Bee Sting Challenge Research Articles

Honey bee venom re-challenge during specific immunotherapy: prolonged cardio-pulmonary resuscitation allowed survival in a case of near fatal anaphylaxis

BackgroundSpecific immunotherapy for patients with honey bee hypersensitivity is commonly applied. Re-challenge with venom is performed to prove protection in individual cases.Case presenationWe report a case of near fatal anaphylaxis with asystole for 24 min in a 35-years-old patient with mastocytosis after honey bee sting challenge, despite 5-years of specific immunotherapy. Successful cardio-pulmonary resuscitation was applied for 32 min.ConclusionThis intervention demonstrates, that in anaphylaxis with cardio-vascular arrest, prolonged cardio-pulmonary resuscitation for up to 40 min may be appropriate to overcome the half-life of massively released histamine. Failure of specific immunotherapy was possibly due to sensitization to the allergen Api m10, potentially underrepresented in commercial honey bee venom extracts. Molecular analyses may provide additional clues to the potentially unsuccessful outcome of venom specific immunotherapy, especially in high-risk patients such as mastocytosis.

Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans.

BackgroundSubcutaneous venom immunotherapy (VIT) represents an effective treatment against bee venom allergy. However, it involves long treatment times, high costs, and the risk of adverse events (AEs). Shorter, safer, and cheaper treatment options are therefore pursued.ObjectiveTo determine the safety, immunogenicity, and efficacy of bee venom intralymphatic immunotherapy (ILIT).MethodsIn an open pilot study, 12 patients received bee venom ILIT in three sessions with 14-day intervals: 0.1–5 μg/dose. Ultrasound imaging was applied to guide an injection and to document the lymph node structure. In a second study, 67 patients from 15 centers in Europe and Australia were randomized to receive four doses of either 10- or 20-μg bee venom ILIT with 28-day intervals. Clinical endpoints included specific IgE and IgG and protection after a bee sting challenge. These studies were performed in the years 2000–2003.ResultsIn a proof-of-concept study, no serious AEs were observed. An increase in allergen-specific IgG1 but no IgG4 and IgE was observed. ILIT induced the protection against a bee sting challenge in 7 out of 8 challenged patients. In a multicenter study, an increase in allergen-specific IgG and IgE was observed, with the highest increase in patients receiving a higher ILIT dose. The study was terminated due to several serious AEs upon the sting challenge provocation after the completion of treatment. However, out of 45 patients challenged, 15 (65%) and 18 (82%) patients in the 10- and 20-μg group, respectively, showed an improvement of two grades or more. No correlation was observed between antibody levels and sting protection.ConclusionsWhile a pilot study suggested the safety and efficacy of bee venom ILIT, a high number of AEs seen after the sting challenge following a randomized study indicate that the immunology protection offered by bee venom ILIT is insufficient. Of note, the bee venom allergen extract used in the two studies were from the two different providers. While the first study used a formulation approved for use in subcutaneous VIT, the second study used a nonapproved formulation never tested in humans. Further studies on approved formulations should be performed to generate conclusive results regarding the safety and efficacy of bee venom ILIT.

Predominant Api m 10 sensitization as risk factor for treatment failure in honey bee venom immunotherapy

Component resolution recently identified distinct sensitization profiles in honey bee venom (HBV) allergy, some of which were dominated by specific IgE to Api m 3 and/or Api m 10, which have been reported to be underrepresented in therapeutic HBV preparations. We performed a retrospective analysis of component-resolved sensitization profiles in HBV-allergic patients and association with treatment outcome. HBV-allergic patients who had undergone controlled honey bee sting challenge after at least 6months of HBV immunotherapy (n=115) were included and classified as responder (n=79) or treatment failure (n=36) on the basis of absence or presence of systemic allergic reactions upon sting challenge. IgE reactivity to a panel of HBV allergens was analyzed in sera obtained before immunotherapy and before sting challenge. No differences were observed between responders and nonresponders regarding levels of IgE sensitization to Api m 1, Api m 2, Api m 3, and Api m 5. In contrast, Api m 10 specific IgE was moderately but significantly increased in nonresponders. Predominant Api m 10 sensitization (>50% of specific IgE to HBV) was the best discriminator (specificity, 95%; sensitivity, 25%) with an odds ratio of 8.444 (2.127-33.53; P=.0013) for treatment failure. Some but not all therapeutic HBV preparations displayed a lack of Api m 10, whereas Api m 1 and Api m 3 immunoreactivity was comparable to that of crude HBV. In line with this, significant Api m 10 sIgG4 induction was observed only in those patients who were treated with HBV in which Api m 10 was detectable. Component-resolved sensitization profiles in HBV allergy suggest predominant IgE sensitization to Api m 10 as a risk factor for treatment failure in HBV immunotherapy.

