Hymenoptera Allergy Research Articles

Management of occupational Hymenoptera allergy

Certain outdoor activities show a particularly high risk for being stung by Hymenoptera species. Avoidance of such stings is preferable for preventing unwanted local or systemic sting reactions. The purpose of this review is to evaluate the current knowledge on risk factors and management of Hymenoptera venom allergy. We will specifically focus on patients with an intense occupational exposure to Hymenoptera venom. Repeated stings were found to increase the risk for subsequent severe anaphylactic sting reactions. The male preponderance for severe anaphylactic sting reactions probably reflects in part a sex-specific occupational exposure being higher in males. When selecting a specific venom for therapy, current knowledge of cross-reactivity between venoms of various species should be considered. If available, venom immunotherapy should be performed using the venom of the culprit insect. Recently, a pilot study also showed the efficacy of venom immunotherapy when treating large local reactions. If an intensely exposed patient presents with a systemic anaphylactic sting reaction, efficacy of venom immunotherapy should be demonstrated by a tolerated sting challenge before allowing this patient to return to his/her occupation. Patients with bee venom allergy and an intense exposure should be treated with an increased maintenance dose of 200 μg bee venom. Patients with a history of large local reactions should be provided with an emergency kit, which should contain oral antihistamines and corticosteroids. In patients in whom local sting reactions induce symptoms of high clinical significance, an off-label use of venom immunotherapy may be discussed.

Serum CTLA-4 and IL-10 in Hymenoptera Venom Immunotherapy. The Immunological Equivalence of Different Induction Protocols

RATIONALE: Cytotoxic T lymphocyte associated gene-4 (CTLA-4) is involved in the activation pathways of T lymphocytes. Circulating CTLA-4 is elevated in patients with hymenoptera allergy and can be downregulated by immunotherapy. We assessed the effects on CTLA-4 of venom immunotherapy given with different induction protocols: conventional (6 weeks), rush (3 days) or ultra rush (1 day).

Epidemiology of allergic reactions to hymenoptera stings in Irish school children

The aim of this was to study generate the first epidemiological data regarding the prevalence of hymenoptera allergy among school children in Ireland. Questionnaires, including six sting-specific questions (1), were distributed to the parents of primary school children aged 6-8 and 11-13, divided equally between rural and urban backgrounds. From 110 schools, 4112 questionnaires were returned. A total of 1544 (37.5%) children had been stung in their lifetime. Among the total, 5.8% of children stung experienced a large local reaction, 3.4% had a mild (cutaneous) systemic reaction (MSR) and 0.8% experienced a moderate/severe systemic reaction (SSR); these figures respectively represent 2.2%, 1.3% and 0.2% of the total study group. On logistic regression analysis, older children and rural children were at a higher risk of being stung (OR 1.7; 95% CI 1.4-2.; OR 1.6; 95% CI 1.4-1.8 respectively). Rural dwellers and asthma sufferers were more likely to experience an SSR (OR 4.3; 95% CI 1.4-13.5 and OR 2.8; 95% CI 1.8-4.3, respectively). Hymenoptera stings are more common in rural than urban dwelling Irish children. Asthma imparted a greater risk of SSR in this study population. Severe reactions are unusual overall, occurring in <1% of those stung, a lower prevalence than in Israeli teenagers but in keeping with other European reports relating to young children.

Allergen-specific immunotherapy for respiratory allergies: From meta-analysis to registration and beyond

