Efficacy and safety of hymenoptera venom immunotherapy.

Background: Being stung by Hymenoptera species can cause life-threatening anaphylaxis. Although venom immunotherapy (VIT) seems to be the most effective treatment, its long-term efficacy, and risk factors for adverse events remain unclear. Objective: The objective was to investigate the long-term efficacy of VIT and evaluate adverse events and risk factors related to this. Method: Patients who received VIT in a tertiary-care adult allergy clinic between January 2005 and July 2022 were included. Patients' data were compared with those of individuals who had been diagnosed with bee and/or wasp venom allergy during the same period but had not received VIT and experienced field re-stings. Results: The study included 105 patients with venom allergy, of whom 68 received VIT and 37 did not receive VIT. Twenty-three patients (34%) completed 5 years of VIT, and the overall mean ± standard deviation VIT duration was 46.9 ± 20.9 months. Re-stings occurred in 5 of 23 patients who completed 5 years of VIT, and none of them developed a systemic reaction. Eighteen patients (40%) experienced re-stings after prematurely discontinuing VIT, of whom eight (44%) developed a systemic reaction. In the control group of patients who did not receive VIT, 26 patients (70.3%) experienced re-stings, and all had systemic reactions (100%), with no change in their median Mueller scores. There was a significant difference in the median Mueller score change between the patients who received VIT and the controls who did not (p = 0.016). A total of 13 patients (19%) experienced adverse events while receiving VIT, which were systemic reactions in nine honeybee VIT. The use of ß-blockers was determined as the most important risk factor (odds ratio 15.9 [95% confidence interval, 1.2-208.8]; p = 0.035). Conclusion: It was confirmed that VIT was effective in both reducing the incidence and the severity of re-sting reactions. These effects were more pronounced in the patients who completed 5 years of VIT.

Complement activation in wasp venom-induced acute kidney injury.

Previous studies have highlighted the significant role of complement activation in kidney injuries induced by rhabdomyolysis, intravascular hemolysis, sepsis, and ischemia-reperfusion. Nevertheless, the specific role and mechanism of complement activation in acute kidney injury (AKI) caused by wasp venom remain unclear. The aim of this study was to elucidate the specific complement pathway activated and investigate complement activation in AKI induced by wasp venom. In this study, a complement-depleted mouse model was used to investigate the role of complement in wasp venom-induced AKI. Mice were randomly categorized into control, cobra venom factor (CVF), AKI, and CVF + AKI groups. Compared to the AKI group, the CVF + AKI group showed improved pathological changes in kidneys and reduced blood urea nitrogen (BUN) levels. The expression levels of renal complement 3 (C3), complement 5 (C5), complement 1q (C1q), factor B (FB), mannose-binding lectin (MBL), and C5b-9 in AKI group were upregulated compared with the control group. Conversely, the renal tissue expression levels of C3, C5, C1q, FB, MBL, and C5b-9 were decreased in the CVF + AKI group compared to those in the AKI group. Complement activation occurs through all three pathways in AKI induced by wasp venom. Furthermore, complement depletion by CVF attenuates wasp venom-induced nephrotoxicity, suggesting that complement activation plays a primary role in the pathogenesis of wasp venom-induced AKI.

Vespa velutina nigrithorax venom allergy: inhibition studies approach for the choice of specific immunotherapy.

Summary: Vespa velutina nigrithorax (VVN), commonly known as Asian wasp because endemic in Asia, represents an alien species in Europe. VVN can induce allergic reactions similar to those caused by other Hymenoptera and death after VVN stings, presumably due to fatal allergic reactions, has been reported. In the treatment of Hymenoptera venom hypersensitivity, specific immunotherapy (VIT) is highly effective. Currently, there is no specific available VIT for VVN, so it is relevant to assess if patients stung by VVN and showing allergic reactions could be treated with the Hymenoptera commercially available extracts Vespa crabro (VC) and Vespula spp (Vspp) or if they need the specific VIT with VVN venom extract. Methods. Four patients with a clinical history of systemic reactions after VVN sting were evaluated. Serum specific IgE were assayed quantitatively with an automated fluoro-enzyme immunoassay ImmunoCAP™ Specific IgE by Phadia™ 1000 System (Thermo Fisher Scientific, Uppsala, Sweden) for VC, Vspp and VVN. Cap inhibition assays were performed incubating serum samples with 200 µl of each venom at increasing concentrations and subsequently specific IgE against each of the venoms were determined in the samples by Phadia™ 250 System (Thermo Fisher Scientific, Uppsala, Sweden). Results. Our results suggested that both Vspp and VC venoms were able to inhibit the specific IgE for VVN, although the VC compared to the Vspp venom showed a higher inhibition. Conclusions. Our inhibition studies suggested that VIT with VC venom, nowadays when there is not specific available VIT for VVN, may be more effective than Vspp VIT in patients with VVN sting reactions.

