rush and ultra-rush venom immunotherapy for hymenoptera allergy

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2/10/2014 Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

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Official reprint from UpToDate

www.uptodate.com2014 UpToDate

AuthorsMarc Serota, MD

Jay M Portnoy, MD

Section EditorDavid B Golden, MD

Deputy EditorAnna M Feldweg, MD

Rush and ultra-rush venom immunotherapy for Hymenoptera allergy

Disclosures

All topics are updated as new evidence becomes available and our peer review processis 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-upphase involves one or three injections per week and extends from 8 to 21 weeks. Conventional schedules for

VIT are shown (table 1and 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, althoughthese 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.
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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 venom-

specific IgG4 were noted 15 days after reaching maintenance. The immunologic changes induced byimmunotherapy 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 four-

day 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 conventionalschedules 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 beta-

blockers 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 albuterolwith 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 cetirizineor fexofenadinestarting 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 patientshyporesponsive 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 5 to 6 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 10 to 12 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.)

th th

th th
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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. JAllergy 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.

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GRAPHICS

Typical conventional dosing schedules for venom immunotherapy:

Schedule 1

Week Concentration, micrograms/mL Volume, mL

1 1 0.05

2 1 0.1

3 1 0.2

4 1 0.4

5 10 0.05

6 10 0.1

7 10 0.2

8 10 0.4

9 100 0.05

10 100 0.1

11 100 0.2

12 100 0.4

13 100 0.6

14 100 0.8

15 100 1

16 100 1

18 100 1

21 100 1

Monthly 100 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, etal (Eds), Mosby Elsevier, Philadelphia 2009. Illustrations used with the permission of Elsevier Inc. All

rights reserved.


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http://www.uptodate.com/contents/rush-and-ultra-rush-venom-immunotherapy-for-hymenoptera-allergy?topicKey=ALLRG%2F16131&elapsedTimeMs=7&sour 10

Typical conventional dosing schedules for venom immunotherapy:

Schedule 2

Week

Injection 1 Injection 2 Injection 3

Concentration,

micrograms/mL

Volume,

mL

Concentration,

micrograms/mL

Volume,

mL

Concentration,

micrograms/mL

Volume,

mL

1 0.01 0.1 0.1 0.1 1 0.1

2 1 0.1 1 0.5 10 0.1

3 10 0.1 10 0.5 10 1

4 100 0.1 100 0.2 - -

5 100 0.2 100 0.3 - -

6 100 0.3 100 0.3 - -

7 100 0.4 100 0.4 - -

8 100 0.5 100 0.5 - -9 100 1 - - - -

Monthly 100 1 - - - -

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 ALK-

Abello 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 Volume (mL) Concentration (micrograms/mL) Dose (micrograms)

1 0.05 1 0.05

1 0.1 1 0.1

1 0.2 1 0.2

1 0.4 1 0.4

1 0.8 1 0.8

1 0.2 10 2

1 0.5 10 5

1 1 10 10

1 0.2 100 20

1 0.2 100 20

2 0.2 100 20

2 0.3 100 30

2 0.5 100 50

3 1 100 100

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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Example of ultrarush venom immunotherapy schedule

Time (minutes) Dose (micrograms)

0 0.1

30 1

60 10

90 20

120 30

150 40

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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One-day rush schedule for venom immunotherapy

Time (min) Volume (mL) Concentration (micrograms/mL)

0 0.05 1

15 0.1 1

30 0.2 1

45 0.4 1

60 0.08 10

75 0.2 10

90 0.5 10

105 0.1 100

120 0.2 100

135 0.2 100

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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One-day rush schedule for venom immunotherapy with subsequent

build-up to full maintenance

Time Volume, mL Concentration, micrograms/mL

Minutes

0 0.05 1

15 0.1 1

30 0.2 1

45 0.4 1

60 0.08 10

75 0.2 10

90 0.5 10

105 0.1 100

120 0.2 100

135 0.2 100

Week

2 0.4 100

3 0.6 100

4 0.8 100

5 1 100

6 1 100

8 1 100

11 1 100

Monthly 1 100

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.

rush and ultra-rush venom immunotherapy for hymenoptera allergy

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