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Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action

David F Graft, MD
Section Editor
David B Golden, MD
Deputy Editor
Anna M Feldweg, MD


Systemic allergic reactions to the venom of insects in the order Hymenoptera (which includes bees, yellow jackets, wasps, hornets, and fire ants) can be life-threatening. Immunotherapy for venom allergy has been available for over four decades and is highly effective. Unfortunately, many patients with sting-induced anaphylactic reactions are not referred to an allergist/immunologist for evaluation and are never offered this potentially lifesaving therapy [1].

The indications for treatment with venom immunotherapy (VIT), as well as patient selection, effectiveness, and mechanism of action, will be reviewed here. Protocols and safety of VIT and the diagnosis of venom allergy are discussed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring" and "Diagnosis of Hymenoptera venom allergy".)


There are three common types of allergic reactions to Hymenoptera sting: anaphylactic reactions, cutaneous systemic reactions, and large local reactions. These are reviewed briefly here and discussed in more detail elsewhere. (See "Bee, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".)

An anaphylactic reaction involves signs and symptoms of immunoglobulin E (IgE)-mediated allergy, typically affecting more than one organ system (table 1). The skin (urticaria and angioedema) is commonly involved, but respiratory or circulatory symptoms are also prominent. 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 [2-4].

A cutaneous systemic reaction (or a generalized cutaneous reaction) consists of signs and symptoms limited to the skin (ie, pruritus, erythema, urticaria, and/or angioedema), which is usually widespread and involves skin that is not contiguous with the sting site. 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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Literature review current through: May 2017. | This topic last updated: Apr 14, 2017.
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  1. Bilò BM, Bonifazi F. Epidemiology of insect-venom anaphylaxis. Curr Opin Allergy Clin Immunol 2008; 8:330.
  2. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299:157.
  3. Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980; 66:1072.
  4. Stoevesandt J, Hain J, Kerstan A, Trautmann A. Over- and underestimated parameters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medication and absence of urticaria/angioedema. J Allergy Clin Immunol 2012; 130:698.
  5. Golden DB, Demain J, Freeman T, et al. Stinging insect hypersensitivity: A practice parameter update 2016. Ann Allergy Asthma Immunol 2017; 118:28.
  6. Golden DBK. Insect allergy. In: Middleton's allergy: Principles and practice, 7th ed, Adkinson NF, Bochner BS, Busse WW, et al (Eds), Mosby, Philadelphia 2009. p.1005.
  7. Reisman RE. Natural history of insect sting allergy: relationship of severity of symptoms of initial sting anaphylaxis to re-sting reactions. J Allergy Clin Immunol 1992; 90:335.
  8. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000; 105:385.
  9. Lantner R, Reisman RE. Clinical and immunologic features and subsequent course of patients with severe insect-sting anaphylaxis. J Allergy Clin Immunol 1989; 84:900.
  10. van der Linden PW, Hack CE, Struyvenberg A, van der Zwan JK. Insect-sting challenge in 324 subjects with a previous anaphylactic reaction: current criteria for insect-venom hypersensitivity do not predict the occurrence and the severity of anaphylaxis. J Allergy Clin Immunol 1994; 94:151.
  11. Golden DB, Breisch NL, Hamilton RG, et al. Clinical and entomological factors influence the outcome of sting challenge studies. J Allergy Clin Immunol 2006; 117:670.
  12. Lange J, Cichocka-Jarosz E, Marczak H, et al. Natural history of Hymenoptera venom allergy in children not treated with immunotherapy. Ann Allergy Asthma Immunol 2016; 116:225.
  13. Golden DB, Kagey-Sobotka A, Norman PS, et al. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med 2004; 351:668.
