- Email: [email protected]
When Can Immunotherapy for Insect Sting Allergy Be Stopped?
Clinical Commentary Review
When Can Immunotherapy for Insect Sting Allergy Be Stopped? Ulrich R. Müller, MDa, and Johannes Ring, MD, PhDb
Bern, Switzerland; and Munich, Germany
INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaciinpractice.org/. Fax or other copies will not be accepted.
claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Ulrich R. Müller, MD, and Johannes Ring, MD, PhD Activity Objectives 1. To understand the risk factors associated with systemic allergic reactions (SAR) to Hymenoptera stings after stopping efficient venom immunotherapy (VIT).
Date of Original Release: May 1, 2015. Credit may be obtained for these courses until June 30, 2016.
2. To understand the recommended duration of VIT.
Copyright Statement: Copyright Ó 2015-2017. All rights reserved.
3. To understand the measures that are helpful to know when stopping VIT in the presence of risk factors for SAR.
Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only
BACKGROUND: Stings by Hymenoptera (honey bees, vespids, ants) can cause systemic allergic reactions (SARs). Venom immunotherapy (VIT) is highly effective and reduces an allergic patient’s risk of a recurrent SAR to less than 5-20%. The risk of a recurrent SAR to a re-sting decreases the longer VIT is continued. The recommended duration of VIT is at least 3 to 5 years. a
Allergy Division, Department of Medicine, Ziegler Hospital, Bern, Switzerland Department of Dermatology and Allergy, Technical University, Munich, Germany, and Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland No funding was received for this work. Conflicts of interest: U. R. Müller receives royalties from UpToDate; has received travel support and honoraria for lectures 2012 - 2014 for the World Immune Regulation Meeting Davos, for Congresses of the European Academy of Allergology and Immunology (EAACI), and for Arbeitsgespräche Insektengiftallergie in München and Fulda. J. Ring has received honoraria for lectures or advisory board from Novartis, Meda, ALK-Abello. Received for publication October 30, 2014; accepted for publication November 14, 2014. Corresponding author: Ulrich R. Müller, MD, Medical Division, Spital Ziegler Spitalnetz Bern, Morillonstr 97, Bern CH-3007, Switzerland. E-mail: ulrich. [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.11.018
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Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: U. R. Müller receives royalties from UpToDate; has received travel support and honoraria for lectures 2012 2014 for the World Immune Regulation Meeting Davos, for Congresses of the European Academy of Allergology and Immunology (EAACI), and for Arbeitsgespräche Insektengiftallergie in München and Fulda. J. Ring has received honoraria for lectures or advisory board from Novartis, Meda, ALK-Abello.
RISK FACTORS: Risk factors for recurrent SARs to a sting after stopping VIT have been identified and discussed:
older age concomitant cardiac and pulmonary disease mast cell disorders, elevated baseline serum tryptase severe reactions before VIT SARs during VIT to treatment injections or stings repeated stings after VIT.
Recommendations concerning stopping VIT: For patients without any of the identified risk factors, VIT should be continued for 5 rather than 3 years. In patients with definite risk factors, a longer duration of VIT has to be discussed before stopping it. In mast cell disorders, VIT for life is recommended. Because of the residual risk of SARs after VIT, all patients are advised to carry an epinephrine autoinjector indefinitely and to continue to take measures to avoid Hymenoptera stings. Ó 2015 American Academy of Allergy, Asthma & Immunology ( J Allergy Clin Immunol Pract 2015;3:324-8) Key words: Hymenoptera venom allergy; Honey bees; Vespids; Venom immunotherapy; Efficacy of VIT; Duration of VIT; Risk factors for recurrence after VIT
J ALLERGY CLIN IMMUNOL PRACT VOLUME 3, NUMBER 3
Stings by insects of the order Hymenoptera, especially from vespids and honey bees, sometimes also from ants (Myrmecia pilosula, Solenopsis invicta), can cause systemic allergic reactions (SARs) due to specific IgE antibodies to the venom injected by these insects. Some of these reactions can be very severe and sometimes even fatal.1 Venom immunotherapy (VIT) is highly effective for the treatment of patients with SARs to Hymenoptera stings. According to controlled studies, more than 95% of patients allergic to the vespid venom of yellow jacket (Vespula spp.), and 80% to 90% of those allergic to honey bee venom (Apis mellifera), will not develop systemic allergic symptoms if re-stung during VIT with monthly subcutaneous injections of 100 mg of the responsible venom.2-10 After the introduction of VIT in the late 1970s, it was initially believed that this therapy had to be continued for life. However, later reports were published that described protection from restings in patients who had stopped VIT for various reasons. Moreover, sensitivity to the venom according to skin tests and specific serum IgE to venoms decrease during VIT, and some patients even lose venom sensitivity according to these tests. Since the 1980s a number of studies have been initiated to determine whether and when VIT could be safely stopped. We will discuss these studies and analyze the risk factors for a recurrent SAR to Hymenoptera stings after the discontinuation of VIT.
DURATION OF VIT Today it is suggested that VIT should be given for a minimum of 3 to 5 years.7-11 This recommendation is based on the following studies: One year of treatment: An early retrospective study evaluated a recurrent SAR to stings in 82 patients who chose to stop VIT after varying amounts of time, with a mean duration of treatment of 14 months.12 Over the ensuing 3 to 4 years, 22% of those who were re-stung had SARs compared with 1% to 3% of patients who remained on VIT. Thus, 1 year of VIT did not provide sufficient protection for nearly one-quarter of patients. At least 3 years of treatment: Several prospective studies evaluated the protection afforded by VIT if it was given for at least 3 years and then stopped.12-19 Most of the patients in these early studies were selected because they showed evidence of a reduction in sensitivity to venom in response to VIT, either through skin tests or serum tests. After 3 years of VIT, 83% to 100% of patients remained protected against recurrent SARs in the first 1 to 3 years after stopping. Most or all of the patients who did develop SARs with stings after stopping VIT had only mild symptoms (Table I). At least 5 years of treatment: Studies of 5 years of treatment show slightly higher rates of protection, even in unselected groups of patients. In one study of Lerch,13 the percentage of patients who developed SARs after stopping VIT was significantly lower (5%) among patients who had received VIT for 50 months compared with 18% among those who received treatment for 33 to 49 months (P < .01). In a study of Golden of 29 adults with vespid venom allergy, there were no recurrent SARs on challenge 1 year after stopping treatment.20 A later study of Golden21 evaluated 74 patients treated with VIT for at least 5 years, who volunteered to stop treatment and undergo periodic testing and sting challenges every 1 to 2
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years. Over the ensuing 2 to 5 years, systemic symptoms occurred in 7/74 patients (9.5%), or in 8/270 challenges (3%), and just 2 reactions required epinephrine injection (Table I).
