Conventional Venom Immunotherapy Research Articles

Adverse reactions in venom immunotherapy protocols: conventional versus ultra-rush

Background Venom immunotherapy (VIT) is an effective treatment in the patients at high risk of anaphylaxis or life-threatening systemic reactions due to Hymenoptera venom allergy. But, systemic and large local reactions can be observed, especially during the build-up phase of VIT. We evaluated the safety of conventional and ultra-rush build-up protocols. Materials and methods Two protocols in 71 patients (39 conventional and 32 ultra-rush protocols) with honeybee and wasp venom allergy were evaluated retrospectively. Patients were diagnosed and selected for VIT according to the criteria established by the European Academy of Allergy and Clinical Immunology. The severity of systemic reactions was evaluated according to the criteria of Mueller. Results Build-up phases were tolerated in 66.2% (n = 47) without any reaction. Allergic adverse reactions were observed in 33.8% (n = 24): large local reactions 22.5% (n = 16) and systemic reactions 11.3% (n = 8). There was no significant difference in the number of adverse reactions comparing patients receiving conventional and ultra-rush protocol. In addition, no association was found between allergic adverse reactions and the following factors: sex, previous systemic sting reactions, honeybee and wasp venom extract. Conclusion We found that both protocols were tolerated in patients with honeybee and wasp venom allergy. Ultra-rush protocol will be preferred for patients and clinicians because of its advantages in terms of time and costs. KEY MESSAGES VIT is the only curative treatment method that reduces the risk of severe reactions after a bee sting and improves the quality of life in patients with Hymenoptera venom allergy. Ultra-rush VIT protocol has advantages such as few injection and time savings. Both ultra-rush and conventional VIT are safe treatments to prevent potentially life-threatening reactions in patients with honeybee and wasp venom allergy.

Review of venom immunotherapy at a regional tertiary paediatric centre.

Bee stings can result in allergic reactions, including anaphylaxis. Venom immunotherapy (VIT) is a definitive cure for bee venom allergy, but controversy surrounds whether accelerated protocols are safe in children. Our primary aim was to assess the safety profile of ultra-rush bee VIT compared with conventional bee VIT at a regional paediatric tertiary centre. We also sought to evaluate the impact of both approaches on time and resource use. Data were collected retrospectively from 14 patients with bee venom allergy who were treated with ultra-rush or conventional bee VIT between 2013 and 2021 at John Hunter Children's Hospital. We compared VIT-associated adverse reactions and use of resources in both these groups. Overall, six patients received ultra-rush bee VIT and eight patients received conventional VIT. The ultra-rush group had a lower rate of systemic reaction (16%) compared with the conventional group (25%). One patient from the conventional group required adrenaline. Ultra-rush patients require fewer injections over a shorter time and fewer hospital visits to complete the protocol. Travel distance for families was significantly reduced. At our regional paediatric tertiary centre, ultra-rush bee VIT was a safe treatment option for children with bee venom allergy. It has many advantages over a conventional approach, especially for patients living in regional or remote areas.

Venom Immunotherapy in High-Risk Patients: The Advantage of the Rush Build-Up Protocol

Background: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. Objective: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). Methods: All of the patients who received VIT and had at least one of the following risk factors were included: current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with β-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. Results: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 μg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. Conclusion: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT.

Rush Venom Immunotherapy in Children

Rush venom immunotherapy (VIT) is highly effective in Hymenoptera venom allergy. Still, specific data regarding its safety and efficiency in children are rather sparse. The objective of this study was to better evaluate the safety and efficiency of rush VIT in this specific age group. Children younger than 16 years with systemic reaction to insect sting involving, at least, one body system other than skin and children aged 16-18 years with any kind of systemic reaction were offered conventional or rush VIT with a build-up phase that lasted 3 days. Eighty-four of 127 children together with their caregivers chose to receive rush VIT. Seventy of them were allergic to bee venom only. There was no difference between the children receiving rush or conventional VIT in the incidence of systemic reactions during the build-up phase (19% and 23.2%, respectively), nor was there any difference in regard to the severity of these reactions. Efficiency was improved with rush VIT, as reflected by a higher number of patients achieving the 100 mcg maintenance dose with the primary protocol (83 of 84 patients, 98.8%, and 39 of 43, 90.7%, for rush and conventional, respectively, P= .04). Rush VIT in children is as safe as and more efficient than conventional VIT.

