Letter to the editor

Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom

Venom-specific immunotherapy (VIT) is a major treatment for patients allergic to Hymenoptera venom. Thus, correct diagnosis of sensitization, identification of the risk factors, and choice of venom for the treatment are the key issues.

We aimed to describe diagnostic and treatment experience data of VIT performed in a single center in Lithuania.

In this retrospective study, we analyzed 9 years of clinical data (severity of the allergic reaction, recognition of the culprit insects, diagnostics, VIT protocol safety and efficacy, sting challenge outcomes) of patients treated with cluster VIT. Sting challenge helped to reveal the influence of venom preparation quality and to adjust the dosage of venom.

Data from 83 patients were analyzed. Double sensitization confirmed by component diagnosis was found in 39.4% (13/33), and double immunotherapy was initiated in 9.1% (n = 3/33). The cluster immunotherapy protocol was used in 81 patients. Systemic reactions occurred in 7.4% (n = 6/81) patients during the build-up phase. VIT failure was related to bee venom immunotherapy and systemic reactions during a build-up phase. The efficacy in the short term of our approach to cluster VIT was confirmed by the sting challenge in 97% (42/43). Nine patients (10.8%, n = 9/83) voluntarily stopped the treatment due to a lack of motivation.

Our protocol regarding the investigation and treatment of patients allergic to Hymenoptera venom has been safe and effective. Patient's motivation to continue VIT is one of the concerns, but the biggest challenge is the patients with bee venom allergy and repeated systemic reactions during VIT.

An accurate diagnosis of IgE-mediated allergies is necessary to inform risk management for severe allergic reactions including anaphylaxis for food, venom, and drug allergies. The most widely available laboratory test for allergy is serum-specific IgE testing, which is routinely used for food allergy and insect sting allergy. Testing for specific IgE is limited by high sensitivity and low specificity, resulting in concern regarding overdiagnosis. Testing of allergen components has led to improved diagnosis for some food and venom allergens. Additional options for laboratory tests, such as epitope analysis, basophil activation, and mast cell activation, are being investigated for their potential to optimize diagnosis and provide predictors for reaction severity and treatment response. In contrast, laboratory testing for drug allergy is more limited because to date, there are no well-validated commercial assays in the United States. Furthermore, it is important to diagnose delayed reactions to medications, because these also significantly affect decision-making regarding therapeutic options for infectious disorders. Reliable tests for both immediate and delayed drug hypersensitivity are much needed, because drug allergy labels can significantly limit treatment options for patients. Research in this area is emerging.

In Hymenoptera venom allergy serologically double-sensitized patients, it is often difficult to identify the culprit insect for venom immunotherapy (VIT).

To evaluate if basophil activation tests (BATs) performed not only with venom extracts but additionally with single component-resolved diagnostics could differentiate between sensitized and allergic individuals and how the test results influenced the physicians’ decision regarding VIT.

BATs were performed with bee and wasp venom extracts and with single components (Api m 1, Api m 10, Ves v 1, and Ves v 5) in 31 serologically double-sensitized patients.

In 28 finally included individuals, 9 BATs were positive and 4 negative for both venoms. Fourteen of 28 BATs showed positive results for wasp venom alone. Two of 10 BATs positive for bee venom were only positive to Api m 1 and 1 of 28 BATs only to Api m 10, but not for whole bee venom extract. Five of 23 BATs positive for wasp venom were only positive for Ves v 5 but negative for wasp venom extract and Ves v 1. Finally, VIT with both insect venoms was recommended in 4 of 28 individuals, with wasp venom alone in 21 of 28 patients and with bee venom alone in 1 of 28. In 2 cases no VIT was recommended.

BATs with Ves v 5, followed by Api m 1 and Api m 10, were helpful for the decision for VIT with the clinically relevant insect in 8 of 28 (28.6%) patients. A BAT with components should therefore be additionally carried out in cases with equivocal results.

