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Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Rush and ultra-rush venom immunotherapy for Hymenoptera allergy Authors Marc Serota, MD Jay M Portnoy, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jan 2014. | This topic last updated: Aug 23, 2012. INTRODUCTION Venom immunotherapy (VIT) to treat systemic allergic reactions to winged Hymenoptera (hornets, yellow jackets, honeybees, and wasps) may be administered according to several different schedules. Accelerated schedules include rush and ultra-rush. This topic review will discuss the advantages and disadvantages of rush and ultra-rush schedules for VIT, indications for accelerated VIT, and provide several specific examples of protocols that have been used successfully. Conventional schedules for VIT are discussed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".) Terminology All forms of subcutaneous immunotherapy (SCIT) are divided into two phases: build-up and maintenance. The build-up phase involves serial injections of increasing amounts of allergen. During this phase, tolerance to the allergen is gradually induced and the patients immune response to the allergen is modified from a Th2 phenotype to a Th1 phenotype [1,2]. In conventional venom immunotherapy (VIT) schedules, the build-up phase involves one or three injections per week and extends from 8 to 21 weeks. Conventional schedules for VIT are shown (table 1 and table 2). The maintenance phase of allergen immunotherapy involves ongoing injections of an immunizing dose of allergen, usually at intervals of three to six weeks. During the maintenance phase, the immune transformation becomes complete. This phase is usually extended for a period of three to five years because shorter durations of treatment are associated with higher rates of recurrent systemic allergic reactions to subsequent stings. (See "Hymenoptera venom immunotherapy: Determining duration of therapy", section on 'Duration of treatment'.) Accelerated protocols for venom immunotherapy are categorized as either rush or ultra-rush schedules, although these terms have not been strictly defined. Accelerated schedules of immunotherapy involve shortening the length of the build-up phase, while the maintenance phase remains the same. The length of the build-up phase depends upon the frequency of the injections and the incremental dose increase between consecutive injections. Thus, accelerated schedules either involve administering more injections per visit, increasing the dose more between consecutive injections, or both. Rush Rush VIT schedules involve administering the build-up phase over two to three consecutive days until the maintenance dose is achieved (table 3) [3]. The maintenance dose is then given at one-week intervals for two doses, then two-week intervals for two doses, then three-week intervals for two doses, then monthly thereafter. Section Editor David B Golden, MD Deputy Editor Anna M Feldweg, MD