Bee-venom allergy in children: long-term predictive value of standardized challenge tests.

Venom immunotherapy (VIT) is able to protect insect venom-allergic patients against life-threatening sting reactions. Standardized sting challenges can be used as a diagnostic tool to check whether VIT is required. No data are available on the long-term predictive value of sting challenge tests. The purpose of this study was to investigate the long-term predictive value of sequential bee-sting challenges with respect to the ability to predict future sting reactions in bee-venom (BV) allergic children. Between 1988 and 1992, 92 BV-allergic children had been challenged with sequential bee stings at intervals of 2-6 weeks to determine the necessity of VIT. In 1996, all 92 families were followed-up using standardized telephone interviews. Until the follow-up, 61 children (66.3%) had experienced at least one natural bee sting. Based on the results of the initial challenge tests, 13 of the 61 patients had been started on VIT. Two of these 13 (15.4%) developed systemic reactions 1 year after VIT of 5 years, of which one was mild and one was severe. Among the 48 re-stung patients who were not treated with VIT, three children (6.3%) experienced mild systemic reactions, whereas 45 children reported no more than a local reaction. The long-term predictive value of sequential bee-sting challenge tests for systemic reactions in children not treated with VIT remained at a level of 93.8% (95% confidence interval: 82.8-98.7%) even over a period of more than 6 years. Based on this data, we conclude that sequential bee-sting challenges are a powerful tool to determine the necessity for VIT in BV-allergic children.

Case report of venom immunotherapy for a patient with large local reactions

Inadvertent Hymenoptera stings reportedly elicit large local reactions in up to 17% of the general population. Current practice parameters do not recommend venom immunotherapy (IT) for these cases. The goal of this case study was to investigate the clinical and immunologic consequences of venom IT in a newly sensitized individual with large local reactions using an intentional sting challenge before and after treatment to document changes in reaction severity. A 47-year-old man became honeybee venom (HBV)-allergic with progressively larger reactions at honeybee sting sites with subsequent stings. Then, a sting on his forefinger produced a large (62 cm) local reaction with swelling throughout the arm that persisted for more than 4 weeks with severe pain. He refused steroid therapy and voluntarily requested venom IT with honeybee-sting challenges to monitor clinical parameters and immunologic changes in his skin and serum before and 7 months post-HBV maintenance IT. A single pre-IT bee sting challenge produced an 11.4-cm wheal with 13-cm erythema at the sting site after 15 minutes, followed by several weeks of edema that involved the entire arm. After rapid escalation of venom IT to maintenance in 7 weeks, a post-maintenance IT sting challenge with two honeybees produced a 3-cm diameter erythema with no wheal at 15 minutes and no late-phase induration. Complete loss of any visible reaction at the field sting site resulted after 13 months of maintenance venom IT. A HBV-specific IgG antibody level >3.5 microg/mL and IgG/IgE antibody molar ratio >500 persisted over the period of venom IT, with venom skin reactivity diminishing 100-fold. These results support venom IT use in the treatment of Hymenoptera venom-sensitive individuals who experience large local reactions and are at risk for repetitive inadvertent stings.

Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy

Background: Antihistamine premedication has been used to increase safety of specific-allergen immunotherapy. Its influence on the efficacy of this treatment has not been studied so far. Objective: The goal was to analyze the influence of antihistamine premedication on long-term efficacy of specific-allergen immunotherapy. Method: Patients included in a double-blind, placebocontrolled trial who received premedication with terfenadine or placebo during initial rush immunotherapy with honeybee venom in 1988/1989 were assessed in a retrospective analysis for the long-term protective effect, as indicated by the tolerance of a bee sting challenge or field sting during immunotherapy. Results: Of the 52 patients who had participated in the 1988/1989 trial, 47 could be reassessed after an average of 3 years. Of these, 45 were still receiving bee venom immunotherapy. A total of 41 patients were stung by bees while receiving immunotherapy (20 of the terfenadine-premedicated group and 21 of the placebo-premedicated group), 17 with in-field stings and 24 with in-hospital sting challenge. Six (29%) of the patients receiving placebo had a mild-to-moderate systemic allergic reaction, whereas none of the patients receiving terfen-adine reacted to the bee sting (P = .012). Conclusions: These results indicate that antihistamine premedication during the initial phase of specific-allergen immunotherapy may enhance the efficacy of this treatment. (J Allergy Clin Immunol 2001;107:81-6.)

Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom

Background: Specific immunotherapy with honeybee venom (BV) is highly effective, but allergic side effects can occur during treatment. Immunotherapy with peptides containing major T-cell epitopes of the relevant allergen or allergens provides an alternative strategy without these problems. Objective: The study investigates the immunologic mechanisms and clinical effects of immunotherapy with T-cell epitope peptides of the major BV allergen, the phospholipase A2 (PLA). Methods: Five patients with IgE-mediated systemic allergic reactions to bee stings were treated with a mixture of three T-cell epitope peptides of PLA. Ten patients allergic to BV receiving whole BV immunotherapy served as control subjects. Increasing doses of the peptide mixture, up to a maintenance dose of 100 μg, were administered subcutaneously within 2 months. The patients were then challenged with PLA and 1 week later with a bee sting. The cellular and humoral immune response was measured in vitro. Results: No allergic side effects were caused by the peptide immunotherapy, and all patients tolerated the challenge with PLA without systemic allergic symptoms. Two patients developed mild systemic allergic reactions after the bee sting challenge. After peptide immunotherapy, specific proliferative responses to PLA and the peptides in peripheral blood mononuclear cells were decreased in successfully treated patients. The production of T H2 and T H1 cytokines was inhibited, and B cells were not affected in their capacity to produce specific IgE and IgG4 antibodies. Their levels increased after allergen challenge in favor of IgG4. Conclusions: Immunotherapy of BV allergy with short T-cell peptides of PLA induces epitope-specific anergy in peripheral T cells and changes the specific isotype ratio in a fashion similar to that of conventional immunotherapy in successfully treated patients. (J Allergy Clin Immunol 1998;101:747-54.)

Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization *

Hyposensitization with been venom leads to full protection in most, but not all patients with IgE-mediated systemic reactions to bee stings. To determine the relationship of clinical reactivity to the release of mediators and to changes of antibody concentrations in the peripheral circulation at a bee sting challenge test. Blood was sampled before (1 min) and at 15, 60 and 180 min after a sting challenge from 19 patients on hyposensitization. Of these six still reacted and 13 were protected. Histamine, mast cell tryptase, bee venom-specific IgE and IgG in the serum, and histamine release from peripheral blood leucocytes (PBL) upon exposure to bee venom were determined. Tryptase above the detection level was found only at 15 (60) min in 4/6 (1/6) patients who reacted. After the sting challenge there was a significant increase of the histamine levels in patients who reacted at 15 min (P < 0.05) and in patients who did react at 60 and 180 min (P < 0.01). The total histamine content of PBL was significantly decreased after 15 and 60 min in patients who reacted (P < 0.01) and in those that did not (P < 0.05). Bee venom-induced histamine release was significantly reduced in patients reacting and those that did not at 15 min (P < 0.05), and was significantly decreased in reactors also at 60 and 180 min (P < 0.05/0.01). Specific IgG antibodies showed a minor decrease (P < 0.05) after the sting challenge in both groups, whereas specific IgE did not change significantly. These results indicate that bee venom anaphylaxis is associated with the release of mediators from both mast cells as well as basophils. Successful hyposensitization does not induce a state of immunological non-reactivity, but rather alters the magnitude and the pattern of mediator release.

Deliberate bee sting challenge of patients receiving maintenance venom immunotherapy at 3-month intervals

Background: A large part of the cost and inconvenience associated with venom immunotherapy (VIT) is related to the need for monthly treatments. Since VIT is advocated for at least 3 to 5 years, and occasionally longer, reducing the number of venom injections may cut down significantly on both cost and inconvenience. Objective: We evaluated whether maintenance VIT given every 3 months is both safe and effective regarding reactions to treatment injections or field re-stings and lack of systemic reaction (SR) to deliberate challenge sting. Methods: The standard 1-month interval was gradually extended to 3 months in 28 patients (mean age 26 years, range 7 to 76) allergic to bee venom (BV), yellow jacket venom, or both venoms. Nineteen patients allergic to BV were deliberately challenged by a live bee sting. In 15 patients the original SR in the field was moderate; in one patient it was mild; and in three patients it was severe. Results: Mean duration receiving standard maintenance VIT before extending the 1-month interval was 17 months. No patient had an SR while receiving the 3-month VIT therapy. Two patients experienced four field re-stings while receiving the 3-month therapy with no reaction. After the live challenge, there was mild urticaria in a single patient; no SR developed in the rest of the patients. Conclusion: For young patients allergic to BV whose initial SR is mild to moderate and who have already received 1-month VIT for longer than 17 months, the maintenance interval may safely be extended to 3 months while preserving its protective activity against re-stings.(J A LLERGY C LIN I MMUNOL 1994;93:997-1001.)

