Venom immunotherapy induces monocyte activation

BACKGROUND: Venom immunotherapy (VIT) is an efficient treatment of hymenoptera venom allergy. The mechanism of VIT is based on the induction of tolerance of allergen-specific Th2 cells. The mechanisms of this T cell modulation are unknown, and could depend on cytokines produced by other cell types such as interleukin (IL)-12, tumour necrosis factor (TNF)-alpha and IL-10 by monocytes. OBJECTIVE: To assess if VIT modifies the monocyte production of IL-12, TNF-alpha and IL-10 during the 45 first days of treatment. METHODS: Fourteen patients and seven controls were included. Blood samples were taken once in controls and at day (D)1, D30 and D45 of VIT in patients. Monocytes were isolated, cultured with and without lipopolysaccharide (LPS), and the culture supernatant was harvested. IL-10, IL-12 and TNF-alpha were assayed in supernatants by ELISA. RESULTS: Baseline cytokine levels were not statistically different between patients and controls. During treatment, an increase of spontaneous monocyte production of IL-12 and TNF-alpha was observed at D15 and D45. The production of IL-10 increased at D15 and D45 but not significantly. After LPS-stimulation, IL-12, TNF-alpha and IL-10 monocyte production was not modified by VIT. CONCLUSION: VIT induces a monocyte activation characterized by a delayed overproduction of IL-12 and TNF-alpha. These cytokines could be relevant to the inhibition of Th2 cells during VIT. Therefore, VIT-induced tolerance could depend not only on the specific action of venom antigens on T cells, but also on a secondary non-specific action of monocytes.     

Venom immunotherapy in the Hymenoptera-allergic pregnant patient

Natural or iatrogenic causes of anaphylaxis are significant risk factors in pregnancy. A 3% to 5% risk of sting anaphylaxis in any pregnant woman with insect-sting allergy untreated with venom immunotherapy (VIT) can be calculated. Insect-sting anaphylaxis has allegedly caused severe fetal abnormalities and is a potential cause of fetal loss and severe maternal morbidity and/or mortality. Hymenoptera anaphylaxis is a highly preventable cause of anaphylaxis, but VIT may itself carry a risk potential, with an appropriate 5% reaction during buildup and 1% reaction risk during maintenance VIT. To assess the safety of VIT in pregnancy, we have gathered data from 26 women with 43 pregnancies. All the women were receiving VIT. One woman was stung early in pregnancy with anaphylaxis resulting. Outcome of pregnancy was normal. Thirty-six of the pregnancies ended normally. There were two mild adverse reactions to VIT, neither of which required treatment. One child was born with multiple congenital abnormalities of unknown cause. Since congenital malformations may occur as frequently as one in 40 live births, these data do not suggest a significant increased risk from VIT during pregnancy.     

Venom immunotherapy: adverse reactions and treatment failure

PURPOSE OF REVIEW: Side effects of venom immunotherapy and lack of efficacy represent significant problems in the treatment of patients allergic to Hymenoptera venom. Among these side effects systemic anaphylactic reactions and large local reactions are the most important. This review aims to discuss new insights in frequency, pathogenesis and handling of these common side effects and of treatment failure during venom immunotherapy. RECENT FINDINGS: Several studies showed that severe side effects due to venom immunotherapy are rare. Recently published studies focus on ultrarush protocols and report good tolerance of an ultrarush venom immunotherapy in which the maintenance dose was reached within several hours or 2 days, respectively. Compared to the use of aqueous extracts (administered according to a rush protocol), frequency of local and also systemic side effects was lower when depot extracts and schedules with a slow conventional dose increase were applied. Concomitant treatment with H1-antihistamines was found to reduce local and mild systemic adverse reactions during venom immunotherapy. Up to 25% of patients are not protected when re-stung while on venom immunotherapy with the usual maintenance dose of 100 microg of venom every 4-8 weeks. These patients can achieve full protection by increasing the maintenance dose. SUMMARY: Conventional dose increase using depot extracts is better tolerated than if aqueous extracts are being administered. Concomitant treatment with H1-antihistamines may be helpful. Increasing the venom dose to 200 microg or even more may be therapeutically effective in patients not protected by a lower maintenance dose. To compare tolerance of different treatment protocols prospective comparative studies are required.     