RISK FACTORS FOR RECURRENT SARS AFTER VIT A number of patient-specific risk factors for the recurrence of an SAR to Hymenoptera stings after VIT were identified by analyzing the studies reviewed above. Other characteristics, such as sex or the presence of atopic disorders, do not influence the risk of a relapse.14,16 Older age Children have a lower risk for recurrent SARs than adults after discontinuing VIT.14-16 In a representative study, SARs were reported in 8.3% of children compared with 13.1% of adults who were stung within 7 years after stopping VIT.13 Other studies reported that only 5% of treated children experienced recurrent SARs when evaluated more than 10 years after VIT compared with a rate of 16% in treated adults.22,23 Severe pretreatment reaction Patients with severe initial sting reactions are at a higher risk for a recurrent SAR both during and after completion of VIT.24 Combining the data from 4 prospective studies that involved 386 patients13,21,25,26 severe relapses were observed in 4/124 (4%) of those with mild initial reactions compared with 38/263 (14.5%) of those with severe pretreatment reactions (P < .001). Bee venom allergy Patients with bee venom allergy are at a higher risk for recurrent SARs than those allergic to vespid venoms, before, during, and after VIT. Before treatment, 51% of bee-allergic patients develop recurrent SARs on sting challenge compared with 25% of those allergic to vespid venoms.27,28 During and after VIT, patients allergic to bee venom remain at higher risk.13,14 In one study on VIT of 3-year duration, the relapse rate in patients allergic to bee venom was 16% compared with 8% of patients allergic to vespid venoms.13 The reasons for this difference are not entirely clear.5,6 The venom content of a honey bee sting (approximately 50 mg) is much higher than that of a vespid sting (3-5 mg). It is also possible that vespid stings are more variable in venom content than bee stings, because vespids retain their stingers after stinging, and thus insects can sting more than once, whereas honey bees lose their stinging apparatus. The higher recurrence of an SAR and side effects during bee VIT may also be explained by the fact that the percentage of venom during a bee sting as compared with the usual maintenance dose of 100 mg is approximately 50%, and for a vespid sting only approximately 5%.5 Systemic reactions to injections or stings during VIT Patients who develop general allergic reactions to VIT injections or to repeat stings during VIT are at higher risk for reactions after VIT.16,20 In one study, those who had systemic reactions to injections during VIT had a 38% chance of relapse compared with a 7% chance among those who tolerated injections.16 Patients who have recurrent SARs during maintenance VIT should be evaluated for mast cell disorders with a baseline serum tryptase level. In addition, a higher maintenance dose of venom is recommended to achieve protection in such individuals.29,30 These issues are discussed separately.
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TABLE I. Results of sting challenge in patients with Hymenoptera venom allergy after stopping venom immunotherapy of at least 3-year duration Author
Number of patients 14
Urbanek
children
Müller16 Keating18 Haugaard17 van Halteren19 Golden20
29 14 86 51 25 75 29 74
Insect
Challenge in years after stopping VIT
Number with SARs (%) at challenge
1 2 1 1 2 1 to 3 1 2 to 5
1 (3) 2 (14) 15 (17) 2 (4) 0 6 (8) 0 7 (9.5)
Honey bee Honey bee Mostly Vespid Vespid Vespid Mostly Vespid
SARs, systemic allergic reactions; VIT, venom immunotherapy.
Extreme sensitivity on diagnostic testing Some studies have reported an association between recurrent SARs after stopping VIT and persistent high sensitivity on diagnostic tests for venom sensitization.23 However, others have not been able to confirm this finding.13,16 Concomitant cardiovascular and chronic pulmonary disease Adults with cardiovascular disease are at an increased risk for a severe SAR to Hymenoptera stings and poor outcomes resulting from stings, including myocardial and cerebrovascular infarction, or even death.31 This is probably also true for patients with chronic pulmonary diseases, such as chronic obstructive pulmonary disease or asthma, although this is less well documented. The medications for cardiovascular disease with b-blockers or angiotensin converting enzyme inhibitors are risk factors for more severe anaphylaxis to Hymenoptera venoms, due to a lower cardiac blood flow in an SAR, especially in coronary heart disease. After sting challenges during VIT, patients on ACEinhibitor treatment developed significantly more SARs than those without this medication (P < .002), whereas there was no significant difference for patients with or without b-blockers.32 ACE inhibitors should therefore be replaced during and after VIT in patients with chronic cardiovascular disease. b-Blockers, however, increase the survival in patients with cardiovascular disease, especially coronary heart disease very significantly, and are difficult to be replaced in this situation.31 Thus, b-blockers may have to be continued during and after VIT in patients with severe cardiovascular disease, because the risk of rare occasional Hymenoptera resting on b-blocker treatment is much lower than that of the continuous heart disease without b-blockers. Mast cell disorders Patients with mast cell disorders can experience severe anaphylaxis with Hymenoptera stings. Most of these patients have skin test or serologic evidence of venom allergy, whereas some do not.30-34 Conversely, a significant percentage of patients with severe shock reactions after Hymenoptera stings have evidence of a mast cell disorder. Up to one-third of patients with severe anaphylactic reactions from stings demonstrate an elevated baseline serum tryptase level (ie, >11.4 ng/mL), whereas an elevated serum tryptase level is observed in less than 5% of an unselected adult population.35-39 Patients with mast cell disorders or elevated baseline serum tryptase and venom allergy can successfully be treated with VIT, but they are at an increased risk for recurrent SARs if treatment is discontinued.38,39 In the presence of severe side effects during VIT in patients with mastocytosis and venom
