Safety of hymenoptera venom immunotherapy: a systematic review.
Topic: Immunotherapy

The efficacy of venom immunotherapy (VIT) in patients with insect sting allergy is not questioned. However, its safety, especially when honeybee is used, is a matter of concern.

PICO
Population: Patients with insect sting allergy
Intervention: Venom immunotherapy (VIT)
Comparison: Standard care or placebo
Outcomes: Safety of VIT, especially when honeybee is used

Included studies:
title: A controlled trial of immunotherapy in insect hypersensitivity.
abstract: Insect hypersensitivity is currently treated by immunization using whole-body extracts. We compared this regimen with immunotherapy using insect venoms or placebo in groups of 20 patients matched for history and sensitivity, as judged by venom skin test, histamine release and IgE antibody to venom. After six to 10 weeks of immunization, systemic reactions to stings occurred in seven of 12, seven of 11, and one of 18 patients treated with placebo, whole-body extract, and venom, respectively. Placebo and whole-body extract gave similar results and were significantly less effective than venom immunotherapy (P less than 0.01). The 14 patients with failure of treatment with whole-body extract and placebo were subsequently provided with venom immunotherapy; one reacted to a subsequent sting. We conclude that venom immunotherapy is clinically superior to therapy on whole-body extract or placebo.
title: A double blind study on immunotherapy with chemically modified honey bee venom: monomethoxy polyethylene glycol-coupled versus crude honey bee venom.
abstract: 24 patients with honey bee sting allergy were treated with either honey bee venom (HBV) or monomethoxy polyethylene glycol-coupled HBV (PEG-HBV) in a double blind trial. Both treatments induced a strong increase in HBV-specific IgG antibodies in most patients. Immunotherapy with PEG-HBV was much better tolerated than that with HBV. Conversely, patients on HBV did considerably better during a sting challenge with a living honey bee. Only 4 developed a large local and one a mild systemic reaction compared to 7 large local and 3 moderate to severe systemic reactions in the PEG-HBV-group. A higher maintenance dose of PEG-HBV may still be well tolerated but prove more effective at reexposure.
title: Efficacy, safety, and modulation of immunologic markers by immunotherapy with honeybee venom: comparison of standardized quality depot versus aqueous extract.
abstract: Venom immunotherapy (IT) is a very effective method for the treatment of Hymenoptera venom allergy. We compared safety, efficacy, and modulation of specific immunologic parameters in 70 patients sensitized to Apis mellifera, treated for > or = 5 years with standardized quality (SQ) aqueous IT, either with a rush (n = 20) or with a cluster (n = 20) induction protocol, or with an SQ depot extract and a cluster induction protocol (n = 30). We made an open, noncontrolled study. Side effects were monitored and the effects of field stings during the maintenance phase of the treatment and after its interruption were recorded. Skin reactivity to Apis was measured by end point dilution and specific serum immunoglobulin E (IgE) were measured by a solid-phase-based assay. The depot IT was better tolerated than aqueous IT with rush induction. This was caused by mainly the lower frequency in the induction phase of systemic side effects (3.4% versus 36.8% [p < 0.0041] on a "per patient" and 0.1% versus 0.9% [p = 0.0092] on a "per dose "basis, respectively). The cluster protocol with the aqueous extract tended to be better tolerated that the rush protocol. About one-half of patients from each group were re-stung during the study and all suffered only minor discomfort. Reduction of skin reactivity and of serum-specific IgE was significant in the three groups (p < 0.02 in all cases). SQ Depot IT to Apis venom allergy administered with a cluster protocol induces less side effects and is equally effective then IT with SQ aqueous extract administered with a rush protocol.
title: The incidence and nature of adverse reactions to injection immunotherapy in bee and wasp venom allergy.
abstract: The incidence, time course and nature of systemic reactions to injections of bee and wasp venom during immunotherapy have been estimated in an open, prospective, single centre study. One hundred and nine survivors of moderate to severe systemic reactions to stings from hymenoptera, received courses of bee or wasp venom by monthly subcutaneous injection for up to 3 years. Systemic reactions were recorded after 7.5% of 946 weekly venom injections during the initial phase of treatment, and after 2.1% of 1789 monthly maintenance injections. In both phases of treatment, reactions were more frequent after bee (17% of initial phase, 7.8% of maintenance treatment) than after wasp (3% of initial phase, 0.3% of maintenance treatment) venom injections. The percentage of patients experiencing at least one reaction was also higher for bee (46%) than for wasp (14%) sensitive patients. Over 80% of reactions began within 30 min of injection, over 90% within 1 h and only two (2%), between 1 and 2 h, the remaining six (5.5%) starting more than 2 h after injection. Only 0.47% of venom injections produced a systemic reaction which was severe enough to require adrenaline treatment. The female patients experienced more reactions (21% of the wasp, 60% of the bee, sensitive) than the males (5.5% wasp, 20% bee). Age and atopy did not appear to be significant risk factors for systemic reactions. We conclude that wasp and bee venom immunotherapy in a conventional dosage regimen was generally well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)
title: Analysis of safety, risk factors and pretreatment methods during rush hymenoptera venom immunotherapy.
