EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy.

Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food allergen immunotherapy (FA-AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy, aims to provide evidence-based recommendations for active treatment of IgE-mediated food allergy with FA-AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post-discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA-AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post-discontinuation is also suggested, but not confirmed. Adverse events during FA-AIT have been frequently reported, but few subjects discontinue FA-AIT as a result of these. Taking into account the current evidence, FA-AIT should only be performed in research centers or in clinical centers with an extensive experience in FA-AIT. Patients and their families should be provided with information about the use of FA-AIT for IgE-mediated food allergy to allow them to make an informed decision about the therapy.

Precision medicine in allergic disease-food allergy, drug allergy, and anaphylaxis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology.

This consensus document summarizes the current knowledge on the potential for precision medicine in food allergy, drug allergy, and anaphylaxis under the auspices of the PRACTALL collaboration platform. PRACTALL is a joint effort of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, which aims to synchronize the European and American approaches to allergy care. Precision medicine is an emerging approach for disease treatment based on disease endotypes, which are phenotypic subclasses associated with specific mechanisms underlying the disease. Although significant progress has been made in defining endotypes for asthma, definitions of endotypes for food and drug allergy or for anaphylaxis lag behind. Progress has been made in discovery of biomarkers to guide a precision medicine approach to treatment of food and drug allergy, but further validation and quantification of these biomarkers are needed to allow their translation into practice in the clinical management of allergic disease.

Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy. METHODS: We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses. RESULTS: We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses. CONCLUSIONS: AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.

Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN).

Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 µm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal.

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.(AU)

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.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study.

OBJECTIVE: To evaluate the effects of dietary intake of the long-chain polyunsaturated fatty acids, arachidonic acid (AA), and docosahexaenoic acid (DHA) on multiple indices of infant growth and development. DESIGN: A double-masked, randomized, parallel trial was conducted with term infants fed formulas with or without AA+DHA for 1 year (N = 239). Reference groups of breastfed infants (N = 165) weaned to formulas with and without AA+DHA were also studied. Infants in the formula groups were randomized at

Detection of peanut allergens in breast milk of lactating women.

CONTEXT: Most individuals who react to peanuts do so on their first known exposure. A potential but unproven route of occult exposure resulting in sensitization to peanut is via breast milk during lactation. OBJECTIVE: To investigate the ability of maternal dietary peanut protein to pass into breast milk during lactation. DESIGN AND SETTING: Clinical investigation conducted at 2 North American hospitals from March 1999 to October 2000. PATIENTS: Twenty-three healthy, lactating women aged 21 to 35 years. INTERVENTION: Each woman consumed 50 g of dry roasted peanuts, after which breast milk samples were collected at hourly intervals. MAIN OUTCOME MEASURES: Presence in breast milk of total peanut protein, analyzed by a sandwich enzyme-linked immunosorbent assay, and 2 major peanut allergens, Ara h 1 and Ara h 2, detected by immunoblot analysis. RESULTS: Peanut protein was detected in 11 of 23 subjects. It was detected in 10 subjects within 2 hours of ingestion and in 1 subject within 6 hours. The median peak peanut protein concentration in breast milk was 200 ng/mL (mean, 222 ng/mL; range, 120-430 ng/mL). Both major peanut allergens Ara h 1 and Ara h 2 were detected. CONCLUSIONS: Peanut protein is secreted into breast milk of lactating women following maternal dietary ingestion. Exposure to peanut protein during breastfeeding is a route of occult exposure that may result in sensitization of at-risk infants.

Classic specific immunotherapy and new perspectives in specific immunotherapy for food allergy.

Food allergy is a major cause of life-threatening hypersensitivity reactions. Food-induced anaphylaxis is the most common reason for someone to present to the emergency department for an anaphylactic reaction. The avoidance of the allergenic food is the only method of preventing further reactions that is currently available for sensitized patients. Strict avoidance of specific foods is the accepted treatment of food-induced allergic reactions but is often an unrealistic therapeutic option for food-induced hypersensitivity reactions for the many reasons previously described. Desirable therapeutic strategies for the treatment and prevention of food allergies must be safe, relatively inexpensive and easily administered. Recent advances in the understanding of the immunological mechanisms underlying allergic disease and better characterization of food allergens have greatly expanded the potential therapeutic options for future use. Several different forms of immunomodulatory therapies are currently under investigation: peptide immunotherapy, mutated protein immunotherapy, allergen DNA immunization, vaccination with immunostimulatory DNA sequences and anti-immunoglobulin E (Anti-IgE) therapy.

The natural history of peanut allergy.

