When can immunotherapy for insect sting allergy be stopped?

BACKGROUND: Stings by Hymenoptera (honey bees, vespids, ants) can cause systemic allergic reactions (SARs). Venom immunotherapy (VIT) is highly effective and reduces an allergic patient's risk of a recurrent SAR to less than 5-20%. The risk of a recurrent SAR to a re-sting decreases the longer VIT is continued. The recommended duration of VIT is at least 3 to 5 years. RISK FACTORS: Risk factors for recurrent SARs to a sting after stopping VIT have been identified and discussed: Recommendations concerning stopping VIT: For patients without any of the identified risk factors, VIT should be continued for 5 rather than 3 years. In patients with definite risk factors, a longer duration of VIT has to be discussed before stopping it. In mast cell disorders, VIT for life is recommended. Because of the residual risk of SARs after VIT, all patients are advised to carry an epinephrine autoinjector indefinitely and to continue to take measures to avoid Hymenoptera stings.

Hymenoptera venom proteins and peptides for diagnosis and treatment of venom allergic patients.

Stings by insects of the order Hymenoptera cause systemic, sometimes life threatening allergic reactions in 1 - 5% of the population in Europe and North America. Responsible for these reactions is an IgE mediated sensitization to proteins of the venoms injected during the stings of social Hymenoptera species, mainly the honey bee (Apis mellifera), vespids like Vespula sp., Polistes sp. and ants, in southern US and central America Solenopsis invicta and in Australia Myrmecia pilosula. The venoms of these insects are composed of low molecular weight substances like biogenic amines, cytotoxic and neurotoxic peptides like melittin, apamin, MCD-peptide and mastoparan, and proteins, mostly enzymes like phospholipase A and hyaluronidase, which are major venom allergens. Immunotherapy with Hymenoptera venoms has been shown to protect 80 to over 95% of patients with a history of systemic allergic sting reaction from further systemic reactions after re-stings. The procedure, safety and efficacy of this treatment and the immune mechanisms involved are discussed. Since ancient times honey bee venom has been used for the treatment of chronic inflammatory disease, especially arthritis. Anti-inflammatory effects of bee venom have been documented in animal experiments. Most clinical studies suggest an antiinflammatory effect as well, but are uncontrolled. The only few controlled studies could not confirm efficacy of treatment with bee venom so far.

Insect venoms.

Insect venoms applied by stings of social Hymenoptera, like honey bees, vespids or ants are -together with foods and drugs - the most frequent elicitors of anaphylaxis in humans. Besides taxonomy, the biology of the responsible social Hymenoptera is important: guidelines based upon its knowledge allow to reduce the risk of further stings in patients with a history of venom anaphylaxis. Epidemiology of venom anaphylaxis has special aspects with regard to prevalence, fatality and natural history. An estimated 200 individuals die every year in Europe from anaphylaxis following Hymenoptera stings. Most of the relevant venom protein allergens have been identified and many of them have been expressed in recombinant form. Proof of venom sensitization is based on skin tests with venoms and serum venom-specific IgE antibodies as standard diagnostic tests. Allergen-specific immunotherapy with Hymenoptera venoms is highly effective and therefore recommended for all patients with a history of Hymenoptera sting anaphylaxis and positive diagnostic tests with the respective venom. Frequent cross-reactions to venoms of different Hymenoptera species may cause difficulties in identifying the responsible species and the selection of the respective venom for immunotherapy.

The problem of anaphylaxis and mastocytosis.

Mastocytosis is a rare disease characterized by an elevated whole body mast cell number. Anaphylaxis is a severe, generalized hypersensitivity reaction with rapid onset. The problem of anaphylaxis and mastocytosis is due to strongly increased mediator release from the elevated mast cell number during allergic reactions. This explains the much higher prevalence of anaphylaxis in mastocytosis than in the general population and its severe and sometimes fatal course. Because of the increased risk of anaphylaxis in mastocytosis, all patients with severe or recurrent anaphylaxis should be analyzed for underlying mastocytosis by estimation of baseline serum tryptase. If this is elevated, patients also should be tested via skin examination for cutaneous mastocytosis and with a bone marrow biopsy. All patients with mastocytosis and anaphylaxis must be instructed about avoiding the responsible elicitors and should carry an emergency kit with adrenaline for self-application. In mastocytosis patients with anaphylaxis due to Hymenoptera stings, venom immunotherapy is recommended for life.

Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy.

