WALKING BACKWARDS: REFLECTING ON THE VALUE OF MENTORS.

The author, Dr. A. Wesley Burks, reflects on his life's work to improve the lives of his patients.

Preliminary Development of the Food Allergy Coping and Emotions Questionnaires for Children, Adolescents, and Young People: Qualitative Analysis of Data on IgE-Mediated Food Allergy from Five Countries.

BACKGROUND: We have previously developed a food allergy-specific developmental model, that explained emotions and coping styles, among children aged 6 to 15years in Ireland. OBJECTIVE: The objective of this study was to investigate the usefulness of the developmental model in a large multicountry data set, including any mediators of coping style, and to use the findings to generate an item pool that will form the basis for 3 age-appropriate self-report questionnaires to measure coping and emotions. METHODS: We conducted deductive thematic analysis on secondary data from interviews with 274 participants aged 6 to 23 years, and 119 parents from Australia, Ireland, Italy, the UK, and the USA. Analysis was undertaken across the entire data set. RESULTS: The Food Allergy Coping and Emotions (FACE) model has 5 major themes: (1) experiences and emotions, (2) search for normality, (3) management and coping, (4) "external mediators," and (5) "internal mediators" (between emotions and coping). These themes were present across countries, but differed according to age. CONCLUSIONS: Early-life experiences provide the foundation for later cognitions and behaviors. The expanded FACE developmental model is useful in explaining emotions and coping styles across different age groups and countries. These data will also be used to generate an age-specific bank of items for the development of 3 (age-specific self-report, and parent proxy) questionnaires to assess emotions and coping in food allergy. Findings provide insight into how particular styles of coping develop and vary from patient to patient and may also guide clinician-patient communication and the development of individualized management strategies.

Erratum to: Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review.

[This corrects the article DOI: 10.1186/s13601-016-0113-z.].

The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming.

Skin barrier structure and function is essential to human health. Hitherto unrecognized functions of epidermal keratinocytes show that the skin plays an important role in adapting whole-body physiology to changing environments, including the capacity to produce a wide variety of hormones, neurotransmitters and cytokine that can potentially influence whole-body states, and quite possibly, even emotions. Skin microbiota play an integral role in the maturation and homeostatic regulation of keratinocytes and host immune networks with systemic implications. As our primary interface with the external environment, the biodiversity of skin habitats is heavily influenced by the biodiversity of the ecosystems in which we reside. Thus, factors which alter the establishment and health of the skin microbiome have the potential to predispose to not only cutaneous disease, but also other inflammatory non-communicable diseases (NCDs). Indeed, disturbances of the stratum corneum have been noted in allergic diseases (eczema and food allergy), psoriasis, rosacea, acne vulgaris and with the skin aging process. The built environment, global biodiversity losses and declining nature relatedness are contributing to erosion of diversity at a micro-ecological level, including our own microbial habitats. This emphasises the importance of ecological perspectives in overcoming the factors that drive dysbiosis and the risk of inflammatory diseases across the life course.

Oral tolerance and allergy.

Food allergy prevalence is increasing in the developed world. It's estimated that each year in the US, anaphylaxis to food results in 30,000 emergency room visits and 150 deaths. Over the past few decades, there has been a tremendous effort to better understand the pathogenesis of food allergy and mechanisms of food tolerance. In this article we review the structural of the gastrointestinal immune system and mechanisms of natural tolerance to food. We then review the factors that may result in the IgE mediated hypersensitivity reaction to food allergens resulting in clinical food allergy. Lastly, we provide a brief review of the efforts to induce immune tolerance to patients with food allergy.

Emerging Approaches to Food Desensitization in Children.

PURPOSE OF REVIEW: The purpose of this review is to highlight the recent advances in food desensitization in children with food allergy. RECENT FINDINGS: Recent advancements in epicutaneous, sublingual, and oral immunotherapy for food allergy in the future may offer children with food allergy and their families a viable option to reduce risk or severity of anaphylaxis with phase III trials ongoing for two of these treatment modalities. Food allergy prevalence in children is estimated to be up to 8%. These children are at risk of significant allergic reactions and anaphylaxis. Food avoidance and use of antihistamines or epinephrine has been the standard of care for these patients. This approach also has a significant socioeconomic effects on patients and their families. Recent advancements in understanding food allergy have allowed for exploring new methods of treatment. There is an increasing interest in oral immunotherapy, epicutaneous immunotherapy, or sublingual immunotherapy for food allergy. There have been also innovative approaches to immunotherapy by modification of food allergens (to make them less allergenic while maintain their immunogenicity) or adding adjunctive treatments (probiotics, anti-IgE, etc.) to increase efficacy or safety.

Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy. METHODS: We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. DISCUSSION: The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT.

Early-life gut microbiome composition and milk allergy resolution.

