A 13-year real-life study on efficacy, safety and biological effects of Vespula venom immunotherapy

Abstract

Background: Hymenoptera venom immunotherapy (VIT) is a clinically effective treatment. However, little is known about its long-term clinical efficacy and biological effects. Several mechanisms have been proposed to account for VIT efficacy, including reduction of specific IgE and induction of allergen-specific IgG₄, but the overall picture remains elusive. We investigated Vespula VIT clinical efficacy up to 8 years after discontinuation and the kinetics of Vespula-specific IgE and IgG₄. Out of 686 consecutive patients we retrospectively selected and analysed a series of 23 patients with Vespula allergy that underwent a 5-year IT course, followed by a prolonged follow-up.

Methods: Clinical efficacy of VIT was assessed as number and severity of reactions to Vespula re-stinging events. The presence of Vespula-specific IgE and IgG₄ was also monitored over time.

Results: During the VIT treatment, patients were protected, reporting no reactions or mild reactions in occasion of re-stinging events. This protection was entirely maintained during the follow-up, up to 8 years. Skin reactivity (reflecting mast cell-bound Vespula-specific IgE) and circulating Vespula-specific IgE levels declined substantially during VIT. Notably, this reduction was maintained over time during the follow-up. Moreover, all the patients were analysed for IgG₄. A robust induction of Vespula-specific IgG₄ was observed during the VIT course, with a substantial decline during the follow-up.

Conclusions: We conclude that Vespula VIT is a clinically effective treatment, which induces long-term protection after discontinuation. The reduction of specific IgE, assessed by skin tests and RAST, closely matches the VIT- induced protection, while the IgG₄ induction seems not to be associated with VIT clinical efficacy in the long term.

Keywords: AIT; Allergen immunotherapy; Hymenoptera venom allergy; Long-term efficacy; VIT; Venom-specific IgE; Venom-specific IgG4.

Fig. 1

Clinical efficacy and safety of VIT. a Re-stinging events were counted and classified according Müller’s grade, during VIT course (left panel) and follow-up (right panel). b Analysis of adverse reactions to injections performed during VIT course

Fig. 2

Kinetics of Vespula-specific IgE. a Kinetics of the bound pool of Vespula-specific IgE assessed by quantitative intradermal skin testing, at the indicated time-points (months). Skin Index represents the ratio between the area of the allergen wheal and the area of the exogenous histamine reference wheal. Intradermal skin tests were performed with a 0.1 μg/ml concentration of Vespula venom. Time-points on x-axis are averages of individual time-point. b Kinetics of circulating pool of Vespula-specific IgE measured using RAST, at the indicated time-points (months; averages of individual time-points). Results are expressed as mean ± SEM. Statistical significance against baseline time-point was calculated by one-way Anova with Bonferroni post-test (N.S.: > 0.01, *p < 0.01, **p < 0.001). Dashed vertical line separates the VIT course from the follow-up

Fig. 3

Kinetics of Vespula-specific IgG₄. a Kinetics of serum Vespula-specific IgG₄ measured using commercial ELISA kit at the indicated time-points, in months (averages of individual time-points). N = 23 patients and 20 healthy controls. Statistical significance against baseline time-point was calculated by one-way Anova with Bonferroni post-test (N.S.: > 0.01, *p < 0.01, **p < 0.001). Dashed vertical line separates the VIT course from the follow-up. b Comparison of measurement (O.D.) obtained with the IgG₄ commercial kit versus the in-house technique at the indicated time-points, in months (averages of individual time-points). N = 6 patients and five healthy controls. Results are expressed as mean ± SEM

Fig. 4

Suggested model of long-lasting immunological changes induced by VIT. Before VIT, Vespula-specific IgE and IgG₄ antibodies are already present in the patients. VIT induces a progressive and steady decline in both bound and circulating pools of IgE. In contrast, IgG₄ levels increase. The IgE levels remain low long after VIT discontinuation, while the IgG₄ decline to pre-VIT values