Underuse of allergen immunotherapy: a call to action

Abstract

Despite its proven effectiveness in treating allergic conditions, allergen immunotherapy (AIT) remains significantly underevaluated in clinical practice. On the contrary, there is a scientific interest in AIT research with more than doubled number of manuscripts published in the last decade respect to the previous years. This gap limits its potential to improve patient outcomes and advance our understanding of allergy management. To address this issue, healthcare professionals, researchers, and policymakers must prioritize comprehensive evaluation of AIT. Increased investment in clinical trials, real-world studies, and education will help clarify its long-term benefits, safety profile, and optimal application across diverse patient populations. Collaborative efforts will ensure that AIT achieves its full potential, ultimately enhancing the quality of life for those affected by allergies.

Keywords

Allergen immunotherapy / Evidence-based medicine / Real-world data / Real-world evidence / Randomized controlled trials

References

[1] Paoletti G, Nappi E, Bragato MC, Valli P, Giovannini M, Gargano D, et al. Allergen immunotherapy in Italy: How, when, and why-A real-world study conducted through a patient association. World Allergy Organ J. 2024; 18: 101015.

[2] Blume SW, Yeomans K, Allen-Ramey F, Smith N, Kim H, Lockey RF, et al. Administration and Burden of Subcutaneous Immunotherapy for Allergic Rhinitis in U.S. and Canadian Clinical Practice. J Manag Care Spec Pharm. 2015; 21: 982-90.

[3] Rampersad A, Siddiqui F, Qiyu ML, Traves D, Makwana N. Allergen immunotherapy in the UK: what’s new? Paediatr Child Health. 2024; 34: 186-92.

[4] Ryan D, Gerth van Wijk R, Angier E, Kristiansen M, Zaman H, Sheikh A, et al. Challenges in the implementation of the EAACI AIT guidelines: A situational analysis of current provision of allergen immunotherapy. Allergy. 2018; 73: 827-36.

[5] Novembre E, Barni S, Mori F. The prescriptive paradox of allergen immunotherapy for respiratory allergic diseases. Ital J Pediatr Allergy Immunol. 2024; 38: 15-8.

[6] Celebi Sözener Z, Mungan D, Cevhertas L, Ogulur I, Akdis M, Akdis C. Tolerance mechanisms in allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2020; 20: 591-601.

[7] Gradman J, Halken S. Can immunotherapy prevent the progression of airway disease? Curr Opin Allergy Clin Immunol. 2025;[Epub ahead of print].

[8] Penagos M, Durham SR. Duration of allergen immunotherapy for inhalant allergy. Curr Opin Allergy Clin Immunol. 2019; 19: 594-605.

[9] Roger A, Arcalá Campillo E, Torres MC, Millan C, Jáuregui I, Mohedano E, et al. Reduced work/academic performance and quality of life in patients with allergic rhinitis and impact of allergen immunotherapy. Allergy Asthma Clin Immunol. 2016; 12: 40.

[10] Creticos PS, Gunaydin FE, Nolte H, Damask C, Durham SR. Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma. J Allergy Clin Immunol Pract. 2024; 12: 1415-27.

[11] Kappen JH, Agache I, Jutel M, Pillai P, Corrigan CJ. Allergen Immunotherapy for Asthma. J Allergy Clin Immunol Pract. 2024; 12: 23-30.

[12] Dhami S, Nurmatov U, Arasi S, Khan T, Asaria M, Zaman H, et al. Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis. Allergy. 2017; 72: 1597-631.

[13] Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, Gerth van Wijk R, et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy. 2018; 73: 765-98.

[14] Wu K, Wu S, Wang L. Efficacy evaluation of allergen-specific immunotherapy in children with asthma: a systematic review and meta-analysis. BMC Pulm Med. 2025; 25: 293.

[15] Dhami S, Kakourou A, Asamoah F, Agache I, Lau S, Jutel M, et al. Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis. Allergy. 2017; 72: 1825-48.