allergy, pretreatment with omalizumab may be helpful.40 A fatal Hymenoptera sting has been reported in a patient with systemic mastocytosis with no previous allergic sting reaction.41 Two female patients with urticaria pigmentosa and vespid allergy died from stings sustained 3 and 9 years after stopping VIT.42 One male bee venom allergic patient died over 10 years after stopping successful bee VIT from a yellow jacket sting.43 Based on such reports, it has been recommended that patients with mastocytosis and Hymenoptera venom allergy receive life-long VIT.44 These patients must also understand that they remain at an elevated risk of an SAR despite treatment by VIT and must carry at least one epinephrine autoinjector at all times.30
Time interval after stopping VIT There appears to be some loss of effect over time after patients stop VIT, although most remain sufficiently protected. Those who experience SARs generally (but not always) have mild symptoms. Protection up to 7 years after discontinuing VIT was analyzed in 4 studies.13,23,25,26 These studies reported complete protection in 80% to 91% of patients, a slightly lower percentage than in studies of the first 3 years after stopping VIT (Table I). In one of these studies,23 limited data of outcomes after 7 to up to 13 years after stopping VIT were reported. Repeated stings after stopping VIT Patients who are stung repeatedly after stopping VIT have a greater risk of eventually having a recurrent SAR compared with those who are stung infrequently.21,23 The severity of SARs tends to increase in response to repeated stings in patients who have discontinued VIT. In one study of 200 patients treated with at least 3 years of VIT, 25 patients were re-stung and 84% of them experienced no reaction or only a mild SAR to the initial posttreatment sting. Additional re-stings after stopping VIT occurred in 17, and these were moderate to severe in 53%.13 Another study reported similar findings.45 Therefore, patients should continue their efforts to avoid being stung after stopping VIT. DECISION TO STOP VIT The decision to continue or stop VIT is usually raised after the patient has received at least 3 and preferably 5 years of maintenance injections. The allergy specialist should consider the patient’s sensitivity according to repeat diagnostic testing, together with individual risk factors, as discussed above, including relevant comorbid conditions and vocational and occupational activities. The patient’s comfort with risk and other preferences must also be taken into consideration. No 2 situations are identical.
J ALLERGY CLIN IMMUNOL PRACT VOLUME 3, NUMBER 3
Candidates for life-long therapy The risk of recurrent SARs among patients who continue VIT indefinitely is believed to remain low. Life-long VIT should be considered for patients with any of the risk factors for recurrent SARs discussed above. These are as follows: Very severe initial and resuscitating SARs as well as a high likelihood of recurrent stings in the future due to occupational or recreational activities. Honey bee allergy and a high likelihood of recurrent stings in the future (eg, bee keepers and their family members, gardeners). Significant severe cardiovascular and pulmonary disease. Recurrent SARs to VIT injections, or recurrent SARs to re-stings during maintenance VIT. Requirement for higher venom doses to achieve adequate protection. Mast cell disorders or an elevated baseline level of serum tryptase.
The role of testing Diagnostic tests are generally repeated when considering discontinuation of VIT, even though none of these tests predicts an individual patient’s risk of recurrent SARs with certainty. However, the information they provide allows the allergy specialist to assess whether the patient has responded as anticipated to treatment: Venom-specific serum IgE values usually rise during the first months of VIT and then fall during the following 3 to 5 years of VIT, to levels below the pretreatment value. However, these changes are not reliably predictive of protection for recurrent SARs. Venom-specific IgG levels usually rise and remain elevated, but do not correlate closely with protection, especially after several years of treatment. After stopping VIT they decrease, but their level is not predictive of protection. A reduction in reactivity on skin testing is seen in most patients, but is not predictive by itself. Persistent high sensitivity on diagnostic tests (either skin or in vitro tests) may be a risk factor for recurrent SARs after stopping VIT. Therefore, continuation of VIT until diagnostic tests show a clear decrease in sensitivity has been recommended in this situation.23 The combination of a negative intradermal skin test at a venom concentration of 1 mcg/mL and the absence of venom specific serum IgE antibodies (ie, <0.35 IU/mL in most laboratories) is associated with a strongly diminished risk of relapse.13,16,46 However, only approximately 25% of patients become skin test negative after 5 to 6 years of VIT20,21 and an even smaller group achieves both negative skin tests and in vitro tests. Thus, if a patient has significant risk factors for recurrent SARs and indications for indefinite VIT, then repeat of testing is not necessary, because the results will not change the decision to continue VIT. Therefore, it is recommended to repeat skin testing and measurement of venom-specific IgE only in those patients in whom VIT is considered to be stopped after 3 to 5 years. The decision to stop VIT is sometimes straightforward. For example, most allergists would readily discontinue treatment in a patient with a history of moderate SARs to stings, in whom both skin tests and venom-specific IgE have become negative after 3 years of VIT. However, if the same patient has a persistently high
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level of serum-specific IgE after 5 years of VIT and was a farmer or gardener, the decision becomes far more difficult.
