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.

EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy.

Hymenoptera venom allergy is a potentially life-threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic-allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life-threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1 -antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence-based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta-analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom-allergic children and adults to prevent further moderate-to-severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence-based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence.

Improving allergy management in the primary care network--a holistic approach.

The incidence, prevalence and costs of allergy have increased substantially in recent decades in many parts of Europe. The dominant model of allergy care within Europe is at the moment specialist-based. This model will become unsustainable and undeliverable with increasing disease prevalence. One solution to increase provision of allergy services is to diversify the providers. A new model for the provision of allergy care in the community with the general practitioner at the forefront is proposed. Pre- and postgraduate allergy education and training, implementation of pathways of care, allergy specialization and political will to generate resources and support are essential to achieve this new model. In parallel the holistic view of allergic diseases should be maintained, including assessment of severity and risk, psychological factors and health-care related costs in the context of the patient-centered decision making process.

Recommendations for assessing patient-reported outcomes and health-related quality of life in clinical trials on allergy: a GA(2)LEN taskforce position paper.

The aim of this Global Allergy and Asthma European Network (GA(2)LEN) consensus report is to provide recommendations for patient-reported outcomes (PROs) evaluation in clinical trials for allergic diseases, which constitute a global health problem in terms of physical, psychological economic and social impact. During the last 40 years, PROs have gained large consideration and use in the scientific community, to gain a better understanding of patients' subjective assessment with respect to elements concerning their health condition. They include all health-related reports coming from the patient, without involvement or interpretation by physician or others. PROs assessment should be performed by validated tools (disease-specific tools when available or generic ones) selected taking into account the aim of the study, the expected intervention effects and the determinant and confounding factors or patient-related factors which could influence PROs. Moreover, each tool should be used exclusively in the patient population following the authors' indications without modification and performing a cross-cultural validation if the tool must be used in a language that differs from the original. The result analysis also suggests that the relevance of PROs results in any interventional study should include a pre-post assessment providing information concerning statistical differences within or among groups, rates of response for the PROs and a minimal important difference for the population. The report underlines the importance of further investigation on some topics, such as the quality assessment of existing PROs tools, the definition of inclusion and exclusion criteria and a more extensive evaluation of the correlation between PROs, besides health-related quality of life, and clinical data.

Prevention of work-related airway allergies; summary of the advice from the Health Council of the Netherlands.

The Health Council of the Netherlands published a report in which the best procedure and method for recommending health-based occupational exposure limits (OELs) for inhaled allergens were identified by evaluating the scientific state of the art. Many respiratory disorders in the workplace arise from inhalation of substances which can cause allergy. To protect workers against respiratory allergy, various preventive measures are taken, one of them being reduction of exposure by setting legally binding standards. These are based on health-based OELs that specify a level of exposure to an airborne substance, a threshold level, below which it may reasonably be expected that there is no risk of adverse health effects. The Council is of the opinion that an OEL should prevent against allergic sensitization, as sensitization plays a crucial biological role and is a prerequisite for the development of allergy. Furthermore, the Council considers it most likely that the exposure level below which no allergic sensitization develops for most allergens is so low, that OELs are difficult to set with the current knowledge and technical feasibilities. An alternative approach is to accept exposure, which carries a small predefined risk in developing allergic sensitization. In addition, it is worth considering periodic screening of exposed workers on allergic sensitization, because timely intervention can prevent worse. The feasibility of periodic screening and what else is needed to comply with the most important criteria, should however be judged case-by-case.

Exercise-induced hypersensitivity syndromes in recreational and competitive athletes: a PRACTALL consensus report (what the general practitioner should know about sports and allergy).

Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI-urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities.

Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper.

Nonallergic rhinitis (NAR) can be defined as a chronic nasal inflammation which is not caused by systemic IgE-dependent mechanisms. It is common and probably affects far more than 200 million people worldwide. Both children and adults are affected. However, its exact prevalence is unknown and its phenotypes need to be evaluated using appropriate methods to better understand its pathophysiology, diagnosis and management. It is important to differentiate between infectious rhinitis, allergic/NAR and chronic rhinosinusitis, as management differs for each of these cases. Characterization of the phenotype, mechanisms and management of NAR represents one of the major unmet needs in allergic and nonallergic diseases. Studies on children and adults are required in order to appreciate the prevalence, phenotype, severity and co-morbidities of NAR. These studies should compare allergic and NAR and consider different age group populations including elderly subjects. Mechanistic studies should be carried out to better understand the disease(s) and risk factors and to guide towards an improved diagnosis and therapy. These studies need to take the heterogeneity of NAR into account. It is likely that neuronal mechanisms, T cells, innate immunity and possibly auto-immune responses all play a role in NAR and may also contribute to the symptoms of allergic rhinitis.