BACKGROUND: It has traditionally been assumed that peanut allergy is rarely outgrown. OBJECTIVE: The goal of this study was to determine the number of children with peanut allergy who become tolerant of peanut. METHODS: Patients aged 4 to 20 years with a diagnosis of peanut allergy were evaluated by questionnaire, skin testing, and a quantitative antibody fluorescent-enzyme immunoassay. Patients who had been reaction free in the past year and had a peanut IgE (PN-IgE) level less than 20 kilounits of antibody per liter (kU(A)/L) were offered an open or double-blind, placebo-controlled peanut challenge. RESULTS: A total of 223 patients were evaluated, and of those, 85 (PN-IgE < 0.35-20.4 kU(A)/L [median 1.42 kU(A)/L]) participated in an oral peanut challenge. Forty-eight (21.5%) patients had negative challenge results and were believed to have outgrown their peanut allergy (aged 4-17.5 years [median 6 years]; PN-IgE < 0.35-20.4 kU(A)/L [median 0.69 kU(A)/L]). Thirty-seven failed the challenge (aged 4-13 years [median 6.5 years]; RAST < 0.35-18.2 kU(A)/L [median 2.06 kU(A)/L]). Forty-one patients with PN-IgE levels less than 20 kU(A)/L declined to undergo challenge, and 97 were not eligible for challenge because their PN-IgE levels were greater than 20 kU(A)/L or they had had a recent reaction. Sixty-seven percent of patients with PN-IgE levels less than 2 kU(A)/L and 61% with levels less than 5 kU(A)/L had negative challenge results. Of those who underwent challenge, PN-IgE levels for those who passed versus those who failed were different at the time of challenge (P = .009), but not at the time of diagnosis (P = .25). CONCLUSION: This study demonstrates that peanut allergy is outgrown in about 21.5% of patients. Patients with low PN-IgE levels should be offered a peanut challenge in a medical setting to demonstrate whether they can now tolerate peanuts.

Food allergens.

A number of advances in the scientific knowledge concerning adverse food reactions have been made in the past few years. Understanding about the nature of the food allergen itself, the molecular characterization of the epitopes on these allergens, the pathophysiology of the clinical reaction, and the diagnostic methods have all been significantly enhanced.

Randomized, double-blind, crossover challenge study in 53 subjects reporting adverse reactions to melon (Cucumis melo).

BACKGROUND: Few studies have evaluated IgE-mediated hypersensitivity to melon with details of clinical reactions confirmed by double-blind, placebo-controlled, food challenges (DBPCFCs). OBJECTIVE: We sought to investigate clinical features (type and severity of reactions, age at onset, results of skin prick and in vitro tests, and incidence of other allergic diseases and associated food allergies) of acute allergic reactions to melon confirmed by DBPCFCs. METHODS: Fifty-three consecutive adult patients complaining of adverse reactions to melon were included in the study. Skin prick tests and detection of specific IgE were performed in all patients with melon, avocado, kiwi, banana, chestnut, latex, pollen, and other offending foods. Patients first underwent an open food challenge, unless they had a convincing history of severe anaphylaxis. Positive open food challenge reactions were subsequently evaluated by DBPCFCs. RESULTS: Actual clinical reactivity was confirmed in 19 (36%) of 53 patients. The most frequent symptom was oral allergy syndrome (n = 14), but two patients experienced life-threatening reactions, including respiratory symptoms and hypotension. The positive predictive value for a skin prick test was 42%, and that for specific IgE measurement was 44%. Forty-five reactions to 15 other foods were confirmed in 18 patients. The most common foods associated with melon allergy were avocado (n = 7), banana (n = 7), kiwi (n = 6), watermelon (n = 6), and peach (n = 5). Onset of melon-induced allergic symptoms occurred from 6 to 45 years (median, 20 years), preceded by seasonal rhinitis, asthma, or both in 88% (15/17). CONCLUSION: About one third of reported reactions to melon are confirmed by means of DBPCFC, which has been proven to be the most reliable procedure in the diagnosis of clinical fruit allergy. Isolated melon allergy is rare, with most patients either having allergic rhinitis, asthma, or both and associated food allergies.

Preparation and functional properties of rice bran protein isolate.

Rice bran protein isolate (RBPI) containing approximately 92.0% protein was prepared from unstabilized and defatted rice bran using phytase and xylanase. The yield of RBPI increased from 34% to 74.6% through the use of the enzymatic treatment. Nitrogen solubilities of RBPI were 53, 8, 62, 78, 82, and 80% at pHs 2.0, 4.0, 6.0, 8.0, 10.0, and 12.0, respectively. Differential scanning calorimetry showed that RBPI had denaturation temperature of 83.4 degrees C with low endotherm (0.96 J/g of protein). RBPI had similar foaming properties in comparison to egg white. But emulsifying properties of RBPI were significantly lower than those of bovine serum albumin. The result of amino acid analysis showed that RBPI had a similar profile of essential amino acid requirements for 2-5-year-old children in comparison to that of casein and soy protein isolate.