Venom immunotherapy: clinical efficacy,safety and contraindications

Venom-specific immunotherapy (VIT) is considered for the treatment of patients with IgE-mediated systemic allergic reactions (SARs) after developing a Hymenoptera venom allergy. Tolerance is achieved in a majority of patients after only a few days or even hours of rush immunotherapy. After VIT discontinuation, the allergy returns in up to 15% of patients. During VIT, the majority of patients have local reactions at the site of venom injections. SARs to VIT are much more frequent in honeybee-treated patients than in wasp-treated patients. Increased baseline serum tryptase and increased allergen-specific sensitivity of basophils are other factors that might be associated with systemic reactions (SRs) during VIT. Severe SRs occur mainly during the build-up phase but can also occur in the maintenance phase of the VIT, even in patients with a well-tolerated dose-increase phase. Pre-treatment with humanized anti-IgE antibodies (omalizumab) is effective in patients with repeated SARs; however, this use of omalizumab is off-label. In highly exposed patients with a history of very severe reactions, there are virtually no absolute contraindications for VIT.     

Venom immunotherapy in patients with allergic reactions to insect stings

Introduction: Allergy to Hymenoptera (Apis mellifera, Vespula species, Polistes species, Vespa crabro) venom can be safely and effectively treated by venom immunotherapy (VIT), which in the 40 years since its introduction has been able to prevent reactions to stings, and to treatment as well, though systemic reactions, occasionally severe, are possible.

Areas covered: We reviewed the recent literature on VIT by searching in PubMed for the terms ‘venom immunotherapy’ and ‘Hymenoptera venom immunotherapy’ to highlight the current status of VIT and the likely development in the coming years.

Expert commentary: VIT, provided the correct choice of the venom and adequate venom preparations and maintenance doses are used, is a treatment of great value in preventing systemic reactions to Hymenoptera stings. A 5-year duration ensures a prolonged tolerance to stings following VIT discontinuation, unless patients suffer from mastocytosis. In fact, due to reports of fatal reactions after stopping VIT, patients with mastocytosis, or with very severe reactions to stings, need an indefinite duration of treatment.     

Venom immunotherapy improves health-related quality of life in patients allergic to yellow jacket venom

BACKGROUND: Venom immunotherapy (VIT) is effective in preventing anaphylactic reactions after insect stings. The effect of VIT on health-related quality of life (HRQL) was studied to evaluate whether this treatment is of importance to patients. OBJECTIVE: We compared HRQL outcomes measured with a disease-specific instrument (Vespid Allergy Quality-of-Life Questionnaire [VQLQ]) in patients allergic to yellow jacket venom treated with VIT or with an adrenalin self-administration device (EpiPen) in an open-label, randomized, controlled trial. METHODS: Consenting patients were block randomized to either VIT or EpiPen. Patients received uniform, standardized information, which specified the risk of their condition and the risks and benefits of both treatment options. HRQL measures took place before and after 1 year of treatment with VIT or EpiPen. RESULTS: Seventy-four patients agreed to be randomized, of whom 36 received VIT and 38 an EpiPen. The mean change in VQLQ score in the group randomized to VIT was 1.07 (95% CI, 0.68-1.46), and this improvement was statistically significant (P <.0001) compared with that seen in the group randomized to the EpiPen, in which this change was -0.43 (95% CI, -0.71 to -0.16). These differences were seen in both men and women, persons with more or less general anxiety, and those stung recently and those stung more than a year before their outpatient department visit. The overall proportion of patients receiving benefit from VIT is 0.72, generating a number needed to treat of 1.4. CONCLUSIONS: VIT results in a clinically important improvement in HRQL in patients allergic to yellow jacket venom in all subgroups studied. Of every 3 patients treated with VIT, 2 patients experience an important improvement in their quality of life.     

Venom immunotherapy modulates interleukin-4 and interferon-gamma messenger RNA expression of peripheral T lymphocytes.

