopy during the follow-up changed by the same magnitude whatever the birth cohort and the change in the number of children (P for interaction >0.7). Conclusion Atopic women did not have a significantly higher fertility rate but they may postpone having their first child compared with non-atopic women. We are unable to confirm the hypothesis that atopy in women may decrease with successive pregnancies. AU - Sunyer, J.* AU - Antò, J.M.* AU - Plana, E.* AU - Janson, C.* AU - Jarvies, D.* AU - Kony, S.* AU - Omenaas, E.R.* AU - Svanes, C.* AU - Wjst, M. AU - Leynaert, B.* C1 - 3134 C2 - 23144 SP - 1028-1032 TI - Maternal atopy and changes in parity. JO - Clin. Exp. Allergy VL - 35 IS - 8 PY - 2005 SN - 0954-7894 ER - TY - JOUR AB - Background Influences of microbial pathogens are crucial for the maturation of the immune system. Caspase-recruitment domain containing protein 15 (CARD15) is a cytosolic receptor involved in bacterial recognition by antigen-presenting cells. CARD15 polymorphisms have been associated with Crohn's disease. Recently, associations with atopic phenotypes have been reported in children. Objective Within a large population of German adults (n=1875), we evaluated eight CARD15 polymorphisms for associations with atopic phenotypes. Methods Subjects were phenotyped by standardized questionnaires and interviews as well as total and allergen-specific IgE measurements. Genotyping was performed using matrix-assisted laser desorption ionization – time of flight mass spectrometry. Haplotypes were estimated using the SAS/Genetics module. Results Subjects with a T allele at rs1077861 had a decreased risk of developing asthma (odds ratio OR=0.648, P=0.013), whereas the presence of an A allele at rs3135500 was significantly associated with an increased risk (OR=1.374, P=0.023). In addition, a CARD15 haplotype revealed to be protective against the development of asthma (OR=0.326, P=0.003). Subjects with an A allele at position rs5743266 or a T allele at rs2066842 had a significantly decreased risk of developing allergic rhinoconjunctivitis with ORs of 0.820 (P=0.049) and 0.801 (P=0.025). Polymorphism rs2066845 showed a significant association with increased total serum IgE (OR=2.155, P=0.006). Conclusion Genetic variants of CARD15 that might result in inappropriate immunomodulation are not only associated with autoimmune diseases but also with atopic disorders. AU - Weidinger, S. AU - Klopp, N. AU - Darsow, U. AU - Jakob, T. AU - Heinrich, J. AU - Behrendt, H. AU - Wichmann, H.-E. AU - Illig, T. C1 - 3500 C2 - 22950 SP - 866-872 TI - Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. JO - Clin. Exp. Allergy VL - 35 IS - 7 PY - 2005 SN - 0954-7894 ER - TY - JOUR AB - Background Atopic Dermatitis (AD), hayfever and asthma are commonly summarized as atopic diseases. The spatial distribution of AD differs from that of asthma and hayfever, suggesting that AD might follow a different risk pattern than these diseases. AD can be differentiated into an allergic extrinsic form (EAD) and a non-allergic intrinsic form (IAD). Only EAD might follow the distribution and risk pattern that have been ascribed to asthma and hayfever. Objective To investigate the distribution and risk factor profile of AD and EAD focusing on environmental factors relating to the hygiene hypothesis. Methods Population-based cross-sectional study on 12 601 children aged 5–7 and 9–11 years from Dresden (Eastern Germany) and Munich (Western Germany). Information was obtained by International Study of Asthma and Allergic Childhood questionnaires, dermatological examinations and skin prick testing. AD-diagnosis ever, current AD-symptoms and visible eczema were investigated with their respective extrinsic forms. Results Maternal and paternal history of AD were equally strong determinants of the child's AD status. Factors related to the hygiene hypothesis like day-care attendance and number of older siblings were not associated with a decreased risk of AD. The proportion of EAD within AD was higher in Eastern than in Western Germany. The determinants of the diseases appeared to be similar for both EAD and IAD. Conclusions There was no evidence of the hygiene hypothesis holding true for AD or EAD. AD might be a separate entity than respiratory atopic diseases. Little is known about the risk factors of AD and factors different from those of respiratory allergic diseases should be considered in future research. AU - Zutavern, A.* AU - Hirsch, T.* AU - Leupold, W.* AU - Weiland, S. AU - Keil, U. AU - von Mutius, E.