Allergen-specific immunotherapy (SIT) is an etiology-based treatment for respiratory and Hymenoptera-allergic diseases. Although introduced a century ago, SIT was not widely accepted for many years until its efficacy in the treatment of both allergic rhinoconjunctivitis and allergic asthma was demonstrated in appropriate double-blind, placebo-controlled trials and its mechanism of action was better understood. The indications for allergen-specific immunotherapy have been specified in consensus reports. Allergen-specific immunotherapy is primarily targeted to benefit patients with Hymenoptera allergy or severe upper and mild to moderate lower allergic respiratory diseases that are poorly controlled by pharmacologic treatments or who are unable or unwilling to use the latter. Several recent developments have helped to reinforce the position of SIT in the overall therapeutic management of respiratory allergies: (1) improvement in the quality of allergen extracts as a result of standardization, (2) better understanding of SIT's mechanism of action, (3) the introduction of sublingual tablets and their rigorous registration as pharmaceutical therapies by regulatory agencies, and (4) rationalization of prescribing patterns. There is a requirement for additional well designed, well executed, randomized trials in adults and children with allergic rhinitis and asthma, with a special focus on optimal patient selection, dosage, and treatment duration. In this review, the authors put into perspective current international expert recommendations on the use of SIT (in relation to levels of clinical evidence) and analyze what is needed for the future.

Approaches to the Management of Presumed Immediate Hymenoptera Venom Allergy and Non-Detectable IgE

Objective: To provide a comprehensive evaluation in patients with a convincing history of immediate insect allergy but negative skin test and/or specific IgE results, adequately addressing the question of how best to manage them. Data sources: Observational peer-reviewed studies and case reports were searched on Pub-Med database from 1998 up to March 2009 using the following keywords: Hymenoptera Allergy &amp; Negative IgE (Negative Skin Tests). Study selection: Studies on supplemental diagnostic tests that provided data from patients with immediate hymenoptera allergy but negative conventional tests results to the offending allergens were selected. In this work, we also included studies providing additional relevant information regarding this issue. Results: Among 43 identified papers only 9 of them presented relevant original data, while the other papers were reviews. In the majority of the cases, the culprit insect was identified with in vitro tests such as Basophil Activation Test, Cellular Allergen Stimulation Test or Western blot, whereas in vivo (less frequently) with sting challenge or dialyzed venom skin test. Conclusions: The management of patients with a convincing history of immediate insect allergy but negative conventional test results requires an adaption of the guidelines including an incorporation of the novel diagnostic tools. Although cellular tests represent equivalent sensitivity and superior specificity as compared with standard ones, these tests still remain supplementary diagnostic tools. In a minority of cases (especially in the developing countries where cellular tests cannot be performed), venom immunotherapy in adult subjects could be taken into account based solemnly on the history of a clear patient’s identification of the culprit insect.

Anaphylaxis due to bee stings causing death in a 58 male with unsuspected gastro-oesophageal adenocarcinoma. did peritumoural mast cells contribute to anaphylaxis?

Aims We report a case of anaphylaxis due to bee stings in a 58-year-old male. Autopsy demonstrated a 12 cm (in greatest dimension) unsuspected gastro-oesophageal adenocarcinoma. Mast cells (MC) are involved in angiogenesis, a process critical to the development of adenocarcinomas. Studies have shown increased MC associated with adenocarcinomas. MC are also a central component of allergic reactions, including anaphylaxis. We aimed to ascertain if there were increased MC associated with this adenocarcinoma, which may have contributed to the anaphylactic process. Method Sections of tumour were evaluated with H&E and toluidine blue stained slides. MC counts were performed. Serology was performed for tryptase and allergen specific IgE. Results Evaluation of toluidine blue slides showed increased peritumoural MC. MC counts were up to 20 per 40 × high power fields. Aggregates of MC were apparent with clusters of 7–8 MC. Serum tryptase measured 4200 mg/L. He had a honey bee venom score of 2. Discussion Anaphylaxis is a complex process. The literature shows an abnormally high number of patients with severe hymenoptera allergy exhibit underlying mastocytosis. In this case, adenocarcinoma may have lead to an increased MC burden, and possibly contributed to the anaphylactic process.