Field sting reactions in patients receiving Hymenoptera venom immunotherapy: real-life experience.

BACKGROUND: Hymenoptera stings can cause systemic allergic reactions (SARs) that are prevented by venom immunotherapy (VIT). Sting challenge tests or field stings are used to evaluate the outcome of VIT. OBJECTIVE: The aim of the study was to investigate the consequences of field stings in patients during or after completion of VIT, and to identify patients at higher risk. METHODS: Patients treated with VIT between 1995 and 2018 were retrospectively evaluated. Contacted patients were invited to the clinic and a questionnaire was conducted regarding the history of field stings. RESULTS: A total of 115 patients (F/M: 45/70, mean age: 38.5 ± 12 years) treated with VIT were included; 74/115 were contacted and asked about field stings after VIT cessation. A history of 73 field stings was reported in 38 patients, 25 of whom were treated with honeybee venom and 13 with common wasp venom. Eighteen of the reactions were SARs [8 with honeybees (1 grade-I, 6 grade-II, 1 grade-III) and 10 with common wasps (1 grade-I, 5 grade-II, 4 grade-III)]. There was no association between the severity of index reactions and field stings with either the honeybee or common wasp. The median duration of VIT was longer in patients showing no reaction than in patients with an SAR. Of the 7 patients on ACE inhibitors or beta-blockers, 1 asthmatic patient developed grade-II SAR due to field stings in the first year of VIT. CONCLUSIONS: This study confirms that VIT lasting at least 3 years is effective in preventing SARs after field stings.

Parasitoid wasp venom manipulates host innate behavior via subtype-specific dopamine receptor activation.

The subjugation strategy employed by the jewel wasp is unique in that it manipulates the behavior of its host, the American cockroach, rather than inducing outright paralysis. Upon envenomation directly into the central complex (CX), a command center in the brain for motor behavior, the stung cockroach initially engages in intense grooming behavior, then falls into a lethargic sleep-like state referred to as hypokinesia. Behavioral changes evoked by the sting are due at least in part to the presence of the neurotransmitter dopamine in the venom. In insects, dopamine receptors are classified as two families, the D1-like and the D2-like receptors. However, specific roles played by dopamine receptor subtypes in venom-induced behavioral manipulation by the jewel wasp remain largely unknown. In the present study, we used a pharmacological approach to investigate roles of D1-like and D2-like receptors in behaviors exhibited by stung cockroaches, focusing on grooming. Specifically, we assessed behavioral outcomes of focal CX injections of dopamine receptor agonists and antagonists. Both specific and non-specific compounds were used. Our results strongly implicate D1-like dopamine receptors in venom-induced grooming. Regarding induction of hypokinesia, our findings demonstrate that dopamine signaling is necessary for induction of long-lasting hypokinesia caused by brain envenomation.

Review of venom immunotherapy at a regional tertiary paediatric centre.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 and difficulties encountered before and during immunotherapy: Double sensitization, systemic reactions, treatment with omalizumab, and high dose VIT.

