Eva-Maria Varga

Long-term clinical efficacy of grass-pollen immunotherapy.

BACKGROUNDnPollen immunotherapy is effective in selected patients with IgE-mediated seasonal allergic rhinitis, although it is questionable whether there is long-term benefit after the discontinuation of treatment.nnnMETHODSnWe conducted a randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. Cutaneous-biopsy specimens obtained 24 hours after intradermal allergen challenge were examined for T-cell infiltration and the presence of cytokine-producing T helper cells (TH2 cells) (as evidenced by the presence of interleukin-4 messenger RNA). A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease.nnnRESULTSnScores for seasonal symptoms and the use of rescue antiallergic medication, which included short courses of prednisolone, remained low after the discontinuation of immunotherapy, and there was no significant difference between patients who continued immunotherapy and those who discontinued it. Symptom scores in both treatment groups (median areas under the curve in 1995, 921 for continuation of immunotherapy and 504 for discontinuation of immunotherapy; P=0.60) were markedly lower than those in the group that had not received immunotherapy (median value in 1995, 2863). Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression.nnnCONCLUSIONSnImmunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity.

Guideline for acute therapy and management of anaphylaxis

S2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB)

European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’

To cite this article: Calderón MA, Larenas D, Kleine‐Tebbe J, Jacobsen L, Passalacqua G, Eng PA, Varga EM, Valovirta E, Moreno C, Malling HJ, Alvarez‐Cuesta E, Durham S, Demoly P. European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’. Allergy 2011; 66: 1345–1359.

Perspectives on allergen‐specific immunotherapy in childhood: An EAACI position statement

To cite this article: Calderon MA, Gerth van Wijk R, Eichler I, Matricardi PM, Varga EM, Kopp MV, Eng P, Niggemann B, Nieto A, Valovirta E, Eigenmann PA, Pajno G, Bufe A, Halken S, Beyer K, Wahn U. Perspectives on allergen‐specific immunotherapy in childhood: An EAACI position statement. Pediatr Allergy Immunol 2012: 23: 300–306.

Design and Recruitment for the GAP Trial, Investigating the Preventive Effect on Asthma Development of an SQ-Standardized Grass Allergy Immunotherapy Tablet in Children with Grass Pollen–Induced Allergic Rhinoconjunctivitis

BACKGROUNDnAllergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published.nnnOBJECTIVEnThe objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial.nnnMETHODSnThe trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities.nnnRESULTSnThe GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries.nnnCONCLUSIONSnTo our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12.

IgE cross-reactivity between the major peanut allergen Ara h 2 and the nonhomologous allergens Ara h 1 and Ara h 3.

BACKGROUNDnAra h 1, a vicilin; Ara h 2, a 2S albumin; and Ara h 3, a legumin, are major peanut allergens. Ara h 2 is an important predictor of clinical reactivity to peanut, but cosensitization to all 3 allergens is correlated with the severity of patients symptoms.nnnOBJECTIVEnWe investigated whether cosensitization to these 3 allergens is caused by IgE cross-reactivity, despite the fact that they do not display obvious structural or sequence similarities.nnnMETHODSnIgE cross-inhibitions were performed with purified Ara h 1, Ara h 2, and Ara h 3 and IgG-depleted sera from 10 patients with peanut allergy. After an in silico search for similar peptides, IgE ELISA inhibition assays with synthetic peptides were performed.nnnRESULTSnAra h 2 inhibited IgE binding to Ara h 1 (average, 86% ± 13%) and Ara h 3 (average, 96% ± 6%). IgE binding to Ara h 2 was inhibited by Ara h 1 by 78% ± 15% and by Ara h 3 by 80% ± 6%. A subsequent sequence comparison showed that these nonhomologous allergens contained several similar surface-exposed peptides. IgE binding to Ara h 2-derived peptides was completely inhibited by Ara h 1 and Ara h 3. A mixture of these peptides reduced IgE binding to Ara h 1 and Ara h 3 by 20% to 60% and to Ara h 2 by 49% to 89%.nnnCONCLUSIONnOccurrence of similar sequences in the 3 major peanut allergens accounts for the high extent of cross-reactivity among them.

EAACI Guidelines on Allergen Immunotherapy: Allergic Rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side‐effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease‐modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunologys (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergen Immunotherapy.” It aims to provide evidence‐based clinical recommendations and has been informed by a formal systematic review and meta‐analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product‐specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short‐term benefit. The strongest evidence for long‐term benefit is documented for grass AIT (especially for the grass tablets) where long‐term benefit is seen. To achieve long‐term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long‐term benefit and use in children.

Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta‐analysis

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis.

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 Immunologys (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.

Time course of serum inhibitory activity for facilitated allergen–IgE binding during bee venom immunotherapy in children

Background Immunotherapy for bee venom allergy is effective and provides long‐term protection. Venom‐specific IgG4 levels are increased but with no correlation with clinical improvement. Following grass pollen immunotherapy, elevation of antigen‐specific IgG4 is accompanied by increases in IgG‐dependent serum inhibitory activity for IgE‐facilitated binding of allergen–IgE complexes to B cells. As this ‘functional’ assay of inhibitory antibodies may be more predictive of clinical efficacy, we investigated the time course of serum inhibitory activity for IgE‐facilitated antigen binding during venom immunotherapy (VIT) in children and following 2 years of VIT withdrawal.