* C1 - 792 C2 - 23075 SP - 1301-1308 TI - Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: Results from a cross-sectional study. JO - Clin. Exp. Allergy VL - 35 IS - 10 PY - 2005 SN - 0954-7894 ER - TY - JOUR AB - Background Atopic diseases develop on a genetic background and are modulated by environmental factors among which some infectious diseases are thought to have a protective influence. Objective The aim of this study was to determine the influence of infectious diseases in younger ages, bacterial and viral, on atopic diseases and sensitization to aero- and foodallergens in adults. Methods A population-based sample of 4262 subjects aged 25–74 years were interviewed concerning their history of infectious disease within the first 18 years of life. Information about allergic disease, including atopic eczema, allergic rhinitis (AR), and asthma was obtained. A blood sample was drawn and analysed for allergen-specific IgE antibodies against food- and aeroallergens. Results Multiple logistic regression analyses identified viral infection to be associated with AR (adjusted odds ratio (OR)=1.39; 95% confidence interval (95% CI): 1.13–1.72) and sensitization to aeroallergens (OR=1.21; 95% CI: 1.05–1.41). Bacterial disease was a negative predictor for atopy development in the subgroup of patients sensitized to nutritional allergens with concomitant atopic eczema (OR=0.34; 95% CI: 0.11–0.99), AR (OR=0.67; 95% CI: 0.42–1.07), or asthma (OR=0.41; 95% CI: 0.19–0.87). Influences of viral and bacterial infection on AR differed with regard to family history of atopic disease. Conclusion In our study population, history of viral infection was consistently positively associated with AR. Our data suggests that bacterial infections might be preventive for specific subgroups of atopy. AU - Resch, A.* AU - Schlipköter, U.* AU - Crispin, A.* AU - Behrendt, H. AU - Heinrich, J. AU - Wichmann, H.-E. AU - Ring, J.* AU - Schäfer, T.* C1 - 3448 C2 - 22193 SP - 1184-1191 TI - Atopic disease and its determinants - a focus on the potential role of childhood infection. JO - Clin. Exp. Allergy VL - 34 IS - 8 PY - 2004 SN - 0954-7894 ER - TY - JOUR AB - Background The human genes coding for integrin β7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. Methods All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose–response curve after bronchial challenge). Results Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. Conclusions These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level. Background The human genes coding for integrin β7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. Methods All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose–response curve after bronchial challenge). Results Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. Conclusions These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level. AU - Vollmert, C. AU - Illig, T. AU - Altmüller, J. AU - Klugbauer, S. AU - Loesgen, S. AU - Dumitrescu, L. AU - Wjst, M. C1 - 2579 C2 - 22465 SP - 1841-1850 TI - Single nucleotide polymorphism screening and association analysis - exclusion of integrin ß7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma. JO - Clin. Exp. Allergy VL - 34 IS - 12 PY - 2004 SN - 0954-7894 ER - TY - JOUR AB - Background The ADAM33 gene has recently been associated with asthma and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. Objective We examined whether polymorphisms in ADAM33 are associated with asthma and related traits in two German populations. Methods We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German asthma family study. Additionally, we tested for association of these SNPs in a case–control sample from the European Community Respiratory Health Study using Armitage's trend test. Results In both studies, we found SNPs that were significantly associated with asthma and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case–control study, SNP ST+7 (P=0.008) was significantly associated with asthma. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. Conclusion This study replicates the recently published association between asthma and ADAM33 gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in ADAM33, unknown regulatory elements or a gene in close proximity is responsible for this association. AU - Werner, M. AU - Herbon, N. AU - Gohlke, H. AU - Altmüller, J. AU - Knapp, M.* AU - Heinrich, J. AU - Wjst, M. C1 - 2665 C2 - 22018 SP - 26-31 TI - Asthma is associated with single-nucleotide polymorphisms in ADAM33. JO - Clin. Exp. Allergy VL - 34 IS - 1 PY - 2004 SN - 0954-7894 ER - TY - JOUR AB - Background Exposure to endotoxin in childhood is currently discussed to protect from the development of allergic diseases. Objective To study the effect of early endotoxin exposure on incidence of atopic sensitization, atopic dermatitis and wheezing until the age of 2 years in infants with different risk status in terms of parental atopy. Methods Data of 1942 infants of an ongoing birth cohort study were analysed by logistic regression. Endotoxin was measured in settled dust of the mothers' mattresses at infants' age of 3 months. Data on allergic symptoms and physicians' diagnoses were gathered by questionnaire. Sensitization to common food and inhalant allergens was assessed by specific serum IgE. Results High endotoxin levels increased the risk of repeated wheeze [adjusted odds ratio (OR) for 4th exposure quartile (Q4) 1.52, 95% confidence interval (CI) 1.08–2.14], but were