BACKGROUND: Venom immunotherapy (VIT) is the most effective treatment method to prevent recurrent systemic reactions to Hymenoptera stings. In this study, the demographic characteristics of VIT patients, the success rates of VIT, the difficulties we encountered during VIT, and solutions for these difficulties in our clinic were presented. METHODS: We retrospectively analyzed patients with venom allergy who applied venom immunotherapy between 2013- 2020. Data on age, gender, Hymenoptera species with the first reaction, grade of the reaction, beekeeping history, skin prick and specific IgE and component results, double sensitization, blood groups, and reactions with VIT and/or sting during built-up and maintenance periods were recorded. RESULTS: A total of 73 patients were enrolled in the study. The median time from the first sting reaction to the application to the allergy outpatient clinic was 12 (0.5-24) months. The first sting reaction of 38 (52.1%) of the patients was with honey bees, and 24 (32.9%) were with wasps. Double positivity was present in 29 (40%) of the patients in prick results and 26 (36%) serologically. There was no correlation between the severity of first reactions and Apis Mellifera or Vespula prick diameters (p = 0.643; r = -0.056; p = 0.462; r = 0.089, respectively). High-dose VIT was administered to 4 patients. Omalizumab has been used as an alternative agent to achieve the maintenance dose in 2 patients with frequent systemic reactions during VIT. DISCUSSION: Most patients were able to tolerate VIT. Double positivity is one of the most common difficulties before VIT. In patients who develop systemic reactions in the VIT maintenance phase, a maintenance dose increase should be considered in the maintenance phase. Adding omalizumab does not seem to be a permanent solution in patients who develop a severe systemic reaction.

Massive Vespa basalis stings induce an envenoming syndrome.

Envenoming syndrome induced by massive Vespa basalis stings is a critical condition. Severe systemic reaction may present with hemolytic activity and rhabdomyolysis, leading diffuse alveolar hemorrhage, adult respiratory distress syndrome, coagulopathy, and multiple organs failure. In severe envenoming syndrome population, extracorporeal membrane oxygenation (ECMO) may be considered for unstable hemodynamic status. However, few studies reported ECMO in venom-induced disseminated intravascular coagulation patients. Here, we provide a case presented with pulmonary hemorrhage due to multiple Vespa basalis stings tried to rescue by veno-arterial extracorporeal membrane oxygenation. We also highlight that early recognition of venom-induced disseminated intravascular coagulation by checking coagulation profile in high risk patients may prevent from poor outcome.

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

BACKGROUND: Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. METHODS: A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively. RESULTS: During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P < .001) although tryptase and IgE were unaltered. CONCLUSION: Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.

Health economic analysis of allergen immunotherapy for the management of allergic rhinitis, asthma, food allergy and venom allergy: A systematic overview.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is developing guidelines for allergen immunotherapy (AIT) for the management of allergic rhinitis, allergic asthma, IgE-mediated food allergy and venom allergy. To inform the development of clinical recommendations, we undertook systematic reviews to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT for these conditions. This study focusses on synthesizing data and gaps in the evidence on the cost-effectiveness of AIT for these conditions. METHODS: We produced summaries of evidence in each domain, and then, synthesized findings on health economic data identified from four recent systematic reviews on allergic rhinitis, asthma, food allergy and venom allergy, respectively. The quality of these studies was independently assessed using the Critical Appraisal Skills Programme tool for health economic evaluations. RESULTS: Twenty-three studies satisfied our inclusion criteria. Of these, 19 studies investigated the cost-effectiveness of AIT in allergic rhinitis, of which seven were based on data from randomized controlled trials with economic evaluations conducted from a health system perspective. This body of evidence suggested that sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) would be considered cost-effective using the (English) National Institute for Health and Clinical Excellence (NICE) cost-effectiveness threshold of £20 000/quality-adjusted life year (QALY). However, the quality of the studies and the general lack of attention to characterizing uncertainty and handling missing data should be taken into account when interpreting these results. For asthma, there were three eligible studies, all of which had significant methodological limitations; these suggested that SLIT, when used in patients with both asthma and allergic rhinitis, may be cost-effective with an incremental cost-effectiveness ratio (ICER) of £10 726 per QALY. We found one economic modelling study for venom allergy which, despite being based largely on expert opinion and plausible assumptions, suggested that AIT for bee and wasp venom allergy is only likely to be cost-effective for very high-risk groups who may be exposed to multiple exposures to venom/year (eg bee keepers). We found no eligible studies investigating the cost-effectiveness of AIT for food allergy. CONCLUSIONS: Overall, the evidence to support the cost-effectiveness of AIT is limited and of low methodological quality, but suggests that AIT may be cost-effective for people with allergic rhinitis with or without asthma and in high-risk subgroups for venom allergy. We were unable to draw any conclusions on the cost-effectiveness of AIT for food allergy.