Methodology for development of the Allergic Rhinitis and its Impact on Asthma guideline 2008 update.

BACKGROUND: We describe the methodology for the 2008 update of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. The methodology differs from the 2001 edition in several respects. The most prominent change is the application of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to compiling evidence, assessing the quality of evidence and grading of recommendations. METHODS AND RESULTS: Representatives of the GRADE working group joined the ARIA guideline panel to achieve these tasks. While most recommendations result from existing systematic reviews, systematic reviews were not always available and the panel compiled the best available evidence in evidence profiles without conducting actual reviews. The panel conducted two meetings and used the GRADE criteria to assess the quality of evidence (four categories of high, moderate, low and very low) and the strength of recommendation (strong and weak) based on weighing up the desirable and undesirable effects of management strategies, considering values and preferences influencing recommendations, and resource implications. The guideline panel has chosen the words 'we recommend'--for strong recommendations and 'we suggest'--for weak recommendations. Both categories indicate the best course of action for a given patient population, but their implementation, requires different considerations as we describe subsequently in this article. CONCLUSIONS: The 2008 update of the ARIA guidelines has become more evidence-based. Future iterations of the guidelines will further be improved by following the described processes even closer, such as ensuring availability of updated high quality systematic reviews for each question.

Nasal hyperreactivity.

Nasal hyperreactivity is an important feature of allergic and non-allergic rhinitis. This paper reviews the possible mechanisms behind hyperreactivity. Distinct mechanisms may play a role in allergic rhinitis--an inflammatory disease--and non-allergic rhinitis, mainly a non-inflammatory disease. In allergic rhinitis, particularly in perennial allergic rhinitis, there is a close connection between allergic response and non-specific hyperreactivity. In non-allergic rhinitis, a pathological entity comprising a heterogeneous series of diseases, understanding and measuring nasal hyperreactivity is much more difficult. A variety of methods to assess nasal hyperreactivity are available. Given the heterogeneity of mechanisms, the various patients groups and the lack of standardization in tests, it is not surprising that measurement of nasal hyperreactivity is not included in the diagnostic arsenal of the clinician.

The long-term effects of capsaicin aqueous spray on the nasal mucosa.

BACKGROUND: Capsaicin has been shown previously to reduce nasal complaints in patients with a non-allergic non-infectious perennial rhinitis. Proposed pathophysiological mechanisms for non-allergic non-infectious perennial rhinitis include a chronic inflammatory disorder of an antigenic or neurogenic nature as well as the possibility of a functional neuronal disorder. We hypothesized that the beneficial effect of capsaicin might be the result of a down-regulation of inflammation (by a reduction of inflammatory cells) or through modulation of neural tissue density. METHODS: Patients were treated with either a placebo or capsaicin spray solution delivering 0.15 mg of capsaicin per nostril once every second or third day for a total of seven treatments. Both sides were treated each visit. Biopsies were taken before and 2 weeks, 3 months and 9 months after the treatment period. Immunohistochemical staining of the biopsy specimen was performed to ascertain the effect of treatment on immunocompetent cell densities (quantitative) and neural tissue densities (semi-quantitative) in the nasal mucosa. RESULTS: Nasal complaints were significantly reduced in the capsaicin-treated group. The number of CD1+, CD25+, CD3+, CD68+, BMK13+, IgE+, tryptase+, and chymase+ cells did not significantly differ between capsaicin and placebo group. No significant differences between both groups were found in pan-neurogenic staining of nasal mucosa using neurofilament and synaptophysine. CONCLUSION: Capsaicin aqueous nasal spray has previously been shown to reduce nasal complaints without affecting cellular homeostasis or overall neurogenic staining up to 9 months after treatment. Immunocompetent cells are not involved in non-allergic non-infectious perennial rhinitis.

Intranasal cold dry air is superior to histamine challenge in determining the presence and degree of nasal hyperreactivity in nonallergic noninfectious perennial rhinitis.

The objective of the study was to compare cold dry air (CDA) and histamine in differentiating patients with nonallergic noninfectious perennial rhinitis (NANIPER) from control subjects. Nasal reactivity (nasal patency, mucus production, and sneezing) in 16 symptomatic nonsmoking patients with NANIPER and seven nonsmoking control subjects was measured with standardized CDA and histamine provocation series in a randomized crossover study. Intranasal CDA resulted in increased mucus production and nasal blockage in a dose-dependent manner in patients with NANIPER but not in control subjects. Sneezing did not occur. The reproducibility of CDA for patency and mucus production was good. Sensitivity for CDA was 87% compared with 100% for histamine. However, specificity was 71% for CDA and 0% for histamine. It is concluded that the new standardized intranasal CDA provocation method uses a recognizable natural nonspecific stimulus and seems to be more suitable than histamine for characterizing and assessing the presence and degree of nasal reactivity in NANIPER.