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Ultra-rush Ultra-rush VIT uses a more rapid one-day build-up phase. The final dose on the first day is typically slightly lower than the full-maintenance dose, although the patient has received a cumulative dose of allergen close to the 100 mcg maintenance dose of an individual venom (table 4) [4]. On the next scheduled visit, the patient usually receives a full-maintenance dose, which is repeated monthly thereafter. Compared with rush schedules, ultra-rush schedules expose the patient to a lower cumulative dose of venom during the build-up phase. ADVANTAGES AND SAFETY OF ACCELERATED IMMUNOTHERAPY Advantages Advantages of accelerated VIT include increased patient convenience and more rapid induction of clinical protection from future stings: Greater convenience Inconvenience is the most common reason patients discontinue conventional immunotherapy. Accelerated schedules involve fewer office visits and are favored by many patients. More rapid onset of clinical benefit Accelerated schedules induce the immunologic changes that occur during the build-up phase more rapidly than conventional schedules. Thus, patients achieve clinical protection sooner. In most patients, protection from recurrent systemic allergic reactions appears to be established within a week of reaching maintenance doses, and may improve further with time [5]. In a study of the ultra-rush protocol mentioned above, two patients with severe past reactions were restung 7 to 15 days after desensitization and developed only local erythema [4]. In addition, significant increases in venomspecific IgG4 were noted 15 days after reaching maintenance. The immunologic changes induced by immunotherapy are reviewed separately. (See "Subcutaneous immunotherapy for allergic disease: Therapeutic mechanisms", section on 'Blocking IgG4 antibodies'.) Reduced risk of dosing errors Dosing errors are one of the leading causes of systemic allergic reactions during SCIT. Accelerated schedules involve fewer doses during the build-up phase, and these doses are administered over a more concentrated time period, so dosing errors are reduced. Safety Accelerated VIT schedules were designed to be performed in the outpatient setting under the supervision of an experienced allergist and nursing staff. There are no data to suggest that patients should routinely be hospitalized to undergo accelerated venom immunotherapy. However, patients should be screened appropriately before any form of subcutaneous immunotherapy is considered. (See 'Contraindications' below.) Among the different Hymenoptera venoms, honeybee is the most likely to induce a systemic allergic reaction in both conventional and accelerated VIT schedules [6,7]. As an example, in a report of patients treated with a fourday rush protocol, systemic allergic reactions occurred in 12 percent of subjects receiving honeybee venom, compared with 2 percent of those receiving yellow jacket venom [7]. No patients required epinephrine. Rates of systemic allergic reactions Both rush and ultra-rush schedules for VIT usually demonstrate similar or lower rates of systemic allergic reactions during the build-up phase compared with conventional schedules [4,7-12]. The specific rate depends upon the schedule used. The authors use a schedule that causes systemic reactions in less than 5 percent of people according to the original publication, although we rarely observe systemic reactions in our practice. This low rate of reactions has been attributed to the use of fewer injections and lower cumulative doses of venom [9,13]. The relationship between systemic reactions, injection number, and cumulative venom dose was illustrated in a study in which three different accelerated VIT schedules were compared [9]. Subjects underwent either a four day, six hour, or 210 minute schedule, and systemic reactions occurred in 28, 29, and 7 percent, respectively. The shorter schedules required fewer injections and lower cumulative doses of venom. Rates of systemic reactions with specific schedules are discussed below. (See 'Specific protocols' below.) In contrast to the above, shorter schedules with fewer injections were associated with more systemic reactions in one well-done study. This study compared the incidence of systemic reactions between a three-visit and 10-visit schedule of VIT in 93 subjects sensitive to jack jumper ant (Myrmecia pilosula) [14]. Although the shorter schedule
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required fewer injections, it was associated with a higher rate of reactions (12 percent) compared with the slower schedule (no systemic reactions). It should be noted that the study used a venom product only available in Australia. In the US, VIT for fire ant (Solenopsis invicta) is administered using whole body extract, so it is difficult to extrapolate the results from the Australian study to VIT with fire ant or other Hymenoptera species. INDICATIONS The indications for subcutaneous immunotherapy (SCIT) of any type are reviewed in detail separately (See "Subcutaneous immunotherapy for allergic disease: Indications and efficacy", section on 'Indications'.) It is our approach to use accelerated schedules for venom immunotherapy (VIT) in preference to conventional schedules since protection from future stings can be achieved with no increase in treatment-related risk. VIT practice parameters state that safe and effective accelerated schedules have been published and are no longer considered experimental [8,15]. Other specific indications for an accelerated VIT schedule include the following: A desire by the patient to minimize the number of visits for treatment, either because of the patients schedule or the distance that the patient lives from the treatment facility. The inability to tolerate conventional VIT: Occasionally, accelerated VIT is used to achieve maintenance in patients who do not tolerate conventional build-up due to recurrent