Elevated and cross-responsive CD1a-reactive T cells in bee and wasp venom allergic individuals.

The role of CD1a-reactive T cells in human allergic disease is unknown. We have previously shown that circulating CD1a-reactive T cells recognize neolipid antigens generated by bee and wasp venom phospholipase, and here tested the hypothesis that venom-responsive CD1a-reactive T cells associate with venom allergy. Circulating T cells from bee and wasp venom allergic individuals, before and during immunotherapy, were exposed to CD1a-transfected K562 cells in the presence of wasp or bee venom. T-cell response was evaluated based on IFNγ, GM-CSF, and IL-13 cytokine production. Venom allergic individuals showed significantly higher frequencies of IFN-γ, GM-CSF, and IL-13 producing CD1a-reactive T cells responsive to venom and venom-derived phospholipase than healthy individuals. Venom-responsive CD1a-reactive T cells were cross-responsive between wasp and bee suggesting shared pathways of allergenicity. Frequencies of CD1a-reactive T cells were initially induced during subcutaneous immunotherapy, peaking by weeks 5, but then reduced despite escalation of antigen dose. Our current understanding of venom allergy and immunotherapy is largely based on peptide and protein-specific T cell and antibody responses. Here, we show that lipid antigens and CD1a-reactive T cells associate with the allergic response. These data have implications for mechanisms of allergy and approaches to immunotherapy.

Transient Coagulopathy Due to Wasp Sting: A Case Report.

BACKGROUND: Insect venom anaphylaxis is a potentially life-threatening disorder. Transient coagulopathy in insect venom anaphylaxis is a rare phenomenon. CASE REPORT: A 41-year-old man presented to the Emergency Department (ED) with hypotension after a run in a park. History and examination revealed signs of anaphylactic shock. A deranged coagulation profile with a normal platelet count led to the diagnosis of wasp sting anaphylaxis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Transient deranged coagulation profile with a normal platelet count may arise from insect venom anaphylaxis. This specific finding may aid the emergency physician in making a diagnosis of anaphylactic shock in an otherwise healthy patient presenting with shock with no apparent cause.

Safety of Ultrarush Venom Immunotherapy: Comparison Between Children and Adults.

BACKGROUND: The ultrarush protocol is an attractive approach in the buildup phase of venom immunotherapy (VIT-UR). However, the degree of risk of VIT-UR in children remains unknown. The objective of this study was to compare the safety of VIT-UR in children and adults. METHODS: We performed a study based on prospectively gathered medical records of children and adults with hymenoptera venom allergy treated with VIT-UR in 3 allergy centers in Poland. RESULTS: The study population comprised 134 children (mean [SD] age, 12.6 [3.7] years; males, 70.1%) and 207 adults (mean age, 42.4 [14.0] years; males, 47.8%). The number of children in the subgroups of bee venom (BV) allergy and wasp venom (WV) allergy were comparable, although sensitization to WV was more predominant in the adult group (70.1%). Skin reactivity to both venoms was more common in children than in adults (P < .001); however, children had higher concentrations of total IgE and specific IgE to BV (both P < .001). Systemic allergic reactions (VIT-SARs) occurred in 6.2% of the patients (3.7% in children and 7.7% in adults; nonsignificant). In adults, SARs occurred more frequently in patients treated with BV than WV extracts (21.4% vs 2.6%; P < .001). The same pattern was observed in children (7.2% vs 0%; P = .058). However, VIT-SARs to BV were less frequent in children than in adults (P = .034). Similarly, no significant relationship was noted between children and adults receiving WV VIT (2.6% vs 0%; nonsignificant). The severity of VIT-SAR did not differ between children and adults. CONCLUSIONS: VIT-UR is safer in children. Age below 18 is not a risk factor for VIT-SARs.