associated with neither sensitization to food allergens nor atopic dermatitis. Stratification by parental atopy showed that there was an association of endotoxin exposure with incidence of repeated wheeze as well as with sensitization to inhalant allergens (P for trend = 0.008 and 0.044, respectively) only in infants with parental atopy, with the highest risk in the 4th exposure quartile (repeated wheeze: ORQ4 1.77, 95% CI 1.14–2.73; sensitization to inhalant allergens: ORQ4 1.69, 95% CI 0.70–4.11). Conclusion Early endotoxin exposure in terms of mattress dust endotoxin levels seemed to increase the risk of atopic reactions to inhalant allergens at the age of 2 years, especially in infants at risk due to parental atopy. Our data disagree with an early protective effect of endotoxin on atopy development until the age of 2 years. AU - Bolte, G.* AU - Bischof, W.* AU - Borte, M.* AU - Lehmann, I.* AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 10261 C2 - 21088 SP - 770-776 TI - Early endotoxin exposure and atopy development in infants : Results of a birth cohort study. JO - Clin. Exp. Allergy VL - 33 IS - 6 PY - 2003 SN - 0954-7894 ER - TY - JOUR AB - Background: Studies investigating the effect of exposure to indoor allergens and endotoxin on human respiratory health usually take dust samples only at one single point of time and consider them to be representative for the indoor biocontaminant burden during a time period of several years. This singly measured biocontaminant concentration is related to adverse respiratory outcomes such as asthma, wheeze or others. Objective: We analysed two repeated measurements of mite and cat allergens in mattress and living room floor dust as well as endotoxin concentrations in living room floor dust. The repeated samples were taken over a time period of about 6 years. We investigated the repeatability over time of their concentrations by determining correlation coefficients and computing within- and between-home variance components. Methods: Our analysis was based on the population of a study on Indoor Factors and Genetics in Asthma (INGA) being carried out in 1995/96 and followed up in 2000/01. Complete data were available from 152 participants. Results: The measured allergen concentrations were low and a considerable percentage of the values was below the limit of detection. The crude Spearman's rank correlation coefficients between the two measurements taken in 1995/96 and 2000/01 ranged from 0.32 to 0.61 for the dust mites allergens, from 0.21 to 0.44 for cat allergen and from 0.35 to 0.51 for endotoxin. Correlations were higher if measurements were performed on the same floor or the same mattress at both sampling time-points. The within-home variance for all measured biocontaminant concentrations was of about the same order as the between-home variance. Conclusion: For studies like ours with low allergen and endotoxin concentrations, the repeatability of these concentrations over a time period as long as 6 years is low and a single measurement does not accurately reflect the true long-term exposure in the homes. AU - Topp, R. AU - Wimmer, K. AU - Fahlbusch, B.* AU - Bischof, W.* AU - Richter, K.* AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 3000 C2 - 22020 SP - 1659-1666 TI - Repeated measurements of allergens and endotoxin in settled house dust over a time period of 6 years. JO - Clin. Exp. Allergy VL - 33 IS - 12 PY - 2003 SN - 0954-7894 ER - TY - JOUR AB -   Background It is widely known and accepted that grass pollen is a major outdoor cause of hay fever. However, it is of virtual importance for grass pollen allergic patients with symptoms all the year round to know the concentration of grass pollen allergens in their homes. Objective The main objective of this study was to quantify the amount of grass pollen allergen in mass units (μg Phl p 5) in dust settled indoors and to detect the distribution of allergenic activity in different sampling locations of homes. Furthermore, we studied the seasonal fluctuation of allergen content in dust samples. Methods We adapted the two site binding assay for detection of group 5 grass pollen allergens in samples from randomly selected homes in Hamburg (n = 371), Erfurt (n = 396), Hettstedt (n = 353), Zerbst (n = 289) and Bitterfeld (n = 226), Germany. Dust samples were collected from floor of living room (LR), bedroom (BR) or children's room (CR) and mattress (MA) during period of June 1995 to August 1998. The amount of the major grass group 5 allergens was detected in μg/g dust. Results Phl p 5 was detected in 67% of the samples analysed (n = 4760). The range was between undetectable (< 0.03 μg/g dust) and 81 μg/g dust. Phl p 5 levels were significantly higher in the dust from LR (geometric mean 0.117 μg/g dust) or BR/CR floors (geometric mean 0.098 μg/g dust) than in mattresses (geometric mean 0.043 μg/g dust). We observed seasonal fluctuation of indoor Phl p 5 levels with peak in June but also annual differences. Thus Phl p 5 content