COUNSELING THE PATIENT WHEN VIT IS STOPPED The allergy specialist should ensure that patients who discontinue VIT understand the following points about their risk for a recurrent SAR: The risk of a recurrent serious reaction is not zero, and may be as high as 10% per sting. Because of the residual risk, the patient should continue to carry an epinephrine autoinjector and take measures to avoid Hymenoptera stings. It is possible to react to one sting and not another, so an uneventful sting does not mean that the patient is definitely “cured” for life of his allergy. Any serious SARs after stopping VIT should be reported to the allergy specialist so that the patient’s situation can be reevaluated. REFERENCES 1. Sasvary T, Müller U. Deaths from insect stings in Switzerland 1978-87. Schweiz Med Wschr 1994;124:1887-94. 2. Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodia FS, Lichtenstein LM. A controlled trial of immunotherapy in insect venom hypersensitivity. N Engl J Med 1978;299:157-61. 3. Müller U, Thurnheer U, Patrizzi R, Spiess J, Hoigné R. Immunotherapy in bee sting hypersensitivity. Allergy 1979;34:369-78. 4. Brown SG, Wiese MD, Blackman KE, Heddle RJ. Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial. Lancet 2003; 361:1001-6. 5. 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;89:529-35. 6. Ruëff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996;51:216-25. 7. Bonifazi F, Jutel M, Biló BM, Birnbaum J, Müller U, Bucher C, et al. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy 2005;60:1459-70. 8. Golden DB, Moffitt J, Nicklas RA, Freeman T, Graft DF, Reisman RE. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. 9. Boyle RJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, Oude Elberink J. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev 2012;10:CD008838. 10. Pesek RD, Lockey RF. Treatment of Hymenoptera venom allergy: an update. Curr Opin Allergy Clin Immunol 2014;14:340-6. 11. Golden DB. Long-term outcome after venom immunotherapy. Curr Opin Allergy Clin Immunol 2010;10:337-41. 12. Golden DB, Johnson K, Addison BI, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Clinical and immunologic observations in patients who stop venom immunotherapy. J Allergy Clin Immunol 1986;77:435-42. 13. Lerch E, Müller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol 1998;101: 606-12. 14. Urbanek R, Forster J, Kuhn W, Ziupa J. Discontinuation of bee venom immunotherapy in children and adolescents. J Pediatr 1985;107:367-71. 15. Von Moos S, Graf N, Johansen P, Müllner G, et al. Risk assessment of Hymenoptera re-sting: implications for decision-making in venom immunotherapy. Int Arch Allergy Immunol 2013;160:86-92. 16. Müller U, Berchtold E, Helbling A. Honey bee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991;87:702-9. 17. Haugaard L, Nørregaard OF, Dahl R. In-hospital sting challenge in insect venom-allergic patients after stopping venom immunotherapy. J Allergy Clin Immunol 1991;87:699-702.
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18. Keating MU, Kagey-Sobotka A, Hamilton RG, Yunginger JW. Clinical and immunologic follow-up of patients who stop venom immunotherapy. J Allergy Clin Immunol 1991;88:339-48. 19. van Halteren HK, van der Linden PW, Burgers JA, Bartelink AK. Discontinuation of yellow jacket venom immunotherapy: follow-up of 75 patients by means of deliberate sting challenge. J Allergy Clin Immunol 1997;100:767-70. 20. Golden DB, Addison BJ, Gadde J, Kagey Sobotka A, Lichtenstein LM. Prospective observations on stopping prolonged venom immunotherapy. J Allergy Clin Immunol 1989;84:162-7. 21. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Discontinuing venom immunotherapy: outcome after five years. J Allergy Clin Immunol 1996;97:579-87. 22. 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;351:668-74. 23. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105:385-90. 24. Müller U. Insect Sting Allergy: Clinical Picture, Diagnosis and Treatment. Stuttgart, New York: Gustav/Fischer; 1990. 25. Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92: 831-6. 26. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol 1998;101:298-305. 27. Blaauw PJ, Smithuis LO. The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venom by means of an in-hospital insect sting. J Allergy Clin Immunol 1985;75:556-62. 28. 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;94:151-9. 29. Ruëff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108: 1027-32. 30. Ruëff F, Placzek M, Przybilla B. Mastocytosis and Hymenoptera venom allergy. Curr Opin Allergy Clin Immunol 2006;6:284-8. 31. Mueller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol 2007;7:337-41. 32. Ruëff F, Vos B, Oude Elberink J, Bender A, Chatelain R, Dugas-Breit S, et al. Predictors of clinical effectiveness of Hymenoptera venom immunotherapy. Clin Exp Allergy 2014;44:736-46.
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33. Müller UR, Horat W, Wüthrich B, Conroy M, Reisman RE. Anaphylaxis after Hymenoptera stings in three patients with urticaria pigmentosa. J Allergy Clin Immunol 1983;72:685-9. 34. Fricker M, Helbling A, Schwartz L, Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients. J Allergy Clin Immunol 1997;100:11-5. 35. Ludolph-Hauser D, Ruëff F, Fries C, Schöpf B, Przybilla B. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357:361-2. 36. Haeberli G, Brönnimann M, Hunziker T, Müller U. Elevated basal serum tryptase and Hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy. Clin Exp Allergy 2003;33: 1216-20. 37. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W. 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;124:1047-54. 38. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De Ferrari L, Lombardo C, et al. Venom immunotherapy in patients with clonal mast cell disorders: Efficacy, safety and practical considerations. J Allergy Clin Immunol Pract 2013;1:474-8. 39. Niedoszytko M, Bonadonna P, Oude Elberink J, Golden D. Epidemiology, diagnosis and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am 2014;34:365-81. 40. Sokol KC, Ghazi A, Kelly BC, Grant A. Omalzumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. J Allergy Clin Immunol Pract 2014;2:266-70. 41. Wagner N, Fritze D, Przybilla B, Hagedorn M, Ruëff F. Fatal anaphylactic sting reaction in a patient with mastocytosis. Int Arch Allergy Immunol 2008;146:162-3. 42. Oude Elberink JN, de Monchy JG, Kors JW, van Doormal JJ, Dubois AE. Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis. J Allergy Clin Immunol 1997;99:153-4. 43. Reimers A, Müller U. Fatal outcome of a Vespula sting in a patient with mastocytosis after specific immunotherapy with honey bee venom. J WAO Org 2005;17:69-70. 44. Bonadonna P, Zanotti R, Müller U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol 2010;10:347-53. 45. Hafner T, DuBuske L, Kosnik M. Long-term efficacy of venom immunotherapy. Ann Allergy Asthma Immunol 2008;100:162-5. 46. Liebermann P, Golden D. When to discontinue venom immunotherapy: the role of retesting to venom. J Allergy Clin Immunol Pract 2013;1:202-3.
