Immunotherapy is a common form of treatment for allergies, one considered very safe. Usually, when a patient has an injection-related reaction, the injection site reddens, feels warm or swells slightly.

These types of reactions can occur right away or during the next few hours. Some patients have the same symptoms, such as hives or itchiness, that they get when exposed to venom through insect bites or stings. In rare cases, immunotherapy causes an anaphylactic reaction.

It almost always take place within 30 minutes of receiving the injection, which is why a patient is asked to remain in the office for that period of time. If a severe reaction occurs, immediate medical care is required.

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Our Location St. Each venom shot visit takes approximately 40 minutes including the minute wait after the shot is received. The second, called rush venom immunotherapy, completes the build-up phase over two days.

Kernerman: For the conventional build-up, it generally takes months range 1 ½ — 5 months to reach the maintenance level. For rush build-up, the maintenance level is reached within two days. Kernerman: Maintenance venom injections are generally given once every six weeks. Kernerman: The maintenance phase typically lasts for years.

This can vary given specific, individual circumstances. Kernerman: If you want to be protected, and you are going to do conventional venom immunotherapy build-up, you would want to start the process by January or February.

For rush therapy, ideally, you would start no later than March. Kernerman: Not too long ago, I diagnosed an 8-year-old boy with a wasp sting allergy. He was prescribed injectable epinephrine and scheduled to start on venom immunotherapy.

The boy, who now had an epinephrine injector, administered this to his father and prevented further progression of the reaction.

They subsequently both did rush venom immunotherapy together and are now protected. They have been stung since being desensitized and have had no significant reactions. Learn More About Venom Immunotherapy. So, reach out to a local medical provider today about your treatment options.

Steven Kernerman. Venom immunotherapy: Is recommended and highly protective for the treatment of potentially life-threatening allergic reactions to venom from stinging insects.

Is sometimes recommended for the treatment of generalised reactions, such as an all over rash. Is not recommended for the treatment of large local swellings.

What should I expect? Venom immunotherapy for insect allergy is given by regular injections for five years in most cases, sometimes longer.

Allergy medicines can still be used to help manage symptoms while undergoing venom immunotherapy. What allergen extracts are available in Australia and New Zealand? Venom immunotherapy products available in Australia and New Zealand include: Honey Bee.

Paper Wasp, Yellow Jacket European Wasp. Jack Jumper Ant. The quality of the allergen is critical for both diagnosis and treatment, therefore only commercially available allergens should be administered. Different brands and different preparations such as aqueous or alum adsorbed are NOT interchangeable for treatment.

Choice of product after informed discussion between the doctor and person being treated or their carer about the most appropriate product for them. A current list of allergen immunotherapy suppliers is available at allergy. How often are venom immunotherapy injections given? Injections start with a very low dose.

A small needle is used which may be uncomfortable, but not very painful. Doses are gradually increased on a regular usually weekly basis, until an effective maintenance dose is reached. It may take two to six months to reach an effective maintenance dose. Once the maintenance dose is reached, injections are usually administered monthly in a medical facility under supervision.

Patients should stay at the medical facility for observation for minutes after a venom immunotherapy injection has been given. In some cases, after the treatment has been maintained for two or more years, the time interval between doses may be extended.

This can be discussed with the supervising specialist. If the injections are given in a local medical practice, periodic review with the responsible Allergy specialist should continue.

Are there any potential reactions to venom immunotherapy injections?

The Hymenoptera insect group includes Apidae and Vespidae subgroups and also the Formicidae, which is beyond the scope of this review. Honeybee stings are generally not more severe but they inject more venom. Bees inject 50— micrograms of venom whereas wasps deliver nearly 3 μg of venom with each sting.

Bees can sting once but wasps have the capacity to sting multiple times 1 — 3. The rate of systemic sting reactions in epidemiological studies in Europe ranged between 0.

The chance of a SR and the chance of life threatening anaphylaxis are related to many factors, including the severity of the preceding reaction, allergy to bee venom, the level of baseline serum tryptase and presence of mastocytosis, increased basophil activation, age and underlying medical conditions 7.

In a recent study by Stoevesandt et al. a systemic reaction rate of The most important risk factors related to systemic reactions during VIT are honeybee venom immunotherapy, rapid dose increase during the build-up phase and probably high basal tryptase levels in vespid allergy but not in honeybee venom allergy 9.

The protective effect of VIT persists for years after stopping treatment. The long term outcome of systemic reactions after discontinuation of VIT is superior in children compared to adults and for vespid venom compared to honeybee VIT 15 — This review aims to discuss first the epidemiology and risk factors of insect venom anaphylaxis, then focuses on the mechanisms of VIT to prevent SSR to insect stings and finally aims to discuss the efficacy, safety and long term effects of VIT as well as the risk factors related to SSR during and after VIT.

The prevalence of being stung by Hymenoptera species during life ranges from The sensitization rate, indicated either by a positive skin prick test or by specific IgE positivity, ranges between 9. In one study children were found to be 3. The rate of systemic sting reactions in epidemiological studies in Europe ranges between 0.

Among these reactions, the anaphylactic shock frequency is between 0. This wide range reflects the lack of consensus on the definition of anaphylaxis, differences in data collection techniques and variability in degree of exposure to stings in different climate conditions 7.

In children, the prevalence of SR is much lower and ranges from 0. Beekeepers are a vulnerable and high risk population for the development of allergic reactions to honeybee stings. In a British beekeeper survey, risk factors for SR were found to be female gender, positive family history of bee venom allergy, premedication with antihistamines before hive attendance and 2 or more years of beekeeping before the first SR According to the European network of severe allergic reactions NORA , In this study, 59 tertiary allergy, dermatology and pediatrics centers from 10 different countries reported 3, anaphylaxis cases Only In population based studies performed during the first decade of the twenty-first century, the rate of anaphylaxis due to insect venom ranged from 7.