Le traitement de l’allergie aux venins d’hyménoptère repose dans un premier temps sur le traitement symptomatique après une piqûre. La plupart des réactions cliniques sont légères à modérées, mais en cas d’anaphylaxie, la rapidité de la prise en charge avec l’utilisation adaptée de l’adrénaline est cruciale pour le pronostic. Au décours de la phase aiguë, le patient doit connaître les mesures de prévention des piqûres d’hyménoptères, avoir la prescription pour une trousse d’urgence à adapter en fonction de la clinique. Le traitement curatif est l’immunothérapie allergénique aux venins d’hyménoptère, qui permet la prévention à long terme des récidives allergiques graves. C’est le seul traitement qui modifie l’histoire naturelle de l’allergie. Actuellement, l’immunothérapie est disponible pour les venins de Vespula, de Poliste et d’abeille. Le choix du venin est fait au terme d’un bilan allergologique (tests cutanés et bilan biologique), parfois complexe en raison des réactions croisées, et pour lequel les outils actuels, notamment biologiques, sont d’une aide diagnostique. L’efficacité et la tolérance de l’immunothérapie allergénique aux venins, aussi bien chez l’adulte que chez l’enfant, ont été largement démontrées. De plus, elle améliore significativement la qualité de vie. Ses indications ont été réévaluées récemment. Cette prise en charge est nécessairement associée à une éducation thérapeutique régulière. L’allergie aux fourmis, pour lesquelles l’immunothérapie n’est pas encore disponible, ainsi qu’aux insectes non hyménoptères tels que les taons et les moustiques, sera également abordée.

Treatment of hymenoptera venom allergy is based on immediate symptomatic treatment after a sting. Most reactions are mild and moderate, but in the case of severe anaphylactic reactions, prompt management and appropriate use of epinephrine are crucial to prognosis. After the acute phase, patient must known measures to prevent hymenoptera stings and have the prescription of an emergency kit according to the clinic. The curative treatment is allergenic immunotherapy to hymenoptera venom, which provides long-term prevention of severe allergic recurrences. It is the only treatment that modifies the natural history of the allergy. Currently, immunotherapy is available for Vespula wasp, Poliste wasp and honeybee. The choice of venom is made after an allergological assessment (skin tests and biological assessment), which is sometimes complex due to cross-reactions, and for which current tools, particularly biological, are of great diagnostic help. Efficacy and good tolerance of venom immunotherapy, in both adults and children, had been widely demonstrated. Moreover, it significantly improves quality of life. Its indications have recently been reassessed. This treatment is necessarily associated with regular therapeutic education. Allergy to ants, for which immunotherapy is not yet available, as well as to non-Hymenopteran insects such as horseflies and mosquitoes, will also be discussed.

En cas de réaction sévère après piqûre d’hyménoptère, il faut confirmer le mécanisme immunoallergique et identifier, de façon précise, l’allergène en vue d’une immunothérapie spécifique. Le bilan est effectué à distance de la réaction initiale (après 4 semaines habituellement). L’anamnèse est l’élément fondamental du diagnostic et doit être rigoureuse. La mise en évidence d’une sensibilisation IgE dépendante repose sur les tests cutanés par intradermoréaction et le dosage d’IgE spécifiques du venin suspecté. Les hyménoptères testés habituellement sont l’abeille, la guêpe Vespula et, surtout, dans les régions du sud, la guêpe poliste. Le dosage d’IgE spécifiques vis-à-vis de certains composants de venin (Api m1, Api m10, Ves v1, Ves v5, Pol d5…) et vis-à-vis de déterminants carbohydrates permet d’affiner le diagnostic, notamment en cas de polysensibilisation ou de doute sur l’identification de l’hyménoptère responsable. Les tests ex vivo (tests d’activation des basophiles) et les tests d’inhibition d’IgE spécifiques peuvent également aider à préciser le diagnostic, dans des situations difficiles, mais restent exceptionnels et peu accessibles. Le dosage des IgG4 spécifiques pour mesurer une éventuelle induction de tolérance est controversé. Le test de provocation est déconseillé.

In case of severe reaction following a hymenoptera sting, the immuno-allergic mechanisms must be confirmed and it is critical to identify precisely the allergen for an eventual venom immunotherapy. The allergological exploration must be postponed from the initial event, usually 4 weeks. A precise history of reaction is the basis of diagnosis and must be rigorous. IgE-dependent reaction is evidenced with intradermal skin tests, and the dosage of specific IgE for Honey bee and Vespula wasp venoms are usually performed together with Polistes venom in south Europe region. Dosages of specific IgE to venom components (Api m1, Api m10, Ves v1, Ves v5, Pol d5…) and Cross-reactive Carbohydrate Determinants help in characterization of the sensitization, especially in case of multiple sensitivity or in case of doubtful identification of the stinging insect. In vitro functional test (Basophil Activation test) and specific IgE-inhibition tests can help solving difficult cases but are not available everywhere. Dosage of specific IgG4 for venom components to measure tolerance induction is still under debate. In vivo, provocation tests with venom are generally not recommended in diagnosis.