The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. In order to evaluate the influence of venom immunotherapy on the T-cell cytokine pattern of allergic reactions, we studied interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA expression of peripheral T lymphocytes from 12 patients undergoing rush venom desensitization, before treatment at Day 0 (D0), at Day 15 (D15) and Day 90 (D90) after treatment, and from seven controls. Antigen-specific T-cell proliferation was also determined. Cytokine mRNA expression was evaluated using in situ hybridization, 24 hr after culture of peripheral T cells with medium, venom, or an unrelated allergen. Allergen-induced T-cell proliferation decreased at D15 and D90 of rush immunotherapy (P < or = 0.02). In venom-stimulated cultures of the patient group, there was a decrease in IL-4 mRNA-positive cells at D15 and D90 (P < or = 0.001). Before desensitization, IFN-gamma mRNA expression was lower in patients than in controls and did not increase after in vitro allergen stimulation. In contrast, after immunotherapy, spontaneous IFN-gamma mRNA expression increased, but only at D90 (P < or = 0.001). The cytokine pattern observed at D90 after immunotherapy was similar to that observed in control subjects. In conclusion, venom immunotherapy induced an altered cytokine mRNA pattern in allergen-stimulated T cells which was dissociated from the early changes of allergen-induced T-cell responsiveness.     

Venom immunotherapy: 10 years of experience with administration of single venoms and 50 micrograms maintenance doses.

For the past 10 years, we have administered venom immunotherapy with single venoms, whenever it is possible, and maintenance doses of 50 micrograms. The choice of venoms was based on clinical history, skin test reactions, and a knowledge of venom cross-reactivity. There have been 258 re-stings in 108 patients with only three systemic reactions (2.7% per patient; 1.2% per sting). Two of these re-stings reactions were very mild, hives and facial edema, in patients who had had initial severe anaphylaxis. Five other patients had transient ill-defined symptoms, not considered allergic after re-stings. The patients covered a wide age range. Twenty-seven patients, nine under age 16 years, had initial dermal reactions only, and 44 patients had severe anaphylaxis. Most patients had multiple positive skin tests. Seventy-five patients received single venoms (yellow jacket, 58; honeybee, 15; hornet, 2), and 30 patients received two venoms. Re-stings occurred from 1 month to 8 years, (mean, 2 years) after starting treatment. Results indicate that this approach with 50 micrograms top doses and single venom immunotherapy may be sufficient in most patients with an associated decrease in the cost as well as possible increased morbidity associated with the use of multiple venom antigens.     

Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy

IgE-mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk, and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies; however, its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable; however, the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march toward regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.     

Snakebite and Snake Venom Ophthalmia

Snakebite is not necessarily snake envenomation. Of about 2,500 known species of snakes, only about 40 are regarded as being dangerous. A snake will not go out of its way to attack a person and even in defense, snakes bite humans usually to dissuade and not to kill.     

Immunotherapy with Yellow Jacket Venom

Thirty-two patients with previous systemic allergic reaction to yellow jacket stings were randomly allocated to three groups receiving immunotherapy with different preparations of yellow jacket venom: 1) extract adsorbed to aluminium hydroxide (Alutard-SQ), 2) Pharmalgen extract or 3) non-adsorbed extract from Allergologisk Laboratorium (ALK aq.). Regular examinations showed a decrease in skin prick test size in nearly all patients. Specific IgE-antibody (RAST and CRIE scores) showed a similar, but not significant tendency to decrease in all three groups. Specific IgG-antibody increased considerably in the Alutard group only; after 2 years, however, no difference could be detected between the three groups. During dose increase, patients treated with ALK aq. generally had smaller local reactions to injections than those treated with Pharmalgen. Few systemic reactions occurred in all three groups. Nineteen patients treated for 2 1/2-3 1/2 years were challenged in-hospital with stings from yellow jackets. No systemic and only minor local reactions occurred. Consequently, with the dose regimens applied all three extracts seem effective even though no common changes in either specific IgE or IgG could be demonstrated.