Expression of Th1, Th2, lymphocyte trafficking and activation markers on CD4+ T-cells of Hymenoptera allergic subjects and after venom immunotherapy

Systemic reactions to Hymenoptera stings can be fatal and represent a reduction in the quality of life. The immune mechanisms involved in venom allergic subjects are barely known. Nevertheless, a shift towards a Th1-type response with an increase in IFNγ levels has been observed after venom immunotherapy (VIT). There is currently no information available about the expression of markers on CD4+ T-cells or their involvement in venom allergy, nor following VIT. For this, we have studied the expression of Th1 and Th2-cell markers, homing receptors and activation markers on CD4+ T-cells of subjects who presented systemic allergic reactions, mainly to Polistes dominulus, and after receiving a 4-month conventional VIT protocol. The markers studied were: CD26 (Th1), CD30 (Th2), CXCR4, CXCR3 (Th1), CCR4 (Th2), CD154 (CD40L), CD152 (CTLA-A), and ICOS. We also determined the IL-4 (Th2) and IFNγ (Th1) intracellular cytokine levels in T-cells and carried out a basophil activation test (BAT). Comparing venom allergic subjects with non-allergic healthy controls, we have found up-regulation of CD26, CXCR4, CXCR3, CD154 and ICOS. Conversely, a down-regulation of CD30, CD154 and CD152 occurred upon immune intervention, whereas the remaining markers were not affected. Equally, VIT has been shown to be effective, as evidenced by the decrease of basophil degranulation and increase of IFNγ levels in T-cells after the fourth month of treatment. These new findings highlight the possible application of these surface molecules as markers to distinguish between symptomatic and asymptomatic subjects sensitized to Hymenoptera venom, as well as revealing information about the immune changes associated with VIT.

Three Days Rush Venom Immunotherapy in Bee Allergy: Safe, Inexpensive and Instantaneously Effective

Background: Rush venom immunotherapy (VIT) is highly effective in vespid venom allergy, but comparable data regarding bee venom (BV) allergy are sparse. We evaluated its safety, efficacy and cost in BV-allergic patients. Methods: Conventional or rush VIT were offered to all patients with systemic reaction to insect sting. Rush VIT was also given to hyperreactive patients who failed to reach the maintenance dose with conventional VIT due to multiple systemic reactions. In BV-allergic patients, honeybee sting challenge was performed within 1 week after reaching the maintenance dose. Results: 179 patients, some of them allergic to more than one venom, received 246 rush VIT courses. Bee VIT was administered to 132 patients (73.7%); 173 patients (96.6%) reached the maintenance dose. The incidence of systemic reactions was 29.6%. They were more common in VIT with BV than with vespid venoms (31.1 and 16.3%, respectively, p = 0.01). After excluding the hyperreactive subgroup (n = 20), this difference was not significant (23.7 and 16%, respectively, p = 0.19). Despite the high incidence of systemic reactions (15 of 20, 75%) among hyperreactive patients, 17 patients (85%) achieved the maintenance dose. Sting challenges resulted in systemic reaction in 4 of 8 (50%) hyperreactive patients and in 2 of 47 (4.3%) ordinary patients. The cost of rush VIT was 41% of that of conventional VIT. Conclusions: Rush VIT with BV is safe, instantaneously effective, less expensive and enables most patients with previous failures of conventional VIT to reach the maintenance dose.

Bee venom immunotherapy – how early is it effective?

