Total Synthesis of a Partial Structure from Arabinogalactan and Its Application for Allergy Prevention.

Arabinogalactan, a microheterogeneous polysaccharide occurring in plants, is known for its allergy-protective activity, which could potentially be used for preventive allergy treatment. New treatment options are highly desirable, especially in a preventive manner, due to the constant rise of atopic diseases worldwide. The structural origin of the allergy-protective activity of arabinogalactan is, however, still unclear and isolation of the polysaccharide is not feasible for pharmaceutical applications due to a variation of the activity of the natural product and contaminations with endotoxins. Therefore, a pentasaccharide partial structure was selected for total synthesis and subsequently coupled to a carrier protein to form a neoglycoconjugate. The allergy-protective activity of arabinogalactan could be reproduced with the partial structure in subsequent in vivo experiments. This is the first example of a successful simplification of arabinogalactan with a single partial structure while retaining its allergy-preventive potential.

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

BACKGROUND: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes. METHODS: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646). RESULTS: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth. CONCLUSION: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.

Hydrophilic Stent Coating Inhibits Platelet Adhesion on Stent Surfaces: Initial Results In Vitro.

BACKGROUND: Endovascular stents and flow diverter stents (FDS) have revolutionized the treatment of intradural aneurysms; however, the need for dual anti-platelet treatment (DAPT) limits their use and can cause additional issues. Therefore, there is a need to develop stent coatings that negate the need for DAPT. METHODS: Two different hydrophilic polymer coatings (HPC-I and HPC-II) were used to coat small nickel titanium plates to initially test the hydrophilic properties of these coatings when applied to nickel titanium. The plates were subsequently incubated with non-medicated whole blood from healthy volunteers for 10 min and stained with a CD61 immunofluorescent antibody that allows detection of adherent platelets. The coatings were applied to FDS wires and were again incubated with non-medicated whole blood from the same volunteers. Scanning electron microscopy was used to detect adherent platelets on the wire surface. RESULTS: The HPC-II coating (1.12 ± 0.4%) showed a significantly lower CD61 +ve cell count (p ≤ 0.001) compared to both uncoated NiTi plates (48.61 ± 7.3%) and those with the HPC-I coating (mean 40.19 ± 8.9%). Minimal adherent platelets were seen on the FDS nickel titanium wires coated with the HPC-II compared to uncoated FDS under electron microscopy. CONCLUSION: There is a significant decrease in the number of adherent CD61 +ve platelets on nickel titanium surfaces coated with the HPC-II coating compared to uncoated surfaces. The coating can be successfully applied to the wires of flow diverters. The results of this study are promising with regard to the development of new anti-thrombogenic endovascular devices.

Nitric oxide dependent signaling via cyclic GMP in dendritic cells regulates migration and T-cell polarization.

Allergic airway inflammation is accompanied by excessive generation of nitric oxide (NO). Beside its detrimental activity due to the generation of reactive nitrogen species, NO was found to modulate immune responses by activating the NO-sensitive Guanylyl Cyclases (NO-GCs) thereby mediating the formation of the second messenger cyclic GMP (cGMP). To investigate the contribution of the key-enzyme NO-GC on the development of Th2 immunity in vivo, we sensitized knock-out (KO) mice of the major isoform NO-GC1 to the model allergen ovalbumin (OVA). The loss of NO-GC1 attenuates the Th2 response leading to a reduction of airway inflammation and IgE production. Further, in vitro-generated OVA-presenting DCs of the KO induce only a weak Th2 response in the WT recipient mice upon re-exposure to OVA. In vitro, these NO-GC1 KO BMDCs develop a Th1-polarizing phenotype and display increased cyclic AMP (cAMP) formation, which is known to induce Th1-bias. According to our hypothesis of a NO-GC1/cGMP-dependent regulation of cAMP-levels we further demonstrate activity of the cGMP-activated cAMP-degrading phosphodiesterase 2 in DCs. Herewith, we show that activity of NO-GC1 in DCs is important for the magnitude and bias of the Th response in allergic airway disease most likely by counteracting intracellular cAMP.

