Research Article

Modification of allergen subcutaneous immunotherapy safety precautions and systemic allergic reaction rate reduction

*Author for correspondence: Tel.: +972 544 727 308;

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

‡Authors contributed equally

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David Mishayev‡

https://orcid.org/0000-0002-8570-6525

Faculty of Medicine, Hebrew University of Jerusalem, 9112102, Israel

‡Authors contributed equally

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Marina Yakovlev

https://orcid.org/0000-0003-4011-4179

Department of Medicine D, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, 7661041, Israel

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Ilan Asher

https://orcid.org/0000-0003-3605-5815

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

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Zev Sthoeger

https://orcid.org/0000-0002-8620-0884

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

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Alex Guri

https://orcid.org/0000-0002-0720-4554

Department of Pediatrics, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, 7661041, Israel

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Daniel Elbirt

https://orcid.org/0000-0002-9056-236X

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

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Shay Nemet‡

https://orcid.org/0000-0002-6198-5099

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

‡Authors contributed equally

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Shira Rosenberg-Bezalel‡

https://orcid.org/0000-0002-5956-341X

Department of Allergy & Clinical Immunology, Kaplan Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel

‡Authors contributed equally

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Published Online:11 Sep 2023https://doi.org/10.2217/imt-2023-0072

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Abstract

Background: Despite their life-threatening potential, medical team mistakes during subcutaneous immunotherapy are rarely discussed. Real data are missing, and a survey study estimated that dosing errors are responsible for 25% of systemic reactions during immunotherapy. To minimize errors, we modified our safety precautions and compared the rates of systemic allergic reactions before and after the change. Methods: Our retrospective comparative cohort study compared systemic allergic reaction rates during 2012–2015 and 2016–2019, after a second check of the injected allergen/s by another nurse/physician was added to the treatment protocol. Results: The rate of systemic allergic reaction per injection was reduced from 0.93 to 0.71%; p = 0.023. Conclusion: A second check prior to injection is beneficial and can reduce the allergic reaction rate during immunotherapy.

Plain language summary

Many people suffer from allergies to dust or pollen, and they might suffer from a running nose when they come into contact with the allergens. This reaction is called hayfever or allergic rhinitis. Immunotherapy is a treatment which can help to treat patients with allergic rhinitis. During treatment, the patients receive injections of small amounts of dust or pollen, and with time become less allergic. The injections themselves might cause allergic reactions such as rash, hives, swelling or trouble breathing. Sometimes these allergic reactions are related to mistakes made by the medical team. In our study we changed safety instruction to add a second check of the materials and amounts before the injections were given to the patient. This was checked by two different nurses. We compared the number of allergic reactions to the shots before and after the change. We found that the number of allergic reactions was 9.3 for 1000 injections before and 7.1 for 1000 injections after the change. We think that a second check of the materials and amounts before giving the injections is helpful and can prevent some of the allergic reactions.