Long-term follow-up of re-sting reactions in children with moderate to severe venom hypersensitivity.

UNLABELLED: Few data exists about re-sting reactions and their prognosis in children with moderate to severe venom hypersensitivity. The reasons behind not consenting to or prematurely ending venom immunotherapy (VIT) and the preparedness of children who refused or quit VIT for future moderate-severe systemic reaction (SR) to re-stings have not been studied. Data on children with moderate to severe SR after Hymenoptera stings was collected for a 17-year period using our database. A standardized questionnaire was administered to patients who accepted to be interviewed at the clinic. These patients were evaluated in terms of their preparedness for future moderate-severe SR to re-stings. A total of 55 children, 75 % of whom commenced on VIT, were included in the analysis. Different reasons exist for not consenting to VIT; the most common of which is living at a distance from the allergy center. There were no differences in terms of the number of re-stung patients (27.7 and 27.2 %, respectively) and moderate-severe SR (60 and 16.6 %, respectively) between children who prematurely ended or who did not consent to VIT and children who completed VIT. Sixty-four percent of the children who refused or discontinued VIT were not prepared for future moderate-severe SR to re-stings. CONCLUSION: Long-term prognosis for re-sting reactions is good in children with moderate to severe SR to venoms. Some of the reasons behind refusing or discontinuing VIT may be related to quality of life issues. Preparedness of children who refused or discontinue VIT in emergencies is very low.

Rush immunotherapy for wasp venom allergy seems safe and effective in patients with mastocytosis.

BACKGROUND: Patients with mastocytosis and wasp venom allergy (WA) may benefit from venom immunotherapy (VIT). However, fatal insect sting reactions have been described in mastocytosis patients despite previous immunotherapy. We investigated the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. OBJECTIVE: To investigate the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. METHODS: We describe nine patients with cutaneous mastocytosis and WA who received VIT. Cutaneous mastocytosis was confirmed by histopathology and systemic mastocytosis was diagnosed according to World Health Organization criteria. VIT was given according to a rush protocol. Given the difference in safety and efficacy of VIT in patients with WA and honeybee venom allergy, we reviewed the literature for VIT with the focus on WA patients with mastocytosis and addressed the difference between patients with cutaneous versus systemic mastocytosis. RESULTS: Nine patients had WA and mastocytosis, of whom six had cutaneous mastocytosis, two combined cutaneous and systemic mastocytosis and one systemic mastocytosis. All patients received rush IT with wasp venom. Most patients had only mild local side effects, with no systemic side effects during the course of VIT. One patient had a systemic reaction upon injection on one occasion, during the updosing phase, with dyspnoea and hypotension, but responded well to treatment. Immunotherapy was continued after temporary dose adjustment without problems. Two patients with a previous anaphylactic reaction were re-stung, without any systemic effects. CONCLUSIONS: VIT is safe in cutaneous mastocytosis patients with WA, while caution has to be made in case of systemic mastocytosis. VIT was effective in the patients who were re-stung.

[Chronic urticaria as an atypical reaction after a vespid bite]. / Urticaria crónica como reacción atípica luego de la picadura de véspidos.

BACKGROUND: Hymenoptera stings can produce IgE-mediated reactions, toxic reactions, or atypical reactions, which are rare. Cold urticaria has been described among the cutaneous manifestations in the atypical ones, but there is only one case of chronic urticaria. CASE REPORT: A 56-year-old female patient experienced palmoplantar pruritus and generalized urticaria 60 minutes after two vespid stings, requiring medical assistance and several cycles of home treatment with oral antihistamines and corticosteroids for resolution in 12 weeks. Allergological studies showed normal tryptase and primary sensitization to Polistes dominula venom. Given the patient's profession, venom immunotherapy was started with Polistes dominula 100% without recurrence of urticaria after its administration. CONCLUSIONS: We present a case of IgE-mediated systemic reaction followed by self-limited chronic urticaria, related chronologically to the same vespid sting trigger.