Effect of grass sublingual tablet immunotherapy is similar in children and adults: A Bayesian approach to design pediatric sublingual immunotherapy trials.

BACKGROUND: Large sample sizes are needed for sublingual immunotherapy (SLIT) trials because of inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size. OBJECTIVE: We sought to describe how a Bayesian framework using prior information from adult trials can be used to improve pediatric SLIT clinical development. METHODS: Data were compiled by using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablets. RESULTS: The treatment effect of timothy grass SLIT-tablets was considered similar between pediatric (n = 795) and adult (n = 2299) data pools, with relative total combined symptom plus medication score improvement versus placebo of 21% (95% CI, 11.0% to 30.4%) and 20% (95% CI, 14.6% to 24.4%), respectively. Phleum pratense-specific IgG4 and IgE-blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablets. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criteria for pediatric trials incorporating information from prior adult trials and thereby reduce the sample size. CONCLUSIONS: Data support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore it is appropriate to use data from adult trials to design feasible trials in children, which might reduce unsafe off-label use by promoting more quickly proper labeling of approved products.

Side effects during subcutaneous immunotherapy in children with allergic diseases.

BACKGROUND: Allergen-specific immunotherapy is the only causal form of therapy for IgE-mediated allergic diseases. Subcutaneous immunotherapy (SCIT) is considered safe and well tolerated in adults, yet there is less evidence of safety in the pediatric population. METHODS: A non-interventional prospective observing longitudinal study was carried out to determine the incidence of local and systemic side effects by SCIT, routinely performed in pediatric patients. A total of 581 pediatric patients were observed in 18 study centers between March 2012 and October 2014, recording 8640 treatments and 10 015 injections. RESULTS: A total of 54.6% of the patients experienced immediate local side effects at least once; delayed local side effects were seen in 56.1%. Immediate systemic adverse reactions occurred in 2.2% of patients; 7.4% experienced delayed systemic side effects. However, severe systemic side effects (grade III in the classification of Ring and Messmer) were seen in 0.03% of all treatments, all appearing within 30 minutes after the injections. No grade IV reactions were observed. In addition, many potential risk factors were investigated, yet only a few were found to be associated with the occurrence of side effects. CONCLUSIONS: Subcutaneous immunotherapy is a safe form of therapy in pediatric patients, with similar rates of local side effects compared to adult patients and low rates of severe systemic side effects. However, local and systemic reactions occurring later than 30 minutes after injection were observed more often than expected, which makes it essential to be attentive on behalf of pediatricians, patients, and parents.

Abridged version of the AWMF guideline for the medical clinical diagnostics of indoor mould exposure: S2K Guideline of the German Society of Hygiene, Environmental Medicine and Preventive Medicine (GHUP) in collaboration with the German Association of Allergists (AeDA), the German Society of Dermatology (DDG), the German Society for Allergology and Clinical Immunology (DGAKI), the German Society for Occupational and Environmental Medicine (DGAUM), the German Society for Hospital Hygiene (DGKH), the German Society for Pneumology and Respiratory Medicine (DGP), the German Mycological Society (DMykG), the Society for Pediatric Allergology and Environmental Medicine (GPA), the German Federal Association of Pediatric Pneumology (BAPP), and the Austrian Society for Medical Mycology (ÖGMM).