Tweetable abstract

Despite life-threatening potential, medical team mistakes during subcutaneous immunotherapy are rarely discussed. Double checking prior to injection is beneficial and reduced the allergic reaction rate from 0.93 to 0.71%; p = 0.023.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Sharma K, Akre S, Chakole S, Wanjari MB. Allergic rhinitis and treatment modalities: a review of literature. Cureus 28(8), 14 (2022).
CASGoogle Scholar
2. Wheatley LM, Togias A. Allergic rhinitis. N. Engl. J Med. 372, 456–463 (2015).
MedlineGoogle Scholar
3. Gálffy G, Emmeluth M, Koltun A et al. Allergic rhinitis therapy decisions during a routine consultation: a multicenter, cross-sectional survey. J. Asthma Allergy 14, 335–345 (2021).
MedlineGoogle Scholar
4. Bousquet J, Khaltaev N, Cruz AA et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 63(Suppl. 86), 8–160 (2008).
MedlineGoogle Scholar
5. Lee TH. Allergy: the unmet need. Clin. Med. 3, 303–305 (2003).
MedlineGoogle Scholar
6. Meltzer EO, Blaiss MS, Naclerio RM et al. Burden of allergic rhinitis: allergies in America, Latin America, and Asia-Pacific adult surveys. Allergy Asthma Proc. 33(Suppl. 1), S113–S141 (2012).
Medline CASGoogle Scholar
7. Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur. Respir. J. 24, 758–764 (2004).
Medline CASGoogle Scholar
8. Pawankar R, Mori S, Ozu C, Kimura S. Overview on the pathomechanisms of allergic rhinitis. Asia. Pac. Allergy 1(3), 157–167 (2011).
MedlineGoogle Scholar
9. Pawankar R. Allergic rhinitis and asthma: are they manifestations of one syndrome? Clin. Exp. Allergy 36(1), 1–4 (2006).
Medline CASGoogle Scholar
10. Sheikh A, Hurwitz B. House dust mite avoidance measures for perennial allergic rhinitis: a systematic review of efficacy. Br. J. Gen. Pract. 53(489), 318–322 (2003).
MedlineGoogle Scholar
11. Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J. Investig. Allergol. Clin. Immunol. 16(3), 148–155 (2006).
Medline CASGoogle Scholar
12. Noon L. Prophylactic inoculation against hay fever. Int. Arch. Allergy Appl. Immunol. 4, 285–288 (1953).
Medline CASGoogle Scholar
13. Frankland AW, Augustin R. Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component. Lancet 266, 1055–1057 (1954).
Medline CASGoogle Scholar
14. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J. Allergy Clin. Immunol. 102, 558–562 (1998).
Medline CASGoogle Scholar
15. Durham SR, Shamji MH. Allergen immunotherapy: past, present and future. Nat. Rev. Immunol. 23(5), 317–328 (2023).
Medline CASGoogle Scholar
16. Bousquet J, Lockey R, Malling HJ et al. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American Academy of Allergy, Asthma and Immunology. Ann. Allergy Asthma Immunol. 81(5), 401–405 (1998).
Medline CASGoogle Scholar
17. Gueguen C, Bouley J, Moussu H et al. Changes in markers associated with dendritic cells driving the differentiation of either Th2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. J. Allergy Clin. Immunol. 137, 545–558 (2016).
Medline CASGoogle Scholar
18. Drazdauskaitė G, Layhadi JA, Shamji MH. Mechanisms of allergen immunotherapy in allergic rhinitis. Curr. Allergy Asthma Rep. 12, 21 (2020).
Google Scholar
19. Shamji MH, Bellido V, Scadding GW et al. Effector cell signature in peripheral blood following nasal allergen challenge in grass pollen allergic individuals. Allergy 70, 171–179 (2015).
Medline CASGoogle Scholar
20. Taudorf E, Weeke B. Orally administered grass pollen. Allergy 38, 561–564 (1983).
Medline CASGoogle Scholar
21. Roberts G, Pfaar O, Akdis CA et al. EAACI Guidelines on Allergen Immunotherapy: allergic rhinoconjunctivitis. Allergy 73(4), 765–798 (2018).
Medline CASGoogle Scholar
22. Dhami S, Nurmatov U, Arasi S et al. Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis. Allergy 72, 1597–1631 (2017).
Medline CASGoogle Scholar
23. Durham SR, Creticos PS, Nelson HS et al. Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: pooled analyses. J. Allergy Clin. Immunol. 13, 1081–1088 (2016).
Google Scholar
24. Scadding GW, Calderon MA, Shamji MH, Immune Tolerance Network GRASS Study Team et al. Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis: the GRASS randomized clinical trial. JAMA 317(6), 615–625 (2017).
Medline CASGoogle Scholar
25. Shamji MH, Larson D, Eifan A et al. Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy. J. Allergy Clin. Immunol. 148(4), 1061–1071 (2021).
Medline CASGoogle Scholar
26. Cox L, Nelson H, Lockey R et al. Allergen immunotherapy: a practice parameter third update. J. Allergy. Clin. Immunol. 127(Suppl. 1), S1–S5 (2011).
MedlineGoogle Scholar
27. Rottem M, Egbarya A. Subcutaneous immunotherapy in northern Israel: efficacy and safety. Isr. Med. Assoc. J. 16(9), 539–534 (2014).