Fatalities from insect stings have been examined previously in a number of studies. A study from Costa Rica reported 52 deaths in a 22 years period accounting to 0.

A recent report from the UK stated 93 deaths from venom anaphylaxis between and , accounting to 0. Especially a previous history of hymenoptera allergy, male sex, older age and delayed adrenaline administration are important risk factors for fatal reactions 31 , Risk factors related to SSR to hymenoptera stings are summarized in Table 1.

Table 1. Mastocytosis is a clonal neoplastic disorder of mast cells that is characterized primarily by cutaneous or systemic subtypes and sometimes by rare forms. Mastocytosis usually involves the somatic KIT DV mutation, shows aberrant CD25 or CD2 expression on mast cells and is frequently accompanied by elevated baseline serum tryptase BST In patients with cutaneous mastocytosis, mast cell aggregates are located only in the skin and this form is mostly diagnosed in infants and children Systemic mastocytosis SM is frequently found in adults and is divided into four subtypes indolent SM, SM associated with a hematological disorder, aggressive SM and mast cell sarcoma ; the most common among these is indolent systemic mastocytosis ISM.

ISM can present with normal BST and lack of skin lesions The prevalence of mastocytosis in patients with hymenoptera venom allergy may be as high as 7. In a considerable number of patients with ISM, hymenoptera venom anaphylaxis HVA may be the first symptom of the disease.

These ISM patients without skin lesions are mostly males with lower BST levels and lower frequency of KIT mutations Anaphylaxis in patients with mastocytosis is mostly characterized by cardiac symptoms, such as hypotension and syncopal episodes, whereas skin symptoms, such as urticaria and angioedema are rare.

Therefore, if a patient with VHA presents with hypotension and syncope without skin symptoms, mastocytosis should be suspected Recently, for the cases of HVA, a scoring system called REMA was developed based on gender, clinical symptoms and BST to identify patients having clonal mast cell systemic disease.

The precise mechanisms for the increased prevelance of HVA in mastocytosis are not well-understood. However, possible explanations for this co-existence are as follows: 1 Increased mast cell burden may lead to higher mediator release in the case of a sting; 2 The perivascular location of the mast cells may cause a direct access of mediators to the systemic circulation, which increase the severity of the reaction; 3 A gain of function mutation, KIT DV, may prevent mast cell apoptosis and increases the proliferation and differentiation of the mast cells, and finally 4 Phospholipase A2, a component of hymenoptera venom may cause a direct mediator release from mast cells VIT seems to be the most appropriate treatment option for patients with mastocytosis and HVA.

VIT is usually well-tolerated, safe and effective. Whether BST increases the risk of adverse events during VIT is not yet clear. Despite the preference for lifelong VIT in patients with mastocytosis, there is no evidence based proof of lifelong treatment in the literature. Initially, the interaction between allergens, epithelial cells and dendritic cells triggers the response produced by the innate immune system and subsequently the adaptive immune responses develop.

Different parts of the immune system are involved in the development of peripheral immune tolerance, and in a network of different cell types, either directly through cell to cell contact or through release of various cytokines and specific antibody production IgE, IgG1, IgG4, IgA.

Further details of VIT mechanisms are shown in Figure 1. Figure 1. Mechanisms of venom allergen immunotherapy. High dose of hymenoptera venom stimulates dendritic cells and induces Treg and B reg cells as well as other B cell subsets that produce allergen specific IgG1, IgG4, and IgA type bloking antibodies.

Several cytokines also take place in the immune tolerance induction and as a result a shift from Th2 to Th1 type immune deviation occurs. Red arrows show blocking activity induced during VIT. LTs, Leukotrienes; PG, Prostaglandins; iTreg, Inducible Tregulatory cells; nTreg, Natural T regulatory cells; Tfh, T follicular hepler cells; Tfr, T Follicular regulatory cells; DC reg, Regulatory dendritic cells; TSLP, Thymic stromal Lymphopoietin.

Initially subcutaneous VIT is associated with transient early increases in serum allergen specific IgE sIgE levels and then there is a decrease in sIgE over several years 48 — AIT is also associated with increases in allergen-specific IgA, IgG1 and IgG4 antibodies, which are called blocking antibodies 48 , Studies with aeroallergens have shown significant increases in serum concentrations of blocking antibodies, up to times in a time and dose dependent manner 52 — The production of blocking antibodies, particularly the IgG4 type, can compete with sIgE for allergen and prevent the allergen-sIgE interaction.

The blockage of allergen-sIgE interactions prevents cross-linking of high-affinity IgE receptors FcεRI on basophils and mast cells, which inhibits degranulation of these cells and may prevent the development of anaphylaxis 55 , One of the major cytokines produced by T regs, IL, not only is involved in the suppression of allergen-specific T effector cells during AIT, but it also inhibits the production of total IgE and specific IgE, while increasing IgG4 levels 59 , In non-allergic beekeepers, the IgG4 serum concentrations are nearly one thousand times higher than the serum specific IgE levels.

