Systemic Allergic Side Effects Research Articles

Sex-related clinical aspects in insect venom anaphylaxis.

Experimental studies, epidemiological data, and clinical observations suggest that the gender factor is involved in the development and manifestation of IgE-dependent allergic diseases. We intend to answer the question if sex-related factors may play a role in Hymenoptera venom allergy (HVA). In the majority of recent studies the frequency of HVA symptoms with respect to both LL and SYS reactions is similar for men and women, while proven sensitization to insect venom is less frequent in women. Studies assessing clinical reactivity in HVA indicate that male sex and vespid venom allergy are factors increasing the risk of severe allergic reactions. Regarding the risk of adverse events associated with gender in the course of venom immunotherapy (VIT), the results of two large EAACI multicenter studies are discordant. In the first study, women showed increased risk of VIT adverse events. In the latter, systemic allergic side effects were not associated with gender. Despite theoretical premises and certain clinical observations indicating an important role of estrogens in allergic diseases, their influence on stinging insects' venom hypersensitivity is not unequivocal and remains still open. Further studies on the safety of VIT in females seem to be advisable.

Epicutaneous allergen administration: is this the future of allergen-specific immunotherapy?

IgE-mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 30% of the population in industrialized countries. Allergen-specific immunotherapy (SIT) either subcutaneously or via the sublingual route is effective, but only few patients (<5%) choose immunotherapy, as treatment takes several years and because allergen administrations are associated with local and, in some cases, even systemic allergic side-effects because of allergen accidentally reaching the circulation. In order to resolve these two major drawbacks, the ideal application site of SIT should have two characteristics. First, it should contain a high number of potent antigen-presenting cells to enhance efficacy and shorten treatment duration. Secondly, it should be nonvascularized in order to minimize inadvertent systemic distribution of the allergen and therefore systemic allergic side-effects. The epidermis, a nonvascularized multilayer epithelium, that contains high numbers of potent antigen-presenting Langerhans cells (LC) could therefore be an interesting administration route. The present review will discuss the immunological rational, history and actual clinical experience with epicutaneous allergen-specific immunotherapy.

Epicutaneous/transcutaneous allergen-specific immunotherapy: rationale and clinical trials

IgE-mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 35% of the population in industrialized countries. Allergen immunotherapy (also called hyposensitization therapy, desensitization or allergen-specific immunotherapy), the administration of gradually increasing amounts of an allergen, either subcutaneously or via the sublingual or oral route is effective. However, only few allergy patients (<5%) choose immunotherapy, as treatment duration is over years and because allergen administrations are associated with local and in some cases even systemic allergic side effects due to allergen accidentally reaching the circulation. Therefore, ideally the allergen should be administered to a site that contains high numbers of potent antigen-presenting cells in order to enhance efficacy and shorten treatment duration, and ideally that site should also be nonvascularized in order to prevent both systemic distribution of the allergen and systemic allergic side effects. The epidermis, a nonvascularized multilayer epithelium that contains high numbers of potent antigen-presenting Langerhans cells, could therefore be an interesting administration route. We have recently reintroduced transcutaneous or epicutaneous allergen-specific immunotherapy (EPIT) as treatment option for IgE-mediated allergies. This method was found efficacious and safe. Few applications of allergens using skin patches with a treatment duration of a few weeks were sufficient to achieve lasting relief. This review gives an overview on the history, the rationale, and the mechanisms of transcutaneous/epicutaneous immunotherapy.

Immunotherapy of hypersensitivity to hymenoptera venom

Insect sting allergy is a common condition with a risk of life-threatening anaphylaxis. After a severe reaction, the fear of being restung can significantly reduce quality of life. Venom immunotherapy (VIT) is a highly effective treatment of the underlying type I-sensitisation. This review addresses the mechanisms of immune modulation by VIT and outlines current clinical application. Although highly effective in the majority of patients, VIT fails in a few individuals. It can also cause systemic allergic side effects, restricting its application to physicians trained in the treatment of anaphylaxis. This review discusses several new strategies to overcome these problems, which are presently a promising focus of research. These include the use of new adjuvants, of recombinant and genetically engineered venom allergens, as well as vaccination with peptides.

Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.