When Can Immunotherapy for Insect Sting Allergy Be Stopped? Ulrich R. Müller, MDa, and Johannes Ring, MD, PhDb
Bern, Switzerland; and Munich, Germany
INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaciinpractice.org/. Fax or other copies will not be accepted.
claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Ulrich R. Müller, MD, and Johannes Ring, MD, PhD Activity Objectives 1. To understand the risk factors associated with systemic allergic reactions (SAR) to Hymenoptera stings after stopping efficient venom immunotherapy (VIT).
Date of Original Release: May 1, 2015. Credit may be obtained for these courses until June 30, 2016.
2. To understand the recommended duration of VIT.
Copyright Statement: Copyright Ó 2015-2017. All rights reserved.
3. To understand the measures that are helpful to know when stopping VIT in the presence of risk factors for SAR.
Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only
BACKGROUND: Stings by Hymenoptera (honey bees, vespids, ants) can cause systemic allergic reactions (SARs). Venom immunotherapy (VIT) is highly effective and reduces an allergic patient’s risk of a recurrent SAR to less than 5-20%. The risk of a recurrent SAR to a re-sting decreases the longer VIT is continued. The recommended duration of VIT is at least 3 to 5 years. a
Allergy Division, Department of Medicine, Ziegler Hospital, Bern, Switzerland Department of Dermatology and Allergy, Technical University, Munich, Germany, and Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland No funding was received for this work. Conflicts of interest: U. R. Müller receives royalties from UpToDate; has received travel support and honoraria for lectures 2012 - 2014 for the World Immune Regulation Meeting Davos, for Congresses of the European Academy of Allergology and Immunology (EAACI), and for Arbeitsgespräche Insektengiftallergie in München and Fulda. J. Ring has received honoraria for lectures or advisory board from Novartis, Meda, ALK-Abello. Received for publication October 30, 2014; accepted for publication November 14, 2014. Corresponding author: Ulrich R. Müller, MD, Medical Division, Spital Ziegler Spitalnetz Bern, Morillonstr 97, Bern CH-3007, Switzerland. E-mail: ulrich. [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.11.018
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Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: U. R. Müller receives royalties from UpToDate; has received travel support and honoraria for lectures 2012 2014 for the World Immune Regulation Meeting Davos, for Congresses of the European Academy of Allergology and Immunology (EAACI), and for Arbeitsgespräche Insektengiftallergie in München and Fulda. J. Ring has received honoraria for lectures or advisory board from Novartis, Meda, ALK-Abello.
RISK FACTORS: Risk factors for recurrent SARs to a sting after stopping VIT have been identified and discussed:
older age concomitant cardiac and pulmonary disease mast cell disorders, elevated baseline serum tryptase severe reactions before VIT SARs during VIT to treatment injections or stings repeated stings after VIT.
Recommendations concerning stopping VIT: For patients without any of the identified risk factors, VIT should be continued for 5 rather than 3 years. In patients with definite risk factors, a longer duration of VIT has to be discussed before stopping it. In mast cell disorders, VIT for life is recommended. Because of the residual risk of SARs after VIT, all patients are advised to carry an epinephrine autoinjector indefinitely and to continue to take measures to avoid Hymenoptera stings. Ó 2015 American Academy of Allergy, Asthma & Immunology ( J Allergy Clin Immunol Pract 2015;3:324-8) Key words: Hymenoptera venom allergy; Honey bees; Vespids; Venom immunotherapy; Efficacy of VIT; Duration of VIT; Risk factors for recurrence after VIT
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Stings by insects of the order Hymenoptera, especially from vespids and honey bees, sometimes also from ants (Myrmecia pilosula, Solenopsis invicta), can cause systemic allergic reactions (SARs) due to specific IgE antibodies to the venom injected by these insects. Some of these reactions can be very severe and sometimes even fatal.1 Venom immunotherapy (VIT) is highly effective for the treatment of patients with SARs to Hymenoptera stings. According to controlled studies, more than 95% of patients allergic to the vespid venom of yellow jacket (Vespula spp.), and 80% to 90% of those allergic to honey bee venom (Apis mellifera), will not develop systemic allergic symptoms if re-stung during VIT with monthly subcutaneous injections of 100 mg of the responsible venom.2-10 After the introduction of VIT in the late 1970s, it was initially believed that this therapy had to be continued for life. However, later reports were published that described protection from restings in patients who had stopped VIT for various reasons. Moreover, sensitivity to the venom according to skin tests and specific serum IgE to venoms decrease during VIT, and some patients even lose venom sensitivity according to these tests. Since the 1980s a number of studies have been initiated to determine whether and when VIT could be safely stopped. We will discuss these studies and analyze the risk factors for a recurrent SAR to Hymenoptera stings after the discontinuation of VIT.
DURATION OF VIT Today it is suggested that VIT should be given for a minimum of 3 to 5 years.7-11 This recommendation is based on the following studies: One year of treatment: An early retrospective study evaluated a recurrent SAR to stings in 82 patients who chose to stop VIT after varying amounts of time, with a mean duration of treatment of 14 months.12 Over the ensuing 3 to 4 years, 22% of those who were re-stung had SARs compared with 1% to 3% of patients who remained on VIT. Thus, 1 year of VIT did not provide sufficient protection for nearly one-quarter of patients. At least 3 years of treatment: Several prospective studies evaluated the protection afforded by VIT if it was given for at least 3 years and then stopped.12-19 Most of the patients in these early studies were selected because they showed evidence of a reduction in sensitivity to venom in response to VIT, either through skin tests or serum tests. After 3 years of VIT, 83% to 100% of patients remained protected against recurrent SARs in the first 1 to 3 years after stopping. Most or all of the patients who did develop SARs with stings after stopping VIT had only mild symptoms (Table I). At least 5 years of treatment: Studies of 5 years of treatment show slightly higher rates of protection, even in unselected groups of patients. In one study of Lerch,13 the percentage of patients who developed SARs after stopping VIT was significantly lower (5%) among patients who had received VIT for 50 months compared with 18% among those who received treatment for 33 to 49 months (P < .01). In a study of Golden of 29 adults with vespid venom allergy, there were no recurrent SARs on challenge 1 year after stopping treatment.20 A later study of Golden21 evaluated 74 patients treated with VIT for at least 5 years, who volunteered to stop treatment and undergo periodic testing and sting challenges every 1 to 2
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years. Over the ensuing 2 to 5 years, systemic symptoms occurred in 7/74 patients (9.5%), or in 8/270 challenges (3%), and just 2 reactions required epinephrine injection (Table I).