The serum IgG4 concentrations are closely correlated with the number stings per year and time spent in beekeeping 31 , In an animal model of bee venom allergy, major bee venom allergen PLA2 was injected into inguinal lymph nodes and an allergen-specific IgG response with the production of IgG2a was observed In another study of peptide VIT, a reduction in allergen-specific IgE and an increase in specific IgG2a were found, both of which had preventive functions against allergen-induced anaphylaxis In contrast, IgG-associated serum IgE-inhibitory activity persisted for several years and correlated with clinical efficacy This suggests that the functional activity of blocking antibodies rather than their levels may be a more accurate measure of clinical efficacy and seems to correlate closely with long term immune tolarance However, this may not be the case for bee venom immunotherapy, where although successful desensitization was accompanied by increases in both IgG4 and IgE-Inhibitory activity, both the elevated specific IgG4 levels and IgE-FAB inhibitory activity returned to baseline within months of discontinuation of VIT and further follow up revealed a more sustained decrease in venom-specific IgE levels 65 representing a putative alternative mechanism of prolonged protection following IgG withdrawal.

VIT shows its action through complex immunological mechanisms. The initial mechanism of action seen on effector cells is mast cell and basophil desensitization 9.

The number of these cells decreases during venom immunotherapy and additionally their thresholds for cytokine release increase with time. During the rush VIT early in the course of treatment there is a decrease in peripheral blood basophil numbers and also in the production and release of basophil derived cytokines, such as IL-4 and IL Basal serum tryptase level, which is a marker of mast cell burden and mast cell function, decreases over time during VIT In patients with VIT, the suppression of surface antigens on blood basophils was shown previously In addition to the changes observed in basophil surface antigens, the amount of histamine released from basophils following sting challenges also decreased in patients with VIT depending on their clinical reactivity Basophil reactivity assessed in the flow-cytometric evaluation of CD63 expression has been shown to be a reliable diagnostic test to diagnose hymenoptera venom allergy Basophil sensitivity, the dose at which half of the maximum basophil response occurs, was suggested to monitor VIT 72 — A new method of functional assay that measures intracellular staining of phycoerythrin-conjugated daimine oxidase DAO has been validated for detecting the amount of histamine released from basophils.

Following allergen stimulation, intracellular DAO levels decrease in proportion to the intracellular histamine released. This reduction was shown in patients treated with vespula VIT, which is important for increasing the threshold for venom to induce an anaphylactic reaction in VIT patients Not only the preformed mediator release but also the production and release of newly generated mediators, such as leukotriene C4 in blood basophils in patients following VIT decreases Following rush VIT a decrease in T-cell expressed and secreted RANTES protein, IL-8 and monocyte chemoattractant protein 1 MCP-1 production have been reported in peripheral blood mononuclear cell PBMC cultures at protein and as well as mRNA levels During the early phases of VIT the mechanisms that start desensitization are not fully understood.

In Bussmann et al. performed a study on patients with rush VIT. They analyzed expression levels of different tolerogenic markers at protein and mRNA levels within the first 5 days of VIT. In studies with aeroallergens, AIT was shown to inhibit early and late phase allergic responses at allergic tissue sites through the suppression of several cytokines and decreases in numbers of eosinophils, mast cells and basophils This information indicates that allergen immunotherapy is effective at both systemic and local levels.

Similar mechanisms are likely to apply to VIT. The development of immune tolerance during VIT has been shown to be related to the modification of T and B cell responses A Th2 to Th1 shift occurs during VIT and an increase in interferon gamma IFN-γ levels is observed parallel to the decrease in IL-4 and IL in whole blood 80 , Th2 responses during VIT are reduced and there is also an increase in Treg cell numbers and functions 80 , Treg cells are divided into 2 subgroups as natural regulatory T nTreg cells, which are characterized by the transcription factor forkhead box P3 FOXP3 , and inducible regulatory T iTreg cells, such as IL producing Tr1 cells and TGF-b producing TH3 cells 83 — This results in a supressive effect on dendritic cell maturation and in MHC class II and costimulatory ligand expressions TGF-b downregulates FceRI expression on Langerhans cells and also upregulates FOXP3 and RUNX and assists CTLA-4 expression on T cells 87 , In beekeepers IL producing Treg cells inhibit the proliferation of PLA-specific effector T cells shortly after the start of bee venom season.

This suppressive effect can be reversed by blocking CTLA-4, PD-1, and IL receptors Additionally induction of indoleamine 2,3-dioxygenase enzyme in dendritic cells, by the effect of Tregs, causes the transformation of inflammatory dendritic cells into regulatory dendritic cells In a similar manner, during VIT, Tr1-type Treg cell proliferation is prominent and the antigen-specific proliferative and cytokine responses against the major bee venom allergen, the phospholipase A2 PLA have been significantly suppressed by the end of first week of VIT The allergen induced secretion of Th2 cytokines, such as IL-4, IL-5, and IL were abolished In addition to IL production, Treg cells can also suppress immune responses via cell-to-cell interactions.

The role of increased IL levels is prominent in the development of clinical and immunological tolerance during VIT. Blockage of IL in PBMC reconstitutes the specific proliferative and cytokine responses. This situation can also be seen in beekeepers who have received multiple bee stings In a study by Nasser et al allergen-induced changes in cytokine mRNA and cellular profiles from cutaneous biopsies were compared before and 3 months after wasp VIT.

Additionally a trend toward an increase in IL mRNA was also observed IL serum levels began to increase from the second day of VIT 78 and on day 28 of treatment, a desensitized condition has arisen in allergen-specific T cells associated with the direct suppressive effects of IL A study by grass pollen immunotherapy has shown a significant decrease in memory T FH cell numbers after immunotherapy Additionally, T FR cells were found to produce more IL compared to T FH cells.

The plasticity between T FH and T FR cells have been shown in the same study suggesting that T FR cells may play important roles in suppressing TH2 responses and allergen specific IgE production during immunotherapy It is likely that similar T FR and T FH cell mechanisms are present during venom imunotherapy as in grass pollen immunotherapy.

