Immunotherapy for Hymenoptera venom allergy compared with real‐life stings: Are we doing our best?

To the Editor, It is known that a Hymenoptera sting cannot be avoided with absolute certainty in a patient affected by Hymenoptera venom allergy (HVA). Venom immunotherapy (VIT) is the only therapeutic tool that can potentially prevent systemic reactions.1 Its rationale is represented by the ability to induce several immunological modifications that determine the establishment of a state of tolerance.2 The first controlled trials of VIT were performed over 40 years ago.1 In time, the category of patients that can benefit from the administration of VIT has been defined, i.e., those whose reaction is represented by systemic manifestations.3 Moreover, its efficacy rates have been highlighted to be 77%–84% and 91%–96% in the treatment of allergy to honeybee and vespid venom,4, 5 respectively. Besides, the advancement of scientific knowledge has outlined both the methods of preparation of the extract of Hymenoptera venom and the characteristics of the duration, efficacy, safety and contraindications of this therapy.6 The same applies to the definition of the treatment protocols, which first provide for an induction phase, according to conventional, clustered, rash or ultra-rush protocols and subsequently a maintenance phase, with a dosage equal to 100 μg and with a duration equal to 3–5 years.3 Over time, some VIT studies were conducted using different dosing regimens for the maintenance phase, ranging from 50 to 250 μg.7 A recent report from a task force of the European Academy of Allergy and Clinical Immunology took into consideration several studies about VIT immunotherapy, highlighting the need for universally accepted standards for dosing protocols, measurement of allergen content in VIT preparations, and selection of clinical endpoints to enable dose-response effects to be compared across studies.7 Furthermore, using higher doses during the maintenance phase could increase protection.3, 7 As part of the maintenance phase, the choice of the dosage of 100 μg dates back to 1978, together with the first controlled study carried out for this purpose.8 Although this first study was carried out in 1978, the 100 μg dosage used in the VIT maintenance phase was adopted in almost all subsequent studies as the evidence of the efficacy of VIT using this dosage was confirmed.3 It has been reported that the amount of venom released during a sting varies in different species of Hymenoptera and even within the same species. In particular, honeybees, yellow jackets, paper wasps and bumblebees release a quantity of venom equal to 59–140, 1.7–3.1, 4.2–17 and 10–31 mcg, respectively.9, 10 The quantity of venom released at each puncture was studied many years ago through two laboratory methods, the Coomassie blue dying binding method and the Lowry assay.10 However, with these methods, it was not possible to rigorously estimate the exact amount of venom released in each sting, as the volume of injected venom can be very variable, specifically in the order of at least five times.10 Moreover, to the best of our knowledge, there is no subsequent confirmation of these data in the literature. Given that the amount of venom that is released during a sting varies in the different species of Hymenoptera, the maintenance dosage of the VIT would appear in the range of the quantity of venom inoculated by the honeybee (100 mcg versus 59–140 mcg), while it would result in several times higher for the vespid VIT, particularly for the yellow jacket (100 mcg versus 1.7–3.1 mcg) and this may be responsible for a lower rate of failure of VIT for the yellow jacket compared to the honeybee (Table 1). Another aspect that could lead to the latter outcome is represented by the quality of venom used for VIT.16 Even if honey bee venom is the one with the most defined characterization concerning its allergenic content, it appears not fully adequately characterized yet. Indeed, for example, it has been established for particular extracts of VIT for honeybees, that the content of the relevant allergens is mainly represented by Api m 1, and the other allergens make up only to 0.6–2% of their dry weight.12 On the other side, it has been shown that honeybee venom, in addition to Api m 1, contains multiple allergens such as Api m 2, Api m 3, Api m 4, Api m 5 and Api m 10. Moreover, it is also known that some patients show a prevalent sensitization for Api m 10, an allergen poorly represented in VIT.12 The latter peculiarity may represent a further cause of the therapeutic failure of some patients treated with VIT preparations for honeybees with low content for Api m 10.16 On the contrary, the allergenic content of particular therapeutic extracts of VIT for yellow jackets contains substantial amounts of Ves v 1 and Ves v 5, which represent two important allergens.12 However, very few data are available regarding the characterization of yellow jacket VIT. In conclusion, for a better and accurate definition of the dose to be administered during VIT, studies with more modern technologies are necessary for the exact quantification of the venom injected by Hymenoptera. Furthermore, comparative studies between different VIT doses may be helpful in identifying the optimal efficacy and safety of the treatment. Finally, the inclusion of all clinically relevant allergens in the array of extracts used for VIT, in agreement with specific individual sensitization, may be advisable especially in a health context increasingly oriented towards precision medicine. On the other hand, given the general high percentage of VIT success, this suggestion appears to be more critical for the patients affected by HVA who undergo VIT in the absence of a response. Fortunately, the latter subjects represent the vast minority of all the patients who suffer from HVA and a specific cost-effectiveness analysis of the topic may be needed. The authors declare that they have no conflict of interests to disclose in relation to this paper. LP and MG designed the work, acquired, analysed the data, drafted the initial manuscript and reviewed the manuscript. FM, FS, SB, RC, SA, CM, LL and LC analysed the data and reviewed the manuscript. EN conceptualized, designed the work, acquired, analysed the data, drafted the initial manuscript and reviewed the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.