Rush Venom Immunotherapy: Ready for Prime Time? David B.K. Golden, MD Baltimore, Md
Allergen immunotherapy requires an induction (build-up, updosing) phase that can be accomplished using various treatment schedules. By far the most commonly used in the United States are “conventional” (traditional, slow) regimens, giving 1 dose every week for 4 to 6 months (sometimes longer). Rush regimens have become increasingly popular in many countries, with a series of doses given throughout each day on consecutive days, reaching the maintenance dose in a few days. Rush immunotherapy is not commonly used for inhalant allergies because it carries a greater risk of adverse reactions than do slower regimens.1 Rush regimens for venom immunotherapy (VIT) have been reported to be relatively safe, but are not widely accepted in the United States. Conﬁno-Cohen et al,2 in this issue of Journal of Allergy and Clinical Immunology In Practice, make a convincing point about the safety of rush VIT by describing the successful treatment of patients considered to be at higher risk: children and those with honeybee allergy.2 The only controlled clinical trial of VIT in the United States used an induction regimen that achieved the maintenance dose after 6 to 8 weekly visits.3 This was termed a “rush regimen” at the time because it was more rapid than the conventional regimens in common use, but has subsequently been called a “modiﬁed rush” or “semi-rush” regimen. Subsequent pivotal trials of immunotherapy with venom extracts from a different manufacturer used a conventional schedule. Both studies showed comparable efﬁcacy, with 98% of treated patients having no systemic reaction to a sting challenge. These initial studies led to the 2 current FDA-approved venom products with their respective recommended regimens (8-week “rush” and conventional). A recent survey of allergists in the United States found that 64% of respondents use the conventional regimen, 31% use the 8-week regimen, and 5% use rush regimens.4 In the following decades there were many reports of VIT using various rush regimens that were described as safe and effective, usually achieving the maintenance dose in several days. Rush VIT became commonplace in some settings but has continued to
Department of Medicine, Johns Hopkins University, Baltimore, Md Conﬂicts of interest: D. B. K. Golden has received consultancy fees from Stallergenes/Greer Laboratories; has received research support and lecture fees from Genentech and Stallergenes/Greer Laboratories; receives royalties from UpToDate; and has received payment for developing educational presentations from PeerView. Received for publication December 1, 2016; accepted for publication December 2, 2016. Corresponding author: David B.K. Golden, MD, 7939 Honeygo Blvd #219, Baltimore, MD 21236. E-mail: [email protected]
J Allergy Clin Immunol Pract 2017;5:804-5. 2213-2198 Ó 2017 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2016.12.031
be viewed warily by allergists in the United States. This is probably due not only to perceived safety concerns but also to differences in systems for delivery of health care. In most areas of the United States, specialists in Allergy-Immunology are relatively nearby. Patients often state that they prefer a series of brief weekly treatment visits rather than taking 2 to 3 days off from their responsibilities to complete a rush VIT regimen. In many other countries, specialty care is often centralized such that patients may have to travel hundreds of miles for consultation and treatment. This would make weekly visits very inconvenient, so rush VIT would be the practical regimen of choice. In the US military, rush VIT is preferred because weekly treatment might delay or complicate the activities of the service member. In the nonrandomized study reported by Conﬁno-Cohen et al, it would have been interesting to know the reasons for the patients’ choice of the rush or conventional regimen. After almost a century of using almost exclusively conventional regimens for inhalant allergen immunotherapy in the United States, rush regimens are widely considered to be suitable for research studies, but not for daily practice. Many hospitals are reluctant to approve admission for rush VIT because they view it as “experimental,” and “not ready for prime time.” The Practice Parameter on Stinging Insect Hypersensitivity states that rush VIT should not be viewed as experimental and can be safely used in routine clinical practice, but very few allergists recommend this treatment regimen. The study reported in this issue by Conﬁno-Cohen et al should make us ask ourselves whether rush VIT should be accepted as routine in our practices? There is ample evidence supporting the safety of rush VIT. There were early reports in small numbers of patients, but Bernstein et al5 showed more than 20 years ago that rush VIT is at least as safe as conventional VIT, and could be used in routine outpatient clinical practice. Their regimen was the basis for the regimen subsequently used by the Israeli group of Goldberg and Conﬁno-Cohen6 in several studies including the one in this issue. There have been numerous publications of rush VIT regimens, but the more articles that were published, the more muddy the waters became. This was due in part to the variety of different regimens reported and the inconsistent nomenclature used to describe these regimens. Ultra-rush regimens were reported but with less consistent safety. However, a careful review of more than a dozen published studies shows no consistent deﬁnition of “rush” and “ultra-rush” regimens. In fact, as pointed out by the authors in this issue, some “ultra-rush” regimens for VIT were no different from other “rush” regimens. And although some ultra-rush regimens are described as single-day regimens (eg, 210 minutes), they generally do not achieve the 100 mg dose until several days of treatment (or longer). There is clearly a need for standardized nomenclature for regimens of immunotherapy. One could deﬁne that conventional regimens achieve the