Recently ILsecreting allergen-specific Breg cells have been identified in bee venom tolerant beekeepers and VIT administered patients Additionally, Breg cells can also show their inhibitory capacity by producing IL and TGF-beta Apart from Treg and B reg cells, ILsecreting natural killer regulatory cells have also been shown to suppress allergen stimulated T cell proliferation in humans and may be important in tolerance induction as other regulatory cell types The effect of allergen immunotherapy on innate lymphoid cells, ILC type 2, has been studied in grass pollen allergy in peripheral blood.

AIT supressed seasonal increases in ILC2s in patients treated with immunotherapy compared to untreated controls The decrease in ILC2s correlated with the self reported symptoms.

In another study of seasonal asthmatic patients, Lombardi et al could not show any change in the number of ILC2s during immunotherapy which was explained by non-seasonal measurements while patients were asymptomatic Up to date, there is no evidence that immunotherapy has any effect on epithelially derived cytokines, such as IL, IL, and TSLP which have regulatory effects on local type 2 inflammation and ILCs During VIT an early desensitization develops within days or even hours depending on the type of immunotherapy protocol used, such as rush and ultrarush type of VIT.

There is a decrease in basophil numbers, preformed mediators and mediator release by time 75 , , Among four different type of histamine receptors histamine receptor type 2 HR2 plays important roles with the peripheral antigen tolerance Basophil supression starts by the activation of histamine type 2 receptors HR2.

H2R decreases allergen-induced FceRI-mediated basophil degranulation and mediator release HR2 is mainly involved in tolerogenic immune responses. It is upregulated in Th2 cells and both suppress allergen stimulated T cell responses and increase IL production in beekeepers 89 which induces the development of peripheral tolerance 76 , , Histamin via HR2, induces IL production by dendritic cells and Th2 cells ; increases the suppressive effect of TGF-b on T cells and decreases IL-4 and IL production whicch are the main Th2 type cytokines Some factors, such as higher amount of allergen transferred during each sting reaction, consistency of the honeybee sting, diversity of the sensitization pattern of honeybee venom are among the proposed factors which may explain the lower success rates related with the honeybee VIT 9.

Considering honeybee venom immunotherapy, usage of component resolved sensitization patterns may help to increase the treatment success. Some patients are sensitized predominantly to Api m 10, which is an underrepresented allergen in some VIT preparations that may cause a treatment failure , During the build-up phase of VIT, if SSR is a problem to reach the maintenance dose, premedication with omalizumab, an anti-IgE antibody, may be an option The dose of venom used during VIT is also important to prevent treatment failure.

Usually a maintenance dose of μg venom during VIT is sufficient for protection 9. When the risk factors are high, as in beekeepers, a higher dose of venom gives better results If a systemic reaction develops following a field sting or sting challenge during a conventional dose of μg, a higher dose, μg, is recommended In one study a relapse rate of 7.

Duration of the VIT is important for the efficacy. One year of treatment has failed in nearly one quarter of patients when they stung in 3—4 years after VIT Studies of at least 5 years of treatment seem to show better protection compared to 3 years of treatment In another study, Golden et al.

evaluated patients treated with VIT for at least 5 years and found a systemic reaction rate of 9. Adverse events are usually mild during VIT. Patients having systemic reactions develop relapse much more frequently compared to those who did not Some of the previous risk factors for systemic adverse events during VIT are no longer considered as important risk factors.

These older risk factors include mastocytosis, ACE inhibitors, beta-blocker use, high specific IgE levels and skin prick test positivity at low test concerntrations 9.

High basal tryptase levels in vespid allergy may be a risk factor for systemic adverse events in VIT 12 but not in honeybee venom allergy Risk factors for relapse of SSR after stopping VIT are given in Table 2.

Table 2. Risk factors for relapse of severe systemic reactions after stopping VIT 9 , 11 , 15 , — Currently, sting challenge is the gold standard to identify the efficacy of VIT and to differentiate the responders from non-responders.

The methods used to monitor VIT are given in Table 3. Table 3. The methods used to monitor Venom immunotherapy VIT 9 , 17 , 74 , , Insect venom allergy is one of the most common causes of anaphylaxis in humans and it is a medical emergency.

Currently there is no biomarker to predict the risk of anaphylaxis. VIT is the most effective treatment for preventing SSR to a sting and decreases the risk of anaphylaxis. However, there are still some questions to be answered, such as cost of effectiveness, effect on quality of life, duration of treatment, optimal dose and means of assessment.

Peripheral tolerance development is the main mechanism during VIT, which is orchestrated by T regulatory cells. T regs produce IL and suppress Th2 immunity and the immune responses shift toward Th1 type inflammation.

Several other mechanisms, such as epithelial cells, several cytokines, dendritic cells, ILC2s and B regulatory cells are also involved in the development of long term immune tolerance. Factors, such as increasing knowledge about risk factors for venom anaphylaxis, better patient education, developing more effective VIT products with less side effects, and finding effective biomarkers to predict future systemic reactions at the individual level, will significantly improve patient care.

US made the literature search, prepared the figure and tables, and wrote the article under the supervision of SD. SD planned the whole body of text, read the manuscript, made the necessary corrections, and detailed the discussion on the mechanisms of immunotherapy.

SD reports grants from ALK, Denmark, personal fees from Anergis, Switzerland, personal fees from Biomay, Austria, personal fees from Allergy Therapeutics, UK, personal fees from ALK, Horsholm, Denmark, personal fees from Allergy Therapeutics, outside the submitted work.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Krishna MT, Ewan PW, Diwakar L, Durham SR, Frew AJ, Leech SC, et al. Diagnosis and management of hymenoptera venom allergy: British society for allergy and clinical immunology BSACI guidelines.