BACKGROUND: Gut microbiota may play a role in the natural history of cow's milk allergy. OBJECTIVE: We sought to examine the association between early-life gut microbiota and the resolution of cow's milk allergy. METHODS: We studied 226 children with milk allergy who were enrolled at infancy in the Consortium of Food Allergy observational study of food allergy. Fecal samples were collected at age 3 to 16 months, and the children were followed longitudinally with clinical evaluation, milk-specific IgE levels, and milk skin prick test performed at enrollment, 6 months, 12 months, and yearly thereafter up until age 8 years. Gut microbiome was profiled by 16s rRNA sequencing and microbiome analyses performed using Quantitative Insights into Microbial Ecology (QIIME), Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), and Statistical Analysis of Metagenomic Profiles (STAMP). RESULTS: Milk allergy resolved by age 8 years in 128 (56.6%) of the 226 children. Gut microbiome composition at age 3 to 6 months was associated with milk allergy resolution by age 8 years (PERMANOVA P = .047), with enrichment of Clostridia and Firmicutes in the infant gut microbiome of subjects whose milk allergy resolved. Metagenome functional prediction supported decreased fatty acid metabolism in the gut microbiome of subjects whose milk allergy resolved (η2 = 0.43; ANOVA P = .034). CONCLUSIONS: Early infancy is a window during which gut microbiota may shape food allergy outcomes in childhood. Bacterial taxa within Clostridia and Firmicutes could be studied as probiotic candidates for milk allergy therapy.

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Vitamin D.

BACKGROUND: The prevalence of allergic diseases is approximately 10 % in infants whose parents and siblings do not have allergic diseases and 20-30 % in those with an allergic first-degree relative. Vitamin D is involved in the regulation of the immune system and it may play a role in the development, severity and course of asthma and other allergic diseases. OBJECTIVE: The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations addressing the use of vitamin D in primary prevention of allergic diseases. METHODS: Our WAO guideline panel identified the most relevant clinical questions and performed a systematic review of randomized controlled trials and non-randomized studies (NRS), specifically cohort and case-control studies, of vitamin D supplementation for the prevention of allergic diseases. We also reviewed the evidence about values and preferences, and resource requirements (up to January 2015, with an update on January 30, 2016). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. RESULTS: Having reviewed the currently available evidence, the WAO guideline panel found no support for the hypothesis that vitamin D supplementation reduces the risk of developing allergic diseases in children. The WAO guideline panel suggest not using vitamin D in pregnant women, breastfeeding mothers, or healthy term infants as a means of preventing the development of allergic diseases. This recommendation does not apply to those mothers and infants who have other indications for prophylactic or therapeutic use of vitamin D. The panel's recommendations are conditional and supported by very low certainty evidence. CONCLUSIONS: WAO recommendations about vitamin D supplementation for the prevention of allergic diseases support parents, clinicians and other health care professionals in their decisions whether or not to use vitamin D in preventing allergic diseases in healthy, term infants.

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Prebiotics.

BACKGROUND: The prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10 % and reaches 20-30 % in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Prebiotics - non-digestible oligosaccharides that stimulate growth of probiotic bacteria - have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention. OBJECTIVE: The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of prebiotics in the prevention of allergy. METHODS: The WAO guideline panel identified the most relevant clinical questions about the use of prebiotics for the prevention of allergy. We performed a systematic review of randomized controlled trials of prebiotics, and reviewed the evidence about patient values and preferences, and resource requirements (up to January 2015, with an update on July 29, 2015). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. RESULTS: Based on GRADE evidence to decision frameworks, the WAO guideline panel suggests using prebiotic supplementation in not-exclusively breastfed infants and not using prebiotic supplementation in exclusively breastfed infants. Both recommendations are conditional and based on very low certainty of the evidence. We found no experimental or observational study of prebiotic supplementation in pregnant women or in breastfeeding mothers. Thus, the WAO guideline panel chose not to provide a recommendation about prebiotic supplementation in pregnancy or during breastfeeding, at this time. CONCLUSIONS: WAO recommendations about prebiotic supplementation for the prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether or not to use prebiotics for the purpose of preventing allergies in healthy, term infants.

Food specific oral immunotherapy: a potential treatment for food allergy.

Food allergy is a potentially life-threatening condition affecting up to 8% of children and up to 2% of adults in westernized countries. There are currently no approved treatments for food allergy apart from avoidance. The apparent increase in incidence of food allergies over the past few decades calls attention to the need for effective, disease-modifying therapies for food allergies. Oral immunotherapy (OIT) is a promising experimental treatment in which food allergic patients consume increasing quantities of food in attempt to increase their threshold for allergic reaction. Studies are ongoing to determine whether OIT is capable of safely inducing not only desensitization but also tolerance to the allergenic foods. This article focuses on recent relevant studies of OIT for the treatment of common food allergies.

