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Background: The long-term protection provided by venom immunotherapy (VIT) is related to the dose administered and to its long duration; the latter, however, becomes inconvenient for patients in countries like Greece, with many islanders or inhabitants of distant mountainous areas. Maintenance interval prolongation reduces the number of office visits - saving time and money - and as a consequence contributes to the patients' compliance. The aim of this prospective study was to evaluate the safety and efficacy of VIT on a progressively prolonged maintenance interval (PPMI)., Method: 450 venom-allergic patients were reviewed for participation in our study; all of them were initially treated with a modified rush or an ultrarush protocol using freshly reconstituted, pure venoms. Upon reaching the maintenance dose, the VIT interval was scheduled to be gradually prolonged - by 1 week each time - aiming at a maximal interval of 26 weeks., Results: 267/450 patients consented to participate in our VIT PPMI protocol: 98 were treated with vespid(s) venom, 142 with honeybee venom, and 27 with both. The mean duration of patient follow-up was 9.1 ± 4.2 years. The majority of systemic reactions due to VIT injections occurred up to the 8-weeks PPMI; few additional reactions were documented in a small fraction (2.9%) of our patient population beyond 9 weeks and up to 16 weeks; all were caused by honeybee VIT. No reactions were observed during VIT administration at the 26-week interval. Ninety-six patients reported 204 field sting occurrences by the culprit insect. Ten systemic reactions (8 mild and 2 moderate in severity) were registered between the 9- and 18-week PPMI; the honeybee was the culprit insect in all cases. 108 field stings by the offending insect were sustained beyond the 20- and up to the 26-week PPMI; there were no reactions at all., Conclusions: Progressively prolonging the VIT maintenance interval up to 26 weeks appears to be safe and efficacious., (© 2018 S. Karger AG, Basel.)

Cross-reactions between Polistes dominula and Vespula species are common in southern Europe. Currently, only CAP-inhibition demonstrates high accuracy in identifying genuine sensitizations, but this method is time-consuming and expensive, so a new approach is required. This study investigates skin tests, molecular diagnostics, total IgE (tIgE), and the Ves v 5/Pol d 5 (or vice versa) ratio. The ratio generated low-accuracy results and poor agreement with CAP-inhibition, and we did not find any agreement between CAP-inhibition test and double values of Ves v 5/Pol d 5. Nevertheless, a slight diagnostic improvement was obtained when Ves v 5/tIgE and Pol d 5/tIgE were measured., (© 2018 S. Karger AG, Basel.)

Background: Skin test reactivity to hymenoptera venom and venom-specific IgE are important for diagnosing venom allergy and deciding on the appropriate allergen for venom immunotherapy (VIT). Longitudinal data on skin test reactivity during VIT and their correlation with venom-specific immunoglobulin (Ig)E and IgG are scarce., Methods: We retrospectively analyzed shifts in skin test reactivity and serum levels of venom-specific IgE and IgG in patients allergic to hymenoptera venom before the initiation of VIT with ultrarush therapy and after ≥3 years of VIT., Results: Fifty-four patients received ultrarush desensitization and subsequent VIT with wasp venom, 26 with honeybee venom, and 8 with both wasp and honeybee venom. Hymenoptera-specific skin test reactivity decreased during VIT in most patients, and became negative in 8% of the wasp-allergic patients and in 25% of the honeybee-allergic patients. Serum levels of venom-specific IgE positively correlated to skin test reactivity before VIT, but did not change significantly during VIT. IgG serum levels and the IgG/IgE ratio increased during VIT in most patients. A high IgG/IgE ratio correlated with low skin test reactivity after ≥3 years of VIT., Conclusions: The correlation between a high venom-specific IgG/IgE ratio and low skin test reactivity after VIT may be interesting for future investigations that assess its role as a potential marker for VIT efficacy., (© 2017 S. Karger AG, Basel.)

Background: Anti-sperm antibodies (ASA) have been described to be involved in immunological infertility. A possible antigen for ASA is the human cysteine-rich secretory protein 2 (CRISP-2), a sperm surface protein important in sperm-oocyte interaction. Furthermore, anti-CRISP-2 antibodies were shown to decrease fertility rates in vitro. Recently, we have reported cross-reacting antibodies recognizing CRISP-2 and antigen 5 from yellow jacket venom (Ves v 5) in human serum., Methods: Here, we investigated anti-Ves v 5 and CRISP-2 antibodies in sera from two groups of donors: MAR+ and MAR- patients., Results: A higher incidence of allergy against hymenoptera venom was found in MAR+ patients. Interestingly, affinity-purified ASA from MAR+ patients' sera reacted against both Ves v 5 and CRISP-2, leading to sperm immobilization. Immunofluorescence analysis showed that ASA bound to the sperm surface, including the head part where CRISP-2 is localized., Conclusion: Taken together, these results showed a higher incidence of antibodies cross-reacting with Ves v 5 and CRISP-2 in MAR+ patients. This leads to the hypothesis that MAR+ patients may have a higher risk to develop wasp allergy., (Copyright © 2012 S. Karger AG, Basel.)