Clin Exp Allergy. doi: PubMed Abstract CrossRef Full Text Google Scholar. Tan JW, Campbell DE. Insect allergy in children. J Paediatr Child Health. Hoffman DR, Jacobson RS. Allergens in hymenoptera venom XII: how much protein is in a sting? Ann Allergy. PubMed Abstract Google Scholar.

Ellis AK, Day JH. Clinical reactivity to insect stings. Curr Opin Allergy Clin Immunol. Mauriello PM, Barde SH, Georgitis JW, Reisman RE. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol. Ludman SW, Boyle RJ. Stinging insect allergy: current perspectives on venom immunotherapy.

J Asthma Allergy. Bilo BM, Bonifazi F. Epidemiology of insect-venom anaphylaxis. Jennings A, Duggan E, Perry IJ, Hourihane JO.

Epidemiology of allergic reactions to hymenoptera stings in Irish school children. Pediatr Allergy Immunol. Sturm GJ, Varga EM, Roberts G, Mosbech H, Bilo MB, Akdis CA, et al.

EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Muller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety.

Rueff F, Vos B, Oude Elberink J, Bender A, Chatelain R, Dugas-Breit S, et al. Predictors of clinical effectiveness of Hymenoptera venom immunotherapy. Rueff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al.

Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.

Mosbech H, Muller U. Side-effects of insect venom immunotherapy: results from an EAACI multicenter study. European Academy of Allergology and Clinical Immunology.

Stoevesandt J, Hain J, Stolze I, Kerstan A, Trautmann A. Angiotensin-converting enzyme inhibitors do not impair the safety of Hymenoptera venom immunotherapy build-up phase. CrossRef Full Text Google Scholar. Golden DB, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM.

Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med. Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. Lerch E, Muller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in patients.

Novembre E, Cianferoni A, Bernardini R, Veltroni M, Ingargiola A, Lombardi E, et al. Epidemiology of insect venom sensitivity in children and its correlation to clinical and atopic features.

Grigoreas C, Galatas ID, Kiamouris C, Papaioannou D. Insect-venom allergy in Greek adults. Incorvaia C, Mauro M, Pastorello EA. Hymenoptera stings in conscripts.

Fernandez J, Blanca M, Soriano V, Sanchez J, Juarez C. Epidemiological study of the prevalence of allergic reactions to Hymenoptera in a rural population in the Mediterranean area. Navarro LA, Pelaez A, de la Torre F, Tenias Burillo JM, Megias J, Martinez I.

Epidemiological factors on hymenoptera venom allergy in a Spanish adult population. J Investig Allergol Clin Immunol.

Fernandez J, Soriano V, Mayorga L, Mayor M. Natural history of Hymenoptera venom allergy in Eastern Spain. Bilo MB, Cichocka-Jarosz E, Pumphrey R, Oude-Elberink JN, Lange J, Jakob T, et al. Self-medication of anaphylactic reactions due to Hymenoptera stings-an EAACI task force consensus statement.

Muller UR. Bee venom allergy in beekeepers and their family members. Richter AG, Nightingale P, Huissoon AP, Krishna MT. Risk factors for systemic reactions to bee venom in British beekeepers. Ann Allergy Asthma Immunol. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, et al.

First European data from the network of severe allergic reactions NORA. Prado M, Quiros D, Lomonte B. Mortality due to Hymenoptera stings in Costa Rica, Rev Panam Salud Publica. Barnard JH. Studies of Hymenoptera sting deaths in the United States.

Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, Bilo BM, Rueff F, Mosbech H, Bonifazi F, Oude-Elberink JN, EAACI Interest Group on Insect Venom Hypersensitivity.

Diagnosis of Hymenoptera venom allergy. Clark S, Camargo CA Jr. Then, during your first couple years of treatment, your maintenance doses will gradually become less frequent: every four weeks, to every eight weeks, and eventually, perhaps even 12 weeks apart.

Studies suggest that treatment can be stopped after three to five years, depending on age and severity. In contrast to honey bees, venom sacs from other stinging insects must be hand-dissected with tweezers. Each sac is only the size of a pinhead, making the process tedious and difficult.

In fact, it takes staff-hours to collect the , sacs needed for one batch of product for immunotherapy. Katherine K. Schlosser is an author and lecturer on native plants and herbs. Despite her allergy to honeybees, wasps, hornets, and yellow jackets, she spends most of her professional and personal life outdoors.

Go more in-depth with these articles on venom immunotherapy:. For instance, young children under the age of 5 are not often candidates due to their inability to communicate symptoms.

There may also be other health factors that prevent you from this type of treatment. The best way to find out if venom immunotherapy is right for you is to talk to a medical provider in your area.

Instead, talk to an allergist about testing and venom immunotherapy. This website uses cookies so that we can provide you with the best user experience possible.

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If you disable this cookie, we will not be able to save your preferences. This means that every time you visit this website you will need to enable or disable cookies again. Home Bee Stings Treatment What Is Venom Immunotherapy? What Is Venom Immunotherapy?

The Specific Allergies Venom Immunotherapy Can Treat Venom immunotherapy can treat allergies to stings from: Honey bees Yellow jackets Wasps Hornets Depending on your allergies, you may receive allergy shots containing insect-specific venom or mixed doses that treat several stinging insect allergies.

ONGOING TREATMENT Venom immunotherapy is an ongoing treatment. Bee sting allergies are serious Find a local medical provider who can determine your risk. Search Now. Discover how venom is collected for immunotherapy. Learn More. DOES IT WORK? Hear a family's success story.