RISK FACTORS FOR RECURRENT SARS AFTER VIT A number of patient-specific risk factors for the recurrence of an SAR to Hymenoptera stings after VIT were identified by analyzing the studies reviewed above. Other characteristics, such as sex or the presence of atopic disorders, do not influence the risk of a relapse.14,16 Older age Children have a lower risk for recurrent SARs than adults after discontinuing VIT.14-16 In a representative study, SARs were reported in 8.3% of children compared with 13.1% of adults who were stung within 7 years after stopping VIT.13 Other studies reported that only 5% of treated children experienced recurrent SARs when evaluated more than 10 years after VIT compared with a rate of 16% in treated adults.22,23 Severe pretreatment reaction Patients with severe initial sting reactions are at a higher risk for a recurrent SAR both during and after completion of VIT.24 Combining the data from 4 prospective studies that involved 386 patients13,21,25,26 severe relapses were observed in 4/124 (4%) of those with mild initial reactions compared with 38/263 (14.5%) of those with severe pretreatment reactions (P < .001). Bee venom allergy Patients with bee venom allergy are at a higher risk for recurrent SARs than those allergic to vespid venoms, before, during, and after VIT. Before treatment, 51% of bee-allergic patients develop recurrent SARs on sting challenge compared with 25% of those allergic to vespid venoms.27,28 During and after VIT, patients allergic to bee venom remain at higher risk.13,14 In one study on VIT of 3-year duration, the relapse rate in patients allergic to bee venom was 16% compared with 8% of patients allergic to vespid venoms.13 The reasons for this difference are not entirely clear.5,6 The venom content of a honey bee sting (approximately 50 mg) is much higher than that of a vespid sting (3-5 mg). It is also possible that vespid stings are more variable in venom content than bee stings, because vespids retain their stingers after stinging, and thus insects can sting more than once, whereas honey bees lose their stinging apparatus. The higher recurrence of an SAR and side effects during bee VIT may also be explained by the fact that the percentage of venom during a bee sting as compared with the usual maintenance dose of 100 mg is approximately 50%, and for a vespid sting only approximately 5%.5 Systemic reactions to injections or stings during VIT Patients who develop general allergic reactions to VIT injections or to repeat stings during VIT are at higher risk for reactions after VIT.16,20 In one study, those who had systemic reactions to injections during VIT had a 38% chance of relapse compared with a 7% chance among those who tolerated injections.16 Patients who have recurrent SARs during maintenance VIT should be evaluated for mast cell disorders with a baseline serum tryptase level. In addition, a higher maintenance dose of venom is recommended to achieve protection in such individuals.29,30 These issues are discussed separately.
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TABLE I. Results of sting challenge in patients with Hymenoptera venom allergy after stopping venom immunotherapy of at least 3-year duration Author
Number of patients 14
Urbanek
children
Müller16 Keating18 Haugaard17 van Halteren19 Golden20
29 14 86 51 25 75 29 74
Insect
Challenge in years after stopping VIT
Number with SARs (%) at challenge
1 2 1 1 2 1 to 3 1 2 to 5
1 (3) 2 (14) 15 (17) 2 (4) 0 6 (8) 0 7 (9.5)
Honey bee Honey bee Mostly Vespid Vespid Vespid Mostly Vespid
SARs, systemic allergic reactions; VIT, venom immunotherapy.
Extreme sensitivity on diagnostic testing Some studies have reported an association between recurrent SARs after stopping VIT and persistent high sensitivity on diagnostic tests for venom sensitization.23 However, others have not been able to confirm this finding.13,16 Concomitant cardiovascular and chronic pulmonary disease Adults with cardiovascular disease are at an increased risk for a severe SAR to Hymenoptera stings and poor outcomes resulting from stings, including myocardial and cerebrovascular infarction, or even death.31 This is probably also true for patients with chronic pulmonary diseases, such as chronic obstructive pulmonary disease or asthma, although this is less well documented. The medications for cardiovascular disease with b-blockers or angiotensin converting enzyme inhibitors are risk factors for more severe anaphylaxis to Hymenoptera venoms, due to a lower cardiac blood flow in an SAR, especially in coronary heart disease. After sting challenges during VIT, patients on ACEinhibitor treatment developed significantly more SARs than those without this medication (P < .002), whereas there was no significant difference for patients with or without b-blockers.32 ACE inhibitors should therefore be replaced during and after VIT in patients with chronic cardiovascular disease. b-Blockers, however, increase the survival in patients with cardiovascular disease, especially coronary heart disease very significantly, and are difficult to be replaced in this situation.31 Thus, b-blockers may have to be continued during and after VIT in patients with severe cardiovascular disease, because the risk of rare occasional Hymenoptera resting on b-blocker treatment is much lower than that of the continuous heart disease without b-blockers. Mast cell disorders Patients with mast cell disorders can experience severe anaphylaxis with Hymenoptera stings. Most of these patients have skin test or serologic evidence of venom allergy, whereas some do not.30-34 Conversely, a significant percentage of patients with severe shock reactions after Hymenoptera stings have evidence of a mast cell disorder. Up to one-third of patients with severe anaphylactic reactions from stings demonstrate an elevated baseline serum tryptase level (ie, >11.4 ng/mL), whereas an elevated serum tryptase level is observed in less than 5% of an unselected adult population.35-39 Patients with mast cell disorders or elevated baseline serum tryptase and venom allergy can successfully be treated with VIT, but they are at an increased risk for recurrent SARs if treatment is discontinued.38,39 In the presence of severe side effects during VIT in patients with mastocytosis and venom