This article is an abridged version of the AWMF mould guideline "Medical clinical diagnostics of indoor mould exposure" presented in April 2016 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with the above-mentioned scientific medical societies, German and Austrian societies, medical associations and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. Apart from allergic bronchopulmonary aspergillosis (ABPA) and mould-caused mycoses, only sufficient evidence for an association between moisture/mould damage and the following health effects has been established: allergic respiratory disease, asthma (manifestation, progression and exacerbation), allergic rhinitis, hypersensitivity pneumonitis (extrinsic allergic alveolitis), and increased likelihood of respiratory infections/bronchitis. In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitizing prevalence of 3-10% in the general population across Europe. Limited or suspected evidence for an association exist with respect to mucous membrane irritation and atopic eczema (manifestation, progression and exacerbation). Inadequate or insufficient evidence for an association exist for chronic obstructive pulmonary disease, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis and cancer. The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, above all the substrate. In the case of indoor moisture/mould damage, everyone can be affected by odour effects and/or mood disorders. However, this is not a health hazard. Predisposing factors for odour effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly with regard to an infection risk are persons on immunosuppression according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch- Institute (RKI) and persons with cystic fibrosis (mucoviscidosis); with regard to an allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma should be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections the reader is referred to the AWMF guideline "Diagnosis and Therapy of Invasive Aspergillus Infections". With regard to mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medicine standpoint it is important that indoor mould infestation in relevant dimension cannot be tolerated for precautionary reasons. With regard to evaluating the extent of damage and selecting a remedial procedure, the reader is referred to the revised version of the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

A Bioassay for the Determination of Lipopolysaccharides and Lipoproteins.

The availability of convenient assays for the detection and quantification of pathogen-associated molecular patterns (PAMPs) is limited. In the case of lipopolysaccharide (LPS) the so-called LAL (limulus amebocyte lysate) test is available, an assay that is performed with the lysate of the blood of the horse shoe crab. Although a sensitive and convenient assay, it lacks specificity, since it is affected by other endotoxins like, for instance, fungal cell walls as well. Here, we describe a bioassay that can be used to detect and quantitate PAMPs in environmental samples. More specific we demonstrate the usage of TLR2 and TLR4/CD14/MD2 transfected Hek293 cells to quantitatively determine bacterial lipoproteins and LPS, respectively. We show the usefulness of these assays to measure LPS in tobacco before and after combustion.

Medical diagnostics for indoor mold exposure.

In April 2016, the German Society of Hygiene, Environmental Medicine and Preventative Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin (GHUP)) together with other scientific medical societies, German and Austrian medical societies, physician unions and experts has provided an AWMF (Association of the Scientific Medical Societies) guideline 'Medical diagnostics for indoor mold exposure'. This guideline shall help physicians to advise and treat patients exposed indoors to mold. Indoor mold growth is a potential health risk, even without a quantitative and/or causal association between the occurrence of individual mold species and health effects. Apart from the allergic bronchopulmonary aspergillosis (ABPA) and the mycoses caused by mold, there is only sufficient evidence for the following associations between moisture/mold damages and different health effects: Allergic respiratory diseases, asthma (manifestation, progression, exacerbation), allergic rhinitis, exogenous allergic alveolitis and respiratory tract infections/bronchitis. In comparison to other environmental allergens, the sensitizing potential of molds is estimated to be low. Recent studies show a prevalence of sensitization of 3-10% in the total population of Europe. The evidence for associations to mucous membrane irritation and atopic eczema (manifestation, progression, exacerbation) is classified as limited or suspected. Inadequate or insufficient evidence for an association is given for COPD, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis, and cancer. The risk of infections from indoor molds is low for healthy individuals. Only molds that are capable to form toxins can cause intoxications. The environmental and growth conditions and especially the substrate determine whether toxin formation occurs, but indoor air concentrations are always very low. In the case of indoor moisture/mold damages, everyone can be affected by odor effects and/or impairment of well-being. Predisposing factors for odor effects can be given by genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for impairment of well-being are environmental concerns, anxieties, conditioning and attributions as well as a variety of diseases. Risk groups that must be protected are patients with immunosuppression and with mucoviscidosis (cystic fibrosis) with regard to infections and individuals with mucoviscidosis and asthma with regard to allergies. If an association between mold exposure and health effects is suspected, the medical diagnosis includes medical history, physical examination, conventional allergy diagnosis, and if indicated, provocation tests. For the treatment of mold infections, it is referred to the AWMF guidelines for diagnosis and treatment of invasive Aspergillus infections. Regarding mycotoxins, there are currently no validated test methods that could be used in clinical diagnostics. From the perspective of preventive medicine, it is important that mold damages cannot be tolerated in indoor environments.

Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.

BACKGROUND: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. OBJECTIVE: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. METHODS: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. RESULTS: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. CONCLUSION: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Allergy-Protective Arabinogalactan Modulates Human Dendritic Cells via C-Type Lectins and Inhibition of NF-κB.

Arabinogalactan (AG) isolated from dust of a traditional farm prevents disease in murine models of allergy. However, it is unclear whether this polysaccharide has immune regulatory properties in humans. The aim of this study was to test the influence of AG on the immune-stimulating properties of human dendritic cells (DCs). Moreover, we sought to identify the receptor to which AG binds. AG was produced from plant callus tissue under sterile conditions to avoid the influence of pathogen-associated molecular patterns in subsequent experiments. The influence of AG on the human immune system was investigated by analyzing its impact on monocyte-derived DCs. To analyze whether the T cell stimulatory capacity of AG-stimulated DCs is altered, an MLR with naive Th cells was performed. We revealed that AG reduced T cell proliferation in a human MLR. In the search for a molecular mechanism, we found that AG binds to the immune modulatory receptors DC-specific ICAM-3 -: grabbing non integrin (DC-SIGN) and macrophage mannose receptor 1 (MMR-1). Stimulation of these receptors with AG simultaneously with TLR4 stimulation with LPS increased the expression of the E3 ubiquitin-protein ligase tripartite motif -: containing protein 21 and decreased the phosphorylation of NF-κB p65 in DCs. This led to a reduced activation profile with reduced costimulatory molecules and proinflammatory cytokine production. Blocking of MMR-1 or DC-SIGN with neutralizing Abs partially inhibits this effect. We conclude that AG dampens the activation of human DCs by LPS via binding to DC-SIGN and MMR-1, leading to attenuated TLR signaling. This results in a reduced T cell activation capacity of DCs.

Influence of an Allergen-Specific Th17 Response on Remodeling of the Airways.

We showed previously that sensitization of mice with dendritic cells (DCs) via the airways depends on activation of these cells with LPS. Allergen-pulsed DCs that were stimulated with low doses of LPS induce a strong Th2 response in vivo. Our objective was to investigate whether airway sensitization of mice by the application of DCs with a phenotype that is able to induce Th17 cells results in increased remodeling of the airways. We generated DCs from the bone marrow of mice and pulsed them with LPS-free ovalbumin. Subsequently, cells were activated with LPS with or without ATP for inflammasome activation. The activated cells were used to sensitize mice via the airways. Intranasal instillation of DCs that were activated with 0.1 ng/ml LPS induced a Th2 response with airway eosinophilia. High doses of LPS, particularly when given in combination with ATP, led to induction of a mixed Th2/Th17 response. Interestingly, we found a correlation between IL-17A production and the remodeling of the airways. Stimulation of mouse fibroblasts with purified IL-17A protein in vitro resulted in transforming growth factor-ß1 secretion and collagen transcription. Interestingly, we found enhanced secretion of transforming growth factor-ß1 by fibroblasts after costimulation with IL-17A and the profibrotic factor wingless-type MMTV integration site family, member 5A (Wnt5a). We showed that an allergen-specific Th17 response in the airway is accompanied by increased airway remodeling. Furthermore, we revealed that increased remodeling is not only based on neutrophilic inflammation, but also on the direct impact of IL-17A on airway structural cells.

Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels.

BACKGROUND: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. OBJECTIVE: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. METHODS: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. RESULTS: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. CONCLUSION: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

Allergy and asthma prevention 2014.

