This document discusses different schedules for venom immunotherapy build-up, including slow, rush, and ultrarush. It provides examples of protocols for rush venom immunotherapy build-up over 3-7 days. Rush schedules have been used for patients at high risk of future severe reactions or side effects from conventional schedules. Studies have found rush schedules to be safe and effective options for venom immunotherapy build-up when done properly over short intervals.

1. Build-up of venom immunotherapy: which
schedule is the best?
Dario Antolin-Amerigo
Hospital Universitario Príncipe de Asturias
Alcalá de Henares, Madrid
Spain

2. Conflicts of Interest
I declare no conflicts of interest.

3. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• A model for the efficacy and reliability of allergen
immunotherapy.
• A great deal of protocols
• Comparison: challenging heterogeneity (variables &
methods)
Slow Rush Ultrarush
Weekly 3-7 days Hours-2 days
15-30 minute intervals

4. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Antihistamines
Medical
Factors
Others Pretreatment Omalizumab
Financial Patient Logistic
Purified
Other
Montelukast Factors
Depot Extract Non
Purified

5. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Pretreatment
Patient
Extract

6. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Rush VIT by Sturm et al (60 min)6
Day 1 Day 2 Day 3 Day 4
0.001 0.8 8 80
0.01 1.0 10 100
0.1 2.0 20
0.79% Bee
0.2 4.0 40 0.12% Vespid
=
0.4 6.0 60
Sturm G Kränke B Rudolph C Aberer W Rush Hymenoptera venom immunotherapy: a safe and practical protocol for
high-risk patients. J Allergy Clin Immunol. 2002 Dec;110(6):928-33.

7. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
1. High risk of future severe reactions: case history
and test results
2. High risk for side effects of venom immunotherapy
(elderly persons with coexisting internal disease)
3. Need protection soon
4. Rural areas
5. Highly sensitized and anxious
6. Highly sensitized children
Sturm G Kränke B Rudolph C Aberer W Rush Hymenoptera venom immunotherapy: a safe and practical protocol for
high-risk patients. J Allergy Clin Immunol. 2002 Dec;110(6):928-33.

8. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Venom Daily
Day concentration Volume, mL Dose, mcg accumulative
mcg/mL dose, mcg
1 0.05 0.05
1 0.1 0.1 Goldberg A, Confino-Cohen R.
Rush venom immunotherapy
1 0.2 0.2 in patients experiencing
recurrent systemic reactions
1 0.4 0.4
to conventional venom
1 0.8 0.8 immunotherapy. Ann Allergy
1 Asthma Immunol. 2003
10 0.2 2 Oct;91(4):405-10.
10 0.5 5
10 1.0 10
100 0.2 20
100 0.2 20 58.55
100 0.2 20
2 100 0.3 30
100 0.5 50 100
3 100 1.0 100 100
There were 15-min intervals between venom injections.

9. Build-up of VIT
The Bonn Rush VIT protocol (100.000 SQ-E=100 mcg insect venom)
Day Preparation Concentration(mcg/mL) Volume (mL) Dose (mcg)
1 (Monday) Lyophilisate 0.000001 0.2 0.0000002
0.00001 0.2 0.000002
0.0001 0.2 0.00002
0.001 0.2 0.0002
2 (Tuesday) Lyophilisate 0.01 0.2 0.002
0.01 0.4 0.004
0.01 0.8 0.008
0.1 0.2 0.02
3 Lyophilisate 0.1 0.4 0.04
(Wednesday)
0.1 0.8 0.08
1 0.2 0.2
1 0.4 0.4
17.9%
4 (Thursday) Lyophilisate 1 0.8 0.8 SRs
10 0.2 0.2
10 0.4 0.4
10 0.8 0.8
5 (Friday) Lyophilisate 100 0.2 20
100 0.3 30
100 0.4 40
100 0.5 50
6 (Monday) Lyophilisate 100 0.6 60 Wenzel J, Meissner-Kraemer M, Bauer R, Bieber T,
100 0.7 70
Gerdsen R. Safety of rush insect venom
100 0.8 80
immunotherapy. The results of a retrospective
7 (Tuesday) Lyophilisate 100 0.9 90
Depot study in 178 patients Allergy. 2003
100 1 100 Nov;58(11):1176-9.
Total Dose 555.55*

10. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
17.9%
SRs
Wenzel J, Meissner-Kraemer M, Bauer R, Bieber T,
Gerdsen R. Safety of rush insect venom
immunotherapy. The results of a retrospective
study in 178 patients Allergy. 2003
Nov;58(11):1176-9.

11. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
210 min Ultra-rush Protocol4
Day Time Injected
venom (mcgr)
0h 0.1
30 min 1
1h 10
1
1.5 h 20 SRs:12.79%
2.5 h 30
3.5 h 40
HBV 30%>YJV
0 50
15 3.2%
30 min 50
45 One injection of 100 mcgr
Monthly One injection of 100 mcgr
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 Jan;33(1):58-64.

12. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
21.2%
adverse
reactions
↓SR↔ ↓# Injections
Brehler R, Wolf H, Kütting B, Schnitker J, Luger T.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 Jun;105(6 Pt 1):1231-5.

13. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Day Dose ml administered Mcgr administered Conc mcg/ml
1 0.10 0.01 0.1
2 0.10 0.1 1
1
3 0.10 1 10
4 0.20 2 10
5
NPA:27.5% 0.30 3 10
2 6 0.35 3.5 10
7 0.35 3.5 10
8 0.10 10 100
3 9 0.15 15 100
PA:2.5%
10 0.15 15 100
11 0.20 20 100
4 12 0.25 25 100
13 0.25 25 100
14 0.30 30 100
5 15 0.35 35 100
16 0.35 35 100
Bilò MB, Cinti B, Brianzoni MF, Braschi MC, Bonifazi M, Antonicelli L.Honeybee venom immunotherapy: a comparative
study using purified and nonpurified aqueous extracts in patients with normal Basal serum tryptase concentrations. J
Allergy (Cairo) 2012;2012:869243.

14. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Mcg
Day Dose interval
administered
1 0.1 30 min
2 1 30 min
3 10 30 min
1
4 20 30 min
5 30 60 min
6 50 60 min
7 7 100
14 8 100
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(2):79-85.

15. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Injection
Dose (mcg) Interval (min)
number
1 0.1 30
SR : 29%
2 1 30 SR : 12%
3 10 30
4 20 60
5 30 60
6 50 180
Köhli-Wiesner A, Stahlberger L, Bieli C, Stricker T, Lauener R. Induction of specific immunotherapy with hymenoptera
venoms using ultrarush regimen in children: safety and tolerance. J Allergy (Cairo). 2012;2012:790910.

16. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Ultrarush initiation Semirush initiation
At 30 min intervals: 0.1 mcg, 1 mcg, 3 mcg, 10 At 20 min intervals: 0.0001 mcg, 0,001 mcg,
Visit 1
mcg, 20 mcg, 30 mcg, then: 0.01 mcg
For those allocated the 50-target: no more Visit 2 At 20 min intervals: 0.01, 0.1 mcg, 0.3 mcg
Visit 1
doses on day 1 Visit 3 At 30 min interval: 0.3mcg, 1mcg, 3 mcg
For those allocated the 100 mcg target: delay Visit 4 At 30 min interval: 3mcg, 10 mcg
60 min and give 40 mcg Visit 5 At 30 min interval: 10mcg, 20 mcg
At 20 min intervals: Visit 6 At 30 min interval: 20 mcg, 30 mcg
For those allocated the 50-target: 25 mcg + 25 For those allocated the 50 mcg target (30 min
Visit 7
Visit 2 mcg interval): 25 mcg, 25 mcg
For those allocated the 100-target 50 mcg + 50 For those allocated the 100mcg (30 min
mcg interval):30 mcg, 40 mcg
Visit 3 Maintenance dose: 50 mcg or 100 mcg Visit 8 For those allocated the 50 mcg target: 50 mcg
For those allocated the 100 mcg target (30 min
interval): 50mcg, 50 mcg
Ultrarush Semirush
Visit 9 For those allocated the 50 mcg target: 50 mcg
65% SRs 29% SRs For those allocated the 100 mcg target (30 min
(12% severe) (0% severe) interval):70 mcg, 30 mcg
Visit 10 Maintenance dose: 50 mcg or 100 mcg.
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 Jul;130(1):162-8.

17. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Ultrarush Semirush
65% SRs 29% SRs
(12% severe) (0% severe)
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 Jul;130(1):162-8.

18. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
%
injections
LLR SR
Group A 1.99% 0
Group B 3.2% 0.9%
Group C 3.6% 0.56%
P=0.27
Patella V, Florio G, Giuliano A, et al. Hymenoptera Venom Immunotherapy: Tolerance and Efficacy of an Ultrarush
Protocol versus a Rush and a Slow Conventional Protocol. J Allergy (Cairo)2012;2012:192192.

19. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Conventional Regimen
0.05, 0.1, 0.2, 0.4 mL (0.05, 0.1, Goldberg A, Yogev A, Confino-Cohen R. Three Days Rush
1 mcg/mL Venom Immunotherapy in Bee Allergy: Safe, Inexpensive and
0.2, 0.4 mcg) Instantaneously Effective. Int Arch Allergy Immunol
0.05, 0.1, 0.2, 0.4 mL (0.5, 1, 2, 4 2011;156:90-98.
10 mcg/mL
mcg)
0.02, 0.05, 0.07, 0.1, 0.2, 0.4,
3 Days Rush VIT
100 mcg/mL 0.6, 0.8, 1 ml (2, 5, 7, 10, 20, 40,
60, 80, 100 mcg)
Day 1
0.05, 0.1, 0.2, 0.4, 0.8 mL (0.05, 0.1, 0.2, 0.4, 0.8
20.8% 1mcg/mL
mcg)
SR
10 mcg/mL
0.2, 0.5, 1 mL (2, 5, 10 mcg)
100 mcg/mL
0.2, 0.2 mL (20, 20 mcg)
29.6% Day 2
SRs
100 mcg/mL 0.2, 0.3, 0.5 mL (20, 30, 50 mcg)
(Bee>V)
Day 3
100 mcg/mL 1 mL (100 mcg)

20. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Day Vial Volume (mL) Dosis (mcg)
1 0.1 0.1
1 0.2 0.2
1 1 0.4 0.4 48 patients
1 0.8 0.8
2 0.2 2 25% LR
2 0.4 4
2 0.8 8 2 patients mild SR
2
3 0.1 10
3 0.2 20
3 0.4 40
3 0.6 60 Vial 1=1 mcg/mL
3 Vial 2=10 mcg/mL
3 0.8 80
3 1 100 Vial 3=100 mcg/mL
Sánchez-Morillas L, Reaño Martos M, Rodríguez Mosquera M, Iglesias Cadarso A, Domínguez Lázaro AR. Safety of rush
immunotherapy with Hymenoptera venom. Allergol Immunopathol (Madr). 2005;33(4):224-7. Spanish.

21. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Dose administered
Time (min)
(mcg)
0.1 0
1 30 7% mild
10 60 SRs
20 90
30 120
40 150
Schiavino D, Nucera E, Pollastrini E, De Pasquale T, Buonomo A, Bartolozzi F, Lombardo C, Roncallo C, Patriarca G.
Specific ultrarush desensitization in Hymenoptera venom-allergic patients. Ann Allergy Asthma Immunol. 2004
Apr;92(4):409-13.

22. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
SEAIC 3 weeks Protocol SEAIC 4 weeks Protocol
Day Vial/ml Dose/ml Dose/mcgr Day Vial/ml Dose/ml Dose/mcgr
3 0.5 5 3 0.5 5
1
4 0.1 10 4 0.1 10
1 4 0.2 20
4 0.2 20 8
4 0.3 30
4 0.2 20
4 0.5 50
4 0.5 50
8 15 4 0.5 50
4 0.5 50
22 4 1 100
22 4 1 100
SEAIC 9 weeks Protocol
Week Vial/ml Dose/ml Dose/mcgr
1 2 0.1 0.1
2 3 0.1 1
3 3 0.5 5
4 4 0.1 10
5 4 0.2 20
6 4 0.4 40
7 4 0.6 60
8 4 0.8 80

23. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• Mediterranean: Vespula germanica & Polistes
dominulus: evenly distributed. Double
sensitization is frequent.
• 37 patients:
– 8% LLR
– Vespula: 0.75% per dose
– Polistes: 0.45% per dose
Moreno C, Barasona MJ, Serrano P, Justicia JL, Ruz JM, Guerra F. Alternating Polistes-Vespula venom
immunotherapy: a therapeutic strategy to resolve a diagnostic deficiency. J Investig Allergol Clin Immunol.
2011;21(1):28-33.

24. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Initiation Phase Maintenance Phase
Day Dose (Mcg) Polistes: Even months
10
Vespula: Odd months
20
1
20
Re-sting: All Negative
50 8% LLR
7 Vespula: 0.75% per dose
50 Polistes: 0.45 % per dose
Moreno C, Barasona MJ, Serrano P, Justicia JL, Ruz JM, Guerra F. Alternating Polistes-Vespula venom
immunotherapy: a therapeutic strategy to resolve a diagnostic deficiency. J Investig Allergol Clin Immunol.
2011;21(1):28-33.

26. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• Large EAACI multicenter study: side-effects.
• Buildup: Median dose of 30 mcg (range 0.01-
150)
• Very mild: 1/3 required treatment
• Female sex
• Rapid dose-increase regimens
• Bee-venom extract
• Pre-existing allergic rhinitis
Mosbech H, Müller U. Side-effects of insect venom immunotherapy: results from an EAACI multicenter study. European
Academy of Allergology and Clinical Immunology. Allergy. 2000 Nov;55(11):1005-10.

27. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• Much lower rate of discontinuation of VIT
• ↑efficacy VIT: inhibition of T helper type 2
cytokine production
• ↑patient comfort
• 180 mg fexofenadine:
– ↓LLRs (64% vs 89%), p<0.05)
– Mild SRs (affecting only the skin) (4% vs 23%;
p<0.05).
Reimers A, Hari Y, Muller U. Reduction of side-effects from ultrarush immunotherapy with honeybee venom by
pretreatment with fexofenadine: a double-blind, placebo-controlled trial. Allergy 2000; 55:484-488.
• Anti-IgE: more rapid and ↑doses.

28. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Purified Aqueous Non Purified Aqueous
Vasoactive amines:
NO Yes
DA, 5-HT, Histamine
Apamine, kinins, mast
cell degranulating ↓ ↑
peptide
SR 2% 6% P=0.57
LLR 9% 24% P=0.02
Total Reactions 11% (0.9% of 30% (2.7% of
(SR+LLR) injections) injections)
Bilò MB Severino M Cilia M et al. The VISYT trial: Venom Immunotherapy Safety and
Tolerability with purified vs nonpurified extracts. Ann Allergy Asthma Immunol. 2009
Jul;103(1):57-61.

29. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Adverse
Effects: Induction Phase (Aqueous)
49% Amount
Amount
Week Vial Dose mcg/mL Time (h) administered
administered mcL
mcg
1 1 1 0.1 0 0.1 0.01
1 2 2 1.0 0.5 0.1 0.1
1 3 3 10 1 0.1 1.0
1 3 4 10 1.5 0.3 3.5
2 3 5 10 0 0.5 5.0
2 3 6 10 0.5 0.5 5.0
3 4 7 100 0 0.1 10
3 4 8 100 0.5 0.1 10
4 4 9 100 0 0.2 20
4 4 10 100 0.5 0.2 20
5 4 11 100 0 0.35 35
5 4 12 100 0.5 0.35 35
6 4 13 100 0 0.5 50
6 4 14 100 0.3 0.5 50

30. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Induction Phase (Depot)
Adverse
Amount
Amount Effects:
Week Vial Dose mcg/mL Time (h) administered
mcL
administered mcg 11.8% (1.7%
1 1 1 0.1 0 0.3 0.03 per dose)
1 1 2 0.1 0.5 1.0 0.1
1 2 3 1.0 1 0.3 0.3
1 2 4 1.0 1.5 1.0 1.0
Aqueous
2 3 5 10 0 0.2 2 Adverse
2 3 6 10 0.5 0.4 4 Effects: 49%
3 3 7 10 0 0.6 6 (5.9% per
3 3 8 10 0.5 1.0 10 dose)
4 4 9 100 0 0.1 10
4 4 10 100 0.5 0.2 20
5 4 11 100 0 0.3 30
5 4 12 100 0.5 0.3 30
6 4 13 100 0 0.5 50
6 4 14 100 0.3 0.5 50
Alessandrini AE, Berra D, Rizzini FL, et al. Flexible approaches in the design of subcutaneous immunotherapy protocols
for Hymenoptera venom allergy. Ann Allergy Asthma Immunol. 2006 Jul;97(1):92-7.

32. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• A great deal of induction regimens: Heterogeneity.
• Controversy about cumulative dose
• The number of injections: incidence of SR (p<0.001)
• Purified extracts better than NPA:↓LLR
• The rate of systemic reactions in rush VIT decreases
with the reduction of the cumulative venom dose.
• Female sex, ↑BTC, rapid dose-increase regimens,
bee-venom extract and pre-existing allergic rhinitis
other treatments and comorbidities: ↑ side effects.

33. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
• The rate of systemic reactions in rush VIT
decreases with the reduction of the
cumulative venom dose
• The frequency and the severity of local
reactions are reduced with pretreatment: ↑
patient comfort
• Pretreatment: ↓discontinuation of VIT and ↑
efficacy

34. Build-up of VIT
Efficacy &
Background Tailor-made Pretreatment Extracts Conclusions
Tolerance
Pros Cons
Surveillance

35. Build-up of VIT
Pretreatment
Patient
Extract

36. Mercedes Rodríguez-Rodríguez
María José Sánchez-González
José Barbarroja-Escudero
Melchor Álvarez-Mon Soto
Hymenoptera Venom Hypersensitivity Committee of the SEAIC
Thank you!!