Learn how an avid gardener continued her passion with immunotherapy. Related Articles. Rush Venom Immunotherapy. How to Treat a Bee Sting.

Some of the most severe reactions eg, sudden hypotension occur in the absence of any skin findings or can be refractory to single or multiple doses of epinephrine [ ]. Reactions involving angioedema of the tongue or throat, which could compromise the airway, are generally excluded from this category and considered anaphylactic reactions [ 5 ].

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View Topic. Font Size Small Normal Large. Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action. Formulary drug information for this topic.

No drug references linked in this topic. Immunotherapy can relieve allergy symptoms, and help reduce the severity of reactions. In many cases, it offers ongoing relief of symptoms that continues after treatment is complete. Immunotherapy is typically performed on adults, or children who are at least 5 years old.

Injections are given on a regular schedule. The allergen is injected into the arm once or twice a week, and in increasingly larger doses, enabling the body to develop a tolerance to it.

This part of the treatment, known as the buildup phase, usually lasts between 3 and 6 months. After that, the maintenance phase of treatment begins, during which the quantity of each dose remains stable, and there are longer intervals, generally between 2 and 4 weeks, between each injection.

Within a year of starting immunotherapy, allergic symptoms should have greatly diminished. Treatment usually continues for 3 to 5 years, at which point symptoms should have disappeared.

Immunotherapy is a common form of treatment for allergies, one considered very safe. Usually, when a patient has an injection-related reaction, the injection site reddens, feels warm or swells slightly. Red arrows show blocking activity induced during VIT.

LTs, Leukotrienes; PG, Prostaglandins; iTreg, Inducible Tregulatory cells; nTreg, Natural T regulatory cells; Tfh, T follicular hepler cells; Tfr, T Follicular regulatory cells; DC reg, Regulatory dendritic cells; TSLP, Thymic stromal Lymphopoietin. Initially subcutaneous VIT is associated with transient early increases in serum allergen specific IgE sIgE levels and then there is a decrease in sIgE over several years 48 — AIT is also associated with increases in allergen-specific IgA, IgG1 and IgG4 antibodies, which are called blocking antibodies 48 , Studies with aeroallergens have shown significant increases in serum concentrations of blocking antibodies, up to times in a time and dose dependent manner 52 — The production of blocking antibodies, particularly the IgG4 type, can compete with sIgE for allergen and prevent the allergen-sIgE interaction.

The blockage of allergen-sIgE interactions prevents cross-linking of high-affinity IgE receptors FcεRI on basophils and mast cells, which inhibits degranulation of these cells and may prevent the development of anaphylaxis 55 , One of the major cytokines produced by T regs, IL, not only is involved in the suppression of allergen-specific T effector cells during AIT, but it also inhibits the production of total IgE and specific IgE, while increasing IgG4 levels 59 , In non-allergic beekeepers, the IgG4 serum concentrations are nearly one thousand times higher than the serum specific IgE levels.

The serum IgG4 concentrations are closely correlated with the number stings per year and time spent in beekeeping 31 , In an animal model of bee venom allergy, major bee venom allergen PLA2 was injected into inguinal lymph nodes and an allergen-specific IgG response with the production of IgG2a was observed In another study of peptide VIT, a reduction in allergen-specific IgE and an increase in specific IgG2a were found, both of which had preventive functions against allergen-induced anaphylaxis In contrast, IgG-associated serum IgE-inhibitory activity persisted for several years and correlated with clinical efficacy This suggests that the functional activity of blocking antibodies rather than their levels may be a more accurate measure of clinical efficacy and seems to correlate closely with long term immune tolarance However, this may not be the case for bee venom immunotherapy, where although successful desensitization was accompanied by increases in both IgG4 and IgE-Inhibitory activity, both the elevated specific IgG4 levels and IgE-FAB inhibitory activity returned to baseline within months of discontinuation of VIT and further follow up revealed a more sustained decrease in venom-specific IgE levels 65 representing a putative alternative mechanism of prolonged protection following IgG withdrawal.

VIT shows its action through complex immunological mechanisms. The initial mechanism of action seen on effector cells is mast cell and basophil desensitization 9.

The number of these cells decreases during venom immunotherapy and additionally their thresholds for cytokine release increase with time. During the rush VIT early in the course of treatment there is a decrease in peripheral blood basophil numbers and also in the production and release of basophil derived cytokines, such as IL-4 and IL Basal serum tryptase level, which is a marker of mast cell burden and mast cell function, decreases over time during VIT In patients with VIT, the suppression of surface antigens on blood basophils was shown previously In addition to the changes observed in basophil surface antigens, the amount of histamine released from basophils following sting challenges also decreased in patients with VIT depending on their clinical reactivity Basophil reactivity assessed in the flow-cytometric evaluation of CD63 expression has been shown to be a reliable diagnostic test to diagnose hymenoptera venom allergy Basophil sensitivity, the dose at which half of the maximum basophil response occurs, was suggested to monitor VIT 72 — A new method of functional assay that measures intracellular staining of phycoerythrin-conjugated daimine oxidase DAO has been validated for detecting the amount of histamine released from basophils.

Following allergen stimulation, intracellular DAO levels decrease in proportion to the intracellular histamine released. This reduction was shown in patients treated with vespula VIT, which is important for increasing the threshold for venom to induce an anaphylactic reaction in VIT patients Not only the preformed mediator release but also the production and release of newly generated mediators, such as leukotriene C4 in blood basophils in patients following VIT decreases Following rush VIT a decrease in T-cell expressed and secreted RANTES protein, IL-8 and monocyte chemoattractant protein 1 MCP-1 production have been reported in peripheral blood mononuclear cell PBMC cultures at protein and as well as mRNA levels During the early phases of VIT the mechanisms that start desensitization are not fully understood.