systemic reactions in response to the injections [3,12]. The literature describes the performance of accelerated VIT in children as young as two years of age [13,16]. In older children, maturity level and the ability to cooperate with the repeated injections required should be considered. In theory, patients with mast cell disorders (eg, systemic mastocytosis or monoclonal mast cell activation syndrome) might tolerate accelerated VIT schedules better than traditional schedules, although this issue has not been formally studied. Cost The cost of an accelerated protocol varies by the length of the procedure and number of injections given. Accelerated protocols involve fewer injections and less venom, but more staff contact time. At the authors institution, the cost of accelerated and conventional VIT are similar. CONTRAINDICATIONS Contraindications to accelerated VIT are the same as those for conventional VIT, since the safety is comparable or better. Patients with asthma should have their symptoms under good control prior to beginning any form of SCIT. Relative contraindications include medical conditions that would impair the patients ability to survive anaphylaxis or treatment for anaphylaxis (eg, cardiovascular disease and severe chronic pulmonary diseases). However, in patients with venom allergy, cardiopulmonary disorders also put the patient at risk for a fatal outcome from a future sting, so each patients situation must be considered individually. These issues, as well as in the use of betablockers or ACE inhibitors in patients needing VIT, are discussed in more detail elsewhere. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients requiring ACE inhibitors or beta blockers' and "Anaphylaxis induced by subcutaneous allergen immunotherapy", section on 'Factors associated with fatal and near-fatal anaphylaxis'.) CONSENT, STAFFING, AND EQUIPMENT The following recommendations about staffing, equipment, and consent are based upon the authors clinical experience with administering rush VIT protocols over a period of 15 to 20 years. Practice parameters have not been developed specifically for accelerated forms of immunotherapy. Informed consent We obtain informed consent after a discussion of the risks and benefits of VIT and a review of the protocol to be used. For children and adolescents 18 years of age and younger, we obtain consent from a parent or legal guardian. The conversation should be documented, signed, and recorded in the patients medical record.
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Staffing and equipment The clinic staff should be trained in administering accelerated VIT, be able to provide close monitoring, and be comfortable with the treatment of anaphylaxis. The following supplies and equipment should be available when administering accelerated VIT: The patients venom extract(s), with the required dilutions VIT administration forms Injection supplies (syringe, alcohol wipes) Peak flow meter and spirometry equipment Equipment for monitoring vital signs: blood pressure cuff, stethoscope, and thermometer Supplies to obtain intravenous access and administer medications and fluids Emergency medications (including weight-appropriate epinephrine autoinjectors and albuterol with nebulizer) We also recommend having a dosing guide at the patients bedside with precalculated doses of all anticipated emergency medications based on the patients weight (particularly important for children), which have been reviewed by at least two health care professionals Premedication We advise treating patients with an H1 antihistamine one hour prior to the accelerated protocol because there is some evidence that this can reduce the incidence of mild systemic reactions: In a randomized trial of 121 patients treated with rush VIT, patients were pretreated with either an H1 antihistamine, the combination of an H1 and H2 antihistamine, or placebo [17]. Mild systemic reactions were observed in one and seven patients in the H1 and placebo groups, respectively. The addition of the H2 antihistamine did not provide additional protection. Local reactions were reduced in the groups receiving either H1 or combination premedication. Two other randomized trials reached similar conclusions [18,19]. However, H1 antihistamines did not appear to prevent serious systemic reactions (eg, hypotension) in any of these studies, although the incidence of such reactions was low. At least one study also suggested that antihistamine premedication improves the efficacy of VIT [20]. The authors practice is to begin accelerated VIT as soon as the diagnosis of venom allergy is made (ie, usually on the same day that the patient is skin tested) to avoid the risk of future stings. Whenever possible, we administer an H1 antihistamine prior to the start of the procedure. We typically give a second generation nonsedating agent, such as cetirizine, loratadine, or fexofenadine, at standard age-appropriate doses. However, it is our experience that patients tolerate the accelerated schedule even without premedication. Thus, if it is practical to pretreat with an H1 antihistamine prior to starting the accelerated VIT schedule there may be some benefit as outlined in the above studies, but this is not required in the practice parameters and should not otherwise delay administration of immunotherapy [8]. A more extensive premedication regimen (such as is used with accelerated aeroallergen immunotherapy) is unnecessary, based on the most recent practice parameters [8], and further delays the administration of VIT. Treatment A nurse obtains a height, weight, vital signs, and baseline pulmonary function test. The patient receives an H1 antihistamine one hour prior to the start of the procedure (preferred but not required based on the available literature and our experience). (See 'Premedication' above.) The clinician examines the patient. The clinician begins the immunotherapy as scheduled on the immunotherapy forms.

