Yes / 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. / European Union's Seventh Framework Programme FP7. Grant Number: 601763

Background: Myrmecia pilosula (the jack jumper ant, JJA) is the principal cause of ant venom anaphylaxis in Australia. Whereas honeybee and wasp venom allergy can be treated by venom immunotherapy (VIT), no such treatment is available for ant sting allergy. In addition, information on the natural history of JJA sting allergy is required to identify those most likely to benefit from immunotherapy. The main objectives of this research were to establish: (i) the prevalence, natural history and determinants of reaction severity for JJA allergy, and; (ii) the efficacy and tolerability of JJA VIT. Methods: A search of the Royal Hobart Hospital (RHH) forensic register, a random telephone survey, and a review of emergency department (ED) presentations were performed. Three hundred eighty-eight JJA allergic volunteers were assessed, including serum venom-specific IgE RAST, and then followed up for accidental stings over a 4-year period. Finally, a randomised double-blind, placebo-controlled, crossover trial of JJA VIT was performed. Laboratory parameters measured during the trial were; leukocyte stimulation index (SI), IL-4 production, IgE RAST, histamine release test (HRT), leukotriene release test (LRT) and basophil activation test (BAT). Intradermal venom skin testing (VST) was also performed at trial entry. Findings: The prevalence of JJA sting allergy was 2.7% in the Tasmanian population, compared to 1.4% for honeybee. People aged 35 or older had a greater risk of both sting allergy and hypotensive reactions. Four deaths were identified, all in adults with significant comorbidities. During follow-up, 79 (70%) of 113 accidental jack jumper stings caused systemic reactions. Only prior worst reaction severity predicted the severity of follow-up reactions, with the majority of people experiencing similar or less severe reactions when stung again. Sixty-eight otherwise healthy JJA allergic adult volunteers were enrolled in the clinical trial. Systemic reactions to therapy were recorded in 34% during VIT. Objectively defined systemic reactions to sting challenges arose in 1/35 after VIT (mild self-limiting urticaria only) versus 21/29 in the placebo group. Treatment with oxygen, intravenous adrenaline infusion and volume resuscitation was effective and well tolerated. Hypotension was always accompanied by a relative bradycardia, which was severe and treated with atropine in two patients. In the placebo group, only VST and HRT were predictive of sting challenge results. Although IgE RAST, leukocyte SI and IL-4 production, LRT and BAT all correlated well with VST, they did not predict sting challenge outcome. After successful VIT, venom-induced leukocyte IL-4 production tended to fall, whereas IgE RAST increased and a natural decline in HRT reactivity was reversed. Interpretation: VIT is highly effective in prevention of JJA sting anaphylaxis and is likely to be of most benefit to people with a history of severe systemic reactions, which usually occur in people aged over 35. Neurocardiogenic mechanisms &/or direct cardiac effects may be important factors in some anaphylaxis deaths. Systemic reactions to immunotherapy are common and require immediate access to resuscitation facilities. The HRT warrants further investigation as a test for selecting those most likely to benefit from VIT. None of the tests evaluated appear to be reliable markers of successful VIT.

The aim of my thesis is the introduction of the systemic mastocytosis and discussion about results of allergen immunotherapy in patients with systemic mastocytosis and its preventive effects against recurrent anaphylactic reactions. Patients with systemic mastocytosis are more prone to severe systemic anaphylactic reactions after Hymenoptera stings than in the general insect venom allergic population patients without elevated basal tryptase. This severe reaction can result in the death of the patient, it is important to prevent it prophylactically. The medication of choice in insect venom allergic patients is hyposensibilization therapy - allergen immunotherapy, which uses venom allergens of causal Hymenoptera (honey bee, yellow jacket). The thesis aims to summarize the results obtained so far about the appropriateness of this treatment in patients with systemic mastocytosis, side-effects during VIT, optimal dosing schedule and duration of treatment in these patients.