allergy, pretreatment with omalizumab may be helpful.40 A fatal Hymenoptera sting has been reported in a patient with systemic mastocytosis with no previous allergic sting reaction.41 Two female patients with urticaria pigmentosa and vespid allergy died from stings sustained 3 and 9 years after stopping VIT.42 One male bee venom allergic patient died over 10 years after stopping successful bee VIT from a yellow jacket sting.43 Based on such reports, it has been recommended that patients with mastocytosis and Hymenoptera venom allergy receive life-long VIT.44 These patients must also understand that they remain at an elevated risk of an SAR despite treatment by VIT and must carry at least one epinephrine autoinjector at all times.30
Time interval after stopping VIT There appears to be some loss of effect over time after patients stop VIT, although most remain sufficiently protected. Those who experience SARs generally (but not always) have mild symptoms. Protection up to 7 years after discontinuing VIT was analyzed in 4 studies.13,23,25,26 These studies reported complete protection in 80% to 91% of patients, a slightly lower percentage than in studies of the first 3 years after stopping VIT (Table I). In one of these studies,23 limited data of outcomes after 7 to up to 13 years after stopping VIT were reported. Repeated stings after stopping VIT Patients who are stung repeatedly after stopping VIT have a greater risk of eventually having a recurrent SAR compared with those who are stung infrequently.21,23 The severity of SARs tends to increase in response to repeated stings in patients who have discontinued VIT. In one study of 200 patients treated with at least 3 years of VIT, 25 patients were re-stung and 84% of them experienced no reaction or only a mild SAR to the initial posttreatment sting. Additional re-stings after stopping VIT occurred in 17, and these were moderate to severe in 53%.13 Another study reported similar findings.45 Therefore, patients should continue their efforts to avoid being stung after stopping VIT. DECISION TO STOP VIT The decision to continue or stop VIT is usually raised after the patient has received at least 3 and preferably 5 years of maintenance injections. The allergy specialist should consider the patient’s sensitivity according to repeat diagnostic testing, together with individual risk factors, as discussed above, including relevant comorbid conditions and vocational and occupational activities. The patient’s comfort with risk and other preferences must also be taken into consideration. No 2 situations are identical.
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Candidates for life-long therapy The risk of recurrent SARs among patients who continue VIT indefinitely is believed to remain low. Life-long VIT should be considered for patients with any of the risk factors for recurrent SARs discussed above. These are as follows: Very severe initial and resuscitating SARs as well as a high likelihood of recurrent stings in the future due to occupational or recreational activities. Honey bee allergy and a high likelihood of recurrent stings in the future (eg, bee keepers and their family members, gardeners). Significant severe cardiovascular and pulmonary disease. Recurrent SARs to VIT injections, or recurrent SARs to re-stings during maintenance VIT. Requirement for higher venom doses to achieve adequate protection. Mast cell disorders or an elevated baseline level of serum tryptase.
The role of testing Diagnostic tests are generally repeated when considering discontinuation of VIT, even though none of these tests predicts an individual patient’s risk of recurrent SARs with certainty. However, the information they provide allows the allergy specialist to assess whether the patient has responded as anticipated to treatment: Venom-specific serum IgE values usually rise during the first months of VIT and then fall during the following 3 to 5 years of VIT, to levels below the pretreatment value. However, these changes are not reliably predictive of protection for recurrent SARs. Venom-specific IgG levels usually rise and remain elevated, but do not correlate closely with protection, especially after several years of treatment. After stopping VIT they decrease, but their level is not predictive of protection. A reduction in reactivity on skin testing is seen in most patients, but is not predictive by itself. Persistent high sensitivity on diagnostic tests (either skin or in vitro tests) may be a risk factor for recurrent SARs after stopping VIT. Therefore, continuation of VIT until diagnostic tests show a clear decrease in sensitivity has been recommended in this situation.23 The combination of a negative intradermal skin test at a venom concentration of 1 mcg/mL and the absence of venom specific serum IgE antibodies (ie, <0.35 IU/mL in most laboratories) is associated with a strongly diminished risk of relapse.13,16,46 However, only approximately 25% of patients become skin test negative after 5 to 6 years of VIT20,21 and an even smaller group achieves both negative skin tests and in vitro tests. Thus, if a patient has significant risk factors for recurrent SARs and indications for indefinite VIT, then repeat of testing is not necessary, because the results will not change the decision to continue VIT. Therefore, it is recommended to repeat skin testing and measurement of venom-specific IgE only in those patients in whom VIT is considered to be stopped after 3 to 5 years. The decision to stop VIT is sometimes straightforward. For example, most allergists would readily discontinue treatment in a patient with a history of moderate SARs to stings, in whom both skin tests and venom-specific IgE have become negative after 3 years of VIT. However, if the same patient has a persistently high
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level of serum-specific IgE after 5 years of VIT and was a farmer or gardener, the decision becomes far more difficult.