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The patient is carefully monitored for signs of local and systemic reactions. Follow-up vital signs and pulmonary function tests are done as needed throughout the procedure. The patient is observed for at least two hours after the final injection. If stable, the patient is discharged with follow-up instructions to return at the next specified day for that particular protocol. SPECIFIC PROTOCOLS Studies of specific protocols for accelerated VIT are reviewed in this section. The composition of the immunotherapy prescription and preparation of the extracts for use in accelerated schedules are not typically different from what would be used for a traditional schedule. Only the dosing schedule is altered. The protocols described here can be performed for one or more venoms. If a mixed vespid product is used, the volumes remain the same and each dose contains the corresponding micrograms of each of the three vespid venoms. In the authors practice, we use a dosing schedule that achieves subtherapeutic but significant doses in one day. When patients initially present for evaluation of possible venom allergy, we suggest that they return for skin testing, and if results are positive, that they remain in the office for desensitization immediately after skin testing. 135 minutes The authors use a one-day protocol that reaches a dose of 20 mcg in 135 minutes, with or without premedication (as previously discussed) (table 5) [21]. After the initial injections are administered, the patient is observed for two hours and is discharged. Injections resume a week later and the remainder of the build-up occurs over the next several weeks, continuing according to the schedule provided by the manufacturer of the venom extract (table 6). For example, if using Hollister-Stier (Spokane, Washington) extracts, the dose increases weekly with 40 mcg, then 60 mcg, then 80 mcg, then 100 mcg. Injections of 100 mcg are then spaced every two weeks, then every three weeks, then every four weeks thereafter. In the original report, 5 percent of patients developed mild systemic reactions, consisting of diffuse urticaria during the first day [21]. The patients we have treated have not developed systemic allergic reactions. 150 minutes A 150-minute protocol was performed in 56 patients (aged 11 to 68 years) without premedications (table 4) [4]. All patients except one completed the ultra-rush desensitization. That patient stopped because of a hypertensive crisis unrelated to the immunotherapy. Seven percent had mild systemic reactions (generalized itching, dizziness without hemodynamic changes, malaise) which did not require epinephrine or discontinuation of the protocol. Mild and moderate local reactions were seen in 18 and 11 percent, respectively. Four hours A four-hour protocol was performed in 67 patients (age 15 to 66 years) using either honeybee or wasp extract [6]. Pretreatment was with cetirizine or fexofenadine starting three days prior to immunotherapy. The protocol involved administration of the following doses (in micrograms): 0.1, 1, 10, and 20 cg at 30 minute intervals, followed by 30 cg and 50 cg at 60-minute intervals. Subjects then received 100 cg on day 7 and 14, and monthly thereafter. The protocol was performed 78 times, and caused no hypersensitivity reactions in 83 percent of these. Systemic reactions developed in 17.5 percent, although none was severe enough to require epinephrine. Two patients had recurrent reactions and were converted to a conventional schedule. Four patients had large local reactions (>10 cm in diameter). One day In another study, 258 (51 children and 207 adults) underwent a one-day ultra-rush protocol [22]. The protocol involved administration of the following doses (in micrograms): 0.1, 1, 10, and 20 cg at 30 minute intervals, followed by 30 cg and 40 cg at 60-minute intervals. Subjects then received 50 cg on day 15, and 100 cg on day 45 and monthly thereafter. Thirty-three subjects (13 percent) experienced a systemic reaction on the first day of the protocol. Of those, 24 were grade 1 or grade 2 and nine were grade 3 or grade 4. Systemic reactions on day 15 (2 patients) and day 45 (1 patient) were uncommon. Two days In another study, 403 subjects (57 bee-allergic and 346 wasp-allergic) underwent a two-day rush protocol [13]. The protocol involved administration of the following doses (in micrograms): 0.01 cg, 0.1 cg, 1 cg, 10 cg, 20 cg, 40 cg, and 80 cg at 60-minute intervals. On day two, subjects received 100 cg at 08:00 and at