indoors reflects also the different quantities of pollen counts of annual courses. During pollination period we found two times higher Phl p 5 levels (0.172 μg/g dust, P < 0.001) than outside of grass pollination season (0.095 μg/g dust). The indoor Phl p 5 levels outside of season seem to be independent of pollination before. We suppose that settled pollen grains or allergenic material from outdoor particles carried indoors via footwear and clothes accumulates in house dust. Conclusion Although we not known how the allergens in settled dust are equilibrated with those in the air, the considerable high level of Phl p 5 in indoor dust even during periods when no grass pollen is present in the atmosphere may be an important cause of pollen-allergy symptoms outside of season. AU - Fahlbusch, B.* AU - Hornung, D.* AU - Heinrich, J. AU - Dahse, H.-M. AU - Jäger, L.* C1 - 21632 C2 - 19779 SP - 1645-1652 TI - Quantification of group 5 grass pollen allergens in house dust. JO - Clin. Exp. Allergy VL - 30 IS - 11 PY - 2000 SN - 0954-7894 ER - TY - JOUR AB - Background Exposure to mite allergens is a major risk factor for sensitization and the development of asthma. Der p 1 and Der f 1 content in homes and probably the proportion of both antigens is highly variable even in the same geographical area. Objective We investigated specific indoor determinants of Der p 1 and Der f 1 concentrations in house dust of two German cities, Erfurt and Hamburg (n = 405 homes). Methods Mite allergen levels were determined using monoclonal antibodies against Der p 1 and Der f 1 by the ELISA method. Indoor relative humidity and temperature were monitored continuously in the homes over 1 week. The characteristics of homes and occupants were assessed by questionnaire to obtain information on factors which may have an impact on the mite antigen concentration in house dust. These determinants were studied by multivariate regression analysis. Results The correlation between concentrations of Der p 1 and Der f 1 inside the homes was weak (r = 0.29–0.35), indicating that different determinants are relevant. Concentrations of the allergens were significantly higher on lower floors (ratios 2–8 times, Der p 1, Der f 1), on old mattresses (ratios 3–13 times, Der p 1, Der f 1), in post-war buildings (ratio 6 times, Der p 1), for non-central heating (ratio 2 times, Der p 1), for old carpets (ratio 3 times, Der p 1) and for the presence of a dog in the house (ratio 3 times, Der f 1). Furthermore, mite concentration increases with raising relative humidity (ratio 1.03 per 1%, Der p 1) and with decreasing temperature (ratio 0.86 per 1 °C, Der p 1) indoors. Conclusion Both Der p 1 and Der f 1 concentrations should be measured in house dust, since they are only weakly correlated and have different determinants. AU - Gross, I. AU - Heinrich, J. AU - Fahlbusch, B.* AU - Jäger, L.* AU - Bischof, W.* AU - Wichmann, H.-E. C1 - 21301 C2 - 19416 SP - 376-382 TI - Indoor determinants of Der p 1 and Der f 1 concentrations in house dust are different. JO - Clin. Exp. Allergy VL - 30 IS - 3 PY - 2000 SN - 0954-7894 ER - TY - JOUR AU - Wjst, M. C1 - 21325 C2 - 19440 SP - 5-10 TI - Specific IgE - on gene fits all ?. JO - Clin. Exp. Allergy VL - 29 (Suppl.4) PY - 1999 SN - 0954-7894 ER - TY - JOUR AU - Nowak, D.* AU - Wichmann, H.-E. AU - Magnussen, H.* C1 - 20933 C2 - 18979 SP - 1043-1046 TI - Asthma an atopy in Western and Eastern communities : cuurent status and open questions. JO - Clin. Exp. Allergy VL - 28 IS - 9 PY - 1998 SN - 0954-7894 ER - TY - JOUR AB - The relationship between month of birth and asthma, hay fever and skin sensitization to mixed grass pollen was analysed in a population-based cross-sectional study in Munich and Bavaria 1989–1990 of 6535 10-year-old children. The relative risk of developing atopic disease is calculated by comparing the prevalence in a single month with the prevalence of all other months. A slightly increased risk of developing allergic skin sensitization for grass pollen (n= 1128) was found for February (odds ratio, 1.3, 95% confidence interval 1.0–1.6), May (1.4, 1.1–1.8) and June (1.3, 1.0–1.6). For hay fever (n= 379) an increase was found for May (1.5, 1.0–2.1) and for allergic asthma (n= 271) for August (1.4, 1.0–2.1). A protective effect was observed for certain months of birth; September for allergic sensitization (0.8, 0.6–1.0), October for asthma (0.6, 0.3–1.0) and November for hay fever (0.6, 0.3–0.9). The occurrence of hay fever and positive prick test is explained by the seasonal variation of atmospheric grass pollen and the peak in August of asthmatic patients by house dust. Date of birth appears therefore to slightly influence the risk of developing an allergic sensitization and allergic diseases. AU - Wjst, M. AU - Dold, S. AU - Reitmeir, P. AU - Stiepel, E. AU - von Mutius, E. C1 - 20375 C2 - 13571 SP - 1026-1031 TI - Month of Birth and Allergic Disease at the Age of 10. JO - Clin. Exp. Allergy VL - 22 IS - 11 PY - 1992 SN - 0954-7894 ER -