Peanut-induced anaphylactic reactions.

Food allergies, particularly to peanuts, are a common cause of anaphylaxis. Approximately 125 people die each year in the USA secondary to food-induced anaphylaxis. Clinical anaphylaxis is a syndrome of diverse etiology and dramatic presentation of symptoms associated with the classic features of type I, IgE-mediated hypersensitivity [1]. Typically the term anaphylaxis connotes an immunologically-mediated event that occurs after exposure to certain foreign substances. This reaction results from the generation and release of a variety of potent biologically active mediators and their concerted effects on various target organs. Anaphylaxis is recognized by cutaneous, respiratory, cardiovascular, and gastrointestinal signs and symptoms occurring singly or in combination. This article focuses on allergic reactions to peanuts that manifest as signs and symptoms involving multiple target organs or the cardiovascular system alone.

Multicenter crossover comparison of the safety and efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin, and Gammagard in patients with primary immunodeficiency diseases.

The safety and clinical efficacy of a liquid, beta-propiolactone-stabilized intravenous gamma-globulin, Intraglobin-F, was evaluated in a multicenter, double-blind study comparing Intraglobin-F to Gamimune-N, Sandoglobulin, or Gammagard. beta-Propiolactone stabilizes the IgG molecule to decrease aggregate formation and is a potent virucidal agent that reduces the risk of viral transmission by intravenous gamma-globulin (IVIG) preparations. Twenty-seven patients with primary immunodeficiency diseases were enrolled at three centers. Each patient received 6 months of therapy with either Intraglobin-F or the IVIG preparation that they had received during the preceding 3 months, then crossed over to the other preparation. Twenty-three patients completed the study. One patient withdrew because of an adverse event, generalized urticaria. A second patient withdrew because of fatigue and perceived decreased efficacy. Adverse reactions were comparable and occurred in 8.7% of the infusions of Intraglobin-F and 6% of the infusions with Sandoglobulin. None were severe or life-threatening. There was no discernible difference in efficacy between any of the products. The number of days when patients noted symptoms in their diaries was similar for Intraglobin-F and the comparison preparations, 4158 vs 4143. Similarly, there were no differences in the number of physician visits (33 vs 22), days missed from work or school (405 vs 404), days with fever (41 vs 47), or days of prophylactic antibiotics (675 vs 642). There was an increase in the number of days when antibiotics were given therapeutically (578 vs 451); most of the difference was attributable to one patient. There also was a difference in the number of days of hospitalization (21 vs 0), but 19 of the days were accounted for by two patients. When the patients were asked to score their feeling of well-being on a scale of 1 to 5, with 1 being entirely well, the mean score for the patients on Intraglobin-F was 1.86 (range, 1.0 to 3.0), compared to 1.85 (range, 1.0 to 3.2) for patients while on the comparison preparations. Trough IgG levels were slightly lower during the period when patients were treated with Intraglobin-F compared to the other products. There were no abnormalities in blood chemistries or hematologic parameters. Thus, Intraglobin-F is comparable to three of the marketed IVIG preparations in efficacy and safety, as well as patient acceptability, and offers the additional benefit of an extra virucidal step to reduce further the risk of transmitting viral infections.

Isolation and characterization of a clone encoding a major allergen (Bla g Bd90K) involved in IgE-mediated cockroach hypersensitivity.

Previous studies have established that atopic individuals living in cockroach-infested housing become sensitized to cockroach aeroallergens and produce IgE antibodies to a variety of proteins. We describe the isolation of a complementary DNA clone from an expression library, constructed with messenger RNA from German (Blattella germanica) cockroaches, which encodes a major allergen involved in mediating cockroach hypersensitivity. Approximately 0.2% of the clones from a lambda ZAP XR cDNA library bound IgE from a patient with cockroach sensitivity. A randomly selected subset of these clones revealed that they were either different isolates of the same gene or members of a closely related gene family. One of the largest clones (a 4 kb insert) from this subset, Bla g Bd90K hybridized to a single mRNA of approximately the same size. DNA sequence analysis showed that this gene consisted of seven 576 bp tandem repeats with a short unique region at either end. No significant sequence homologies were found between the cockroach clone and any other gene reported in the GenBank database. Serum from 17 of 22 (77%) patients with cockroach hypersensitivity identified IgE-binding recombinant protein expressed from clone Bla g Bd90K in Escherichia coli XL-Blue cells as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis/immunoblot analysis. This recombinant protein migrates with a molecular weight (90 kd) apparently similar to one identified in whole body extracts. We have identified and isolated a cDNA that encodes a major cockroach allergen (Bla g Bd90K) present in German cockroaches.