Die Wespengiftallergie stellt eine typische allergische Sofortreaktion dar. Für diese IgE-vermittelten, pathologischen Immunreaktionen ist die spezifische Immuntherapie (IT) die einzige zur Zeit zur Verfügung stehende kausale Therapie. Die Wirkmechanismen sind trotz intensiver Bemühungen weiterhin nicht vollständig aufgeklärt. Als wichtigste These wird zur Zeit eine Verlagerung des pathologischen, TH2-dominierten Zytokinmilieus in Richtung "normales" TH1-Milieu diskutiert. Es wurde auch eine reduzierte Mediatorfreisetzung von Effektorzellen, eine verminderte Leukozytenproliferation, eine verminderte Endorganantwort und charakteristische Ig-Titer-Veränderungen mit initialem Anstieg und längerfristigem Abfall des sIgE und Anstieg des sIgG4 beschrieben. In der vorliegenden Arbeit wurde der Einfluß der IT auf periphere B-Zellen hinsichtlich ihrer Ig-Produktion und ihres Phänotyps untersucht. 15 Patienten mit systemischen Reaktionen nach Wespenstich, Nachweis von spezifischem IgE und positivem Hauttest, bei denen eine Schnell-Immuntherapie eingeleitet wurde, wurden vor Beginn der Therapie (Tag 1), am Tag ihrer Entlassung (Tag 6), also einen Tag, nachdem die Erhaltungsdosis von 100 µg erreicht wurde, und vor der 2. ambulanten Allergeninjektion am 26. Tag untersucht. Die Expression von CD5, CD23, CD32, CD40, CD54, CD86, CD95, HLA-I-ABC und HLA-II-DR wurde auf peripheren mononukleären Blutzellen durchflußzytometrisch bestimmt. Anti-CD19 FITC wurde als spezifischer B-Zellmarker benutzt. Die Serum-Titer des Gesamt-IgE, Wespengift-spezifischen IgE und Wespengift-spezifischen IgG4 wurden mittels ELISA bestimmt. Zur statistischen Auswertung wurde der Wilcoxontest für nicht-parametrische, verbundene Daten benutzt. Die Expression von CD54, CD5, CD32 und HLA-II-DR wurde durch die IT signifikant und die von CD23 tendentiell modifiziert. So war die Expression dieser Moleküle auf der Oberfläche peripherer B-Zellen am Tag 6 im Vergleich zum Ausgangswert vom Tag 1 reduziert. Am 26. Tag wurden wieder Werte auf der Höhe der Ausgangswerte vom Tag 1 gemessen. Dagegen veränderte sich die Expression von CD40, CD86, CD95 und HLA-I-ABC während der untersuchten Zeitpunkte nicht. Die Ig-Titer veränderten sich in der für die IT charakteristischen Weise. So stieg nach 3 Wochen der Gesamt-IgE-, sIgE- und sIgG4-Titer hochsignifikant an. Die Expression der untersuchten Oberflächenmoleküle ist als Indikator für Veränderungen der Aktivationslage und des funktionellen Status der Zellen während der IT zu interpretieren. So spricht die Reduktion der Expression von CD32, CD54 und HLA-II für eine verminderte Aktivierungslage der peripheren B-Zellen. Ferner deutet die Reduktion von CD5 und CD32 auf eine Anergie der B-Zellen hin. Durch die reduzierte Expression von CD23 und CD54 könnte die T-B-Zell-Interaktion verschlechtert werden, die für die Effektorfunktionen beider Zellen bedeutsam ist.Einen wesentlichen Beitrag zur Wirksamkeit der IT könnte auch die verminderte Expression des HLA-II leisten, da HLA-II für die Ag-Präsentation essentiell ist. In dieser Arbeit wurde gezeigt, daß die spezifische Immuntherapie einen Einfluß nicht nur auf die Ig-Produktion der B-Zellen hat, sondern auch auf deren Phänotyp. Dies könnte Hinweise auf bisher nicht bekannte Mechanismen bieten, die an der Wirksamkeit der IT beteiligt sind. / Wasp-venom allergy is a typical IgE-mediated allergic reaction. Specific immunotherapy (IT) is the only currently available causal therapy for IgE-mediated allergies. The mechanisms responsible for the efficacy of IT are still not fully understood. So far, the main focus of research has been on changes of T-helper cell (TH) cytokine production with a shift from TH2 to TH1 cytokines. Reduced mediator secretion from effector cells of allergic reactions, decreased leukocyte proliferation, lowered responsiveness of end organs and changes in immunoglobulin levels have been reported as well. The purpose of this study was to investigate the influence of IT on phenotype and Ig-production of B-lymphocytes. 15 venom allergic patients with a history of systemic reactions after a wasp sting and venom-specific skin test reactivity as well as serum IgE were investigated before VIT (day 1), one day after reaching maintenance dose of 100 µg (day 6) during inpatient rush VIT, and again on day 26 during continued outpatient maintenance therapy. Changes in the serum levels of total IgE, allergen-specific IgE (sIgE) and sIgG4 were measured by ELISA. Expression of CD5, CD23, CD32, CD40, CD54, CD86, CD95, HLA-I-ABC and HLA-II-DR on double labeled B cells was studied by flow cytometry of peripheral blood mononuclear cells. On day 6, cell surface expression of CD54, CD5, CD32 and HLA-II-DR was decreased significantly in intensity and numbers of positive cells, compared to day 1, while on day 26, expression of these molecules approached again baseline levels. Furthermore, a trend to decreased CD23 was noted on day 6. No changes were observed for CD40, CD86, CD95 and HLA-I-ABC. Levels of total IgE, sIgE and sIgG4 showed a significant increase after 26 days of VIT. These data show that initiation of rush VIT has profound effects on B-cell phenotype and Ig-production. Reduced expression of surface molecules can be interpreted as a reduction of activation status of B-cells as well as reduced ability to present antigen and to costimulate other leukocytes. B cells may thus be additional direct or indirect targets of high dose antigen therapy and contribute to the efficacy of IT.