Measurement of IgE antibodies against purified grass pollen allergens (Lol p 1, 2, 3 and 5) during immunotherapy.

BACKGROUND: IgE titres tend to rise early after the start of immunotherapy, followed by a decline to pre-immunotherapy levels or lower. OBJECTIVES: We were interested to know whether the early increase in IgE antibodies includes new specificities of IgE, and whether these responses persist. METHODS: Sera of 64 patients undergoing grass pollen immunotherapy were tested for IgE against four purified grass pollen allergens: Lol p 1, 2, 3, and 5. At least two serum samples were taken, one before the start of therapy and one between 5 and 18 months after the first immunization (mean: 10 months). RESULTS: The mean IgE responses to Lol p 1, 2 and 3 showed a moderate but not significant increase. In contrast, the mean IgE response to Lol p 5 showed a significant decrease of > 30%. IgE against total Lohum perenne pollen extract moderately increased (> 20%), showing that a RAST for total pollen is not always indicative for the development of IgE against its major allergens. For > 40% of the patients it was found that IgE against one or more of the four allergens increased, while IgE against the remaining allergen(s) decreased. For 10 sera the ratio of IgE titres against at least two allergens changed by at least a factor of 5. The changes in specific IgE also included conversions from negative (< 0.1 RU) to positive (0.6 to 5.0 RU) for five patients. For two patients, the induction of these 'new' IgE antibodies against major allergens was shown to result in a response that was persistent over several years. CONCLUSION: Although active induction of new IgE specificities by immunotherapy was not really proven, the observations in this study indicate that monitoring of IgE against purified (major) allergens is necessary to evaluate changes in specific IgE in a reliable way.

Selective effect of levocabastine on histamine receptor and histamine release from human leukocytes and guinea pig isolated tissue.

BACKGROUND: Levocabastine is a potent histamine H1 receptor antagonist used topically in the treatment of patients with allergic rhinitis. It has been suggested that antihistamines also have anti-inflammatory properties. OBJECTIVE: The present study was performed to investigate whether levocabastine, in addition to the anti-H1 receptor activity, has anti-inflammatory properties and thus is able to modulate the release of histamine and cytokines, such as interleukin 5 from human leukocytes and isolated tissues. METHODS: Leukocytes suspensions were prepared by dextran sedimentation of peripheral venous blood drawn from allergic and healthy volunteers. Leukocytes obtained from allergic volunteers were preincubated for 30 minutes with levocabastine (doses 10(-8) M to 10(-6) M) and thereafter incubated with allergen. Leukocytes obtained from healthy volunteers were incubated for zero to three hours with levocabastine (doses 10(-14) M to 10(-3) M). Histamine release was measured by an automated fluorometric method. Interleukin-5 release was measured by enzyme linked immunoassay. Contractile responses to histamine on guinea pig trachea and lung parenchyma as well as the release of histamine and interleukin-5 by the tissues were investigated in the absence or presence of levocabastine and/or the histamine H2 receptor antagonist cimetidine. RESULTS: Levocabastine did not influence allergen-induced histamine release from leukocytes obtained from allergic volunteers. High concentrations (10(-4)and 10(-3) M) of levocabastine, however, caused release of histamine from leukocytes obtained from healthy volunteers as well as guinea pig airway smooth muscle tissues. Pretreatment with levocabastine dose-dependently decreased the contractile response to histamine, showing an irreversible competitive mechanism. Interleukin 5 release from human leukocytes and by guinea pig airway smooth muscle was not detectable. CONCLUSIONS: These findings indicate that the H1 receptor blocker, levocabastine, has probably no anti-inflammatory properties, measured as histamine release, and that the histamine release from both human leukocytes and guinea pig trachea and lung parenchyma is significantly increased by the drug only at high concentrations.

Drug-dependent exercise-induced anaphylaxis.

Exercise-induced anaphylaxis (EIA) is well known and may be food-dependent. We describe a patient with a history of anaphylaxis during exercise after taking nafylpropion acid (Naprosyne), a nonsteroidal anti-inflammatory drug. An exercise-challenge test after Naprosyne intake induced bronchoconstriction. The combination of history and challenge tests suggests that intolerance or allergy to drugs may present as EIA.

Allergy to bumblebee venom. I. Occupational anaphylaxis to bumblebee venom: diagnosis and treatment.

