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Cho, Lee, Park, Kwon, and Kim: Safety of ultrarush allergen subcutaneous immunotherapy in children with allergic disease



Ultrarush immunotherapy (ultra-RIT) is more convenient and higher compliant than conventional immunotherapy, but it has rarely used in clinical practice due to severe systemic reactions. This study aimed to determine the safety of ultra-RIT in children and adolescents.


We investigated 19 patients who received ultra-RIT with the same schedule between January 2011 and May 2016. They were sensitized to house dust mites (HDMs) and/or pollen and had their symptoms associated with positive allergens. Over a 1-day hospitalization period, all patients received ultra-RIT subcutaneously 3 times, increasing at hourly intervals. Systemic reactions were classified according to the World Allergy Organization grade system.


Systemic reactions occurred in 14 patients (73.7%). The mean time to adverse reactions after the last injection was 36 minutes, and the majority of systemic reactions were pruritus and urticaria. In addition, the injection of HDM alone or HDM plus pollen caused more than grade 2 systemic reactions in about 50% each of the patients.


Since ultra-RIT caused a higher incidence of systemic reactions in children and adolescents, it should be carried out cautiously in the hospitalization rather than the office.

Figures and Tables

Fig. 1

Protocol for ultrarush immunotherapy. Novo-Helisen Depot (Allergopharma Joachim Ganzer KG, Reinbeck, Germany) with allergen concentration 5,000 units/mL was injected 3 times at 1-hour interval for 3 hours subcutaneously.10 Third injected dose was 50% maximal allergen dose. Maintenance treatment was started at 2 weeks after rapid induction. Antihistamine was taken 1 week prior to immunotherapy and two more weeks before the next visit. BP, blood pressure; HR, heart rate; RR, respiratory rate.

Table 1

Demographic characteristics in patients with ultrarush subcutaneous immunotherapy

Characteristic Total (n=19) Ultrarush IT cases P-value
Continuation (n=14) Dropout* (n=5)
Age (yr) 12.1 ± 3.9 10.7 ± 2.2 15.8 ± 5.4 0.103
Male sex 13 (68.4) 10 (71.4) 3 (60) 0.637
Eosinophil count (/µL) 305.3 ± 336.6 230.0 ± 300.3 516.0 ± 375.9 0.176
Total IgE (IU/mL) 522.8 ± 968.0 258.3 ± 235.9 1,263.2 ± 1,762.1 0.272
Allergen 0.203
 House dust mite 11 (57.9) 9 (64.3) 2 (40.0)
 House dust mite with pollen§ 7 (36.8) 5 (35.7) 2 (40.0)
 Pollen§ 1 (5.3) 0 (0) 1 (20.0)
Disease 0.356
 Asthma only 1 (5.3) 1 (7.1) 0 (0)
 AR only 8 (42.1) 4 (28.6) 4 (80.0)
 AR & asthma 6 (31.6) 5 (35.7) 1 (20.0)
 AR & AD 2 (10.5) 2 (14.3) 0 (0)
 AR & AC 2 (10.5) 2 (14.3) 0 (0)

Values are presented as mean±standard deviation or number (%).

IT, immunotherapy; AR, allergic rhinitis; AD, atopic dermatitis; AC, allergic conjunctivitis.

*Those who gave up immunotherapy were classified among the 19 patients who underwent ultrarush allergen immunotherapy. There was no statistical significance comparing the continuation and dropout groups with Student t-test. There was no statistical significance in the both groups, tested by chi-square test. §Pollen includes tree pollen (alder, hazel, and birch), grass (rye and timothy), and weeds (mugwort and ragweed).

Table 2

Systemic reactions grade of ultrarush subcutaneous immunotherapy

WAO SR grade* No. of patients (%) Mean onset time of SR (min) No. of epinephrine IM (%)
Grade 1 6 (42.9) 140.3 2 (33.3)
 Urticaria 3 287.7 1
 Angioedema 1 165 1
 Cough 1 143 0
 Eye Itching 1 270 0
Grade 2 5 (35.7) 154.5 2 (33.3)
 Urticaria and dyspnea 2 232.5 0
 Urticaria and wheezing 3 131.3 2
Grade 3 3 (21.4) 142.1 2 (33.3)
 Angioedema and dyspnea with urticaria 1 245 0
 Urticaria and wheezing 2 195 2
Grade 4 0 - -
Grade 5 0 - -
Total 14 (100) 154.5 (range, 70–403) 6 (42.9)

WAO SR, World Allergy Organization systemic reaction; IM, intramuscular.