  14. Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med 1990; 323:1601.
  15. Schuberth KC, Kwiterovich KA, Kagey-Sobotka A. Starting and stopping venom immunotherapy in children with insect allergy. J Allergy Clin Immunol 1988; 81:200 (Abstract).
  16. Graft DF, Schuberth KC, Kagey-Sobotka A, et al. A prospective study of the natural history of large local reactions after Hymenoptera stings in children. J Pediatr 1984; 104:664.
  17. Mauriello PM, Barde SH, Georgitis JW, Reisman RE. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol 1984; 74:494.
  18. Pucci S, Antonicelli L, Bilò MB, et al. Shortness of interval between two stings as risk factor for developing Hymenoptera venom allergy. Allergy 1994; 49:894.
  19. Goldberg A, Confino-Cohen R. Bee venom immunotherapy - how early is it effective? Allergy 2010; 65:391.
  20. Oude Elberink JN, de Monchy JG, Golden DB, et al. Development and validation of a health-related quality-of-life questionnaire in patients with yellow jacket allergy. J Allergy Clin Immunol 2002; 109:162.
  21. Confino-Cohen R, Melamed S, Goldberg A. Debilitating beliefs and emotional distress in patients given immunotherapy for insect sting allergy: a prospective study. Allergy Asthma Proc 2009; 30:546.
  22. Oude Elberink JN, De Monchy JG, Van Der Heide S, et al. Venom immunotherapy improves health-related quality of life in patients allergic to yellow jacket venom. J Allergy Clin Immunol 2002; 110:174.
  23. Reisman RE, Dvorin DJ, Randolph CC, Georgitis JW. Stinging insect allergy: natural history and modification with venom immunotherapy. J Allergy Clin Immunol 1985; 75:735.
  24. Graft DF, Schuberth KC, Kagey-Sobotka A, et al. Assessment of prolonged venom immunotherapy in children. J Allergy Clin Immunol 1987; 80:162.
  25. Golden DB, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980; 92:620.
  26. Carballada F, Boquete M, Núñez R, et al. Follow-up of venom immunotherapy (VIT) based on conventional techniques and monitoring of immunoglobulin E to individual venom allergens. J Investig Allergol Clin Immunol 2010; 20:506.
  27. Müller U, Thurnheer U, Patrizzi R, et al. Immunotherapy in bee sting hypersensitivity. Bee venom versus wholebody extract. Allergy 1979; 34:369.
  28. Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev 2012; 10:CD008838.
  29. Brown SG, Wiese MD, Blackman KE, Heddle RJ. Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial. Lancet 2003; 361:1001.
  30. Müller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol 1992; 89:529.
  31. Müller U, Berchtold E, Helbling A. Honeybee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991; 87:702.
  32. Bonifazi F, Jutel M, Biló BM, et al. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy 2005; 60:1459.
  33. Ruëff F, Bilò MB, Jutel M, et al. Sublingual immunotherapy with venom is not recommended for patients with Hymenoptera venom allergy. J Allergy Clin Immunol 2009; 123:272.
  34. Patriarca G, Nucera E, Roncallo C, et al. Sublingual desensitization in patients with wasp venom allergy: preliminary results. Int J Immunopathol Pharmacol 2008; 21:669.
  35. Golden DB, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA 1989; 262:240.
  36. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007; 120:S25.
  37. Valentine MD. Insect-sting anaphylaxis. Ann Intern Med 1993; 118:225.
  38. Müller UR. Bee venom allergy in beekeepers and their family members. Curr Opin Allergy Clin Immunol 2005; 5:343.
  39. Graft DF. Insect sting allergy. Med Clin North Am 2006; 90:211.
  40. Schwartz HJ, Golden DB, Lockey RF. Venom immunotherapy in the Hymenoptera-allergic pregnant patient. J Allergy Clin Immunol 1990; 85:709.
  41. Pitsios C, Demoly P, Bilò MB, et al. Clinical contraindications to allergen immunotherapy: an EAACI position paper. Allergy 2015; 70:897.
  42. Tunon-de-Lara JM, Villanueva P, Marcos M, Taytard A. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. Lancet 1992; 340:908.