MedlineGoogle Scholar
28. Elizur A, Katz Y. Allergen immunotherapy: the good, the bad, and the unknown. Isr. Med. Assoc. J. 16(9), 580–582 (2014).
MedlineGoogle Scholar
29. Coop CA, Tankersley MS. Patient perceptions regarding local reactions from allergen immunotherapy injections. Ann. Allergy Asthma Immunol. 101, 96–100 (2008).
MedlineGoogle Scholar
30. Epstein TG, Liss GM, Berendts KM, Bernstein DI. AAAAI/ACAAI Subcutaneous Immunotherapy surveillance study (2013–2017): fatalities, infections, delayed reactions, and use of epinephrine autoinjectors. J. Allergy Clin. Immunol. Pract. 7(6), 1996–2003 (2019). • Data gathered on 54.4 million allergen immunotherapy injection visits (2008–2016) showed an estimated systemic allergic reaction rate of 0.087%.
MedlineGoogle Scholar
31. Bernstein DI, Wanner M, Borish L et al. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J. Allergy Clin. Immunol. 113(6), 1129–1136 (2004).
MedlineGoogle Scholar
32. Dong X, Huang N, Li W et al. Systemic reactions to dust mite subcutaneous Immunotherapy: a 3-year follow-up study. Allergy Asthma Immunol. Res. 8(5), 421–427 (2016).
MedlineGoogle Scholar
33. 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. 16(1), 1–6 (2020).
MedlineGoogle Scholar
34. Epstein TG, Liss GM, Murphy-Berendts K et al. Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: national surveillance study on allergen immunotherapy (2008–2013). Ann. Allergy Asthma Immunol 116(4), 354–359 (2016).
MedlineGoogle Scholar
35. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J. Allergy Clin. Immunol. 117(1), 169–175 (2020). •• In a survey of fatal and near-fatal reactions administered to practicing allergists, 273 physicians estimated that 25% of the allergic reactions during immunotherapy resulted from medical team mistakes.
Google Scholar
36. Kowalski ML, Ansotegui I, Aberer W et al. Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement. World Allergy Organ. J. 9(1), 33 (2016).
MedlineGoogle Scholar
37. Schiappoli M, Ridolo E, Senna G et al. A prospective Italian survey on the safety of subcutaneous immunotherapy for respiratory allergy. Clin. Exp. Allergy. 39(10), 1569–1574 (2009).
Medline CASGoogle Scholar
38. Aue A, Ho J, Zhu R, Kim H, Jeimy S. Systemic reactions to subcutaneous allergen immunotherapy: real-world cause and effect modelling. Allergy Asthma Clin. Immunol. 17(1), 65 (2021). • A total of 4242 injections of subcutaneous immunotherapy were performed over a period of 12 months. Of these, ten injections resulted in a systemic reaction requiring epinephrine administration (0.24%). Major risk factors included seasonal exacerbation of allergic rhinitis, uncontrolled asthma and an error in route of administration.
MedlineGoogle Scholar
39. Mellerup MT, Hahn GW, Poulsen LK, Malling H. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment. Clin. Exp. Allergy. 30(10), 1423–1429 (2000). • Since 1990, three different clustered induction regimens of allergen immunotherapy have been investigated in 657 patients (10,369 injections). A total of 454 systemic (immediate and late) reactions were observed in 257 patients, corresponding to 4.4% of the injections and 39.1% of the patients.
Medline CASGoogle Scholar
40. Scherer K, Schindler C, Arnold A, Bach S, Bircher AJ. Analysis of an unusual cluster of systemic reactions to subcutaneous specific immunotherapy with respiratory allergens in one allergy center. Int. Arch. Allergy Immunol. 157(3), 318–320 (2012).
Medline CASGoogle Scholar
41. Sánchez-Borges M, Bernstein DI, Calabria C. Subcutaneous immunotherapy safety: incidence per surveys and risk factors. Immunol. Allergy Clin. North Am. 40(1), 25–39 (2020).
MedlineGoogle Scholar
42. Ragusa FV, Passalacqua G, Gambardella R et al. Nonfatal systemic reactions to subcutaneous immunotherapy: a 10-year experience. J. Investig. Allergol. Clin. Immunol. 7(3), 151–154 (1997).
Medline CASGoogle Scholar
43. Phillips JF, Lockey RF, Fox RW, Ledford DK, Glaum MC. Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. Allergy Asthma Proc. 32(4), 288–294 (2011).
Medline CASGoogle Scholar
44. Mustafa SS, Bingemann T, Blue H, Conn K, Hanley T, Ramsey A. Systemic reactions to subcutaneous immunotherapy: effects of dosing and aeroallergen content. Ann. Allergy Asthma Immunol. 123(3), 284–287 (2019).
Medline CASGoogle Scholar
45. Nettis E, Giordano D, Ferrannini A, Tursi A. Systemic reactions to allergen immunotherapy: a review of the literature. Immunopharmacol. Immunotoxicol. 25(1), 1–11 (2003).
MedlineGoogle Scholar