*In 2010, the WAO systemic adverse events in subcutaneous immunotherapy was as follows: Grade 1 was defined as the presence of sign and/or symptom of 1 organ, such as skin, upper respiratory tract, conjunctival symptoms and so on. Grade 2 was defined as the presence of signs or symptoms involving one or more organs, such as lower respiratory, gastrointestinal, or uterine cramps. Grade 3 was a lower respiratory condition with no response to inhaled bronchodilator therapy. Grade 4 was classified as respiratory symptoms due to respiratory failure or cardiovascular symptoms, and grade 5 as death.1 Epinephrine treatment was performed in cases involving more than 2 organs with dyspnea, and also in failure of first treatment. There was no response to inhalation therapy for dyspnea.

Table 3

Side effects during ultrarush subcutaneous immunotherapy according to allergen and allergic disease

Variable Total number No. of SR (%) SR ≥ grade 2*, n (%) P-value
Allergen 0.710
 HDM 11 9 (81.8) 5 (45.6) 0.637
 HDM with pollen 7 4 (57.1) 2 (50.0)
Disease 0.625
 Asthma only 1 1 (7.1) 0 (0) 0.668
 AR only 8 6 (42.9) 4 (50.0)
 AR & asthma 6 4 (28.6) 3 (37.5)
 AR & AD 2 2 (14.3) 0 (0)
 AR & AC 2 1 (7.1) 1 (12.5)

SR, systemic reaction; HDM, house dust mites; AR, Allergic Rhinitis; AC, allergic conjunctivitis; AD, atopic dermatitis.

*Grade 2 or more was accompanied by dyspnea or low respiratory symptoms. According to allergen or allergic disease all systemic reactions were analyzed using the chi-square statistical method. According to allergen or allergic disease grade 2 or more systemic reactions were analyzed using the chi-square statistical method.


1. Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015; 136:556–568.
2. Roche AM, Wise SK. Subcutaneous immunotherapy. Int Forum Allergy Rhinol. 2014; 4:Suppl 2. S51–S54.
3. Cox L. Accelerated immunotherapy schedules: review of efficacy and safety. Ann Allergy Asthma Immunol. 2006; 97:126–137.
4. Des Roches A, Paradis L, Menardo JL, Bouges S, Daurés JP, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol. 1997; 99:450–453.
5. Purello-D'Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy. 2001; 31:1295–1302.
6. Rhodes BJ. Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. Ann Allergy Asthma Immunol. 1999; 82:281–286.
7. Hyun SE, Kim HY, Kwak JH, Shin YH, Seo JY, Han MY. Safety and efficacy of the ultra-rush immunotherapy with extracts of Dermatophagoides pteronyssinus in children. Korean J Pediatr. 2008; 51:868–873.
8. Kim ME, Kim JE, Sung JM, Lee JW, Choi GS, Nahm DH. Safety of accelerated schedules of subcutaneous allergen immunotherapy with house dust mite extract in patients with atopic dermatitis. J Korean Med Sci. 2011; 26:1159–1164.
9. Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000; 162(4 Pt 1):1403–1406.
10. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000; 161:309–329.
11. The Korean Academy of Asthma, Allergy and Clinical Immunology. The Korean Academy of Pediatric Allergy and Respiratory Disease. Korean Guideline for Asthma [Internet]. Seoul: The Korean Academy of Asthma, Allergy and Clinical Immunology;The Korean Academy of Pediatric Allergy and Respiratory Disease;2015. cited 2017 Mar 28. Available from:
12. Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010; 126:466–476.
13. Esch RE. Allergen immunotherapy: what can and cannot be mixed? J Allergy Clin Immunol. 2008; 122:659–660.
14. Calderón MA, Cox L, Casale TB, Moingeon P, Demoly P. Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: looking at the published evidence. J Allergy Clin Immunol. 2012; 129:929–934.
15. Lee KU, Kim KE. A study on the method of exclusion on unnecessary allergens from the vaccines for immunotherapy. J Asthma Allergy Clin Immunol. 1988; 8:150–164.
16. Lee KY, Kim KE. Diagnosis and management of allergic disease. Seoul: Hangukeuihaksa;2001.
17. Calabria CW. Accelerated immunotherapy schedules. Curr Allergy Asthma Rep. 2013; 13:389–398.
18. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. the World Allergy Organization subcutaneous immunotherapy systemic reaction grading system. J Allergy Clin Immunol. 2010; 125:569–574. 574.e1–574.e7.
19. Schaefer P. Urticaria: evaluation and treatment. Am Fam Physician. 2011; 83:1078–1084.
20. Kemp SF, Lockey RF, Simons FE. World Allergy Organization ad hoc Committee on Epinephrine in anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008; 63:1061–1070.
21. Nahm DH. Present and future of allergen immunotherapy for allergic diseases. J Korean Med Assoc. 2015; 58:433–440.
22. Incorvaia C, Mauro M, Ridolo E, Puccinelli P, Liuzzo M, Scurati S, et al. Patient's compliance with allergen immunotherapy. Patient Prefer Adherence. 2008; 2:247–251.
23. Nam YH, Lee SK. Physician's recommendation and explanation is important in the initiation and maintenance of allergen immunotherapy. Patient Prefer Adherence. 2017; 11:381–387.
24. Goldberg A, Confino-Cohen R. Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy. Ann Allergy Asthma Immunol. 2003; 91:405–410.
25. Hejjaoui A, Ferrando R, Dhivert H, Michel FB, Bousquet J. Systemic reactions occurring during immunotherapy with standardized pollen extracts. J Allergy Clin Immunol. 1992; 89:925–933.
26. 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; 127:1 Suppl. S1–S55.
27. Brehler R, Klimek L, Pfaar O, Hauswald B, Worm M, Bieber T. Safety of a rush immunotherapy build-up schedule with depigmented polymerized allergen extracts. Allergy Asthma Proc. 2010; 31:e31–e38.
28. Morais-Almeida M, Arêde C, Sampaio G, Borrego LM. Ultrarush schedule of subcutaneous immunotherapy with modified allergen extracts is safe in paediatric age. Asia Pac Allergy. 2016; 6:35–42.
29. Cardona R, Lopez E, Beltrán J, Sánchez J. Safety of immunotherapy in patients with rhinitis, asthma or atopic dermatitis using an ultra-rush buildup. A retrospective study. Allergol Immunopathol (Madr). 2014; 42:90–95.
30. Portnoy J, Bagstad K, Kanarek H, Pacheco F, Hall B, Barnes C. Premedication reduces the incidence of systemic reactions during inhalant rush immunotherapy with mixtures of allergenic extracts. Ann Allergy. 1994; 73:409–418.
31. Akmanlar N, Altintaş DU, Güneşer KS, Yilmaz M, Bingöl G. Comparison of conventional and rush immunotherapy with der PI in childhood respiratory allergy. Allergol Immunopathol (Madr). 2000; 28:213–218.
32. Kartal O, Gulec M, Caliskaner Z, Musabak U, Sener O. Safety of subcutaneous immunotherapy with inhalant allergen extracts: a single-center 30-year experience from Turkey. Immunopharmacol Immunotoxicol. 2015; 37:280–286.
33. Gastaminza G, Algorta J, Audicana M, Etxenagusia M, Fernández E, Muñoz D. Systemic reactions to immunotherapy: influence of composition and manufacturer. Clin Exp Allergy. 2003; 33:470–474.
34. Winther L, Arnved J, Malling HJ, Nolte H, Mosbech H. Side-effects of allergen-specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy. 2006; 36:254–260.
35. Borchers AT, Keen CL, Gershwin ME. Fatalities following allergen immunotherapy. Clin Rev Allergy Immunol. 2004; 27:147–158.
36. Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int. 2014; 23:282–319.

Ja Kyoung Kim

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