Background: Rush venom immunotherapy (VIT) is highly effective in vespid venom allergy, but comparable data regarding bee venom (BV) allergy are sparse. We evaluated its safety, efficacy and cost in BV-allergic patients., Methods: Conventional or rush VIT were offered to all patients with systemic reaction to insect sting. Rush VIT was also given to hyperreactive patients who failed to reach the maintenance dose with conventional VIT due to multiple systemic reactions. In BV-allergic patients, honeybee sting challenge was performed within 1 week after reaching the maintenance dose., Results: 179 patients, some of them allergic to more than one venom, received 246 rush VIT courses. Bee VIT was administered to 132 patients (73.7%); 173 patients (96.6%) reached the maintenance dose. The incidence of systemic reactions was 29.6%. They were more common in VIT with BV than with vespid venoms (31.1 and 16.3%, respectively, p = 0.01). After excluding the hyperreactive subgroup (n = 20), this difference was not significant (23.7 and 16%, respectively, p = 0.19). Despite the high incidence of systemic reactions (15 of 20, 75%) among hyperreactive patients, 17 patients (85%) achieved the maintenance dose. Sting challenges resulted in systemic reaction in 4 of 8 (50%) hyperreactive patients and in 2 of 47 (4.3%) ordinary patients. The cost of rush VIT was 41% of that of conventional VIT., Conclusions: Rush VIT with BV is safe, instantaneously effective, less expensive and enables most patients with previous failures of conventional VIT to reach the maintenance dose., (Copyright © 2011 S. Karger AG, Basel.)

Background: Specific immunotherapy with allergen is the only causative treatment for IgE-mediated allergies such as stinging insect allergy or hay fever and works by the induction of blocking antibodies and regulatory T lymphocytes., Objective: Does a hypothetical obstruction of tumor surveillance presupposing the induction of regulatory T cells really justify detaining immunotherapy to oncologic patients as suggested by recent guidelines?, Methods: We report 6 patients (4 female, 2 male) suffering or having suffered from stage 1 cancer (4 melanomas, 1 lung cancer, 1 breast cancer) and concomitant IgE-mediated allergy. Four of them had a history of severe anaphylactic reactions to the insect yellow jacket, the 5th suffered from allergic rhinoconjunctivitis to dust mites, and the 6th to grass/rye pollen., Results: Between 2004 and 2010, subcutaneous immunotherapy was safely performed in 5 patients without signs of tumor reactivation. The cancer in 2 of them was diagnosed immediately after specific immunotherapy had been initiated and in another 2 the active cancer phase had already finished years before; the 5th suffered from a relapse around the time of the initiation of immunotherapy. At the time of the writing of the manuscript, 4 of them had already concluded 3 years of treatment, another one almost 1 year. The melanoma in the 6th patient was diagnosed 5 months after reaching the maintenance dose. Immunotherapy with grass/rye pollen was aborted in this patient based on current guidelines., Conclusions: Specific immunotherapy was safely administered in patients suffering concomitantly from IgE-mediated allergy and lower stage cancer., (Copyright © 2011 S. Karger AG, Basel.)

The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin's barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin's role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation., (Copyright © 2010 S. Karger AG, Basel.)

We report on a 33-year-old female patient with indolent systemic mastocytosis and urticaria pigmentosa who died of an anaphylactic reaction after a yellow jacket sting. As she had no history of previous anaphylactic sting reaction, there was no testing performed in order to detect hymenoptera venom sensitization. But even if a sensitization had been diagnosed, no venom immunotherapy (VIT) would have been recommended. It is almost certain that VIT would have saved her life and it is most likely that VIT is indicated in some patients with mastocytosis with no history of anaphylactic sting reaction. However, no criteria have been established in order to allow a selection of mastocytosis patients eligible for such a 'prophylactic' VIT., ((c) 2008 S. Karger AG, Basel.)

Background: Local reactions (LRs) are a very frequent side effect of specific immunotherapy with allergens and can impair patients' adherence. Antihistamine pretreatment--originally introduced as a safety measure to reduce anaphylactic side effects--has been the only treatment option for LRs so far, although these swellings usually do not appear immediately but after hours. We were interested whether pretreatment with the leukotriene antagonist montelukast would be better suited for preventing those reactions than pretreatment with the antihistamine desloratadine., Methods: Fifteen patients with a history of severe anaphylactic reactions to hymenoptera stings were enrolled into a prospective, double-blind, randomized, placebo-controlled pilot study. We selected a rush immunotherapy protocol consisting of 19 injections of hymenoptera venom administered over 5 consecutive days, where the majority is developing LRs, and counted the number of injections until an LR of >3 cm occurred. The patients were randomized to 3 treatment groups: premedication with placebo, 10 mg montelukast and 5 mg of the antihistamine desloratadine., Results: Compared with placebo, the occurrence of LRs (>3 cm) was significantly delayed by montelukast (p < 0.01, analysis of variance) but not by desloratadine (p = 0.19). The difference between montelukast and desloratadine was close to significant (p = 0.054). Itching, recorded on a scale from 0 to 5, did not differ between the 3 groups., Conclusion: Montelukast can be useful in the prevention of LRs after specific immunotherapy., (2007 S. Karger AG, Basel)