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11:00 AM. Systemic reactions were seen in 8.8 and 11 percent of bee- and wasp-allergic subjects, respectively, which were lower than rates with more prolonged protocols. MANAGEMENT OF ADVERSE REACTIONS Systemic reactions Systemic reactions to accelerated VIT are rare, and the best approach for continuing immunotherapy has not been formally studied. Empirically, there are two options for proceeding with treatment once the patients has been treated and returned to baseline: Resume the accelerated schedule on the following day, which theoretically takes advantage of the patients hyporesponsive state immediately after a systemic reaction Convert to a conventional schedule Since there are no studies evaluating either approach, the decision to try one approach over another requires a discussion between patient and clinician, and considerations of the patients preferences. As with conventional immunotherapy, patients who develop systemic reactions should be treated for anaphylaxis and observed for a period of time once symptoms have resolved. Patients with mild to moderate reactions that respond promptly and completely to treatment can usually be observed in the clinic for two hours and discharged to home. However, it may be more appropriate to hospitalize a patient with a more severe reaction or with symptoms that do not respond promptly to treatment. Likewise, patients who live far from medical care or have little home support may be better served by hospitalization. There is a risk of biphasic reactions with anaphylaxis from any cause and the risk factors for recurrent symptoms are unclear, although these have rarely been reported in the rush immunotherapy literature. Deciding on the best immediate aftercare for a patient with a systemic reaction obviously required clinical judgement. (See "Biphasic and protracted anaphylaxis", section on 'Possible risk factors'.) The patient should then return at the next scheduled day based on the individual protocol (most commonly in one week) to resume injections. We (the authors) believe it important not to extend this time period by even a few days, as it is our observation that patients who wait longer than a week tend to experience more systemic reactions in the remaining build-up. We resume treatment with the dose that caused the reaction. There is no utility based on the available literature for continuing antihistamine medications during the maintenance phase of therapy. Large local reactions Local reactions at the site of the injections are seen in up to 20 percent of patients [4,6]. Some patients find the injections themselves painful similar to a mild sting. Large local reactions are treated symptomatically (eg, with ice and acetaminophen), as with conventional immunotherapy. We do not terminate rush or ultra-rush VIT for large local reactions, unless the patient is too uncomfortable to continue. In most cases, we wait a few minutes longer between injections to allow treatment to start taking effect, and then continue the protocol. INFORMATION FOR PATIENTS Patients with venom allergy who are undergoing venom immunotherapy should be equipped with at least two doses of self-injectable epinephrine. The patient should be educated about how and when epinephrine should be administered. The teaching record is signed by the patient and clinician. UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)
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Basics topics (see "Patient information: Anaphylaxis (The Basics)" and "Patient information: Epinephrine auto-injectors (The Basics)") Beyond the Basics topics (see "Patient information: Anaphylaxis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Anaphylaxis treatment and prevention (Beyond the Basics)" and "Patient information: Use of an epinephrine autoinjector (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Accelerated schedules involve a shortened build-up phase, while the maintenance-phase remains the same as conventional immunotherapy. The build-up phase is shortened by administering more injections per visit, increasing the dose more between consecutive injections, or both. (See 'Terminology' above.) Accelerated protocols for venom immunotherapy (VIT) are categorized as either rush or ultra-rush schedules, although these terms are not strictly defined. Rush VIT schedules involve administering the build-up phase over two to three consecutive days until the maintenance dose is achieved (table 3). Ultra-rush VIT uses a more rapid one-day build-up phase, although the final dose on that day is usually lower than full-maintenance (table 4). In both cases, the patient returns to complete the remainder of the injections weekly, then biweekly, then monthly. (See 'Terminology' above.) Advantages of accelerated VIT include increased patient convenience and more rapid induction of clinical protection from future stings. In most patients, protection from recurrent systemic allergic reactions appears to be established within a week of reaching maintenance doses. (See 'Advantages' above.) Rates of systemic allergic reactions with both rush and ultra-rush VIT are similar or lower than rates with conventional VIT. This has been attributed to