Marianne van Hage

Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle – the PARSIFAL study

Background:  The prevalence of allergic diseases has increased rapidly in recent decades, particularly in children. For adequate prevention it is important not only to identify risk factors, but also possible protective factors. The aim of this study was to compare the prevalence of allergic diseases and sensitization between farm children, children in anthroposophic families, and reference children, with the aim to identify factors that may protect against allergic disease.

A WAO - ARIA - GA²LEN consensus document on molecular-based allergy diagnostics

Molecular-based allergy (MA) diagnostics is an approach used to map the allergen sensitization of a patient at a molecular level, using purified natural or recombinant allergenic molecules (allergen components) instead of allergen extracts. Since its introduction, MA diagnostics has increasingly entered routine care, with currently more than 130 allergenic molecules commercially available for in vitro specific IgE (sIgE) testing.MA diagnostics allows for an increased accuracy in allergy diagnosis and prognosis and plays an important role in three key aspects of allergy diagnosis: (1) resolving genuine versus cross-reactive sensitization in poly-sensitized patients, thereby improving the understanding of triggering allergens; (2) assessing, in selected cases, the risk of severe, systemic versus mild, local reactions in food allergy, thereby reducing unnecessary anxiety for the patient and the need for food challenge testing; and (3) identifying patients and triggering allergens for specific immunotherapy (SIT).Singleplex and multiplex measurement platforms are available for MA diagnostics. The Immuno-Solid phase Allergen Chip (ISAC) is the most comprehensive platform currently available, which involves a biochip technology to measure sIgE antibodies against more than one hundred allergenic molecules in a single assay. As the field of MA diagnostics advances, future work needs to focus on large-scale, population-based studies involving practical applications, elucidation and expansion of additional allergenic molecules, and support for appropriate test interpretation. With the rapidly expanding evidence-base for MA diagnosis, there is a need for allergists to keep abreast of the latest information. The aim of this consensus document is to provide a practical guide for the indications, determination, and interpretation of MA diagnostics for clinicians trained in allergology.

Peanut allergy: Clinical and immunologic differences among patients from 3 different geographic regions

BACKGROUND Peanut allergy affects persons from various geographic regions where populations are exposed to different dietary habits and environmental pollens. OBJECTIVE We sought to describe the clinical and immunologic characteristics of patients with peanut allergy from 3 countries (Spain, the United States, and Sweden) using a molecular component diagnostic approach. METHODS Patients with peanut allergy from Madrid (Spain, n = 50), New York (United States, n = 30), Gothenburg, and Stockholm (both Sweden, n = 35) were enrolled. Clinical data were obtained either from a specific questionnaire or gathered from chart reviews. IgE antibodies to peanut extract and the peanut allergens rAra h 1, 2, 3, 8 and 9, as well as to cross-reactive birch (rBet v 1) and grass (rPhl p 1, 5, 7, and 12) pollen allergens, were analyzed. RESULTS American patients frequently had IgE antibodies to rAra h 1 to 3 (56.7% to 90.0%) and often presented with severe symptoms. Spanish patients recognized these 3 recombinant peanut allergens less frequently (16.0% to 42.0%), were more often sensitized to the lipid transfer protein rAra h 9 (60.0%), and typically had peanut allergy after becoming allergic to other plant-derived foods. Swedish patients detected rAra h 1 to 3 more frequently than Spanish patients (37.1% to 74.3%) and had the highest sensitization rate to the Bet v 1 homologue rAra h 8 (65.7%), as well as to rBet v 1 (82.9%). Spanish and Swedish patients became allergic to peanut at 2 years or later, whereas the American children became allergic around 1 year of age. CONCLUSIONS Peanut allergy has different clinical and immunologic patterns in different areas of the world. Allergen component diagnostics might help us to better understand this complex entity.

Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.

Breast-feeding in relation to asthma, lung function, and sensitization in young schoolchildren

BACKGROUND The evidence from previous studies on beneficial effects of breast-feeding in relation to development of asthma is conflicting. OBJECTIVE To investigate the relation between breast-feeding and asthma and/or sensitization during the first 8 years of life. METHOD In a birth cohort, children were followed up to 8 years by questionnaires at ages 2 months and 1, 2, 4, and 8 years to collect information on exposures and health effects. Determination of serum IgE antibodies to common inhalant and food allergens was performed at 4 and 8 years. Longitudinal analyses were applied by using general estimated equations. The study population consisted of 3825 children (93% of the original cohort), of whom 2370 gave blood and 2564 performed lung function measurements at 8 years. RESULTS Children exclusively breast-fed 4 months or more had a reduced risk of asthma during the first 8 years of life (adjusted odds ratio [OR], 0.63; 95% CI, 0.50-0.78) compared with children breast-fed less than 4 months. At 8 years, reduced risks of sensitization (adjusted OR, 0.79; 95% CI, 0.64-0.99) and asthma in combination with sensitization (adjusted OR, 0.59; 95% CI, 0.37-0.93) were seen among children exclusively breast-fed 4 months or more. This group also had a significantly better lung function measured with peak expiratory flow. CONCLUSION Breast-feeding for 4 months or more seems to reduce the risk of asthma up to 8 years. At this age, a reduced risk was observed particularly for asthma combined with sensitization. Furthermore, breast-feeding seems to have a beneficial effect on lung function.