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maintenance dose in months, semi-rush in weeks, rush in days, and ultra-rush in hours.7 Rush VIT has been reported to be safe not only in routine clinical practice but also in a number of potentially high-risk situations. Patients who cannot achieve the maintenance dose because of repeated systemic reactions can be safely and effectively treated with rush VIT, as can patients with mastocytosis.6,8 Rush VIT has also been shown to be useful in honeybee allergic patients as well as those with ﬁre ant allergy.9,10 The report by Conﬁno-Cohen et al is focused on the use of rush VIT in children. Are children different from adults with regard to VIT? The indication for VIT is the same at any age. The recommended maintenance dose of VIT has always been 100 mg for children and adults, but recent studies suggest that a 50 mg maintenance dose is as effective as 100 mg in children.11,12 The recommended duration of VIT is 3 to 5 years. In adults, 5 years has been reported to be superior to 3 years.13,14 There has been no comparative study in children, but the long-term outcome in children treated for a mean of 3.5 years was as good as in adults treated for 5 years.15 As noted by the authors in this issue, the regimen for induction of VIT has not been studied as extensively in children as in adults. Conﬁno-Cohen et al provide good evidence for the safety and efﬁcacy of rush VIT in children. The authors also showed that rush VIT was more efﬁcient in achieving the maintenance dose. In fact, as previously demonstrated in adults, the children who had systemic reactions during conventional VIT had no difﬁculty reaching the maintenance dose when switched to the rush regimen. It is also noteworthy that VIT is clinically effective as soon as the maintenance dose is reached, even with rush VIT.9 Thus, evidence for the safety of rush VIT has been reported in routine clinical use and in high-risk patients, and now in children as well. If we have not yet been willing to believe in the safety of rush VIT for the average patient, might we be convinced now that it has been demonstrated in children and adults, in patients with repeated systemic reactions or mastocytosis, and in patients with honeybee or ﬁre ant allergy? The report in this issue, along with accumulated evidence to date, suggests that if we would just try it, we might conclude that rush VIT is not just for special
circumstances, but is indeed ready for prime time in our daily practice. REFERENCES 1. Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011;127:S1-55. 2. Conﬁno-Cohen R, Rosman Y, Goldberg A. Rush venom immunotherapy in children. J Allergy Clin Immunol Pract 2017;5:799-803. 3. Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61. 4. Golden DB, Demain J, Freeman T, Graft D, Tankersley M, Tracy J, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol 2017;118:28-54. 5. Bernstein JA, Kagan SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy 1994;73:423-8. 6. Goldberg A, Conﬁno-Cohen R. Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy. Ann Allergy 2003;91:405-10. 7. Brown SG, Wiese MD, van Eeden P, Stone SF, Chuter CL, Gunner J, et al. Ultrarush versus semirush initiation of insect venom immunotherapy: a randomized controlled trial. J Allergy Clin Immunol 2012;130:162-8. 8. Bonadonna P, Zanotti R, Caruso B, Castellani L, Perbellini O, Colarossi S, et al. Allergen speciﬁc immunotherapy is safe and effective in patients with systemic mastocytosis. J Allergy Clin Immunol 2008;121:256-7. 9. Goldberg A, Yogev A, Conﬁno-Cohen R. Three days rush venom immunotherapy in bee allergy: safe, inexpensive, and instantaneoulsy effective. Int Arch Allergy Immunol 2011;156:90-8. 10. Tankersley MS, Walker RL, Butler WK, Hagan LL, Napoli DC, Freeman TM. Safety and efﬁcacy of an imported ﬁre ant rush immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol 2002;109:556-62. 11. Houliston L, Nolan R, Noble V, Pascoe E, Hobday J, Loh R, et al. Honeybee venom immunotherapy in children using a 50-mcg maintenance dose. J Allergy Clin Immunol 2011;127:98-9. 12. Konstantinou GN, Manoussakis E, Douladiris N, Hatziioannou A, Giavi S, Saxoni-Papageorgiou P, et al. A 5-year venom immunotherapy protocol with 50 mcg maintenance dose: safety and efﬁcacy in school children. Pediatr Allergy Immunol 2011;22:393-7. 13. 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. 14. Lerch E, Muller U. Long-term protection after stopping venom immunotherapy. J Allergy Clin Immunol 1998;101:606-12. 15. Golden DBK, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Outcomes of allergy to insect stings in children with and without venom immunotherapy. N Engl J Med 2004;351:668-74.