Advances in Allergen-Specific Immunotherapy

After several decades of controversies, allergen specific immunotherapy (SIT) was recognized as an effective treatment for respiratory and hymenoptera allergy by the World Health Organization in 1998. SIT involves the administration (usually subcutaneous) of increasing doses of allergen in order to achieve a hyposensitization. Moreover, SIT is the only allergen-specific treatment capable of modifying the natural history of the disease. During the last 25 years, there was an impressive development of basic and clinical research in the field of SIT, with the goal of improving the safety, the efficacy and ameliorating the knowledge on the mechanisms of action. In this regard, the sublingual route (SLIT) was extensively studied and, recently, validated. SLIT can be considered a milestone in the history of SIT, since it is expected to change the clinical practice. In parallel, the growing detailed knowledge of the immunological mechanisms of SIT has provided the opportunity to explore new forms of specific hyposensitization, such as the use of adjuvants (bacterial and DNA-based), recombinant and engineered allergens, allergenic peptides and chimeric molecules. The last frontier seems to be the manipulation of genoma with replicons and allergen-encoding plasmids.

How much specific is the association between hymenoptera venom allergy and mastocytosis?

The preferential association of mastocytosis with hymenoptera sting reactions is well known, but there is no data on the prevalence of clonal mast cell disorders in subjects with severe systemic reactions due to foods or drugs. Patients with food- or drug-induced severe systemic reactions, including anaphylaxis, and increased serum tryptase were studied for the presence of mastocytosis, and compared with a population of patients with hymenoptera allergy. The aetiological role of foods or drugs was assessed according to current recommendations. Systemic reactions were graded in severity according to the procedure described by Mueller. Serum tryptase was considered increased if the level was >11.4 ng/ml. Subjects with increased tryptase had dermatological evaluation and Bone marrow(BM) aspirate-biopsy, which included histology/cytology, flow cytometry and detection of KIT mutations. A total of 137 subjects (57 male, mean age 42 years) were studied. Of them, 86 proved positive for drugs and 51 for foods. Overall, out of 137 patients, only nine (6.6%) had a basal tryptase >11.4 ng/ml, and only two (1.5%) were diagnosed with mastocytosis. This was clearly different from patients with hymenoptera allergy, where 13.9% had elevated tryptase and 11.1% had a clonal mast cell disorder. The association of clonal mast cell disorders with hymenoptera allergy seems to be more specific than that with food- or drug-induced systemic reactions.

Serum Ctla-4 In Hymenoptera Venom Allergy And Its Modulation By Specific Immunotherapy

BACKGROUND: Cytotoxic T lymphocyte associated gene-4 (CTLA-4) is now recognized as a negative regulatory factor for activated lymphocytes, and may be therefore involved in the pathogenic mechanism of allergies. We assessed the levels of the soluble form of CTLA-4 molecule in subjects with a pure IgE mediated disease, hymenoptera venom allergy, and its modulation by immunotherapy. METHODS: Thirty patients with grade III-IV reactions, sensitized to hymenoptera only, and receiving specific immunotherapy were enrolled. Serum CTLA-4 and Interleukin-10 were assayed in the serum at baseline and after the 6-week induction phase of immunotherapy. Specific IgE and IgG4 were also measured, Serum CTLA-4 was also measured in 27 patients with allergic rhinitis, as well as in 44 healthy subjects. ELISA methods and Western blotting were used. RESULTS: Serum CTLA-4 was undetectable in almost all healthy controls and rhinitis patients, whereas it was raised in hymenoptera venom patients (median 17.5 range 0.1-95 ng/mL). Its concentration significantly decreased after immunotherapy induction (median 3.3, range 0.1-34.5 ng/mL; p = 0.0004), in parallel with a significant increase in interleukin-10 (p = 0.0001). No change at all was seen in IgE and IgG4 concentrations. CONCLUSIONS: Soluble CTLA-4 in serum clearly discriminates the subjects with hymenoptera allergy from those with respiratory allergy and normals. In addition it may represent an early marker of the immunological effects of specific immunotherapy.

Cross reactivity between European Hornet and Yellow Jacket venoms.

