Albrecht Bufe

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.

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).

Background: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma.Methods: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele‐specific cis‐effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells.Results: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10⁻⁶) and ORMDL2 (P = 4.9 × 10⁻⁵) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease‐associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo‐ and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.Conclusions: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.

Background: Patients with asthma may be more susceptible to adverse events (AEs) with sublingual immunotherapy tablet (SLIT‐tablet) treatment, such as severe systemic reactions and asthma‐related events. Using data from eight trials of grass SLIT‐tablet in subjects with allergic rhinitis with/without conjunctivitis (AR/C), AE frequencies were determined in adults and children with and without reported asthma.Methods: Data from randomized, double‐blind, placebo‐controlled trials of Timothy grass SLIT‐tablet MK‐7243 (2800 BAU/75 000 SQ‐T, Merck/ALK‐Abelló) were pooled for post hoc analyses. Subjects with uncontrolled and severe asthma were excluded from the trials. Frequencies for treatment‐emergent AEs (TEAEs), local allergic swelling (mouth or throat), systemic allergic reactions, and asthma‐related treatment‐related AEs (TRAEs) were calculated.Results: Among adults (n = 3314) and children (n = 881), 24% and 31%, respectively, had reported asthma. No serious local allergic swellings or serious systemic allergic reactions occurred in subjects with asthma treated with SLIT‐tablet. There was no evidence of increased TEAEs, systemic allergic reactions, or severe local allergic swellings in adults or children with asthma treated with grass SLIT‐tablet versus subjects without asthma in or outside of pollen season. There were 6/120 asthma‐related TRAEs assessed as severe with grass SLIT‐tablet and 2/60 with placebo, without a consistent trend among subjects with and without asthma (5 and 3 events, respectively).Conclusions: In the AR/C subjects with reported well‐controlled mild asthma included in these studies, grass SLIT‐tablet did not increase TEAE frequency, severe local allergic swelling, or systemic allergic reactions versus subjects without asthma. There was no indication that treatment led to acute asthma worsening.

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, pre‐biotics, 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.

Background Genome‐wide association studies (GWAS) repeatedly identified 1q23 (FCER1A), 5q31 (RAD50‐IL13 and IL4), and 12q13 (STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine‐mapping and re‐genotyping of the three loci using 1000 Genomes Project datasets. Methods Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI‐TOF‐MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene‐by‐gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. Results Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single‐nucleotide polymorphisms (SNPs) were associated with strongly elevated IgE levels. Gene‐by‐gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. Conclusion This fine‐mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation.

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.