COUNSELING THE PATIENT WHEN VIT IS STOPPED The allergy specialist should ensure that patients who discontinue VIT understand the following points about their risk for a recurrent SAR: The risk of a recurrent serious reaction is not zero, and may be as high as 10% per sting. Because of the residual risk, the patient should continue to carry an epinephrine autoinjector and take measures to avoid Hymenoptera stings. It is possible to react to one sting and not another, so an uneventful sting does not mean that the patient is definitely “cured” for life of his allergy. Any serious SARs after stopping VIT should be reported to the allergy specialist so that the patient’s situation can be reevaluated. REFERENCES 1. Sasvary T, Müller U. Deaths from insect stings in Switzerland 1978-87. Schweiz Med Wschr 1994;124:1887-94. 2. Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodia FS, Lichtenstein LM. A controlled trial of immunotherapy in insect venom hypersensitivity. N Engl J Med 1978;299:157-61. 3. Müller U, Thurnheer U, Patrizzi R, Spiess J, Hoigné R. Immunotherapy in bee sting hypersensitivity. Allergy 1979;34:369-78. 4. Brown SG, Wiese MD, Blackman KE, Heddle RJ. Ant venom immunotherapy: a double-blind, placebo-controlled, crossover trial. Lancet 2003; 361:1001-6. 5. 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;89:529-35. 6. Ruëff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996;51:216-25. 7. Bonifazi F, Jutel M, Biló BM, Birnbaum J, Müller U, Bucher C, et al. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy 2005;60:1459-70. 8. Golden DB, Moffitt J, Nicklas RA, Freeman T, Graft DF, Reisman RE. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127:852-4. 9. Boyle RJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, Oude Elberink J. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev 2012;10:CD008838. 10. Pesek RD, Lockey RF. Treatment of Hymenoptera venom allergy: an update. Curr Opin Allergy Clin Immunol 2014;14:340-6. 11. Golden DB. Long-term outcome after venom immunotherapy. Curr Opin Allergy Clin Immunol 2010;10:337-41. 12. Golden DB, Johnson K, Addison BI, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Clinical and immunologic observations in patients who stop venom immunotherapy. J Allergy Clin Immunol 1986;77:435-42. 13. Lerch E, Müller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol 1998;101: 606-12. 14. Urbanek R, Forster J, Kuhn W, Ziupa J. Discontinuation of bee venom immunotherapy in children and adolescents. J Pediatr 1985;107:367-71. 15. Von Moos S, Graf N, Johansen P, Müllner G, et al. Risk assessment of Hymenoptera re-sting: implications for decision-making in venom immunotherapy. Int Arch Allergy Immunol 2013;160:86-92. 16. Müller U, Berchtold E, Helbling A. Honey bee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991;87:702-9. 17. Haugaard L, Nørregaard OF, Dahl R. In-hospital sting challenge in insect venom-allergic patients after stopping venom immunotherapy. J Allergy Clin Immunol 1991;87:699-702.
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18. Keating MU, Kagey-Sobotka A, Hamilton RG, Yunginger JW. Clinical and immunologic follow-up of patients who stop venom immunotherapy. J Allergy Clin Immunol 1991;88:339-48. 19. van Halteren HK, van der Linden PW, Burgers JA, Bartelink AK. Discontinuation of yellow jacket venom immunotherapy: follow-up of 75 patients by means of deliberate sting challenge. J Allergy Clin Immunol 1997;100:767-70. 20. Golden DB, Addison BJ, Gadde J, Kagey Sobotka A, Lichtenstein LM. Prospective observations on stopping prolonged venom immunotherapy. J Allergy Clin Immunol 1989;84:162-7. 21. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Valentine MD, Lichtenstein LM. Discontinuing venom immunotherapy: outcome after five years. J Allergy Clin Immunol 1996;97:579-87. 22. 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;351:668-74. 23. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105:385-90. 24. Müller U. Insect Sting Allergy: Clinical Picture, Diagnosis and Treatment. Stuttgart, New York: Gustav/Fischer; 1990. 25. Reisman RE. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92: 831-6. 26. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol 1998;101:298-305. 27. Blaauw PJ, Smithuis LO. The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venom by means of an in-hospital insect sting. J Allergy Clin Immunol 1985;75:556-62. 28. 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;94:151-9. 29. Ruëff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108: 1027-32. 30. Ruëff F, Placzek M, Przybilla B. Mastocytosis and Hymenoptera venom allergy. Curr Opin Allergy Clin Immunol 2006;6:284-8. 31. Mueller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immunol 2007;7:337-41. 32. Ruëff F, Vos B, Oude Elberink J, Bender A, Chatelain R, Dugas-Breit S, et al. Predictors of clinical effectiveness of Hymenoptera venom immunotherapy. Clin Exp Allergy 2014;44:736-46.
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33. Müller UR, Horat W, Wüthrich B, Conroy M, Reisman RE. Anaphylaxis after Hymenoptera stings in three patients with urticaria pigmentosa. J Allergy Clin Immunol 1983;72:685-9. 34. Fricker M, Helbling A, Schwartz L, Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients. J Allergy Clin Immunol 1997;100:11-5. 35. Ludolph-Hauser D, Ruëff F, Fries C, Schöpf B, Przybilla B. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357:361-2. 36. Haeberli G, Brönnimann M, Hunziker T, Müller U. Elevated basal serum tryptase and Hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy. Clin Exp Allergy 2003;33: 1216-20. 37. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W. 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;124:1047-54. 38. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De Ferrari L, Lombardo C, et al. Venom immunotherapy in patients with clonal mast cell disorders: Efficacy, safety and practical considerations. J Allergy Clin Immunol Pract 2013;1:474-8. 39. Niedoszytko M, Bonadonna P, Oude Elberink J, Golden D. Epidemiology, diagnosis and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am 2014;34:365-81. 40. Sokol KC, Ghazi A, Kelly BC, Grant A. Omalzumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. J Allergy Clin Immunol Pract 2014;2:266-70. 41. Wagner N, Fritze D, Przybilla B, Hagedorn M, Ruëff F. Fatal anaphylactic sting reaction in a patient with mastocytosis. Int Arch Allergy Immunol 2008;146:162-3. 42. Oude Elberink JN, de Monchy JG, Kors JW, van Doormal JJ, Dubois AE. Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis. J Allergy Clin Immunol 1997;99:153-4. 43. Reimers A, Müller U. Fatal outcome of a Vespula sting in a patient with mastocytosis after specific immunotherapy with honey bee venom. J WAO Org 2005;17:69-70. 44. Bonadonna P, Zanotti R, Müller U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol 2010;10:347-53. 45. Hafner T, DuBuske L, Kosnik M. Long-term efficacy of venom immunotherapy. Ann Allergy Asthma Immunol 2008;100:162-5. 46. Liebermann P, Golden D. When to discontinue venom immunotherapy: the role of retesting to venom. J Allergy Clin Immunol Pract 2013;1:202-3.