abstract: The safety profile of venom immunotherapy is a relevant issue. We evaluated the frequency of severe adverse events (SAE), associated risk factors, retrospective comparison of pretreatment protocols including solely H1 receptor blockers and a combination of H1 and H2 receptor blockers during rush Hymenoptera venom immunotherapy.
title: Immunotherapy with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ): immunologic and clinical results of a prospective study over 3 years.
abstract: This prospective study over 3 years investigated the safety, immunogenicity, and effectiveness of immunotherapy (IT) with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ, ALK Laboratories) in patients with previous, severe, systemic, IgE-mediated, anaphylactic reactions to Hymenoptera stings. Seventeen patients were treated with honeybee venom (BV), 13 with yellow-jacket venom (YJV), and 5 with both. No severe reactions to IT were noted. Only 3 BV-allergic patients experienced mild systemic reactions of grades I or II (1 per 139 injections) during the increase phase. As for the immunologic data, there was a significant decrease in specific IgE antibodies after 1 year, and a significant increase in specific IgG and IgG4 antibodies on reaching the maintenance dose, with a further rise after 1, 2, and 3 years. Moreover, a significant decrease in anti-IgE autoantibodies was observed in the BV group. Out of the 11 patients that were occasionally restung by the relevant insect (totaling 19 stings in all), only one patient developed mild systemic allergic symptoms after a third sting. In view of these results, we consider IT with aluminum hydroxide adsorbed insect venom extracts to be safe, immunogenic, and effective. The low rate of side-effects may be due to the slow release of the venom in the aluminum hydroxide adsorbed form.
title: Survey of patients after discontinuing venom immunotherapy.
abstract: Venom immunotherapy rapidly reduces the risk of a systemic sting reaction in adults from 30% to 70% to less than 2%. When venom immunotherapy is stopped after 5 years or longer, the risk of a systemic sting reaction is 5% to 15% during the first few years after stopping treatment. It is uncertain whether systemic sting reactions will occur more than 5 years after discontinuing venom immunotherapy and whether treatment can be safely stopped in some patients after less than 5 years.
title: The safety of cluster immunotherapy with aluminium hydroxide-adsorbed honey bee venom extract.
abstract: Venom immunotherapy (VIT) with aqueous extracts is considered a life-saving treatment in insect allergy, but systemic side effects are quite common, especially in patients sensitized to Apis mellifera venom. Only a few studies are available regarding depot VIT administered according to the standard weekly schedule, while no data are available for cluster VIT with depot preparations. This study was designed to compare the tolerance of aqueous cluster or rush VIT versus cluster depot VIT in patients sensitized to Apis mellifera. Fifty-five patients with a history of systemic reaction (grade II to IV according to Müller) after an Apis mellifera sting were divided at random into 3 groups. Forty patients were treated with aqueous VIT (20 according to a cluster schedule and 20 according to a rush schedule) and 15 with Depot VIT according to a cluster schedule. All local and systemic side effects were recorded. Four patients belonging to the aqueous-cluster, 4 belonging to the aqueous-rush, and 1 belonging to the depot-cluster schedule had large local reactions after VIT (p < 0.009). Systemic side effects were recorded in 1, 7 and 0 patients (p < 0.003) respectively. No statistically significant difference was found between the two cluster regimens in the frequency of side effects. Depot VIT administered according to a cluster schedule was well tolerated, and its tolerance is better than aqueous-rush VIT for Apis mellifera.
title: Specific ultrarush desensitization in Hymenoptera venom-allergic patients.
abstract: Hymenoptera venom hypersensitivity is an epidemiologically important problem. The only effective treatment in the management of venom-allergic patients with a history of generalized reactions to insect sting is specific immunotherapy.
title: A modified ultrarush insect venom immunotherapy protocol for children.