393 Sequentiell bee sting challenge (SBSC) before hyposensitization therapy (HST) in children with bee venom allergy (BVA)

393 Sequentiell bee sting challenge (SBSC) before hyposensitization therapy (HST) in children with bee venom allergy (BVA)

Sub-class of IgG anti-bee venom antibody produced during bee venom immunotherapy and its relationship to long-term protection from bee stings and following termination of venom immunotherapy.

The IgG sub-class antibody response to bee venom in the four sub-classes was investigated in ten patients during and after venom immunotherapy. All patients tolerated a bee sting challenge 1, 2 and 3 years after the start of treatment as well as 1 and 2 years after treatment was stopped. Anti-phospholipase A2 (PLA2) antibodies were of IgG1 and IgG4 sub-class and rose early in treatment, IgG1 anti-PLA2 fell to pre-treatment levels after 3 years in contrast to IgG4 anti-PLA2 levels, which remained high during maintenance therapy and declined relatively little in the 2 years after the termination of treatment. This data shows that IgG4 antibodies are maintained in the absence of monthly maintenance injections and suggests that they may provide long lasting clinical protection from insect stings.

SUBCLASS TYPING OF SPECIFIC IGG ANTIBODIES IN ALLERGEN IMMUNOTHERAPY

Allergen immunotherapy results in the production of allergen specific antibodies. We investigated whether antibody response in one or more of the four IgG subclasses may be correlated to the clinical improvement. 10 patients suffering from systemic reactions to bee stings were hyposensitized over 3 years. All patients tolerated a bee stingchallenge one, two, and 3 years after the start of treatment, and after bee venom immunotherapy was discontinued. Almost all of the IgG antibodies were restricted to IgG1 and IgG4 subclasses. Although both rose during treatment, IgG4 were maintained at high levels when immunotherapy was discontinued. In conclusion, in serum from normal individuals IgG1 is the predominant main protective antibody. IgG4 subclass specific antibodies appear as a result of a repeat antigenic stimulation as in allergen immunotherapy. Our findings of persisting clinical protection and IgG4 predominant immune response support the protective role of IgG4 in allergic individuals undergoing a venom hyposensitization treatment.

The prognostic significance of specific IgG antibodies in insect sting allergy.

Specific IgG antibodies against bee venom and bee venom components were studied in the serum of 40 bee-sting patients, 60 bee keepers, and 31 control subjects. The highest titres were observed in successfully hypothesized patients and in bee keepers. Subclass-typing in bee-sting allergic patients showed the highest antibody levels in subclass IgG2, followed by IgG3, IgG 4 and IgG1. During hyposensitization, a rise in specific IgG antibodies in all subclasses and against bee venom and all its components was found. The allergic reaction to bee stings disappeared with the rise of specific IgG antibodies, as demonstrated by a bee-sting challenge. After 6 months of hyposensitization therapy, the specific IgG antibodies remained above, and the specific IgE antibodies fell below, the pretreatment levels.

Enzyme-linked immunosorbent assay of allergen-specific IgG antibodies in bee sting allergic patients hyposensitized with pure bee venom

An ELISA is presented for detection of IgG antibodies to bee venom. By this method, sera of 11 bee sting allergic patients, who were treated with rapid hyposensitization with pure bee venom, were tested. The highest antibody titers were observed after 30 days of treatment, a maximum rise of 7.4 +/- 1.5 log 2-titer steps. Pure bee venom is shown to be more potent immunologically than whole body bee extract. Prediction of the clinical success, measured by tolerance to a bee sting challenge, is not yet possible using venom specific IgG determinations.

Immunotherapy in Bee-Sting Anaphylaxis

After nine months of immunotherapy with commercially prepared wholebody bee extract, a beekeeper's wife experienced anaphylaxis after a controlled bee-sting challenge. High risk of future bee stings prompted a decision to attempt desensitization with honeybee venom. This was extracted from the bee into Coca solution and administered parenterally in increasing daily doses until an equivalent of one venom sac was given per day. This maintenance dosage was continued for a month. Anaphylaxis did not occur after another bee-sting challenge. Therapy has been maintained with venom. With this treatment, there has been an increase in the level of IgG-blocking antibody and a fall in IgE titer to bee venom (radioallergosorbent test [RAST]).