Summary Background: Cross-reactions between venoms may be responsible for multiple diagnostic positivities in hymenoptera allergy. There is limited data on the cross-reactivity between Vespula spp and Vespa crabro, which is an important cause of severe reactions in some parts of Europe. We studied by CAP-inhibition assays and immunoblotting the cross-reactivity between the two venoms. Methods: Sera from patients with non discriminative skin/CAP positivity to both Vespula and Vespa crabro were collected for the analyses. Inhibition assays were carried out with a CAP method, incubating the sera separately with both venoms and subsequently measuring the specific IgE to venoms themselves. Immunoblotting was performed on sera with ambiguous results at the CAP-inhibition. Results: Seventeen patients had a severe reaction after Vespa crabro sting and proved skin and CAP positive also to vespula. In 11/17 patients, Vespula venom completely inhibited IgE binding to VC venom, whereas VC venom inhibited binding to Vespula venom only partially (<75%). In 6 subjects the CAP-inhibition provided inconclusive results and their sera were analysed by immunoblotting. The SDS-PAGE identified hyaluronidase, phospholipase A1 and antigen 5 as the main proteins of the venoms. In 5 sera the levels of IgE against antigen 5 of Vespa crabro were higher than IgE against Vespula germanica, thus indicating a true sensitisation to crabro. Conclusion: In the case of multiple positivities to Vespa crabro and Vespula spp the CAP inhibition is helpful in detecting the cross-reactivities.

Systemic Reactions After Hymenoptera Sting And Raised Serum Tryptase Strongly Suggest Clonal Mast Cells Disorders

BACKGROUND: Anaphylaxis following a hymenoptera sting has been reported in patients with mastocytosis, but few data exist regarding the disease's prevalence in patients with hymenoptera allergy.METHODS: Using bone marrow (BM) histology/cytology, flow cytometry (FC), and detection of KIT mutations, we assessed the prevalence of mastocytosis in patients with both systemic reactions to hymenoptera and increased serum tryptase (sBT).RESULTS: Forty-four out of 379 patients (11.6%) with systemic reactions to sting had increased sBT (>11.4 ng/mL, 95th percentile of normal subjects), and 70.5% of them had a history of sting-induced anaphylaxis. Thirty-four patients underwent a BM analysis. Histology fulfilled major WHO diagnostic criteria in 42.4% of cases. Abnormal mast cells (MCs) were identified by FC and cytology in 78.8% and 61.8% of patients, respectively. A codon 816 KIT mutation was detected in 58.1% of patients. The diagnosis was indolent systemic mastocytosis (ISM) in 61.7% of cases (11.8% with Urticaria Pigmentosa) and Monoclonal MC Activation Syndrome (MMAS) in 26.5%. In particular, 96.4% of patients with anaphylaxis were classified as ISM or MMAS.CONCLUSIONS: Based on the results of the approach utilized in our study, the concomitant presence of systemic reactions (especially anaphylaxis) following hymenoptera sting and raised sBT suggests that a BM examination is indicated in order to diagnose clonal MC disease. BACKGROUND: Anaphylaxis following a hymenoptera sting has been reported in patients with mastocytosis, but few data exist regarding the disease's prevalence in patients with hymenoptera allergy. METHODS: Using bone marrow (BM) histology/cytology, flow cytometry (FC), and detection of KIT mutations, we assessed the prevalence of mastocytosis in patients with both systemic reactions to hymenoptera and increased serum tryptase (sBT). RESULTS: Forty-four out of 379 patients (11.6%) with systemic reactions to sting had increased sBT (>11.4 ng/mL, 95th percentile of normal subjects), and 70.5% of them had a history of sting-induced anaphylaxis. Thirty-four patients underwent a BM analysis. Histology fulfilled major WHO diagnostic criteria in 42.4% of cases. Abnormal mast cells (MCs) were identified by FC and cytology in 78.8% and 61.8% of patients, respectively. A codon 816 KIT mutation was detected in 58.1% of patients. The diagnosis was indolent systemic mastocytosis (ISM) in 61.7% of cases (11.8% with Urticaria Pigmentosa) and Monoclonal MC Activation Syndrome (MMAS) in 26.5%. In particular, 96.4% of patients with anaphylaxis were classified as ISM or MMAS. CONCLUSIONS: Based on the results of the approach utilized in our study, the concomitant presence of systemic reactions (especially anaphylaxis) following hymenoptera sting and raised sBT suggests that a BM examination is indicated in order to diagnose clonal MC disease.

Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels

Anaphylaxis after Hymenoptera stings has been reported in subjects with mastocytosis, but few data exist regarding disease prevalence in populations allergic to these insects. The incidence of clonal mast cell (MC) disorders in subjects with both systemic reactions to Hymenoptera stings and increased serum baseline tryptase (sBT) levels was assessed by using bone marrow (BM) aspirates and biopsy specimens. Subjects with a history of a systemic reaction caused by a Hymenoptera sting underwent the standard diagnostic work-up for Hymenoptera allergy, and sBT levels were measured. Subjects with an increased sBT level had BM evaluation that included histology/cytology, flow cytometry, and detection of KIT mutations. Forty-four (11.6%) of 379 subjects with systemic reactions had increased sBT levels (>11.4 ng/mL), and 31 (70.5%) of these had a history of anaphylaxis. Thirty-four subjects with increased sBT levels underwent a BM analysis. Histology detected diagnostic or subdiagnostic MC infiltrates in 22 (65%) of 34 patients. Abnormal MCs were identified by means of flow cytometry and cytology in 26 (78.8%) of 33 and 20 (58.8%) of 34 subjects, respectively. A KIT mutation was detected in 17 (54.8%) of 31 subjects. The diagnosis was indolent systemic mastocytosis in 21 (61.7%) of 34 subjects and monoclonal MC activation syndrome in 9 (26.5%) of 34 subjects. All subjects with anaphylaxis had one of those 2 disorders. The concomitant presence of systemic reactions (especially anaphylaxis) after Hymenoptera stings and increased sBT levels strongly suggests that a BM examination is indicated for the diagnosis of clonal MC disease.

Sublingual immunotherapy for large local reactions caused by honeybee sting: A double-blind, placebo-controlled trial

Sublingual immunotherapy (SLIT) proved effective and safe in respiratory allergy, and thus its use in hymenoptera allergy can be hypothesized. We sought to assess, in a proof-of-concept study, whether SLIT might potentially be beneficial in hymenoptera allergy. The sting challenge in large local reactions (LLRs) was used to test this hypothesis. We performed a randomized, double-blind, placebo-controlled study involving patients with LLRs who were monosensitized to honeybee. After the baseline sting challenge, they were randomized to either SLIT or placebo for 6 months. The treatment (Anallergo, Florence, Italy) involved a 6-week build-up period, followed by maintenance with 525 microg of venom monthly. The sting challenge was repeated after 6 months. Thirty patients (18 male patients; mean age, 44.5 years) were enrolled, and 26 completed the study, with 1 dropout in the active group and 3 dropouts in the placebo group. In the active group the median of the peak maximal diameter of the LLRs decreased from 20.5 to 8.5 cm (P = .014), whereas no change was seen in the placebo group (23.0 vs 20.5 cm, P = not significant). The diameter was reduced more than 50% in 57% of patients. One case of generalized urticaria occurred in a placebo-treated patient at sting challenge. No adverse event caused by SLIT was reported. Honeybee SLIT significantly reduced the extent of LLRs, and its safety profile was good. Although LLRs are not an indication for immunotherapy, this proof-of-concept study suggests that SLIT in hymenoptera allergy deserves further investigation. Trials involving systemic reactions and dose-ranging studies are needed.

Sublingual Immunotherapy With Honeybee Venom Is Effective In Patients With Large Local Reactions Due To Bee Sting. A Randomised, Double Blind Placebo Controlled Trial

Hymenoptera venom immunotherapy confers protection against hymenoptera sting, and effectiveness of VIT can be demonstrated by reduction of size of large local reactions. Venom immunotherapy is given by injections, but sublingual immunotherapy (SI) proved effective in respiratory allergy, thus its use in hymenoptera allergy can be hypothesized. We evaluated efficacy of SI with honeybee venom assessing effect on large local reactions under controlled sting challenges.

