Safety and adverse reactions in subcutaneous allergen immunotherapy: a review
Keywords:
Allergen immunotherapy, safety, systemic reactions, fatalities, uncontrolled asthma, Hymenoptera venom immunotherapy, pathophysiological mechanismsAbstract
Background. Allergen immunotherapy (AIT) is the only treatment which acts on the causes of allergic diseases by modifying their natural history. In the eighties subcutaneous immunotherapy (SCIT) with high biological power allergen extracts caused a number of severe systemic reactions and also fatalities in the UK and the US, resulting in its limitation and in the introduction of other routes of administration. A decisive advance for SCIT safety was understanding that the major cause of mortality was injecting the allergen extract to patients with uncontrolled asthma at the time of injection.
Areas covered. This awareness resulted in a significant decrease in fatalities, but not in their abolition. In 2019, an increase in SCIT-related mortality was observed, suggesting to continue the research for still unidentified factors favoring severe reactions, such as the administration of a wrong extract or of allergen doses higher than listed, unintentional intravenous administration, and missed dose reduction after protracted interruption. Moreover, in the context of the improving of the safety, the role played in tolerance-promoting by adjuvants such as CpG oligodeoxynucleotides has to be taken into account, as well as the potential preventive effect performed by the monoclonal anti-IgE antibody omalizumab against the exacerbation of severe reactions during SCIT.
Conclusion. The safety of SCIT is good, but the research to improve it further must continue. In particular, the pathophysiological mechanisms related to AIT for inhalants and for Hymenoptera venom should be studied, based on the evident diversity demonstrated by the complete absence of fatal reactions to Hymenoptera venom immunotherapy from its introduction in comparison with the history of serious and fatal offenses examined in this review.
References
Frati, F.; Incorvaia, C.; Lombardi, C.; Senna, G. Allergen immunotherapy: 100 years, but it does not look like. Eur Ann Allergy Clin Immunol 2012; 44:99-106.
Pfaar O, Bachert C, Bufe A, 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(8):282-319.
Bem, J.L.; Breckenridge, A.M.; Mann, R.D.; Rawlins, M.D. Review of yellow cards (1986): report to the Committee on the Safety of Medicines. Br J Clin Pharmacol 1988;26:679-689
Lockey, R.F.; Benedict, L.M.; Turkeltaub, P.C.; Bukantz, S.C. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79:660-677
Frew, A.J. Injection immunotherapy. British Society for Allergy and Clinical Immunology Working Party. BMJ 1993;307:919-923
Malling HJ. Minimising the risks of allergen-speci¬ c injection immunotherapy. Drug Saf 2000;23:323–32
Hunt, K.J.; Valentine, M.D.; Sobotka, A.K.; Benton, A.W.; Amodio, F.J.; Lichtenstein, L.M. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-161
Kosnik, M.; Korosec, P. Venom immunotherapy: clinical efficacy, safety and contraindications. Expert Rev Clin Immunol 2015;11:877-884
Incorvaia, C.; Frati, F.; Puccinelli, P.; Riario-Sforza, G.G.; Dal Bo, S. Dose dependence of efficacy and safety of subcutaneous immunotherapy. Monaldi Arch Chest Dis 2006;65:41-43,
Carnes, J.; Gallego, M.T.; Moya, R.; Iraola, V. Allergoids for Allergy Treatment. Recent Pat Inflamm Allergy Drug Discov 2018;12:110-119
Mosges, R.; Passali, D.; Di Gioacchino, M. Worldwide surveys on anaphylaxis to sublingual immunotherapy with house dust mite tablets are urgently needed. Clin Transl Allergy 2021; 11
Passalacqua, G.; Canonica, G.W. Allergen-specific sublingual immunotherapy for respiratory allergy. BioDrugs 2001;15:509-519
Epstein, T.G.; Liss, G.M.; Murphy-Berendts, K.; Bernstein, D.I. Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013). Ann Allergy Asthma Immunol 2016;116:354-359
Epstein, T.G.; Murphy-Berendts, K.; Liss, G.M.; Bernstein, D.I. Risk factors for fatal and nonfatal reactions to immunotherapy (2008-2018): postinjection monitoring and severe asthma. Ann Allergy Asthma Immunol 2021;127:64-69
Epstein, T.G.; Liss, G.M.; Berendts, K.M.; Bernstein, D.I. AAAAI/ACAAI Subcutaneous Immunotherapy Surveillance Study (2013-2017): Fatalities, Infections, Delayed Reactions, and Use of Epinephrine Autoinjectors. J Allergy Clin Immunol Pract 2019;7:1996-2003
Borchers, A.T.; Keen, C.L.; Gershwin, M.E. Fatalities following allergen immunotherapy. Clin Rev Allergy Immunol 2004;27:147-158
Sanchez-Borges, M.; Bernstein, D.I.; Calabria, C. Subcutaneous Immunotherapy Safety: Incidence per Surveys and Risk Factors. Immunol Allergy Clin North Am 2020;40:25-39,
Dhamija, Y.; Epstein, T.E.G.; Bernstein, D.I. Systemic Allergic Reactions and Anaphylaxis Associated with Allergen Immunotherapy. Immunol Allergy Clin North Am 2022;42:05-119
Montamat, G.; Leonard, C.; Poli, A.; Klimek, L.; Ollert, M. CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance. Front Immunol 2021;12:590054
Pfaar, O.; Bousquet, J.; Durham, S.R.; Kleine-Tebbe, J.; Larche, M.; Roberts, G.; Shamji, M.H.; Gerth van Wijk, R. One hundred and ten years of Allergen Immunotherapy: A journey from empiric observation to evidence. Allergy 2022;77:454-468
Businco, L.; Zannino, L.; Cantani, A.; Corrias, A.; Fiocchi, A.; La Rosa, M. Systemic reactions to specific immunotherapy in children with respiratory allergy: a prospective study. Pediatr Allergy Immunol 1995;6:44-47
Robertson, K.; Montazeri, N.; Shelke, U.; Jeimy, S.; Kim, H. A single centre retrospective study of systemic reactions to subcutaneous immunotherapy. Allergy Asthma Clin Immunol 2020;16:93
Sanchez-Villalobos, J.Y.; Caballero-Lopez, C.; Lopez-Garcia, A.I.; Rivero-Yeverino, D.; Arana-Munoz, O.; Papaqui-Tapia, J.S.; Rios-Lopez, J.J.; Payan-Diaz, J.H.; Lopez-Romero, C.D.; Villada-Villada, E. [The effectiveness and safety of subcutaneous immunotherapy for inhalable allergens in patients with respiratory allergies after one year of treatment]. Rev Alerg Mex 2020;67:309-315
Lim, C.E.; Sison, C.P.; Ponda, P. Comparison of Pediatric and Adult Systemic Reactions to Subcutaneous Immunotherapy. J Allergy Clin Immunol Pract 2017;5:1241-1247
Sani, S.; Gupta, R.; Fonacier, L.; Aquino, M. Risk stratification of systemic reactions to subcutaneous immunotherapy: A retrospective study. Allergy Asthma Proc 2019;40:338-342,
Ayats-Vidal, R.; Riera-Rubio, S.; Valdesoiro-Navarrete, L.; Garcia-Gonzalez, M.; Larramona-Carrera, H.; Cruz, O.A.; Bosque-Garcia, M. Long-term outcome of omalizumab-assisted desensitisation to cow's milk and eggs in patients refractory to conventional oral immunotherapy: real-life study. Allergol Immunopathol (Madr) 2022;50:1-7