We describe six patients with severe occasional anaphylaxis, caused by stings of bumblebees. Sensitization to bumblebee venom was confirmed by intracutaneous tests and RAST with purified bumblebee venom. Three patients changed their occupation and will probably not be stung by bumblebees in the future. The other patients started immunotherapy with newly purified bumblebee venom extract. After 1 year of treatment, no severe side-effects had occurred and clinical benefit in two patients could be demonstrated, as both skin sensitivity or serum IgE to bumblebee venom had decreased. Moreover, both patients were unresponsive to in-hospital sting challenge.

Cutaneous adverse reactions after intra-articular injection of triamcinolone acetonide.

A patient is described with a disseminated morbilliform and partially persistent urticarial dermatitis following intra-articular injections of triamcinolone acetonide. A delayed-type hypersensitivity to triamcinolone acetonide was observed after patch and intradermal testing. However, an immediate-type hypersensitivity to this drug was not observed. A delayed-type sensitization to betamethasone, dexamethasone and prednisolone, but not to hydrocortisone was also observed after patch testing. Intradermal tests with these representatives of corticosteroids were all negative. Although little is known yet about the relationship between immediate and delayed-type hypersensitivity and the side-effects of oral use of corticosteroids, the absence of positive skin tests to corticosteroids other than triamcinolone acetonide may indicate a safe use of these drugs orally or via injection.

Effect of Fluticasone propionate Aqueous Nasal Spray Treatment on Platelet Activating Factor and Eicosanoid Production By nasal Mucosa in Patients with A house Dust Mite Allergy.

The relationship between the release of platelet activating factor (PAF), leukotriene C(4)/D(4)/E(E) (LTC(4)/D(4)/E(4)) and prostaglandin D(2) (PGD(2)) from nasal mucosa in vivo was examined in 24 rhinitis patients allergic to the house dust mite (HDM). During a double blind placebo controlled cross-over study 200 mug fluticasone propionate aqueous nasal spray (FPANS) was administered twice daily for two weeks. In response to allergen provocation (100, 1 000, 10 000 Bu/ml) and during the 9.5 h after this challenge the nasal fluid was obtained by washing the nose with saline and the levels of PAF, LTC(4)/D(4)/E(4) and PGD(2), as indicators of mediator release, were measured at the following time-points: baseline (t = - 1/2), allergen provocation with 10 000 Bu/ml (t = 0), 3.5 and 7.5 h (late phase). After allergen provocation the levels of the mediators increased in the nasal fluids of placebo treated patients (x-fold increase to baseline: PAF, 15; LTC(4)/D(4)/E(4), 12; PGD(2), 1.5). In fluids of patients treated with FPANS these levels tended to decrease. At the time of provocation the levels of PAF, LTC(4)/D(4)/E(4) and PGD(2) showed a significant correlation. The results indicate that these mediators can be used as markers of allergic reactions against house dust mites and that fluticasone propionate aqueous nasal spray tended to reduce the release of mediators of inflammation correlated with beneficial effects on clinical symptoms in this type of allergic reactions.

Nasal hyperreactivity and its effect on early and late sequelae of nasal challenge with house-dust mite extract.

For a study on the relationship between nasal hyperreactivity to histamine and the nasal response to allergen, 14 rhinitis patients allergic to house-dust mites were challenged with histamine and 5 days later with a house-dust mite (HDM) extract. According to symptom scores, after allergen challenge two groups of patients were distinguished, i.e., isolated early and dual responders. The nasal response to histamine was significantly correlated with the amount of secretion (r = 0.71; p = 0.0039) and the number of sneezes (r = 0.78; p = 0.0016) induced by the HDM extract during the early reaction. The amount of allergen-induced secretion could be predicted from the response to histamine, skin reactivity to allergen, and blood eosinophils (multiple r = 0.90; p < 0.0001). Late-phase symptoms appearing between 3.5 and 9.5 hour after allergen challenge could be predicted from histamine responsiveness and skin reactivity (multiple r = 0.67; p = 0.004). Compared with early responders (LAR-) (n = 8), patients with early and late symptoms (LAR+) (n = 6) were characterized by a higher secretory responsiveness to histamine (p = 0.033), increased production of leukotrienes determined in nasal lavage fluid during the early response (p = 0.033), and elevated albumin levels occurring between 3.5 and 9.5 hours after challenge (p = 0.043). Late-phase symptoms were significantly correlated with albumin influx (r = 0.73; p = 0.001) and leukotrienes production (r = 0.60; p = 0.011) during the early reaction. In summary, nasal responsiveness to HDM extract was found to be closely associated with pre-existent nasal hyperreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergy to pistachio nuts.

Three patients with adverse food reactions due to pistachio and mango were studied. Specific IgE against these tropical stone fruits of the Anacardiaceae family could be demonstrated, indicating type I allergic reactions. Methods are described to detect these specific antibodies in a reproducible way.