the use of fewer injections and lower cumulative doses of venom during the build-up phase. The specific rate depends upon the schedule used. Accelerated VIT is performed in the outpatient setting. (See 'Safety' above.) The indications and contraindications for accelerated VIT are the same as those for conventional VIT because the safety is similar. In addition, rush or ultra-rush VIT may be tolerated in patients who are having difficulty reaching maintenance with a conventional build-up schedule because of recurrent systemic reactions to the injections. (See 'Indications' above and 'Contraindications' above.) We suggest premedicating all patients with an H1 antihistamine before beginning an accelerated VIT protocol (Grade 2B). We typically give a second generation nonsedating agent, such as cetirizine, loratadine, or fexofenadine, at standard age-appropriate doses. (See 'Premedication' above.) Several rush and ultra-rush VIT schedules have been published. The authors use a one-day protocol that reaches a dose of 20 mcg in 135 minutes, with or without premedication, with which they have not seen systemic reactions (table 5). (See 'Specific protocols' above.) Large local reactions are treated symptomatically (eg, with ice and acetaminophen), as with conventional immunotherapy. In patients who do develop systemic reactions, we suggest discontinuing the accelerated protocol and converting the patient to a conventional build-up schedule (Grade 2C). (See 'Management of adverse reactions' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Larch M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev
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Immunol 2006; 6:761. 2. 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. 3. Goldberg A, Confino-Cohen R. Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy. Ann Allergy Asthma Immunol 2003; 91:405. 4. Schiavino D, Nucera E, Pollastrini E, et al. Specific ultrarush desensitization in Hymenoptera venom-allergic patients. Ann Allergy Asthma Immunol 2004; 92:409. 5. Mller U, Hari Y, Berchtold E. Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy. J Allergy Clin Immunol 2001; 107:81. 6. Roll A, Hofbauer G, Ballmer-Weber BK, Schmid-Grendelmeier P. Safety of specific immunotherapy using a four-hour ultra-rush induction scheme in bee and wasp allergy. J Investig Allergol Clin Immunol 2006; 16:79. 7. Sturm G, Krnke B, Rudolph C, Aberer W. Rush Hymenoptera venom immunotherapy: a safe and practical protocol for high-risk patients. J Allergy Clin Immunol 2002; 110:928. 8. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1. 9. Birnbaum J, Charpin D, Vervloet D. Rapid Hymenoptera venom immunotherapy: comparative safety of three protocols. Clin Exp Allergy 1993; 23:226. 10. Gorska L, Chelminska M, Kuziemski K, et al. Analysis of safety, risk factors and pretreatment methods during rush hymenoptera venom immunotherapy. Int Arch Allergy Immunol 2008; 147:241. 11. Kalogeromitros D, Makris M, Koti I, et al. A simple 3-day "rush" venom immunotherapy protocol: documentation of safety. Allergol Immunopathol (Madr) 2010; 38:69. 12. Oren E, Chegini S, Hamilos DL. Ultrarush venom desensitization after systemic reactions during conventional venom immunotherapy. Ann Allergy Asthma Immunol 2006; 97:606. 13. Brehler R, Wolf H, Ktting B, et al. Safety of a two-day ultrarush insect venom immunotherapy protocol in comparison with protocols of longer duration and involving a larger number of injections. J Allergy Clin Immunol 2000; 105:1231. 14. Brown SG, Wiese MD, van Eeden P, et al. Ultrarush versus semirush initiation of insect venom immunotherapy: a randomized controlled trial. J Allergy Clin Immunol 2012; 130:162. 15. Golden DB, Moffitt J, Nicklas RA, et al. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011; 127:852. 16. Laurent J, Smiejan JM, Bloch-Morot E, Herman D. Safety of Hymenoptera venom rush immunotherapy. Allergy 1997; 52:94. 17. Brockow K, Kiehn M, Riethmller C, et al. Efficacy of antihistamine pretreatment in the prevention of adverse reactions to Hymenoptera immunotherapy: a prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 1997; 100:458. 18. Berchtold E, Maibach R, Mller U. Reduction of side effects from rush-immunotherapy with honey bee venom by pretreatment with terfenadine. Clin Exp Allergy 1992; 22:59. 19. Reimers A, Hari Y, Mller U. Reduction of side-effects from ultrarush immunotherapy with honeybee venom by pretreatment with fexofenadine: a double-blind, placebo-controlled trial. Allergy 2000; 55:484. 20. Mller UR, Jutel M, Reimers A, et al. Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy. J Allergy Clin Immunol 2008; 122:1001. 21. Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994; 73:423. 22. Birnbaum J, Ramadour M, Magnan A, Vervloet D. Hymenoptera ultra-rush venom immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy 2003; 33:58. Topic 16131 Version 4.0