Immunological basis of food allergy (IgE-mediated, non-IgE-mediated, and tolerance).

Food allergy includes a number of diseases that present with adverse immunological reactions to foods and can be IgE-mediated, non-IgE-mediated, or a combination of both mechanisms. IgE-mediated food allergy involves immediate hypersensitivity through the action of mast cells, whereas non-IgE-mediated food allergy is most commonly cell-mediated. These food allergies are thought to occur as a result of a breakdown in oral tolerance and, more specifically, from an aberrant regulatory T-cell response. Ongoing studies of experimental treatments for food allergy strive to induce oral tolerance and to teach us more about the pathogenesis of food allergy.

Administration of a probiotic with peanut oral immunotherapy: A randomized trial.

BACKGROUND: Coadministration of a bacterial adjuvant with oral immunotherapy (OIT) has been suggested as a potential treatment for food allergy. OBJECTIVE: To evaluate a combined therapy comprising a probiotic together with peanut OIT. METHODS: We performed a double-blind, placebo-controlled randomized trial of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) in children (1-10 years) with peanut allergy. The primary outcome was induction of sustained unresponsiveness 2 to 5 weeks after discontinuation of treatment (referred to as possible sustained unresponsiveness). Secondary outcomes were desensitization, peanut skin prick test, and specific IgE and specific IgG4 measurements. RESULTS: Sixty-two children were randomized and stratified by age (≤5 and >5 years) and peanut skin test wheal size (≤10 and >10 mm); 56 reached the trial's end. Baseline demographics were similar across groups. Possible sustained unresponsiveness was achieved in 82.1% receiving PPOIT and 3.6% receiving placebo (P < .001). Nine children need to be treated for 7 to achieve sustained unresponsiveness (number needed to treat, 1.27; 95% CI, 1.06-1.59). Of the subjects, 89.7% receiving PPOIT and 7.1% receiving placebo were desensitized (P < .001). PPOIT was associated with reduced peanut skin prick test responses and peanut-specific IgE levels and increased peanut-specific IgG4 levels (all P < .001). PPOIT-treated participants reported a greater number of adverse events, mostly with maintenance home dosing. CONCLUSION: This is the first randomized placebo-controlled trial evaluating the novel coadministration of a probiotic and peanut OIT and assessing sustained unresponsiveness in children with peanut allergy. PPOIT was effective in inducing possible sustained unresponsiveness and immune changes that suggest modulation of the peanut-specific immune response. Further work is required to confirm sustained unresponsiveness after a longer period of secondary peanut elimination and to clarify the relative contributions of probiotics versus OIT.

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics.

BACKGROUND: Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20-30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention. OBJECTIVE: The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy. METHODS: We identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations. RESULTS: Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence. CONCLUSIONS: WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.

Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy.

BACKGROUND: History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy. OBJECTIVE: We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk. METHODS: Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study. RESULTS: There was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01). CONCLUSION: Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA.

Oral and sublingual immunotherapy.

Allergic diseases have continued to increase throughout the developed world. Subcutaneous immunotherapy has been a mainstay of treatment for allergic rhinitis and asthma, however, some patients are precluded from treatment. On the other hand, in the case of food allergy, treatments simply do not exist. Oral and sublingual immunotherapy, with its superior safety and ease of administration, offers an alternative for patients with allergic rhinitis and asthma and has also been promising as a potential treatment for food allergy. The review summarizes significant advances from the past year including further data on the effectiveness of existing treatments, preliminary data on novel treatments, and further understanding of the mechanisms of these new therapies.

Peanut allergens alter intestinal barrier permeability and tight junction localisation in Caco-2 cell cultures.

BACKGROUND/AIMS: Allergen absorption by epithelia may play an important role in downstream immune responses. Transport mechanisms that can bypass Peyer's patches include transcellular and paracellular transport. The capacity of an allergen to cross via these means can modulate downstream processing of the allergen by the immune system. The aim of this study was to investigate allergen-epithelial interactions of peanut allergens with the human intestinal epithelium. METHODS: We achieved this using the human Caco-2 cell culture model, exposed to crude peanut extract. Western and immunofluorescence analysis were used to identify the cellular and molecular changes of peanut extract on the intestinal epithelium. RESULTS: Following exposure of Caco-2 cells to peanut extract, binding of the peanut allergens Ara h 1 and Ara h 2 to the apical cellular membrane and transcytosis across the monolayers were observed. Additionally, the co-localisation of the transmembrane tight junction proteins occludin, JAM-A and claudin-1, with the intracellular adhesion protein ZO-1 was modified. CONCLUSION: Disruption of Caco-2 barrier integrity through tight junction disruption may enable movement of peanut proteins across the intestinal epithelium. This accounts for peanut's increased allergenicity, compared to other food allergens, and provides an explanation for the potency of peanut allergens in immune response elicitation.