Asthma and allergic diseases have become one of the epidemics of the 21st century in developed countries. Much of the success of other areas of medicine, such as infectious diseases, lies on preventive measures. Thus, much effort is also being placed lately in the prevention of asthma and allergy. This manuscript reviews the current evidence, divided into four areas of activity. Interventions modifying environmental exposure to allergens have provided inconsistent results, with multifaceted interventions being more effective in the prevention of asthma. Regarding nutrition, the use of hydrolyzed formulas in high-risk infants reduces the incidence of atopic dermatitis, while there is for now not enough evidence to recommend other dietary modifications, prebiotics, probiotics, or other microbial products. Pharmacologic agents used until now for prevention have not proved useful, while there is hope that antiviral vaccines could be useful in the future. Allergen-specific immunotherapy is effective for the treatment of allergic patients with symptoms; the study of its value for primary and secondary prevention of asthma and allergy is in its very preliminary phases. The lack of success in the prevention of these disorders lies on their complexity, which involves many genetic, epigenetic, and environmental interactions. There is a need to identify target populations, involved mechanisms and interactions, and the best interventions. These must be effective, feasible, implementable, and affordable.

Economic evaluation of SQ-standardized grass allergy immunotherapy tablet (Grazax(®)) in children.

BACKGROUND: Grass pollen-induced rhinoconjunctivitis is a common allergic respiratory disorder affecting over 20% of the UK population in terms of quality of life and sleep, work, and school patterns. The SQ-standardized grass allergy immunotherapy tablet (AIT) has been demonstrated as a disease-modifying treatment which gives a sustained effect even after completion of a treatment course. The objective of this study was to provide an economic assessment of whether treatment with the SQ-standardized grass AIT, Grazax(®) (Phleum pratense) in combination with symptomatic medications is preferable to the standard of care using symptomatic medications only. The analysis was performed for children with grass pollen-induced rhinoconjunctivitis, with or without concomitant asthma, in the UK. METHODS: The model evaluated the two treatment regimens in a cohort of 1,000 children from a payer's perspective. Treatment was modeled in terms of management of symptoms, impact on resource use, and development of allergic asthma. The analysis modeled the use of SQ-standardized grass AIT and the sustained effects of treatment over a 9-year time horizon (ie, 3 years of treatment, with modeled long-term benefits). Data inputs were drawn from a recent clinical trial, published studies, and databases. RESULTS: SQ-standardized grass AIT improves patient outcomes, generating an incremental cost per quality-adjusted life year gained of £12,168. This is below commonly accepted thresholds in the UK. CONCLUSION: The resulting incremental cost per QALY falls below commonly accepted willingness to pay thresholds. Therefore, the SQ-standardized grass AIT is a cost-effective option for the treatment of grass pollen-induced rhinoconjunctivitis in the UK pediatric population.

S3-Guideline on allergy prevention: 2014 update: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Society for Pediatric and Adolescent Medicine (DGKJ).

The continued high prevalence of allergic diseases in Western industrialized nations combined with the limited options for causal therapy make evidence-based primary prevention necessary. The recommendations last published in the S3-guideline on allergy prevention in 2009 have been revised and a consensus reached on the basis of an up-to-date systematic literature search. Evidence was sought for the period between May 2008 and May 2013 in the Cochrane and MEDLINE electronic databases, as well as in the reference lists of recent review articles. In addition, experts were surveyed for their opinions. The relevance of retrieved literature was checked by means of two filter processes: firstly according to title and abstract, and secondly based on the full text of the articles. Included studies were given an evidence grade, and a bias potential (low/high) was specified for study quality. A formal consensus on the revised recommendations was reached by representatives of the relevant specialist societies and (self-help) organizations (nominal group process). Of 3,284 hits, 165 studies (one meta-analysis, 15 systematic reviews, 31 randomized controlled trials, 65 cohort studies, 12 case-control studies and 41 cross-sectional studies) were included and evaluated. Recommendations on the following remain largely unaltered: full breastfeeding for 4 months as a means of allergy prevention (hypoallergenic infant formula in the case of infants at risk); avoidance of overweight; fish consumption (during pregnancy/lactation and in the introduction of solid foods for infants); vaccination according to the recommendations of the German Standing Committee on Vaccination (Ständige Impfkommission, STIKO); avoidance of air pollutants and tobacco exposure and avoidance of indoor conditions conducive to the development of mold. The assertion that a reduction in house-dust mite allergen content as a primary preventive measure is not recommended also remains unchanged. The introduction of solid foods into infant diet should not be delayed. In the case of children at risk cats should not be acquired as domestic pets. Keeping dogs is not associated with an increased risk of allergy. The updated guideline includes a new recommendation to consider the increased risk of asthma following delivery by cesarean section. Additional statements have been formulated on pre- and probiotic agents, psychosocial factors, medications, and various nutritional components. Revising the guideline by using an extensive evidence base has resulted not only in an endorsement of the existing recommendations, but also in modifications and in the addition of new recommendations. The updated guideline enables evidence-based and up-to-date recommendations to be made on allergy prevention. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1007/s40629-014-0022-4 and is accessible for authorized users.

Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD).

The present guideline (S2k) on allergen-specific immunotherapy (AIT) was established by the German, Austrian and Swiss professional associations for allergy in consensus with the scientific specialist societies and professional associations in the fields of otolaryngology, dermatology and venereology, pediatric and adolescent medicine, pneumology as well as a German patient organization (German Allergy and Asthma Association; Deutscher Allergie- und Asthmabund, DAAB) according to the criteria of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). AIT is a therapy with disease-modifying effects. By administering allergen extracts, specific blocking antibodies, toler-ance-inducing cells and mediators are activated. These prevent further exacerbation of the allergen-triggered immune response, block the specific immune response and attenuate the inflammatory response in tissue. Products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modified allergens are used for SCIT in the form of aqueous or physically adsorbed (depot) extracts, as well as chemically modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets. The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints. The EMA stipulates combined symptom and medication scores as primary endpoint. A harmonization of clinical endpoints, e. g., by using the combined symptom and medication scores (CSMS) recommended by the EAACI, is desirable in the future in order to permit the comparison of results from different studies. The current CONSORT recommendations from the ARIA/GA2LEN group specify standards for the evaluation, presentation and publication of study results. According to the Therapy allergen ordinance (TAV), preparations containing common allergen sources (pollen from grasses, birch, alder, hazel, house dust mites, as well as bee and wasp venom) need a marketing authorization in Germany. During the marketing authorization process, these preparations are examined regarding quality, safety and efficacy. In the opinion of the authors, authorized allergen preparations with documented efficacy and safety, or preparations tradeable under the TAV for which efficacy and safety have already been documented in clinical trials meeting WAO or EMA standards, should be preferentially used. Individual formulations (NPP) enable the prescription of rare allergen sources (e.g., pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted. Allergic rhinitis and its associated co-morbidities (e. g., bronchial asthma) generate substantial direct and indirect costs. Treatment options, in particular AIT, are therefore evaluated using cost-benefit and cost-effectiveness analyses. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy, but is heavily dependent on patient compliance. Meta-analyses provide unequivocal evidence of the efficacy of SCIT and SLIT for certain allergen sources and age groups. Data from controlled studies differ in terms of scope, quality and dosing regimens and require product-specific evaluation. Therefore, evaluating individual preparations according to clearly defined criteria is recommended. A broad transfer of the efficacy of certain preparations to all preparations administered in the same way is not endorsed. The website of the German Society for Allergology and Clinical Immunology (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: Deutsche Gesellschaft für Allergologie und klinische Immunologie) provides tables with specific information on available products for AIT in Germany, Switzerland and Austria. The tables contain the number of clinical studies per product in adults and children, the year of market authorization, underlying scoring systems, number of randomized and analyzed subjects and the method of evaluation (ITT, FAS, PP), separately given for grass pollen, birch pollen and house dust mite allergens, and the status of approval for the conduct of clinical studies with these products. Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis in adulthood is well-documented in numerous trials and, in childhood and adolescence, in a few trials. Efficacy in house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. Only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date. SCIT has been well investigated for individual preparations in controlled bronchial asthma as defined by the Global Initiative for Asthma (GINA) 2007 and intermittent and mild persistent asthma (GINA 2005) and it is recommended as a treatment option, in addition to allergen avoidance and pharmacotherapy, provided there is a clear causal link between respiratory symptoms and the relevant allergen. The efficacy of SLIT in grass pollen-induced allergic rhinoconjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. New controlled trials (some with high patient numbers) on house dust mite allergy provide evidence of efficacy of SLIT in adults. Compared with allergic rhinoconjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen allergic children, adolescents and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults. Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. In this context, those products for which the appropriate effects have been demonstrated should be considered. SCIT or SLIT with pollen or mite allergens can be performed in patients with allergic rhinoconjunctivitis using allergen extracts that have been proven to be effective in at least one double-blind placebo-controlled (DBPC) study. At present, clinical trials are underway for the indication in asthma due to house dust mite allergy, some of the results of which have already been published, whilst others are still awaited (see the DGAKI table "Approved/potentially completed studies" via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When establishing the indication for AIT, factors that favour clinical efficacy should be taken into consideration. Differences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justifiably indicated despite the presence of contraindications. SCIT injections and the initiation of SLIT are performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction. Patients must be fully informed about the procedure and risks of possible adverse events, and the details of this process must be documented (see "Treatment information sheet"; available as a handout via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treatment should be performed according to the manufacturer's product information leaflet. In cases where AIT is to be performed or continued by a different physician to the one who established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate proof of efficacy is available from clinical trials. Treatment adherence among AIT patients is lower than assumed by physicians, irrespective of the form of administration. Clearly, adherence is of vital importance for treatment success. Improving AIT adherence is one of the most important future goals, in order to ensure efficacy of the therapy. Severe, potentially life-threatening systemic reactions during SCIT are possible, but - providing all safety measures are adhered to - these events are very rare. Most adverse events are mild to moderate and can be treated well. Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Systemic reactions have been described in SLIT, but are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT. The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of i. m. epinephrine. Details on the acute management of anaphylactic reactions can be found in the current S2 guideline on anaphylaxis issued by the AWMF (S2-AWMF-LL Registry Number 061-025). AIT is undergoing some innovative developments in many areas (e. g., allergen characterization, new administration routes, adjuvants, faster and safer dose escalation protocols), some of which are already beinginvestigated in clinical trials. Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, Sitter H, Umpfenbach U, Wedi B, Wöhrl S, Worm M, Kleine-Tebbe J. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases - S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int 2014;23:282-319.