Har, D.; Lee, M.J. Systemic reaction rates with omalizumab, subcutaneous immunotherapy, and combination therapy in children with allergic asthma. Allergy Asthma Proc 2019;40:35-40
Massanari, M.; Nelson, H.; Casale, T.; Busse, W.; Kianifard, F.; Geba, G.P.; Zeldin, R.K. Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. J Allergy Clin Immunol 2010:125;383-389
Bernaola, M.; Hamadi, S.A.; Lynch, D.M.; Marquis, K.A.; Silver, J.N.; Castells, M.C.; Hsu, J.T. Successful administration of omalizumab by desensitization protocol following systemic reactions in 12 patients. J Allergy Clin Immunol Pract 2021;9:2505-2508
Valdesoiro-Navarrete, L.; Leon, M.E.; Rodriguez, M.; Indiveri, M.; Ayats, R.; Larramona, H.; Gonzalez, M.G.; de la Cruz, O.A.; Garcia, M.B. Combination therapy of specific aeroallergens immunotherapy and omalizumab, in children with severe asthma. Allergol Immunopathol (Madr) 2022;50:1-6
Klimek, L.; Jutel, M.; Akdis, C.; Bousquet, J.; Akdis, M.; Bachert, C.; Agache, I.; Ansotegui, I.; Bedbrook, A.; Bosnic-Anticevich, S.; et al. Handling of allergen immunotherapy in the COVID-19 pandemic: An ARIA-EAACI statement. Allergy 2020;75:1546-1554
Pfaar, O.; Hamelmann, E.; Klimek, L.; Taube, C.; Vogelberg, C.; Wagenmann, M.; Werfel, T.; Worm, M. Allergen immunotherapy during the COVID-19 pandemic-A survey of the German Society for Allergy and Clinical Immunology. Clin Transl Allergy 2022:12
Masieri, S.; Bachert, C.; Ojeda, P.; Kim, C.K.; Cavaliere, C.; Ciprandi, G.; Study Group on, A.I.T.; Vaccinations. Allergen Immunotherapy management during vaccinations: An international survey. World Allergy Organ J 2021:14:100601
Savouré M, Bousquet J, Jaakkola JJK, Jaakkola MS, Jacquemin B, Nadif R. Worldwide prevalence of rhinitis in adults: A review of definitions and temporal evolution. Clin Transl Allergy. 2022;12(3):e12130.
Lombardi C, Passalacqua G, Gargioni S, Senna G, Ciprandi G, Scordamaglia A, Canonica GW. The natural history of respiratory allergy: a follow-up study of 99 patients up to 10 years. Respir Med. 2001;95(1):9-12
Wise SK, Lin SY, Toskala E et al.
International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018;8:108-352.
Gonzalez-de-Olano, D.; Alvarez-Twose, I.; Vega, A.; Orfao, A.; Escribano, L. Venom immunotherapy in patients with mastocytosis and hymenoptera venom anaphylaxis. Immunotherapy 2011;3:637-651
Bonadonna, P.; Zanotti, R.; Muller, U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol 2010;10:347-353
Sampath, V.; Abrams, E.M.; Adlou, B.; Akdis, C.; Akdis, M.; Brough, H.A.; Chan, S.; Chatchatee, P.; Chinthrajah, R.S.; Cocco, R.R.; et al. Food allergy across the globe. J Allergy Clin Immunol 2021;148:1347-1364
Costa, C.; Coimbra, A.; Vitor, A.; Aguiar, R.; Ferreira, A.L.; Todo-Bom, A. Food allergy-From food avoidance to active treatment. Scand J Immunol 2020;91:e12824
Incorvaia C, Ridolo E, Mauro M, Pucciarini F, Heffler E, Canonica GW. Venom Immunotherapy and Aeroallergen Immunotherapy: How Do Their Outcomes Differ? Front Allergy. 2022;3:854080.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Erminia Ridolo, Cristoforo Incorvaia, Carlo Cavaliere, Jan W. Schroeder, Gualtiero leo, Francesca Nicoletta, Alessandro Barone
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
How to Cite