Basophil-activation tests in Hymenoptera allergy

Despite recent advances in our understanding of basophil biology and discovery of new markers for basophil activation, tests measuring basophil activation are not widely utilized in Hymenoptera allergy. Studies of the basophil-activation test in Hymenoptera allergy were examined and the clinical utility of this test was assessed. It has been demonstrated that the results of basophil-activation tests correlate quite well with those of serum IgE testing or skin-prick tests. Many studies compare test outcomes with history in patients and nonallergic controls, so that specificity in sensitized but clinically nonreactive individuals remains unknown. Although one study showed that the basophil-activation test might predict immunotherapy side effects, this could not be confirmed in a second study, and no role has been established for the basophil-activation test in the monitoring of venom immunotherapy. The basophil-activation test has no extra value in assessing sting challenges, although experience is limited. The measurement of basophil-activation markers may be useful in detecting IgE-mediated sensitization but the relevance for application of the basophil-activation test in prediction of clinical reactivity in Hymenoptera allergy is very limited. For this reason, this test currently has no established role in the diagnosis and management of patients with insect sting allergy.

The Effects of Rush Immunotherapy on Hymenoptera Allergy

The Effects of Rush Immunotherapy on Hymenoptera Allergy

Analysis of the burden of treatment in patients receiving an EpiPen for yellow jacket anaphylaxis

Venom immunotherapy (VIT) is a treatment with established efficacy for the prevention of repeated anaphylactic reactions in patients with Hymenoptera allergy, which also allows patients to discontinue carrying an EpiPen. Despite their merits, both treatments can have negative aspects potentially important to patients. We examined possible negative aspects of the EpiPen in comparison with VIT as perceived by patients. Positive and negative aspects of both treatments were measured by using a burden of treatment questionnaire together with statements about the EpiPen. One hundred ninety-three patients were included, of whom 94 consented to randomization: 47 received VIT, and 47 received the EpiPen. Of the remaining 99, 75 chose VIT, and 26 chose the EpiPen. Of the patients receiving VIT, 91.5% were (extremely) positive about their treatment, and 85% would choose VIT again. Of the patients receiving the EpiPen, only 48% were positive about their treatment, and even of these patients, 68% preferred to be treated with VIT after 1 year of carrying the EpiPen. Although most patients indicated that it is reassuring to carry an EpiPen and makes them feel safe, many patients also indicated that it is inconvenient and troublesome. Especially patients who were negative about the EpiPen indicated that they would not dare use the EpiPen if necessary and were afraid at possible side effects. In contrast to VIT, the EpiPen is perceived as burdensome by most patients with venom allergy. For most patients, an EpiPen is an unsuitable definitive treatment. As VIT enables patients with venom allergy to get rid of the EpiPen, patients should be offered VIT.

Alergia a veneno de himenópteros. Novos métodos de diagnóstico.

During the past years, the number of patients with both anaphylaxis to hymenoptera sting and negative IgE detected by conventional methods has been increasing. To obviate this problem new assays have been tried, such as Western blot and in vitro challenge tests involving basophil activation, with either the measurement of histamine and sulphidoleukotrien released (CAST--Cellular Antigen Stimulation Test) or the detection of activation markers on the cell surface with flow cytometric analysis (Flow CAST). In this paper the principles of these assays as well as their diagnostic value in hymenoptera allergy are briefly reviewed.

Beta Blockers, Ace Inhibitors, and Angiotensin Receptor Blockers in Hymenoptera Allergy: A 5 Year Chart Review

RATIONALE: Patients taking beta blockers (BBs) or ace inhibitors (ACEIs) may have severe or refractory systemic reactions (SRs) when receiving venom immunotherapy (VIT). It is not currently known if angiotensin receptor blockers (ARBs) play a similar role. We examined the role of BBs, ACEIs, and ARBs in the evaluation and treatment of suspected hymenoptera allergy.

Mastocytosis and Hymenoptera allergy.

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. 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. 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.