BACKGROUND: H1 antihistamines increase safety during allergen-specific immunotherapy and might influence the outcome because of immunoregulatory effects. OBJECTIVE: We sought to analyze the influence of 5 mg of levocetirizine (LC) on the safety, efficacy, and immunologic effects of ultrarush honeybee venom immunotherapy (BVIT). METHOD: In a double-blind, placebo-controlled study 54 patients with honeybee venom allergy received LC or placebo from 2 days before BVIT to day 21. Side effects during dose increase and systemic allergic reactions (SARs) to a sting challenge after 120 days were analyzed. Allergen-specific immune response was investigated in skin, serum, and allergen-stimulated T-cell cultures. RESULTS: Side effects were significantly more frequent in patients receiving placebo. Four patients receiving placebo dropped out because of side effects. SARs to the sting challenge occurred in 8 patients (6 in the LC group and 2 in the placebo group). Seven SARs were only cutaneous, and 1 in the placebo group was also respiratory. Difference of SARs caused by the sting challenge was insignificant. Specific IgG levels increased significantly in both groups. Major allergen phospholipase A(2)-stimulated T cells from both groups showed a slightly decreased proliferation. The decrease in IFN-gamma and IL-13 levels with placebo was not prominent with LC, whereas IL-10 levels showed a significant increase in the LC group only. Decreased histamine receptor (HR)1/HR2 ratio in allergen-specific T cells on day 21 in the placebo group was prevented by LC. CONCLUSIONS: LC reduces side effects during dose increase without influencing the efficacy of BVIT. LC modulates the natural course of allergen-specific immune response and affects the expression of HRs and cytokine production by allergen-specific T cells.

Bee venom allergy in beekeepers and their family members.

PURPOSE OF REVIEW: To analyze prevalence of allergic sting reactions, including the clinical and diagnostic features as well as management options in a population heavily exposed to honeybee stings such as beekeepers and their family members. RECENT FINDINGS: The higher sting frequency is associated with an increased prevalence of allergic sting reactions. Major risk factors for allergic sting reactions in beekeepers are: fewer than 10 annual stings, an atopic constitution and symptoms of upper respiratory allergy during work in the beehive. Bee venom allergic beekeepers have higher levels of bee venom-specific IgG but lower skin sensitivity and bee venom-specific IgE than normally exposed bee venom allergic patients. Safety of bee venom immunotherapy is higher in beekeepers than in allergic controls, while efficacy of this treatment is similar in both groups. SUMMARY: Beekeepers and their family members are at an increased risk of severe sting anaphylaxis and therefore need especially careful instruction with regard to avoidance of re-exposure, emergency treatment and specific immunotherapy with bee venom.

Use of beta-blockers during immunotherapy for Hymenoptera venom allergy.

BACKGROUND: Beta-blockers may aggravate anaphylactic reactions and interfere with treatment. There is therefore concern about their use in patients who have a history of anaphylaxis or are on allergen immunotherapy. Immunotherapy is the best available treatment for prevention of life-threatening anaphylaxis to Hymenoptera stings, which is often observed in elderly patients who have cardiovascular disease and therefore are on beta-blocker treatment. OBJECTIVE: To analyze the risk of beta-blocker treatment during venom immunotherapy. METHODS: We screened all 1682 patients with Hymenoptera venom allergy seen during a period of 34 months for immunotherapy, cardiovascular disease, and treatment with beta-blockers. RESULTS: Of the 1389 patients in whom immunotherapy was recommended, 11.2% had cardiovascular disease, and 44 of these were on beta-blockers before immunotherapy. In 31 of those, the drug was replaced before starting treatment. In 3 with coronary heart disease and 1 with severe ventricular arrhythmia, the drug was continued throughout immunotherapy. In 9, it was reintroduced after reaching the maintenance dose. In an additional 12 patients, beta-blockers were newly started during immunotherapy. Of 25 patients on beta-blockers during immunotherapy, 3 (12%) developed allergic side effects, compared with 23 (16.7%) of 117 with cardiovascular disease but without beta-blockers. Systemic allergic symptoms after re-exposure by sting challenge or field sting were observed in 1 of 7 (14.3%) with and 4 of 29 (13.8%) without beta-blockade. No severe reactions to treatment or sting reexposure were observed in patients with beta-blockade. CONCLUSION: Combination of beta-blockers with venom immunotherapy may be indicated in heavily exposed patients with severe cardiovascular disease.

Recent developments and future strategies for immunotherapy of insect venom allergy.

PURPOSE OF REVIEW: Hymenoptera venom allergy may cause life-threatening, sometimes even fatal, allergic reactions and thus may be associated with a serious reduction in the quality of life. Venom immunotherapy is effective in the majority of patients with this allergy. Treatment failures do however occur and immunotherapy may cause frequent systemic allergic side effects, especially in honeybee venom-allergic patients. New strategies to improve safety and efficacy of this treatment are therefore of general interest. RECENT FINDINGS: Among these new strategies are premedication with antihistamines: this definitely reduces side effects and based on recent in-vitro experiments and one clinical controlled study may even improve efficacy by modulating the T-cell response through interference with histamine receptors on these cells. Furthermore, during recent years the cDNA of most major allergens of bee and vespid venoms has been cloned and these allergens have been expressed in recombinant form. This allows for the preparation of patient-tailored extracts, with or without reduction of their allergenicity, for example by using unrefolded or point-mutated recombinant allergens. Yet another approach is the use of non IgE binding peptide fragments of the allergen with preserved T-cell epitopes for immunotherapy. Such preparations of bee venom phospholipase A2 have been used successfully in pilot studies. Finally, DNA vaccination with phospholipase A2 sequence plasmids has proved effective in one experimental study in sensitized mice. SUMMARY: A number of new strategies for venom immunotherapy, mostly based on genetic engineering, have been described and we await their use in clinical medicine.