abstract: The prevalence of insect venom allergy in the European population is approximately 5%. Hymenoptera venom allergy is an important epidemiological problem. Ten to 40 deaths are reported annually in Germany. In contrast to conventional dose increase schedules lasting a minimum of 5 days, shorter protocols reduce the patient's stay in the hospital and provide an earlier protection toward stings. Clinical studies on ultrarush protocols have been published for adult patients, but very little data are currently available for children. Therefore, we investigated the safety and tolerability of a shortened insect venom immunotherapy (VIT) in children and adolescents. Forty-three children and adolescents (aged 4-18 years) with insect venom allergy were treated in this study. Five children were hyposensitized according to the ultrarush protocol with nine injections (as suggested by Brehler et al. (Safety of a two-day ultrarush insect VIT protocol in comparison with protocols of longer duration and involving a larger number of injections. J Allergy Clin Immunol 105:1231-1235,2000); 38 children received the modified ultrarush schedules with only eight subcutaneous injections. With both protocols the maintenance dose (100 microg) was achieved in 24 hours. Twenty-five patients (58.1%) showed no reaction after the injections. In 11 patients (25.6%), extensive erythema (>5 cm, maximum of 20 cm) was found at the injection site. Erythema and edema (>5 cm, maximum of 15 cm) were observed in seven patients (16.2%). The maintenance dose was well tolerated, with no systemic reaction in any patient. The modified ultrarush protocol for insect VIT used in this study showed very good tolerability and safety in children and adolescents. This dose regimen can increase compliance by shortening inpatient stay and reduces hospital costs.
title: Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety.
abstract: Venom immunotherapy (VIT) for Hymenoptera allergy is accepted as safe and effective. However, widely varying success rates and frequencies of side effects are reported. Differences between various Hymenoptera species could account for these diverging results. We therefore analyzed 205 patients with a history of systemic allergic reactions to either honeybee (148 patients) or yellow jacket stings (57 patients) during VIT. All patients had a positive skin test to the respective venom before VIT, were monitored for side effects of VIT, and submitted to a sting challenge while they were receiving VIT. Patients with honeybee-venom allergy had a higher sensitivity in both skin tests (p less than 0.05) and RAST (p less than 0.001) than patients with yellow jacket-venom allergy. They developed systemic side effects to VIT injections significantly more often (41% versus 25%; p less than 0.01) and also reacted more frequently to the sting challenge (23% versus 9%; p less than 0.01) than patients with yellow jacket-venom allergy. We conclude that results obtained from studies on the allergy to one Hymenoptera venom cannot be extrapolated to allergies to other Hymenoptera venoms.
title: Efficacy of antihistamine pretreatment in the prevention of adverse reactions to Hymenoptera immunotherapy: a prospective, randomized, placebo-controlled trial.
abstract: Some clinical studies suggest that a combination of an H1- and H2-antagonist may be effective in the prophylaxis of allergic reactions.
title: Flexible approaches in the design of subcutaneous immunotherapy protocols for Hymenoptera venom allergy.
abstract: Venom immunotherapy is an effective method for the treatment of Hymenoptera venom allergy. Different extracts and treatment schedules are available.
title: Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis.
abstract: Rapid venom immunotherapy regimens have been developed to provide safe protection to individuals who have experienced Hymenoptera anaphylaxis by administering greater than 50 micrograms of venom over two to three hours on treatment day 1. A rapid venom immunotherapy protocol which consisted of administration of a cumulative dose of 58.55 micrograms of each venom on treatment day 1 followed by an accelerated build-up over 3 weeks to a final maintenance dose of 100 micrograms per venom was developed by our group in 1984.
title: Immunotherapy with yellow jacket venom. A comparative study including three different extracts, one adsorbed to aluminium hydroxide and two unmodified.
abstract: Thirty-two patients with previous systemic allergic reaction to yellow jacket stings were randomly allocated to three groups receiving immunotherapy with different preparations of yellow jacket venom: 1) extract adsorbed to aluminium hydroxide (Alutard-SQ), 2) Pharmalgen extract or 3) non-adsorbed extract from Allergologisk Laboratorium (ALK aq.). Regular examinations showed a decrease in skin prick test size in nearly all patients. Specific IgE-antibody (RAST and CRIE scores) showed a similar, but not significant tendency to decrease in all three groups. Specific IgG-antibody increased considerably in the Alutard group only; after 2 years, however, no difference could be detected between the three groups. During dose increase, patients treated with ALK aq. generally had smaller local reactions to injections than those treated with Pharmalgen. Few systemic reactions occurred in all three groups. Nineteen patients treated for 2 1/2-3 1/2 years were challenged in-hospital with stings from yellow jackets. No systemic and only minor local reactions occurred. Consequently, with the dose regimens applied all three extracts seem effective even though no common changes in either specific IgE or IgG could be demonstrated.
title: Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.
abstract: Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors.