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BACKGROUND: The increased incidence of bee-sting allergy among beekeepers is well known, whereas Hymenoptera hypersensitivity among forestry workers, who are frequently stung by Hymenoptera, is not well understood. OBJECTIVE: To elucidate the nature of Hymenoptera hypersensitivity among forestry workers and analyze the mechanism involved in Hymenoptera-induced systemic reactions. METHODS: A questionnaire was administered and yellow jacket venom-specific IgE antibody titers measured in 323 forestry workers and 100 age-matched office workers with little occupational exposure to Hymenoptera stings as a control group. RESULTS: From the questionnaire it was found that the percentage of systemic reactions to Hymenoptera stings was significantly greater in the forestry workers than in the control subjects (P < .01). The number of sting exposures was significantly higher in the forestry workers than in the control subjects (P < .01) and was closely correlated with episodes of systemic reaction. Yellow jacket venom-specific IgE antibody titers were significantly higher in forestry workers with episodes of systemic reaction compared with those with only local or large local reactions to Hymenoptera (P < .05), although more than half of these subjects had undetectable IgE antibody titers to yellow jacket venom. IgE antibody titers against yellow jacket venom were closely correlated with those of paper wasp (rs = .802, P < .001), which is another frequent source of Hymenoptera stings. In workers with episodes of sting exposure within the most recent 3 years, the period from the last sting was not correlated with yellow jacket venom-specific IgE antibody titers. CONCLUSIONS: The number of sting exposures may contribute to systemic reactions to Hymenoptera sting, and some mechanism other than IgE mediated hypersensitivity may also be involved in Hymenoptera-induced systemic reactions.
A total of 248 patients with systemic reactions to Hymenoptera envenomation were studied. There were 138 adults and 110 children. Twenty-eight of these 248 (11.3%) had family members with histories consistent with Hymenoptera anaphylaxis. These included five mothers and sons, two sister pairs, three pairs of sister-brother, one pair brother-brother, and one pair father-daughter. In one extended family, a father, mother, son, and mother's sister had Hymenoptera sensitivity. Ninety-six consecutive allergic patients without Hymenoptera sensitivity served as controls, and of these, 3.1% had family members with Hymenoptera sensitivity. The occurrence of Hymenoptera sensitivity in families of patients with Hymenoptera sensitivity is statistically different from our controls (11.3% vs 3.1%, p = 0.0195). There appears to be a hereditary aspect for Hymenoptera sting sensitivity.
In Japan, approximately 40 persons die annually from anaphylaxis caused by Hymenoptera stings. Venom immunotherapy is considered safe and effective for the treatment of allergic systemic reactions caused by Hymenoptera stings in patients with Hymenoptera allergy. We studied the efficacy and safety of rush immunotherapy in patients who had a history of systemic reactions to Hymenoptera stings in Japan. Between 1988 and 2002, 95 patients with a history of systemic reactions to Hymenoptera stings were investigated. The stings originated from honeybees in 5 patients, yellow jackets in 28, wasps in 48, both yellow jackets and wasps in 9, and both yellow jackets and honeybees in 5. All patients had venom-specific IgE antibodies in sera (RAST score > or = 2) and received rush immunotherapy with venom extracts at our hospital. Forty-three patients had 63 field re-stings during immunotherapy. Of these patients, 41 (95.3%) with 59 field re-stings (93.7%) had no systemic reactions. Two patients (4.7%) with four field restings (6.3%) had anaphylactic shock. Although anaphylactic reactions developed in two patients (2.1%) during rush immunotherapy with honeybee venom and one patient (1.1%) during maintenance therapy wasp venom, systemic adverse reactions were mitigated by treatment with antihistamines before venom injection. Our results show that immunotherapy is safe and effective for the prevention of systemic reactions to Hymenoptera re-stings in patients with Hymenoptera allergy. We therefore recommend that patients who are allergic to Hymenoptera venom prophylactically receive immunotherapy.
BACKGROUND: Systemic allergic reactions to Hymenoptera venom occur in a percentage that varies from 0.4 to 3.3%. Epidemiological studies indicate that from 15 to 25% of the general population can be sensitized to different Hymenoptera venom as well as the fact that the degree of exposure may be related to the prevalence found in those studies. OBJECTIVE: The objective of this study was to evaluate the prevalence of insect sting allergy and the venom sensitization in a rural population to three Hymenoptera previously found in the area: Polistes dominulus (Pd), Vespula germanica (Vg) and honey bee (Hb). METHODS: A rural community located in the south-east of Spain, close to the Mediterranean Sea, was selected since the stinging Hymenoptera having been previously identified. A random sample of 310 subjects from the village census was studied. A questionnaire and a serum sample were obtained from every patient. The evaluation was conducted by a family doctor, who focused on the reactions to Hymenoptera sting, age, sex, occupation, atopia, previous Hymenoptera sting, stinging insect, interval to last sting and average stings per year. RAST to Hymenoptera venoms were also determined. RESULTS: The prevalence of systemic reactions was 2.3% (57.6% of them had a positive RAST). Large local reactions were found in 26.4% (only 28.5% of them had a positive RAST). Asymptomatic sensitization (positive RAST) was observed in 16.4% of subjects without reaction. Only a weak correlation between subjects with less than 3 years' interval to last sting exposure and positive RAST results was noted, whether they presented with a clinical reaction or not (P < 0.05). CONCLUSIONS: The prevalence of systemic sting reactions in our rural community is higher than other general populations in the same Mediterranean area, and similar to other rural populations studied. The degree of exposure influences not only the prevalence found but also the detection of specific serum IgE.
We investigated the putative association between the parasitic lifestyle and an accelerated rate of mt genetic divergence, compositional bias, and gene rearrangement, employing a range of parasitic and nonparasitic Diptera and Hymenoptera. Sequences were obtained for the cox1, cox2, 16S, 28S genes, the regions between the cox2 and atp8 genes, and between the nad3 and nad5 genes. Relative rate tests indicated generally that the parasitic lifestyle was not associated with an increased rate of genetic divergence in the Diptera but reaffirmed that it was in the Hymenoptera. Similarly, a departure from compositional stationarity was not associated with parasitic Diptera but was in parasitic Hymenoptera. Finally, mitochondrial (mt) gene rearrangements were not observed in any of the dipteran species examined. The results indicate that these genetic phenomena are not accelerated in parasitic Diptera compared with nonparasitic Diptera. A possible explanation for the differences in the rate of mt molecular evolution in parasitic Diptera and Hymenoptera is the extraordinary level of radiation that has occurred within the parasitic Hymenoptera but not in any of the dipteran parasitic lineages. If speciation events in the parasitic Hymenoptera are associated with founder events, a faster rate of molecular evolution is expected. Alternatively, biological differences between endoparasitic Hymenoptera and endoparasitic Diptera may also account for the differences observed in molecular evolution.
In our country approximately forty people die every year from anaphylaxis caused by hymenoptera stings. Between 1988 and 1996, 48 patients, who had experienced a systemic reaction to hymenoptera sting and were proved to have specific IgE antibodies to wasp, yellow or both (RAST score > or = 2), received rush immunotherapy (RIT) using venom extracts in our hospital. Fifteen patients had re-sting after RIT. Fourteen out of the 15 patients showed only local reaction to the hymenoptera re-sting and one patient had mild generalized symptoms. Although one patient showed mild generalized uriticaria during RIT, no adverse reaction occurred during and after RIT in the other subjects. Follow-up studies on the titers of serum total IgE antibodies and hymenoptera specific IgE and IgG4 antibodies revealed that total and specific IgE antibodies transiently increased one month after RIT and returned to their baseline values by 6 months after RIT, while specific IgG4 antibodies continued to gradually increase up to al least 3 years after RIT. These results demonstrates that RIT is effective in prevention of a systemic reaction to hymenoptera re-sting and an increase in the titer of hymenoptera specific IgG4 antibodies may at least partly explain the efficacy of RIT.
INTRODUCTION: The natural history of stings, the clinical reaction of the patient and in vivo and in vitro tests are necessary parameters to assess before initiating Hymenoptera venom immunotherapy. In the decision to initiate immunotherapy with Hymenoptera venom, it is not usual to evaluate the natural history of the disease, which seems to be self-limiting and therefore of variable clinical significance. OBJECTIVES: Our aim was to determine the natural history of Hymenoptera hypersensitivity over 4 consecutive years in a rural Mediterranean population. METHODS: An epidemiological study of Hymenoptera sting reactions and possible sensitivity was carried out in 145 randomly selected subjects out of a rural Mediterranean population of 600. Seventy-two subjects, including those with a history of anaphylaxis, completed the 4-year study. The nature of their clinical reactions, age, sex, history of atopy, profession, family history of reactions to Hymenoptera insects, time elapsed since the last sting, number of stings and specific IgE and IgG were determined (the latter, to the three most important insects in the area: Apis mellifera, Polistes dominulus, and Vespula germanica). RESULTS: Of the 72 subjects, four subjects had systemic reactions (SR), 23 had large local reaction (LLR) and all the others (117) was minor local reactions. None who had experienced an SR had a repeat SR when re-stung over the 4-year study. Of those with LLR, 12 subjects had the same type of reaction and 11 experienced more mild local reactions when re-stung. In the SR and local reaction groups, IgE to honey bee (Hb) increased significantly during the study period, whereas in those with only LLR, specific IgE to wasp (Polistes) decreased. Specific IgG to Polistes and Vespula (wasps) decreased significantly, whereas there was no change in the specific IgG to Hb in any of the groups. The number of stings per year decreased at the end of the study in all groups, but positive-specific IgG was higher in subjects with the greatest number of stings. On multivariate analysis using logistic regression, the existence of specific IgE to bee venom, male sex, being an agricultural worker, age of over 16 years and more than five stings per year are seen as individual or co-factors for developing SR or LLR. CONCLUSIONS: The prevalence of SR was 2.8% in our Mediterranean population. The evolution of IgE and IgG throughout the 4-year study differed depending on the Hymenoptera studied. Adult male agricultural workers are at greater risk of having SR or LLR, especially when they have specific IgE to Hb and suffer from more than five stings every 4 years.
BACKGROUND: For most people, Hymenoptera stings produce a transient, local inflammatory reaction (pain, redness, swelling). However, for those who are allergic to components of this venom, the reactions can be severe, frightening, and sometimes fatal. Specific immunotherapy (SIT) has been the only means of desensitizing patients who have experienced a systemic reaction to this venom. OBJECTIVE: This meta-analysis was conducted to compare the effects of SIT in the treatment of Hymenoptera venom hypersensitivity. METHODS: All studies of SIT in the treatment of Hymenoptera venom hypersensitivity published in English between the years 1966 and 1996 were identified through a MEDLINE search. Because of the ethical difficulties involved in designing a double-blind, placebo-controlled study in this patient population, most of the studies were open and not placebo-controlled. One author (R.N.R.) extracted data from the studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Data were extracted from 8 studies involving 453 patients; 1 study was conducted in adults (n = 20), 2 in children (n = 188), and 5 in all ages (n = 245). The symptoms of Hymenoptera venom hypersensitivity were prevented in 80 (79%) of the 101 patients receiving SIT versus 49 (36%) of 136 comparison patients. The symptoms were not prevented in 21 (21%) of the patients receiving SIT versus 87 (64%) of the comparison patients (OR 2.20, 95% CI 1.72 to 2.81). CONCLUSION: The findings of this meta-analysis support the conclusion that SIT is effective in the treatment of Hymenoptera venom hypersensitivity.
BACKGROUND: Anaphylaxis to the bite of Diptera and specifically the bite of the Tabanidae family (horsefly) have been sparsely documented. The coexistent hypersensitivity to both the order Diptera and Hymenoptera has not been documented. METHODS: We present a patient who experienced anaphylaxis to both insect species. Venom skin testing and RAST revealed sensitivity to several members of the Hymenoptera order. Prick, intradermal and RAST with whole body extracts of Tabanidae species is also documented in this patient. Twenty patients who are sensitive to Hymenoptera and have been bitten by horseflies but have had no reaction to the horsefly bite were used as controls. RESULTS: An anaphylactic reaction to horsefly bite has been documented in a 56-year-old white male. This patient also demonstrated evidence of anaphylactic reaction to Hymenoptera envenomation. In controls consisting of 20 patients with Hymenoptera sensitivity, there was no clinical history of reaction to horsefly bite despite the presence of positive prick and/or positive intradermal tests and/or positive RAST to mixed Tabanidae species extract. CONCLUSIONS: Skin testing to horsefly by prick and/or intradermal testing using whole body insect extract is not useful in making a diagnosis of Tabanidae hypersensitivity. RAST using Tabanidae species as antigen is similarly useless in making a diagnosis of Tabanidae hypersensitivity. In vivo and in vitro diagnosis of horsefly hypersensitivity may be achieved when the salivary gland antigen of the horsefly becomes available.
PURPOSE OF REVIEW: Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. RECENT FINDINGS: Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 microg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. SUMMARY: Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended.
BACKGROUND: In sensitized subjects Hymenoptera stings may provoke the awakening of mediated systemic reactions of I type IgE, which can sometimes be serious. Considering the type of work performed activity and the high frequency of reported hymenoptera sting episodes, a sample of 206 Forestry Department agents was surveyed who worked outside urban areas in the Marche Region. OBJECTIVES: The aim of the study was to analyse the prevalence of stings and their possible systemic reactions, as well as to evaluate the type of occupational risks involved. METHODS: A total of 206 agents were examined and questioned about the number of stings suffered during work and about the kind of subsequent skin and systemic reactions; they were then classified according to the method proposed by H.L. Mueller. RESULTS: 179 agents reported having suffered from hymenoptera stings and, of these, 53 subjects (29,6%) remembered that one episode at least occurred during work. Among 175 operators (98%), 4 had a regular reaction, with appearance of a generalized urticaria and uneasiness. In the remaining 4 agents (2%) there was a local extensive reaction, which was not associated with systemic reactions and they were all referred to allergological examination. 19 agents (10,6%) suffered more than 5 stings altogether, but none developed a systemic reaction. 87% of the subjects practised self-medication, 7% reported to the casualty department of the local hospital or to their own doctor, and 6% undertook no cure at all. CONCLUSIONS: Epidemiological studies agree in recognizing that, in the general population, the percentage of systemic reactions after one or more hymenoptera stings varies from 0,15% to 3,3%. In categories of workers occupationally at risk, the prevalence of systemic reactions varies from 4,5% to 26%. The prevalence of systemic reactions in Forestry Department agents was 2%, which is similar to the prevalence in the general population. Therefore, rather than occupational risk, there appeared to be a generic risk made more serious by working conditions for Forestry Department agents due to their possible exposure to hymenoptera stings. The occupational health physician needs to monitor these events, due to the fact that frequent exposure to stings, above all occurring within a short period of time (less than two months) favours an increase in the tendency to develop systemic reactions, with a more serious prognosis, especially when working in isolated conditions.
The Hymenoptera venom study, a study based on case histories, skin test results and adverse reactions, immunotherapy and adverse reactions, and treatment efficacy, for 3236 Hymenoptera-allergic subjects, was begun in 1979 after the Food and Drug Administration approval of Hymenoptera venoms. Eighty-four Fellows and Members of the American Academy of Allergy and Immunology participated in the study. All subjects had a history of an adverse reaction to one or more Hymenoptera insects. The mean age was 30 1/2 years (range 1 to 83 years). Male subjects accounted for 61.5% and female subjects, 38.5%; 3.1% were beekeepers and 32.3% were atopic. Demographic data were similar for subgroups. There was an average of 2.7 history stings per subject. At least one systemic reaction (SR) was reported by 2866 subjects (89%); 2219 (69%) experienced an SR after their most recent sting before entry into the study, and 70% had experienced only a single SR. Moderate to severe SRs were equally likely after stings of yellow jacket, white-faced hornet, and yellow hornet (65%), honeybee (67%), or wasp (70%), although historical SRs were reported more often after stings of yellow jacket, white-faced hornet, or yellow hornet (30%) than after honeybee (19%) or wasp (14%) stings. No association was noted between the number of stings per episode and severity of the SR. Fifty-one percent of SRs were reported as occurring within 10 minutes of sting; however, the onset of a moderate to severe SR sometimes occurred at 301 or more minutes after a sting episode. Of 2219 subjects with an SR after their most recent sting before entry into the study, 68% received epinephrine for treatment.
BACKGROUND: Positive skin test results to multiple venoms in patients with Hymenoptera venom allergy may result from IgE antibody cross-reactivity among venom proteins. To avoid treatment with unnecessary and costly venoms, we have developed a venom RAST inhibition test that identifies individuals in whom a positive venom IgE RAST result is due to cross-reactive venom-specific IgE antibody. METHODS: Serum samples (n = 412) were collected over 5 years from patients with clinically characterized Hymenoptera venom allergy who had positive skin test results to more than one venom. Venom allergosorbent was added to serum containing IgE antivenin and buffer or 100 micrograms of homologous or heterologous venom. Bound IgE was detected with radiolabeled anti-human IgE. Intraassay variation less than 10% coefficient of variation and homologous venom inhibition greater than 80% were required for acceptance of data. A "cross-reactivity index" (CRI) was computed as a ratio of percent inhibition produced by heterologous versus homologous venom. RESULTS: Of the 412 sera-venom combinations analyzed, 41 (10%) were excluded because of incomplete homologous venom inhibition. Of the 371 remaining sera, 82% (n = 305) were studied for IgE anti-Polistes wasp venom (PWV) cross-reactivity with yellow jacket venom (YJV) and the other 66 for other venom specificity cross-inhibitions. Of the serum samples tested, 36.4% (111 of 305) contained IgE anti-PWV venom of which the binding to solid-phase PWV was inhibited with soluble YJV to a level that produced CRIs greater than 95%. We believe that this constitutes complete inhibition and demonstrates exclusively YJV cross-reactive antibody in these samples. The remaining 63.6% had CRIs from 0% to 95%, indicating IgE specific for a spectrum of unique and cross-reactive PWV allergens. Only 4.3% (13 of 305) had CRIs less than 5%, which is consistent with IgE restricted to PWV unique allergens. The degree of the IgE anti-PWV inhibition to solid-phase PWV by YJV was independent of the IgE anti-PWV level. CONCLUSIONS: This study shows that one third of patients with Hymenoptera venom allergy evaluated with positive YJV- and PWV-reactive IgE in the skin and/or serum were identified as candidates for exclusion of PWV from their immunotherapy regimen because their IgE anti-PWV was more than 95% cross-inhibitable with YJV. Cost analysis of the venom RAST inhibition test and a conventional 5-year Hymenoptera venom immunotherapy program indicates that this serologic evaluation is cost-effective.
The genomes of two parasitoid wasps, Diadromus pulchellus and Eupelmus vuilleti, and the honey bee, Apis mellifera, contain few interspersed repeated sequences corresponding to transposons (Tn). This suggests that the genomic organisation of Hymenoptera could be due to the elimination of deleterious Tn in haploid males. We have used restriction-fragment length polymorphism analysis to show that nondeleterious Tn are present in the DNA (rDNA) encoding ribosomal RNA of twelve species of Hymenoptera. Sequence analysis of the 28S rDNA type-I and type-II insertion-rich regions of 80 species showed that this region is very highly conserved (95.8%). A consensus sequence and restriction map of the rDNA region were established. These sequence data were used to develop a strategy for detecting inserted elements in the rDNA fragments containing type-I or type-II insertion sites, and this strategy was used to screen twelve hymenopteran species and four non-Hymenoptera control species. The rDNA fragments from the Hymenoptera and control species contained inserted sequences in the area where type-I and type-II elements are inserted in the 28S rDNA retrotransposon-rich region of Diptera and Lepidoptera. The hymenopteran genomes therefore appear to contain repeated elements, the mobility and nature of which remain to be determined.
PURPOSE OF REVIEW: Mastocytosis is a rare disease with associations with anaphylactic reactions to Hymenoptera stings. The purpose of this review is to examine these associations with regard to prevalence, diagnosis, treatment and prognosis in the insect-venom-allergic population. RECENT FINDINGS: Systemic mastocytosis is overrepresented in the Hymenoptera-allergic population and is associated with an increased risk of more-severe reactions following field stings or sting challenges, lack of sensitization to venoms by skin test or radioallergosorbent test, increased side effects to venom immunotherapy, reduced efficacy of venom immunotherapy and treatment failures. Serum tryptase determinations are a simple and reliable screening procedure for systemic mastocytosis. Patients with elevated values should be referred to specialized centers for confirmatory diagnosis including bone marrow histology. SUMMARY: The diagnosis of systemic mastocytosis should be considered in Hymenoptera-allergic patients showing any of the management problems associated with this disease. Patients with mastocytosis and Hymenoptera allergy require special attention, mainly because of reduced safety and efficacy of venom immunotherapy. Whether or not venom immunotherapy is given, such patients should continue to carry an Epipen indefinitely.
The purpose of diagnostic procedure is to classify a sting reaction by history, identify the underlying pathogenetic mechanism, and identify the offending insect. Diagnosis of Hymenoptera venom allergy thus forms the basis for the treatment. In the central and northern Europe vespid (mainly Vespula spp.) and honeybee stings are the most prevalent, whereas in the Mediterranean area stings from Polistes and Vespula are more frequent than honeybee stings; bumblebee stings are rare throughout Europe and more of an occupational hazard. Several major allergens, usually glycoproteins with a molecular weight of 10-50 kDa, have been identified in venoms of bees, vespids. and ants. The sequences and structures of the majority of venom allergens have been determined and several have been expressed in recombinant form. A particular problem in the field of cross-reactivity are specific immunoglobulin E (IgE) antibodies directed against carbohydrate epitopes, which may induce multiple positive test results (skin test, in vitro tests) of still unknown clinical significance. Venom hypersensitivity may be mediated by immunologic mechanisms (IgE-mediated or non-IgE-mediated venom allergy) but also by nonimmunologic mechanisms. Reactions to Hymenoptera stings are classified into normal local reactions, large local reactions, systemic toxic reactions, systemic anaphylactic reactions, and unusual reactions. For most venom-allergic patients an anaphylactic reaction after a sting is very traumatic event, resulting in an altered health-related quality of life. Risk factors influencing the outcome of an anaphylactic reaction include the time interval between stings, the number of stings, the severity of the preceding reaction, age, cardiovascular diseases and drug intake, insect type, elevated serum tryptase, and mastocytosis. Diagnostic tests should be carried out in all patients with a history of a systemic sting reaction to detect sensitization. They are not recommended in subjects with a history of large local reaction or no history of a systemic reaction. Testing comprises skin tests with Hymenoptera venoms and analysis of the serum for Hymenoptera venom-specific IgE. Stepwise skin testing with incremental venom concentrations is recommended. If diagnostic tests are negative they should be repeated several weeks later. Serum tryptase should be analyzed in patients with a history of a severe sting reaction.
According to most textbooks, diagnostic tests with Hymenoptera venoms are reliable, and immunotherapy with these venoms in Hymenoptera-venom-allergic patients leads in near to 100% to full protection. Careful analysis of the literature shows however that the specificity of diagnostic tests is far from perfect and that both efficacy and tolerance, especially in patients receiving honeybee venom immunotherapy, are still suboptimal. The major allergens of honeybee and vespid venoms are now available in recombinant form. Preliminary trials analyzing diagnostic tests with recombinant allergens in honeybee venom allergy are promising: the specificity is clearly increased in both skin testing and in determining venom-specific IgE antibodies when compared to natural venom allergens. An important recent finding is the frequent association of severe Hymenoptera venom allergy and elevated basal serum levels of the mast-cell-specific enzyme tryptase. Elevated levels are found in up to 30% of the patients with a history of severe shock reactions following Hymenoptera stings. The current findings indicate that basal tryptase levels indicating an increased mast cell load are much more frequent than previously thought and are a risk factor for severe or even fatal sting reactions. Premedication with antihistamines in the initial phase of venom immunotherapy reduced both local and systemic allergic side effects in several controlled studies. In a retrospective analysis of one of these trials it was found that reexposure during immunotherapy resulted in significantly more systemic allergic reactions in patients on placebo than on antihistamine premedication, suggesting that initial antihistamine premedication might increase the efficacy of venom immunotherapy. Different ways of allergen modification for venom immunotherapy have been proposed. While the results with chemical modifications were not convincing, recent studies with T-cell epitope peptides from the major bee venom allergen phospholipase A(2) look promising. Patient-tailored cocktails of recombinant venom allergens or isoforms thereof may be another possibility in the future. A number of prospective studies analyzing the duration of venom immunotherapy required for long-term protection have been published in the last decade. While most patients are still fully protected 1 year after discontinuation of therapy, relapses may occur in up to 20% of patients reexposed many years after treatment. Various risk factors for such relapses have been identified.