Low maintenance dose in honeybee venom immunotherapy and basophil‐based tests

To the Editor, The recently reported article by Louise Houliston and colleagues in the latest number of Journal of Allergy and Clinical Immunology suggests to use a 50-lg maintenance dose for honeybee venom immunotherapy (VIT) in children instead of the recommended dose of 100 lg (1): VIT has been shown to be an effective and safe treatment for preventing sting-induced anaphylaxis in patients with systemic reactions to hymenoptera stings, but a remaining problem is the relative effectiveness and safety of different immunotherapy protocols used with respect to maintenance dose, injection interval, and duration. The suggestion to halve the recommended dose is justified because a smaller injection volume should be better tolerated with a lower cost of VIT; actually, this seems to be also the experience of other groups (2). The mechanism of allergen immunotherapy has not yet been clarified (3) and few papers have claimed a direct involvement of basophils, besides to lymphocytes, in the mechanism of immunotherapy (4). What is the real participation of basophilic cells in the hypo-sensitization/ desensitization induced by dose maintenance in VIT? Desensitization of basophils to specific allergens during the updosing phase of injection immunotherapy may contribute to the clinical effect of immunotherapy (5) while both the allergen dose and the cell activation state can change dramatically the response of basophil to VIT, leading to a bimodal behavior (6). While it is worth of consideration the suggestion to use a less concentrated maintenance dose, as addressed by some Authors (1, 2), it looks like rather frustrating that there are not significant differences with results published using 100 lg and that in adults the protection rate to challenge hymenoptera stings is about 79% in subjects who received 50 lg compared to a more reassuring 96% in those receiving 100 lg (1). Some Author has even criticized the opportunity of honeybee VIT in children (7). Although specific immunotherapy should be recommended for adults and children with moderate to severe reactions, there is no need to prescribe it for children with skin reactions alone, especially if the exposure is very sporadic (7). A direct involvement of basophil if suggested in VIT mechanism should change the overall perspective about the application and performance of basophil activation tests (BATs) in hymenoptera allergy and immunotherapy: what kind of useful information could give to clinicians performing a BAT for bee venom immunotherapy (8)? Evidence has reported that in basophils aqueous extracts of honey bee venom used for skin diagnosis and immunotherapy elicit a biphasic response following an IgE-mediated activation (6): this evidence raises questions about the allergen dose and the response machinery of cells involved in hypersensitivity. Moreover, a dose range of honey bee venom higher than 10 lg/ml exhibits an activation of basal basophil function, what might explain the initial side-effect reaction due to the injection of hymenoptera venom (1, 6). Skin tests and serum IgEs, besides to anamnesis, represent the commonest strategies to diagnose hymenoptera sting allergy and follow up therapy. In patients with positive skin tests or specific IgE to both honeybee and wasp venom, IgE inhibition test can identify sensitizing allergen only in around 15% and BAT increases the identification rate to around one-third of double positive patients (9). In these circumstances BAT is also diagnostic in majority of patients with systemic reactions after insect stings when no specific IgE in serum is detectable: high basophil sensitivity to allergen is associated with a risk of side effects during VIT. The activatory effect observed with honey bee venom on basophil function in vitro (6) suggests also that persistence of high basophil sensitivity also predicts a treatment failure of VIT (9). These issues indicate that BAT is a useful tool for better selection of allergen for immunotherapy, for identification of patients prone to side effects and patients who might be treatment failures. Of course, long term studies are needed to evaluate the accuracy of the test and the feasibility of BAT in giving reliable information about VIT doses and maintenance protocols. However, a general agreement on this perspective has not yet been reached. As in vitro diagnosis of wasp venom sensitization by specific serum IgE has a sensitivity of only 60–80%, additional in vitro tests are desirable (10). Certainly, BAT is a helpful tool for the complementation of routine diagnostic tests such as specific IgE as it increases sensitivity of in vitro detection of sensitization but, anyway, this in vitro method could not offer a forthright alternative to the sting challenge in monitoring successful VIT. Basophil function scavenging during specific immunotherapy should not have been excluded, however, from a desiderable successful diagnostic protocol. The introduction of basophil investigation in the routine diagnostic panel on VIT and hymenoptera allergy might give insights also on basophil Pediatric Allergy and Immunology