In Bussmann et al. performed a study on patients with rush VIT. They analyzed expression levels of different tolerogenic markers at protein and mRNA levels within the first 5 days of VIT. In studies with aeroallergens, AIT was shown to inhibit early and late phase allergic responses at allergic tissue sites through the suppression of several cytokines and decreases in numbers of eosinophils, mast cells and basophils This information indicates that allergen immunotherapy is effective at both systemic and local levels.

Similar mechanisms are likely to apply to VIT. The development of immune tolerance during VIT has been shown to be related to the modification of T and B cell responses A Th2 to Th1 shift occurs during VIT and an increase in interferon gamma IFN-γ levels is observed parallel to the decrease in IL-4 and IL in whole blood 80 , Th2 responses during VIT are reduced and there is also an increase in Treg cell numbers and functions 80 , Treg cells are divided into 2 subgroups as natural regulatory T nTreg cells, which are characterized by the transcription factor forkhead box P3 FOXP3 , and inducible regulatory T iTreg cells, such as IL producing Tr1 cells and TGF-b producing TH3 cells 83 — This results in a supressive effect on dendritic cell maturation and in MHC class II and costimulatory ligand expressions TGF-b downregulates FceRI expression on Langerhans cells and also upregulates FOXP3 and RUNX and assists CTLA-4 expression on T cells 87 , In beekeepers IL producing Treg cells inhibit the proliferation of PLA-specific effector T cells shortly after the start of bee venom season.

This suppressive effect can be reversed by blocking CTLA-4, PD-1, and IL receptors Additionally induction of indoleamine 2,3-dioxygenase enzyme in dendritic cells, by the effect of Tregs, causes the transformation of inflammatory dendritic cells into regulatory dendritic cells In a similar manner, during VIT, Tr1-type Treg cell proliferation is prominent and the antigen-specific proliferative and cytokine responses against the major bee venom allergen, the phospholipase A2 PLA have been significantly suppressed by the end of first week of VIT The allergen induced secretion of Th2 cytokines, such as IL-4, IL-5, and IL were abolished In addition to IL production, Treg cells can also suppress immune responses via cell-to-cell interactions.

The role of increased IL levels is prominent in the development of clinical and immunological tolerance during VIT. Blockage of IL in PBMC reconstitutes the specific proliferative and cytokine responses. This situation can also be seen in beekeepers who have received multiple bee stings In a study by Nasser et al allergen-induced changes in cytokine mRNA and cellular profiles from cutaneous biopsies were compared before and 3 months after wasp VIT.

Additionally a trend toward an increase in IL mRNA was also observed IL serum levels began to increase from the second day of VIT 78 and on day 28 of treatment, a desensitized condition has arisen in allergen-specific T cells associated with the direct suppressive effects of IL A study by grass pollen immunotherapy has shown a significant decrease in memory T FH cell numbers after immunotherapy Additionally, T FR cells were found to produce more IL compared to T FH cells.

The plasticity between T FH and T FR cells have been shown in the same study suggesting that T FR cells may play important roles in suppressing TH2 responses and allergen specific IgE production during immunotherapy It is likely that similar T FR and T FH cell mechanisms are present during venom imunotherapy as in grass pollen immunotherapy.

Recently ILsecreting allergen-specific Breg cells have been identified in bee venom tolerant beekeepers and VIT administered patients Additionally, Breg cells can also show their inhibitory capacity by producing IL and TGF-beta Apart from Treg and B reg cells, ILsecreting natural killer regulatory cells have also been shown to suppress allergen stimulated T cell proliferation in humans and may be important in tolerance induction as other regulatory cell types The effect of allergen immunotherapy on innate lymphoid cells, ILC type 2, has been studied in grass pollen allergy in peripheral blood.

AIT supressed seasonal increases in ILC2s in patients treated with immunotherapy compared to untreated controls The decrease in ILC2s correlated with the self reported symptoms. In another study of seasonal asthmatic patients, Lombardi et al could not show any change in the number of ILC2s during immunotherapy which was explained by non-seasonal measurements while patients were asymptomatic Up to date, there is no evidence that immunotherapy has any effect on epithelially derived cytokines, such as IL, IL, and TSLP which have regulatory effects on local type 2 inflammation and ILCs During VIT an early desensitization develops within days or even hours depending on the type of immunotherapy protocol used, such as rush and ultrarush type of VIT.

There is a decrease in basophil numbers, preformed mediators and mediator release by time 75 , , Among four different type of histamine receptors histamine receptor type 2 HR2 plays important roles with the peripheral antigen tolerance Basophil supression starts by the activation of histamine type 2 receptors HR2.

H2R decreases allergen-induced FceRI-mediated basophil degranulation and mediator release HR2 is mainly involved in tolerogenic immune responses. It is upregulated in Th2 cells and both suppress allergen stimulated T cell responses and increase IL production in beekeepers 89 which induces the development of peripheral tolerance 76 , , Histamin via HR2, induces IL production by dendritic cells and Th2 cells ; increases the suppressive effect of TGF-b on T cells and decreases IL-4 and IL production whicch are the main Th2 type cytokines Some factors, such as higher amount of allergen transferred during each sting reaction, consistency of the honeybee sting, diversity of the sensitization pattern of honeybee venom are among the proposed factors which may explain the lower success rates related with the honeybee VIT 9.