ANTECEDENTES: La picadura de himenópteros puede producir reacciones mediadas por IgE, reacciones tóxicas o reacciones atípicas poco frecuentes. Dentro de las manifestaciones cutáneas por reacciones atípicas se incluye urticaria por frío, y sólo existe un informe de caso de urticaria crónica. REPORTE DE CASO: Paciente femenina de 56 años, quien 60 minutos después de recibir dos picaduras de véspidos manifestó prurito palmoplantar y urticaria generalizada, precisando asistencia sanitaria y varios ciclos de tratamiento domiciliario con antihistamínicos y corticosteroides por vía oral, con curación completa luego de 12 semanas. El estudio alergológico reportó: concentración de triptasa normal y sensibilización primaria al veneno de Polistes dominula. Debido a la profesión de la paciente se inició inmunoterapia con veneno de Polistes dominula al 100%, sin recurrencia de la urticaria después de la administración. CONCLUSIÓN: El caso aquí expuesto combina una reacción sistémica mediada por IgE seguida de urticaria crónica, de curso autolimitado, cronológicamente relacionada con el mismo desencadenante (picadura de véspidos).

Venom immunotherapy for preventing allergic reactions to insect stings.

BACKGROUND: Venom immunotherapy (VIT) is commonly used for preventing further allergic reactions to insect stings in people who have had a sting reaction. The efficacy and safety of this treatment has not previously been assessed by a high-quality systematic review. OBJECTIVES: To assess the effects of immunotherapy using extracted insect venom for preventing further allergic reactions to insect stings in people who have had an allergic reaction to a sting. SEARCH METHODS: We searched the following databases up to February 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), AMED (from 1985), LILACS (from 1982), the Armed Forces Pest Management Board Literature Retrieval System, and OpenGrey. There were no language or publication status restrictions to our searches. We searched trials databases, abstracts from recent European and North American allergy meetings, and the references of identified review articles in order to identify further relevant trials. SELECTION CRITERIA: Randomised controlled trials of venom immunotherapy using standardised venom extract in insect sting allergy. DATA COLLECTION AND ANALYSIS: Two authors independently undertook study selection, data extraction, and assessment of risk of bias. We identified adverse events from included controlled trials and from a separate analysis of observational studies identified as part of a National Institute for Health and Clinical Excellence Health Technology Assessment. MAIN RESULTS: We identified 6 randomised controlled trials and 1 quasi-randomised controlled trial for inclusion in the review; the total number of participants was 392. The trials had some risk of bias because five of the trials did not blind outcome assessors to treatment allocation. The interventions included ant, bee, and wasp immunotherapy in children or adults with previous systemic or large local reactions to a sting, using sublingual (one trial) or subcutaneous (six trials) VIT. We found that VIT is effective for preventing systemic allergic reaction to an insect sting, which was our primary outcome measure. This applies whether the sting occurs accidentally or is given intentionally as part of a trial procedure.In the trials, 3/113 (2.7%) participants treated with VIT had a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8%) untreated participants (risk ratio [RR] 0.10, 95% confidence interval [CI] 0.03 to 0.28). The efficacy of VIT was similar across studies; we were unable to identify a patient group or mode of treatment with different efficacy, although these analyses were limited by small numbers. We were unable to confirm whether VIT prevents fatal reactions to insect stings, because of the rarity of this outcome.Venom immunotherapy was also effective for preventing large local reactions to a sting (5 studies; 112 follow-up stings; RR 0.41, 95% CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favour of VIT 1.21 points on a 7-point scale, 95% CI 0.75 to 1.67).We found a significant risk of systemic adverse reaction to VIT treatment: 6 trials reported this outcome, in which 14 of 150 (9.3%) participants treated with VIT and 1 of 135 (0.7%) participants treated with placebo or no treatment suffered a systemic reaction to treatment (RR 8.16, 95% CI 1.53 to 43.46; 2 studies contributed to the effect estimate). Our analysis of 11 observational studies found systemic adverse reactions occurred in 131/921 (14.2%) participants treated with bee venom VIT and 8/289 (2.8%) treated with wasp venom VIT. AUTHORS' CONCLUSIONS: We found venom immunotherapy using extracted insect venom to be an effective therapy for preventing further allergic reactions to insect stings, which can improve quality of life. The treatment carries a small but significant risk of systemic adverse reaction.