Mastocytosis and/or elevated basal serum tryptase may be associated with severe anaphylaxis. To analyse Hymenoptera venom-allergic patients with regard to basal tryptase in relation to the severity of sting reactions and the safety and efficacy of venom immunotherapy. Basal serum tryptase was measured in 259 Hymenoptera venom-allergic patients (158 honey bee, 101 Vespula). In 161 of these (104 honey bee, 57 Vespula), a sting challenge was performed during venom immunotherapy. Nineteen of the 259 patients had an elevated basal serum tryptase. Evidence of cutaneous mastocytosis as documented by skin biopsy was present in 3 of 16 patients (18.8%). There was a clear correlation of basal serum tryptase to the grade of the initial allergic reaction (P<0.0005). Forty-one of the 161 sting challenged patients reacted to the challenge, 34 to a bee sting and 7 to a Vespula sting. Thereof, 10 had an elevated basal serum tryptase, i.e. 1 (2.9%) of the reacting and 2 (2.9%) of the non-reacting bee venom (BV) allergic individuals, as compared to 3 (42.9%) of the reacting and 4 (8%) of the non-reacting Vespula venom-allergic patients. Thus, there was a significant association between a reaction to the sting challenge and an elevated basal serum tryptase in Vespula (chi2=6.926, P<0.01), but not in BV-allergic patients. Systemic allergic side-effects to venom immunotherapy were observed in 13.9% of patients with normal and in 10% of those with elevated basal serum tryptase. An elevated basal serum tryptase as well as mastocytosis are risk factors for severe or even fatal shock reactions to Hymenoptera stings. Although the efficacy of venom immunotherapy in these patients is slightly reduced, most of them can be treated successfully. Based on currently available data, lifelong treatment has to be discussed in this situation.

Recent developments and future strategies for immunotherapy of insect venom allergy

Hymenoptera venom allergy may cause life-threatening, sometimes even fatal, allergic reactions and thus may be associated with a serious reduction in the quality of life. Venom immunotherapy is effective in the majority of patients with this allergy. Treatment failures do however occur and immunotherapy may cause frequent systemic allergic side effects, especially in honeybee venom-allergic patients. New strategies to improve safety and efficacy of this treatment are therefore of general interest. Among these new strategies are premedication with antihistamines: this definitely reduces side effects and based on recent in-vitro experiments and one clinical controlled study may even improve efficacy by modulating the T-cell response through interference with histamine receptors on these cells. Furthermore, during recent years the cDNA of most major allergens of bee and vespid venoms has been cloned and these allergens have been expressed in recombinant form. This allows for the preparation of patient-tailored extracts, with or without reduction of their allergenicity, for example by using unrefolded or point-mutated recombinant allergens. Yet another approach is the use of non IgE binding peptide fragments of the allergen with preserved T-cell epitopes for immunotherapy. Such preparations of bee venom phospholipase A2 have been used successfully in pilot studies. Finally, DNA vaccination with phospholipase A2 sequence plasmids has proved effective in one experimental study in sensitized mice. A number of new strategies for venom immunotherapy, mostly based on genetic engineering, have been described and we await their use in clinical medicine.

Recombinant Hymenoptera venom allergens.

Hymenoptera venoms, instead of the previously used whole body extracts, were introduced in the late 1970s for the diagnosis and treatment of IgE-mediated allergic reactions to stings by insects of the order Hymenoptera, such as honey bees and vespids (1, 2). Insect venom allergy is often considered as a model for IgE-mediated allergy: Diagnostic tests (skin tests and radioallergosorbant assays, RAST) are thought to be reliable, and specific immunotherapy with venoms is claimed to be safe and highly effective. However on closer looks the specificity of the main diagnostic tests (prick tests or intracutaneous skin tests with insect venom extracts, and tests for venom-specific serum IgE antibodies) is far from perfect. Up to 20% of individuals with no history of systemic sting reactions have positive tests. On the other hand only 30–50% of those with positive tests will react to a subsequent sting by the respective insect (3). According to a sting provocation test during venom immunotherapy around 95% of patients allergic to vespid stings are completely protected and do not develop any generalized allergic symptoms, while the complete protection rate achieved for those allergic to honey bee venom is only 80–90% (3, 4). Systemic allergic side-effects to immunotherapy injections may occur in 20–40% of patients during immunotherapy with honey bee venom and 5–10% during immunotherapy with vespid venoms (4). There is therefore considerable potential for improvement of both diagnosis and immunotherapy of Hymenoptera venom allergy. Thanks to modern molecular biology technology, recombinant venom allergens are available today and offer several promising approaches to achieve such an improvement. Expression of various recombinant allergens from Hymenoptera venoms