Considering honeybee venom immunotherapy, usage of component resolved sensitization patterns may help to increase the treatment success. Some patients are sensitized predominantly to Api m 10, which is an underrepresented allergen in some VIT preparations that may cause a treatment failure , During the build-up phase of VIT, if SSR is a problem to reach the maintenance dose, premedication with omalizumab, an anti-IgE antibody, may be an option The dose of venom used during VIT is also important to prevent treatment failure.

Usually a maintenance dose of μg venom during VIT is sufficient for protection 9. When the risk factors are high, as in beekeepers, a higher dose of venom gives better results If a systemic reaction develops following a field sting or sting challenge during a conventional dose of μg, a higher dose, μg, is recommended In one study a relapse rate of 7.

Duration of the VIT is important for the efficacy. One year of treatment has failed in nearly one quarter of patients when they stung in 3—4 years after VIT Studies of at least 5 years of treatment seem to show better protection compared to 3 years of treatment In another study, Golden et al.

evaluated patients treated with VIT for at least 5 years and found a systemic reaction rate of 9. Adverse events are usually mild during VIT. Patients having systemic reactions develop relapse much more frequently compared to those who did not Some of the previous risk factors for systemic adverse events during VIT are no longer considered as important risk factors.

These older risk factors include mastocytosis, ACE inhibitors, beta-blocker use, high specific IgE levels and skin prick test positivity at low test concerntrations 9. High basal tryptase levels in vespid allergy may be a risk factor for systemic adverse events in VIT 12 but not in honeybee venom allergy Risk factors for relapse of SSR after stopping VIT are given in Table 2.

Table 2. Risk factors for relapse of severe systemic reactions after stopping VIT 9 , 11 , 15 , — Currently, sting challenge is the gold standard to identify the efficacy of VIT and to differentiate the responders from non-responders.

The methods used to monitor VIT are given in Table 3. Table 3. The methods used to monitor Venom immunotherapy VIT 9 , 17 , 74 , , Insect venom allergy is one of the most common causes of anaphylaxis in humans and it is a medical emergency.

Currently there is no biomarker to predict the risk of anaphylaxis. VIT is the most effective treatment for preventing SSR to a sting and decreases the risk of anaphylaxis. However, there are still some questions to be answered, such as cost of effectiveness, effect on quality of life, duration of treatment, optimal dose and means of assessment.

Peripheral tolerance development is the main mechanism during VIT, which is orchestrated by T regulatory cells. T regs produce IL and suppress Th2 immunity and the immune responses shift toward Th1 type inflammation.

Several other mechanisms, such as epithelial cells, several cytokines, dendritic cells, ILC2s and B regulatory cells are also involved in the development of long term immune tolerance.

Factors, such as increasing knowledge about risk factors for venom anaphylaxis, better patient education, developing more effective VIT products with less side effects, and finding effective biomarkers to predict future systemic reactions at the individual level, will significantly improve patient care.

US made the literature search, prepared the figure and tables, and wrote the article under the supervision of SD. SD planned the whole body of text, read the manuscript, made the necessary corrections, and detailed the discussion on the mechanisms of immunotherapy.

SD reports grants from ALK, Denmark, personal fees from Anergis, Switzerland, personal fees from Biomay, Austria, personal fees from Allergy Therapeutics, UK, personal fees from ALK, Horsholm, Denmark, personal fees from Allergy Therapeutics, outside the submitted work.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Immunotherapy can relieve allergy symptoms, and help reduce the severity of reactions. In many cases, it offers ongoing relief of symptoms that continues after treatment is complete.

Immunotherapy is typically performed on adults, or children who are at least 5 years old. Injections are given on a regular schedule. The allergen is injected into the arm once or twice a week, and in increasingly larger doses, enabling the body to develop a tolerance to it. This part of the treatment, known as the buildup phase, usually lasts between 3 and 6 months.

After that, the maintenance phase of treatment begins, during which the quantity of each dose remains stable, and there are longer intervals, generally between 2 and 4 weeks, between each injection.

Within a year of starting immunotherapy, allergic symptoms should have greatly diminished. Treatment usually continues for 3 to 5 years, at which point symptoms should have disappeared.

Immunotherapy is a common form of treatment for allergies, one considered very safe. Usually, when a patient has an injection-related reaction, the injection site reddens, feels warm or swells slightly.

These types of reactions can occur right away or during the next few hours. Some patients have the same symptoms, such as hives or itchiness, that they get when exposed to venom through insect bites or stings. In rare cases, immunotherapy causes an anaphylactic reaction. It almost always take place within 30 minutes of receiving the injection, which is why a patient is asked to remain in the office for that period of time.

If a severe reaction occurs, immediate medical care is required. We gradually increase the dose over time during the build-up phase of your treatment. You may have weekly injections during this phase. During your maintenance phase you may have injections about each month.

Some patients can stop maintenance therapy after a while, but others need to continue for longer treatment times. Venom immunotherapy. Symptoms of Insect Allergies : Pain Swelling Redness Flushing or hives Itching Anaphylaxis: Difficulty breathing Difficulty swallowing Anxiety Fainting Decreased blood pressure and shock Causes of Insect Allergies : Insect allergies are caused by the injected venom and the stinger should be removed quickly with your fingernail.

How does Venom Immunotherapy Work? What Insects allergies can be treated with venom immunotherapy? Immunotherapy is available to treat allergies to stings from: Honeybees Yellowjackets Hornets Wasps What to Expect During Venom Immunotherapy? Allergen immunotherapy allergy shots. Balloon Sinuplasty.

Chronic Rhinitis — RhinAer. Cluster immunotherapy. Drug desensitization. Eustachian Tube Balloon Dilation. Immunoglobulin replacement therapy. Nasal Obstruction — VivAer. Patch testing chemical allergy. Peanut desensitization.