46. Aaronson DW, Gandhi TK. Incorrect allergy injections: allergists' experiences and recommendations for prevention. J. Allergy Clin. Immunol. 113(6), 1117–1121 (2004). •• An email survey of 1717 allergists reported that 58% of responders reported an event in which a patient had received an injection meant for another patient and 74% of responders reported that patients had received an incorrect amount of vaccine. Therefore, allergy injections are a potential safety concern.
MedlineGoogle Scholar
47. Kim L, Nevis I, Potts R, Eeuwes C, Dominic A, Kim HL. Patients on subcutaneous allergen immunotherapy are at risk of intramuscular injections. Allergy Asthma Clin. Immunol. 10(1), 22 (2014).
MedlineGoogle Scholar
48. Patel S, Rossow KL, Williams BJ, Li JT, Rank MA. Errors in allergen immunotherapy administration: a systems assessment. Ann. Allergy Asthma Immunol. 110(3), 205–206 (2013). •• Retrospectively evaluated errors in allergen immunotherapy administration and identified five errors in 3193 injections during a 6-month period (0.2% errors).
MedlineGoogle Scholar
49. Greineder DK. Risk management in allergen immunotherapy. J. Allergy Clin. Immunol. 98(6), 330–334 (1996).
Google Scholar
50. Dursun AB, Sin BA, Oner F, Misirligil Z. The safety of allergen immunotherapy (IT) in Turkey. J. Investig. Allergol. Clin. Immunol. 16(2), 123–128 (2006).
Medline CASGoogle Scholar
51. Windom HH, Lockey RF. An update on the safety of specific immunotherapy. Curr. Opin. Allergy Clin. Immunol. 8(6), 571–576 (2008).
MedlineGoogle Scholar
52. Nelson MR, Petersen MM, Wolverton WO, Mikita CP. Allergen immunotherapy extract treatment set preparation: making a safer and higher quality product for patients. Curr. Allergy Asthma Rep. 13(4), 399–405 (2013). • A review of allergen immunotherapy preparation recommendations and best practices based on published national guidelines is presented.
Medline CASGoogle Scholar
53. Di Bona D, Magistà S, Masciopinto L et al. Safety and treatment compliance of subcutaneous immunotherapy: A 30-year retrospective study. Resp. Med. 161(1), (2020). • A retrospective analysis of 2200 patients who received subcutaneuos immunotherapy over 30 years. Asthma, female sex and build-up phase were associated with systemic allergic reactions.
Google Scholar
54. Tsabouri S, Mavroudi A, Feketea G, Guibas GV. Corrigendum: Subcutaneous and sublingual immunotherapy in allergic asthma in children. Front. Pediatr. 5, 187 (2017).
MedlineGoogle Scholar
55. Cappella A, Durham SR. Allergen immunotherapy for allergic respiratory diseases. Hum. Vaccin. Immunother. 8(10), 499–512 (2012).
MedlineGoogle Scholar
56. Calderón MA, Vidal C, Rodríguez Del Río P, on behalf of EASSI doctors' group et al. European survey on adverse systemic reactions in allergen immunotherapy (EASSI): a real-life clinical assessment. Allergy 72, 462–472 (2017).
Medline CASGoogle Scholar
57. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, year 3: what practices modify the risk of systemic reactions? Ann. Allergy Asthma Immunol. 110(4), 274–278 (2013).
MedlineGoogle Scholar
58. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Survey of fatalities from skin testing and immunotherapy 1985–9. J. Allergy Clin. Immunol. 92(1), 6–15 (1993).
Medline CASGoogle Scholar
59. Roy SR, Sigmon JR, Olivier J, Moffitt JE, Brown DA, Marshall GD. Increased frequency of large local reactions among systemic reactors during subcutaneous allergen immunotherapy. Ann. Allergy Asthma Immunol. 99(1), 82–86 (2007).
MedlineGoogle Scholar
60. Ohashi Y, Nakai Y, Murata K. Effect of pretreatment with fexofenadine on the safety of immunotherapy in patients with allergic rhinitis. Ann. Allergy Asthma Immunol. 96(4), 600–605 (2006).
MedlineGoogle Scholar
61. Rank MA, Bernstein DI. Improving the Safety of Immunotherapy. J. Allergy Clin. Immunol. In Prac. 2(2), 131–135 (2014).
MedlineGoogle Scholar

Vol. 15, No. 16

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History

Received 22 March 2023

Accepted 21 August 2023

Published online 11 September 2023

Published in print November 2023

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Author contributions

K Mahlab-Guri, D Mishayev, S Nemet, S Rosenberg-Bezalel substantially contributed to the conception and design of the work; the acquisition, analysis and interpretation of data for the work; drafted the work and revised it critically for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. M Yakovlev, I Asher, Z Sthoeger, A Guri and D Elbirt substantially contributed to the acquisition, analysis and interpretation of data for the work, revised the work critically for important intellectual content, approved the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors thank Tali Bdolach-Avram for statistical analysis.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

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