Different FCER1A polymorphisms influence IgE levels in asthmatics and non-asthmatics.

BACKGROUND: Recently, three genome-wide association studies (GWAS) demonstrated FCER1A, the gene encoding a ligand-binding subunit of the high-affinity IgE receptor, to be a major susceptibility locus for serum IgE levels. The top association signal differed between the two studies from the general population and the one based on an asthma case-control design. In this study, we investigated whether different FCER1A polymorphisms are associated with total serum IgE in the general population and asthmatics specifically. METHODS: Nineteen polymorphisms were studied in FCER1A based on a detailed literature search and a tagging approach. Polymorphisms were genotyped by the Illumina HumanHap300Chip (6 polymorphisms) or MALDI-TOF MS (13 polymorphisms) in at least 1303 children (651 asthmatics) derived from the German International Study of Asthma and Allergies in Childhood II and Multicentre Asthma Genetics in Childhood Study. RESULTS: Similar to two population-based GWAS, the peak association with total serum IgE was observed for SNPs rs2511211, rs2427837, and rs2251746 (mean r(2) > 0.8), with the lowest p-value of 4.37 × 10(-6). The same 3 polymorphisms showed the strongest association in non-asthmatics (lowest p = 0.0003). While these polymorphisms were also associated with total serum IgE in asthmatics (lowest p = 0.003), additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrated associations with total serum IgE in asthmatics only (lowest p = 0.01). CONCLUSIONS: These data suggest that FCER1A polymorphisms not only drive IgE levels in the general population but that specific polymorphisms may also influence IgE in association with asthma, suggesting that disease-specific mechanisms in IgE regulation exist.