Although the effectiveness of venom immunotherapy (VIT) in bee venom (BV) allergy has been well established over the past 30 years, no previous study has demonstrated its efficacy immediately after reaching the maintenance dose (MD). We examined the effectiveness of bee VIT within a week after the MD was achieved. Bee venom allergic patients underwent conventional or rush VIT. Within 1 week after reaching the 100 microg MD, patients were challenged with a live bee sting. Seventy-nine of 107 patients (73.8%) who reached the MD agreed to be challenged. Seventy patients (88.6%) tolerated the sting uneventfully. Four patients (5.1%) developed a very mild local transient rash and continued to receive the 100 microg MD. In five patients (6.3%), the sting resulted in a mild-moderate systemic reaction. In four of these, the MD was increased to 200-250 microg. All four patients uneventfully tolerated a repeated sting that was performed within 1 week after achieving the increased MD in three patients and after 14 months in the fourth patient. Bee VIT is effective in most patients immediately after the conventional MD has been reached. In the minority of patients who are not protected with this dose, an increased MD will provide appropriate protection immediately after it is achieved. Thus, the dosage of the MD seems to be the major factor affecting protection from re-stings rather than the accumulated venom dose or the duration on the MD.

Ultrarush venom desensitization after systemic reactions during conventional venom immunotherapy

Rush and ultrarush venom immunotherapy (VIT) protocols are safe and effective in patients with Hymenoptera hypersensitivity. However, these protocols have typically been used instead of conventional VIT and not in patients who have experienced adverse reactions during conventional VIT. To date, there are no reports of using an ultrarush VIT protocol to desensitize patients with a history of severe systemic reactions during conventional VIT. To determine whether ultrarush VIT can be safely administered to a high-risk patient with a history of severe systemic reactions to conventional VIT. Premedication with 40 mg of prednisone, 180 mg of fexofenadine, and 150 mg of ranitidine orally twice daily was initiated. The patient received VIT to mixed vespid and wasp in a medical intensive care unit via a 13-step buildup on day 1 followed by a 2-step buildup on day 2. Immunotherapy was begun with a dose of 0.005 microg of mixed vespid and 0.002 microg of wasp venom and achieved a total dose of 300 microg of mixed vespid and 100 microg of wasp venom. The patient tolerated the procedure with minimal adverse effects. She subsequently received maintenance dosing in the outpatient clinic weekly for 4 weeks and bimonthly for 8 weeks, and she continues monthly maintenance VIT. We report the first successful use of ultrarush VIT in a high-risk patient with a history of severe systemic reactions during conventional VIT. This protocol should be considered in patients with a history of allergy to vespids or wasps who require VIT but cannot reach a maintenance dose with conventional VIT owing to systemic reactions.

Specific immunotherapy in honeybee venom allergy: a comparative study using aqueous and aluminium hydroxide adsorbed preparations

For the immunotherapy of Hymenoptera venom allergy various preparations and treatment protocols are in use. However, controlled studies making direct comparisons of the efficacy and safety of different regimens are rare. To assess prospectively different venom immunotherapy (VIT) protocols using an aqueous or an aluminium hydroxide adsorbed allergen preparation for the treatment of honeybee venom (HBV) allergy. Sixty-five HBV allergic patients (42 males, 23 females; aged 17-75 years) with a history of systemic anaphylactic reactions (SARs) to honeybee stings were treated according to three different regimens. During the incremental phase, patients in group A (n = 21) or B (n = 21) received an aqueous preparation according to a rush protocol. Patients in group C (n = 23) were treated with conventional ("slow") VIT using an aluminium hydroxide adsorbed depot preparation. The maintenance dose was 100 microg venom in all groups. Maintenance treatment in group A was performed with the aqueous preparation administered every 4 weeks, whereas in groups B and C the depot preparation was administered every 8 weeks (group B) or every 4 weeks (group C). A sting challenge test with a living honeybee was performed in 49 patients, 6-12 months after reaching the maintenance dose. Another seven patients were stung accidentally by a honeybee ("field sting"). Treatment with the aqueous preparation evoked large local reactions more frequently than the depot preparation in the dose increase phase [53/693 (7.6%) vs 8/206 (3.9%); P = 0.059] and also in the course of maintenance therapy [85/172 (49.4%) vs 58/478 (12.1%); P < 0.001]. During the dose increase phase, systemic side-effects seemed to occur more frequently in patients on rush VIT with the aqueous preparation compared to patients initially treated with the conventional schedule using the depot preparation [13/42 (31.0%) vs 3/23 (13.0%); not significant). When re-stung by the culprit insect, SARs were observed in 3/20 patients (15.0%) in group A, 2/18 (11.1%) in group B and 3/18 (16.7%) in group C (not significant). The aluminium hydroxide adsorbed HBV preparation caused fewer large local reactions than the aqueous preparation. The therapeutic efficacy of the three treatment protocols did not differ.

Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy

An unknown number of venom-allergic patients fail to reach the maintenance dose (MD) during the build-up period of conventional venom immunotherapy (VIT) due to recurrent systemic reactions (SRs). To establish an alternative VIT protocol that will enable these patients to reach a full protective MD. Venom-allergic patients who had experienced recurrent SRs during the build-up period of conventional VIT underwent rush VIT. Of the 9 patients who participated in this study, the 6 who underwent 8 treatment courses tolerated the rush VIT well and reached the MD within 3 days. In 3 of these patients, mild cutaneous SRs were overcome with loratadine. In 2 patients who experienced recurrent and more severe SRs, the original 3-day rush VIT had to be modified and extended to 5 days until the MD was reached. In a single patient who experienced an anaphylactic reaction, VIT was discontinued. Rush VIT is an appropriate therapeutic alternative that enables most patients with recurrent SRs throughout the build-up period of conventional VIT to reach a full protective MD.

Impaired secretion of interleukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy.

Allergen immunotherapy (IT) is a successful treatment associated with decreased Th2 cytokine production by allergen-specific T cells. We have previously demonstrated (Faith et al., J Immunol 1997; 159:53-57) that inhibition of Th2 cytokine production in vitro correlates with impaired tyrosine kinase activity through the TCR. The transcription factor complex, nuclear factor of activated T cells (NF-AT), which regulates Th2 cytokine production is controlled by the activity of tyrosine kinases. To address whether decreased Th2 cytokine production by allergen-specific CD4+ T cells following IT is correlated with altered translocation and nuclear expression of the NF-AT family member, NF-AT2, and the activator protein 1 (AP1) component of NF-AT, jun B. T cell lines specific for insect venom phospholipase A2 (PLA) were derived from patients prior to and during conventional venom IT. Nuclear expressions of NF-AT and jun B were assessed following stimulation through the TCR. Th1 and Th2 cytokine and IL-10 production by insect venom-specific T cells were also determined. Results were compared with a well-established model system in which anergy was induced in cloned, allergen-specific Th2 cells. Impaired translocation and decreased expression of NF-AT2 and jun B were detected in PLA-specific T cell lines derived from bee venom-allergic individuals following 16 weeks treatment compared to pre-treatment. These results correlated with significantly reduced production of IL-4 and IL-13 and significantly increased production of IFN-gamma and IL-10 by PLA-specific T cells. Impaired IL-4 and IL-13 production also correlated with defective nuclear expression of NF-AT2/jun B in cloned, anergic allergen-specific Th2 cells. These results suggested that optimal production of IL-4 and IL-13 by allergen-specific T cells is dependent on the nuclear expression of NF-AT2 and jun B. Thus, specific inhibition of NF-AT2/jun B might be an option in novel and improved forms of allergen IT.

Mathematical Modelling of Venom Immunotherapy

Allergic hypersensitivity of type I for hymenoptera venoms is the most frequent reason for acute IgE-mediated anaphylactic reactions. The subcutaneous injection of increasing doses of purified allergen followed by long-term administration of an adequate maintenance dose over a period of 3–5 years called venom immunotherapy (VIT) has been proven to be a very effective treatment achieving protection in about 96% of allergic patients. Even though the principle of hyposensitisation has been introduced already 90 years ago, the underlying immunoregulatory mechanisms of VIT remain poorly understood. Recent studies suggest a shift in cytokine production from a Th2 to a Th1 cytokine profile during therapy. In this paper, a mathematical model for T-cell regulation and a model for mast cell/basophil desensitisation are presented and analysed to explain the mechanism of conventional rush and ultra-rush VIT.

Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses

Background: Up to 20% of patients allergic to Hymenoptera venom are not protected by conventional venom immunotherapy (VIT) with 100 μg of any single venom. Objective: We sought to evaluate the efficacy of an increased venom dose in patients allergic to Hymenoptera venom still reacting systemically to a sting challenge despite immunotherapy with 100 μg of venom every 4 weeks. Methods: In this retrospective study patients were included who still had reacted systemically to a sting challenge with a living bee or wasp despite VIT with a maintenance dose of 100 μg every 4 weeks. The maintenance dose was increased to 150 or 200 μg every 4 weeks, and a second sting challenge was performed. If a patient reacted again, the dose was further increased. Baseline mast-cell tryptase levels were assessed by using a fluoroenzyme immunoassay in stored patient sera. Results: While receiving a maintenance dose of 100 μg of venom every 4 weeks for 7 to 38 months, 18 patients reacted systemically to a bee sting and 22 reacted to a wasp sting. After an increase of the maintenance dose to 150 μg, 2 of 4 patients allergic to bee venom (BV) and 6 of 6 patients allergic to yellow jacket venom (YJV) no longer reacted systemically to the sting challenge. The respective rates of full protection were 13 of 14 and 15 of 16 in patients with an increase of the maintenance dose to 200 μg from the start. Of those 4 individuals not protected by the first dose increase, one patient allergic to BV (prior dose of 150 μg) and one patient allergic to YJV (prior dose of 200 μg) did not react systemically to a further sting challenge while receiving 200 μg of BV or 250 μg of YJV, respectively. One patient allergic to BV who had a systemic reaction to the sting challenge while receiving 150 μg was not protected after a dose increase to 200 μg; she later received a dose of 400 μg of BV, and no further sting challenge was performed. The patient allergic to BV who still reacted systemically after a first dose increase to 200 μg was a female patient with urticaria pigmentosa. She had repeated systemic adverse reactions to further BV immunotherapy, necessitating discontinuation of the treatment; however, she tolerated well VIT with 200 μg of YJV. In all other patients, no unusual adverse reactions to the increased venom doses were observed. Baseline serum tryptase levels were elevated above 13.5 μg/L (95th percentile in normal subjects) in 9 (28.1%) of 32 patients. Conclusions: The majority of patients allergic to Hymenoptera venom who still reacted systemically to a sting challenge despite VIT with a dose of 100 μg every 4 weeks can be fully protected by an increased maintenance dose. This dose increase is well tolerated by most patients. The rather high proportion of patients with elevated baseline serum tryptase levels necessitates further investigation of a possible association between mastocytosis and treatment failure of conventionally dosed VIT. (J Allergy Clin Immunol 2001;108:1027-32.)

Modulation of T-cell response to phospholipase A 2 and phospholipase A 2–derived peptides by conventional bee venom immunotherapy

Background: Immunologic mechanisms of desensitization are still incompletely understood. Safer methods of immunotherapy with reduced risks of anaphylaxis need to be developed. Objective: To study the effects of conventional venom immunotherapy (VIT) on phospholipase A 2(PLA 2)-specific T cells and on T-cell reactivity to short and long synthetic peptides that map the PLA 2 molecule. Method: Proliferation of a CD4 + cell–enriched peripheral blood mononuclear cell fraction and cytokine secretion by T cell lines from patients hypersensitive to bee venom and undergoing VIT in response to PLA 2 and PLA 2 synthetic peptides were measured. Results: T-cell proliferation in response to three synthetic peptides, 40 to 60 amino acids long and mapping the entire PLA 2 molecule with an overlap of 10 residues (1 to 59, 51 to 99, and 90 to 134) steadily increased during the first 14 weeks of VIT corresponding to the treatment period with incremental doses of antigen. These results are in contrast to the low proliferation indices obtained with short (15 amino acid–long) peptides, and the inability to characterize the immunodominant region of the molecule with short peptides. At the end of VIT (after 3 to 5 years), there was correspondingly, a marked decrease in T cell responsiveness to PLA 2 and to its long synthetic peptides. This response was paralleled by a shift in the pattern of cytokine secretion by T cell lines from a T H0-type to a T H1-type pattern. Conclusion: After a transient increase in T-cell proliferation, late VIT was characterized by T-cell hyporesponsiveness to allergen and by modulation of cytokine secretion from a T H 0-type to a T H 1-type pattern. Because of their capacity to recruit multiple T-cell epitopes, long peptides mapping the entire PLA 2 molecule appear to be efficient T cell stimulators and may represent potential candidates for peptide immunotherapy. (J Allergy Clin Immunol 1997;100:96-103.)