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GRAPHICS Typical conventional dosing schedules for venom immunotherapy: Schedule 1

Week
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 21 Monthly 1 1 1 1 10 10 10 10 100 100 100 100 100 100 100 100 100 100 100

Concentration, micrograms/mL

Volume, mL
0.05 0.1 0.2 0.4 0.05 0.1 0.2 0.4 0.05 0.1 0.2 0.4 0.6 0.8 1 1 1 1 1

Injections are generally given weekly. The maintenance dose is achieved in most patients at week 15, after which the interval between injections is extended from weekly to every two weeks, and then to monthly. This schedule is based upon the package insert for Hollister-Stier venom extracts (Spokane, WA).
Original figure modified for this publication. Reproduced with permission from: Golden DBK. Insect Allergy. In: Middleton's Allergy: Principles & Practice, 7th ed, Adkinson NF Jr, Bochner BS, Busse WW, et al (Eds), Mosby Elsevier, Philadelphia 2009. Illustrations used with the permission of Elsevier Inc. All rights reserved.

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Typical conventional dosing schedules for venom immunotherapy: Schedule 2

Injection 1 Week
Concentration, micrograms/mL 0.01 1 10 100 100 100 100 100 100 100 Volume, mL 0.1 0.1 0.1 0.1 0.2 0.3 0.4 0.5 1 1

Injection 2
Concentration, micrograms/mL 0.1 1 10 100 100 100 100 100 Volume, mL 0.1 0.5 0.5 0.2 0.3 0.3 0.4 0.5 -

Injection 3
Concentration, micrograms/mL 1 10 10 Volume, mL 0.1 0.1 1 -

1 2 3 4 5 6 7 8 9 Monthly

Injections 1, 2, and 3 are given at 30 min intervals on days when more than one injection is administered (reading from left to right across table in the week 1 row). During weeks 1 through 3, the patient receives 3 injections per visit. During weeks 4 through 8, the patient receives two injections per visit. Maintenance is achieved by approximately week 8. Thereafter, the patient receives one injection per visit and the interval between visits is extended from weekly to monthly. This schedule is based upon the package insert for ALKAbello venom extracts (Round Rock, TX).
Original figure modified for this publication. Reproduced with permission from: Golden DBK. Insect Allergy. In: Middleton's Allergy: Principles & Practice, 7th ed, Adkinson NF Jr, Bochner BS, Busse WW, et al (Eds), Mosby Elsevier, Philadelphia 2009. Illustrations used with the permission of Elsevier Inc. All rights reserved.

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Three-day rush schedule for Hymenoptera venom immunotherapy

Day
1 1 1 1 1 1 1 1 1 1 2 2 2 3

Volume (mL)
0.05 0.1 0.2 0.4 0.8 0.2 0.5 1 0.2 0.2 0.2 0.3 0.5 1

Concentration (micrograms/mL)
1 1 1 1 1 10 10 10 100 100 100 100 100 100

Dose (micrograms)
0.05 0.1 0.2 0.4 0.8 2 5 10 20 20 20 30 50 100

The time interval between doses on days one and two is 15 minutes. Once the maintenance dose of 100 micrograms is reached, it is then given at one-week intervals for two doses, then two-week intervals for two doses, then three-week intervals for two doses, then monthly thereafter.
Reproduced from: Goldberg A, Confino-Cohen R. Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy. Ann Allergy Asthma Immunol 2003; 91:405. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

Example of ultrarush venom immunotherapy schedule

Time (minutes)
0 30 60 90 120 150 0.1 1 10 20 30 40

Dose (micrograms)

Patients are observed for at least two hours after completion of the initial series of injections. The maintenance dose of 100 micrograms was then given on day 15 and once per month thereafter.
Reproduced from: Schiavino D, Nucera E, Pollastrini E, et al. Specific ultrarush desensitization in Hymenoptera venom-allergic patients. Ann Allergy Asthma Immunol 2004; 92:409. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

One-day rush schedule for venom immunotherapy

Time (min)
0 15 30 45 60 75 90 105 120 135

Volume (mL)
0.05 0.1 0.2 0.4 0.08 0.2 0.5 0.1 0.2 0.2 1 1 1 1 10 10 10 100 100 100

Concentration (micrograms/mL)

Once the above doses have been administered, the patient receives weekly injections to continue the buildup for the next eight weeks. After that, injections are administered once every four weeks.
Reproduced from: Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994; 73:423. Table used with the permission of Elsevier Inc. All rights reserved.

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Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

One-day rush schedule for venom immunotherapy with subsequent build-up to full maintenance
Time
Minutes 0 15 30 45 60 75 90 105 120 135 Week 2 3 4 5 6 8 11 Monthly 0.4 0.6 0.8 1 1 1 1 1 100 100 100 100 100 100 100 100 0.05 0.1 0.2 0.4 0.08 0.2 0.5 0.1 0.2 0.2 1 1 1 1 10 10 10 100 100 100

Volume, mL

Concentration, micrograms/mL

The accelerated portion of the protocol is shown at the top, followed by subsequent weekly visits to reach full maintenance, as recommended by the manufacturer of the venom extract being administered. In this example, the subsequent build-up follows the schedule recommended by Hollister-Stier (Spokane, Washington). This is the protocol used by the authors.
Accelerated initial protocol from: Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994; 73:423. If ALK-Abello (Round Rock, Texas) extracts were used, the schedule in the package insert could be followed to complete the build-up phase.

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