Bacterial and fungal agents in house dust and wheeze in children: the PARSIFAL study

Background Growing up on a farm and an anthroposophic lifestyle are associated with a lower prevalence of allergic diseases in childhood. This might be related to increased inhalatory exposure to microbial agents.

Peanut component Ara h 8 sensitization and tolerance to peanut

BACKGROUND Isolated Ara h 8 sensitization is suggested to be associated with no or mild symptoms among peanut-sensitized subjects. OBJECTIVE We sought to investigate the occurrence of systemic reactions in children with isolated sensitization to Ara h 8. METHODS Participants were 144 children sensitized to Ara h 8 (≥ 0.35 kU(A)/L) but not to Ara h 1, Ara h 2, or Ara h 3 (<0.35 kU(A)/L). An open oral challenge with peanut was performed in those subjects who did not consume peanut regularly, and an extended IgE reactivity profile was obtained. If the child had a documented history of systemic reactions up to grade I anaphylaxis, double-blind, placebo-controlled food challenges were performed. RESULTS One hundred twenty-nine (89.5%) children were either peanut consumers or did not react to peanut challenge. Another 14 (9.7%) children experienced oral cavity symptoms at the first 2 but not subsequent challenge doses. At the time of the double-blind, placebo-controlled food challenge, 1 boy with a previous mild systemic reaction to peanut experienced lip swelling, stomach cramping, and objective tiredness. Reanalysis of IgE levels showed an increase in peanut IgE levels from 1.5 to 8.8 kU(A)/L, but IgE levels to Ara h 8 remained stable and IgE levels to Ara h 1, Ara h 2, and Ara h 3 were all still less than 0.35 kU(A)/L. The IgE level to Ara h 6 was 0.45 kU(A)/L. CONCLUSION Isolated Ara h 8 sensitization indicates tolerance to peanuts in almost all cases. However, sensitization against thus far unidentified determinants in peanut might cause symptoms in rare cases.

Cytokine and Antibody Responses in Birch-Pollen-Allergic Patients Treated with Genetically Modified Derivatives of the Major Birch Pollen Allergen Bet v 1

Background: Recently, recombinant hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, were used to treat birch-pollen-allergic patients in a double-blind, placebo-controlled, multi-centre immunotherapy study. The aim of this study was to evaluate the effects of vaccination with aluminium-hydroxide-adsorbed recombinant Bet v 1 derivatives versus placebo on T-cell, cytokine and antibody responses in a subgroup of patients. Methods: Blood was drawn from patients of the Swedish centre (n = 27; rBet v 1 fragments: n = 10; rBet v 1 trimer: n = 8, and placebo-aluminium hydroxide: n = 9) before the start and after completion of the treatment. PBMC were stimulated with rBet v 1 and analysed for cytokine (IL-4, IL-5, IL-10, IL-12, IL-13 and IFN-γ)-secreting cells by ELISpot. Bet v 1-specific antibody levels in serum (IgG1–4, IgE and IgA) were measured by ELISA. Skin prick tests with defined Bet v 1 concentrations were performed before and 10–11 months after the beginning of the study. Results: Bet v 1-specific IgG levels, consisting of IgG1, IgG2 and IgG4, were significantly increased after treatment with recombinant allergen derivatives. Treatment with rBet v 1 trimer led to a significant (p < 0.05) reduction of Bet v 1-reactive IL-5- and IL-13-producing cells, reflecting a reduced Th2 response. In addition, a decreased number of Bet v 1-reactive IL-4 producing (p = 0.07) and an increase of IL-12-producing (p = 0.06) cells was noted in the trimer-treated patients. In contrast to placebo, active treatment resulted in significantly reduced immediate-type skin reactions to Bet v 1 even 10–11 months after treatment. Conclusion: Vaccination with recombinant hypoallergenic Bet v 1 derivatives induces a Bet v 1-specific IgG response and leads to reduced skin reactivity in allergic patients. A reduction of Bet v 1-specific Th2 responses was observed in trimer-treated patients, which may reflect the intrinsic property of this allergen derivative.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

Traffic-related air pollution and development of allergic sensitization in children during the first 8 years of life

BACKGROUND The role of exposure to air pollution in the development of allergic sensitization remains unclear. OBJECTIVE We sought to assess the development of sensitization until school age related to longitudinal exposure to air pollution from road traffic. METHODS More than 2500 children in the birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) from Stockholm, Sweden, were followed with repeated questionnaires and blood sampling until 8 years of age. Outdoor concentrations of nitrogen oxides, as a marker of exhaust particles, and particles with an aerodynamic diameter of less than 10 μm (PM(10)), mainly representing road dust, were assigned to residential, day care, and school addresses by using dispersion models. Time-weighted average exposures were linked to levels of IgE against common inhalant and food allergens at 4 and 8 years of age. RESULTS Air pollution exposure during the first year of life was associated with an increased risk of pollen sensitization at 4 years of age (odds ratio, 1.83; 95% confidence interval, 1.02-3.28) for a 5th to 95th difference in exposure to nitrogen oxides. At 8 years, there was no general increase in the risk of sensitization; however, the risk of food sensitization was increased, particularly among children free of sensitization at 4 years of age (odds ratio, 2.30; 95% confidence interval, 1.10-4.82). Results were similar by using PM(10). No associations between air pollution exposure after the first year of life and sensitization were seen. CONCLUSION Traffic-related air pollution exposure does not seem to increase the overall risk of sensitization to common inhalant and food allergens up to school age, but sensitization to certain allergens might be related to exposure during infancy.