  43. Ober AI, MacLean JA, Hannaway PJ. Life-threatening anaphylaxis to venom immunotherapy in a patient taking an angiotensin-converting enzyme inhibitor. J Allergy Clin Immunol 2003; 112:1008.
  44. Ruëff F, Przybilla B, Biló MB, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009; 124:1047.
  45. Stoevesandt J, Hosp C, Kerstan A, Trautmann A. Hymenoptera venom immunotherapy while maintaining cardiovascular medication: safe and effective. Ann Allergy Asthma Immunol 2015; 114:411.
  46. Rank MA, Oslie CL, Krogman JL, et al. Allergen immunotherapy safety: characterizing systemic reactions and identifying risk factors. Allergy Asthma Proc 2008; 29:400.
  47. White KM, England RW. Safety of angiotensin-converting enzyme inhibitors while receiving venom immunotherapy. Ann Allergy Asthma Immunol 2008; 101:426.
  48. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1.
  49. Caviglia AG, Passalacqua G, Senna G. Risk of severe anaphylaxis for patients with Hymenoptera venom allergy: Are angiotensin-receptor blockers comparable to angiotensin-converting enzyme inhibitors? J Allergy Clin Immunol 2010; 125:1171; author reply 1171.
  50. Müller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hymenoptera venom allergy. J Allergy Clin Immunol 2005; 115:606.
  51. Golden DB, Moffitt J, Nicklas RA, et al. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011; 127:852.
  52. Niedoszytko M, de Monchy J, van Doormaal JJ, et al. Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy. Allergy 2009; 64:1237.
  53. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract 2013; 1:474.
  54. González de Olano D, Alvarez-Twose I, Esteban-López MI, et al. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 2008; 121:519.
  55. Ruëff F, Przybilla B, Biló MB, et al. Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol 2010; 126:105.
  56. Bonadonna P, Zanotti R, Pagani M, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy 2009; 64:1379.
  57. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008; 63:226.
  58. Guenova E, Volz T, Eichner M, et al. Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly. Allergy 2010; 65:919.
  59. Golden DB, Kelly D, Hamilton RG, Craig TJ. Venom immunotherapy reduces large local reactions to insect stings. J Allergy Clin Immunol 2009; 123:1371.
  60. Mosbech H, Frew AJ. The immunologic response to Hymenoptera venoms. In: Monograph on insect allergy, 4th ed, Levine MI, Lockey RF (Eds), American Academy of Allergy Asthma and Immunology, Milwaukee 2003. p.75.
  61. Dreschler K, Bratke K, Petermann S, et al. Impact of immunotherapy on blood dendritic cells in patients with Hymenoptera venom allergy. J Allergy Clin Immunol 2011; 127:487.
  62. Kerstan A, Albert C, Klein D, et al. Wasp venom immunotherapy induces activation and homing of CD4(+)CD25(+) forkhead box protein 3-positive regulatory T cells controlling T(H)1 responses. J Allergy Clin Immunol 2011; 127:495.
  63. Varga EM, Francis JN, Zach MS, et al. Time course of serum inhibitory activity for facilitated allergen-IgE binding during bee venom immunotherapy in children. Clin Exp Allergy 2009; 39:1353.
  64. Jutel M, Akdis M, Blaser K, Akdis CA. Are regulatory T cells the target of venom immunotherapy? Curr Opin Allergy Clin Immunol 2005; 5:365.
  65. Lessof MH, Sobotka AK, Lichtenstein LM. Effects of passive antibody in bee venom anaphylaxis. Johns Hopkins Med J 1978; 142:1.
  66. Golden DB, Lawrence ID, Hamilton RH, et al. Clinical correlation of the venom-specific IgG antibody level during maintenance venom immunotherapy. J Allergy Clin Immunol 1992; 90:386.
  67. McHugh SM, Deighton J, Stewart AG, et al. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy. Clin Exp Allergy 1995; 25:828.
  68. Jutel M, Pichler WJ, Skrbic D, et al. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol 1995; 154:4187.
  69. Pereira-Santos MC, Baptista AP, Melo A, et al. Expansion of circulating Foxp3+)D25bright CD4+ T cells during specific venom immunotherapy. Clin Exp Allergy 2008; 38:291.
  70. Nasser SM, Ying S, Meng Q, et al. Interleukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy. Eur J Immunol 2001; 31:3704.