Background: Patients with mastocytosis may suffer from severe hypotension after wasp or bee stings. In these patients, no specific IgE is detectable, but they usually have skin lesions and an elevated serum tryptase level., Methods: We report on 6 patients who were referred to our department because of severe hypotension following bee or wasp stings without cutaneous lesions., Results: In 3 patients, the baseline serum tryptase level was elevated (26, 36, and 67 ng/ml, respectively), and investigation of their bone marrow revealed systemic mastocytosis (SM). In the remaining 3 patients, serum tryptase levels were <20 ng/ml, and bone marrow histology and tryptase immunohistochemistry did not reveal diagnostic mast cell infiltrates. However, in 1 patient, three minor SM criteria were demonstrable leading to the diagnosis SM, and in the 2nd patient, two minor SM criteria, including an aberrant mast cell phenotype, were found. In the 3rd patient, no minor SM criteria were detected., Conclusions: All patients with unexplained hypotension after hymenoptera stings should undergo a thorough investigation for major and minor SM criteria regardless of the tryptase level or presence of skin lesions, in order to diagnose or exclude SM or a related subdiagnostic condition (1 or 2 minor SM criteria) tentatively termed monoclonal mast cell activation syndrome., (Copyright 2007 S. Karger AG, Basel.)

Background: Venom sac extract of yellow jackets Vespula vulgaris was toxic in mice when injected intraperitoneally but not toxic when injected subcutaneously. Necropsy showed the toxicity to be an inflammatory response., Methods: Venom peptide and protein fractions were tested to identify the inflammatory components. The active components were tested to establish whether they might function as adjuvant for venom protein-specific antibody response., Results: Venom toxicity required the synergistic action of two venom components, a mast cell degranulating peptide mastoparan and phospholipase A1. Both components stimulated prostaglandin E(2) release from murine peritoneal cells and macrophages. Mastoparan showed a weak activity to enhance IgE and IgG1 responses to a yellow jacket venom protein Ves v 5 in BALB/c mice. It was not possible to assess the adjuvant activity of phospholipase A1 because of its suppression of Ves v 5-specific response. Melittin, a mast cell degranulating peptide from bee venom, was inactive as an adjuvant for Ves v 5-specific response., Conclusion: Yellow jacket venom contains two inflammatory components, mastoparan and phospholipase A1. Our findings suggest that mastoparan can function as a weak adjuvant for TH2 cell-associated antibody response., (Copyright 2003 S. Karger AG, Basel)

Background: Bee and wasp venom extracts contain potent allergens capable of inducing severe clinical reactions. To analyze immediate-type hypersensitivity to defined hymenoptera venom components, a recently developed in vitro test was applied that is based on the upregulation of CD203c expression on basophils., Methods: CD203c expression on blood basophils of 9 healthy donors and 39 patients allergic to bee and/or wasp venom was analyzed by flow cytometry before and after activation with the purified bee venom allergens phospholipase A2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 4), or the purified wasp venom allergens phospholipase A1 (Ves v 1), hyaluronidase (Ves v 2) and the recombinant antigen 5 (Ves v 5). Venom-induced CD203c upregulation on basophils was compared with skin tests and assessment of specific IgE. Basophils of nonresponders were preincubated with 10 ng/ml interleukin-3 (IL-3) prior to allergen stimulation., Results: CD203c upregulation on basophils was induced by defined hymenoptera venom components in 35/39 patients with a diagnosed allergy to wasp and/or bee venom. Twenty-seven of the 34 tested patients with wasp allergy showed CD203c upregulation in response to Ves v 5, 26 of these patients also reacted with Ves v 2 and 17 with Ves v 1. Nine of 13 patients with bee allergy reacted with Api m 1, 13 individuals with Api m 2 and none of these patients with the minor allergen Api m 4. A diagnosed wasp allergy could also be confirmed in the prestimulated basophils (IL-3) of 2 nonresponder individuals who failed to upregulate CD203c in response to IgE receptor cross-linking prior to culture with IL-3., Conclusions: Flow-cytometric determination of CD203c upregulation on basophils activated by molecularly defined allergens is a powerful method to identify the precise allergen reactivity in sensitized individuals., (Copyright 2002 S. Karger AG, Basel)