[16] Hur G, Lee J, Park H. Allergen immunotherapy for the treatment of respiratory allergies in the elderly. Curr Opin Allergy Clin Immunol. 2017; 17: 304-8.

[17] Özdemiral C, Gurel DI, Sahiner U. Allergen-specific immunotherapy at the extremes of age: below 5 years and elderly: evidence beyond indications? Curr Opin Allergy Clin Immunol. 2024; 24: 510-9.

[18] Incorvaia C, Ciprandi G, Nizi MC, Makri E, Ridolo E. Subcutaneous and sublingual allergen-specific immunotherapy: a tale of two routes. Eur Ann Allergy Clin Immunol. 2020; 52: 245-57.

[19] Schmidlin KA, Bernstein DI. Safety of allergen immunotherapy in children. Curr Opin Allergy Clin Immunol. 2023; 23: 514-9.

[20] Incorvaia C, Cavaliere C, Schroeder JW, Leo G, Nicoletta F, Barone A, et al. Safety and adverse reactions in subcutaneous allergen immunotherapy: a review. Acta Biomed. 2023; 94: e2023172.

[21] Canonica GW, Bachert C, Hellings P, Ryan D, Valovirta E, Wickman M, et al. Allergen Immunotherapy (AIT): a prototype of Precision Medicine. World Allergy Organ J. 2015; 8: 31.

[22] Casale TB, Bousquet J. Allergen Immunotherapy: A Long Way Gone and a Long Way to Go. J Allergy Clin Immunol Pract. 2021; 9: 1839-40.

[23] Sahiner UM, Giovannini M, Escribese MM, Paoletti G, Heffler E, Alvaro Lozano M, et al. Mechanisms of Allergen Immunotherapy and Potential Biomarkers for Clinical Evaluation. J Pers Med. 2023; 13: 845.

[24] Veneziani I, Landolina N, Ricci B, Rossi O, Moretta L, Maggi E. How the Immune System Responds to Allergy Immunotherapy. Biomedicines. 2022; 10: 2825.

[25] Golebski K, Layhadi JA, Sahiner U, Steveling-Klein EH, Lenormand MM, Li RCY, et al. Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity. 2025; 58: 2137.

[26] López-Sanz C, Jiménez-Saiz R, Esteban V, Delgado-Dolset MI, Perales-Chorda C, Villaseñor A, et al. Mast Cell Desensitization in Allergen Immunotherapy. Front Allergy. 2022; 3: 898494.

[27] Cosmi L, Santarlasci V, Angeli R, Liotta F, Maggi L, Frosali F, et al. Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-gamma- and interleukin-10-production. Clin Exp Allergy. 2006; 36: 261-72.

[28] Martín-Cruz L, Palomares O. Allergen-Specific Immunotherapy and Trained Immunity. Allergy. 2025; 80: 677-89.

[29] Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021; 147: 1865-77.

[30] Petrarca C, Lanuti P, Petrosino MI, Di Pillo S, Mistrello G, Compalati E, et al. Peripheral effector memory regulatory T cells are incremented and functionally enhanced in successful mite monomeric allergoid sublingual immunotherapy. Allergy. 2021; 76: 2208-11.

[31] Zeng Y, Xiao H, Gao S, Li J, Yang C, Zeng Q, et al. Efficacy and immunological changes of sublingual immunotherapy in pediatric allergic rhinitis. World Allergy Organ J. 2023; 16: 100803.

[32] Di Gioacchino M, Della Valle L, Mangifesta R, Lumaca A, Cipollone F, Frati F, et al. Real-Life Effectiveness of Subcutaneous Immune Therapy with Carbamylated Monomeric Allergoids on Mite, Grass, and Pellitory Respiratory Allergy: A Retrospective Study. J Clin Med. 2022; 11: 7384.

[33] Wang Z, Wang N, Liang X, Wei L, Song Y, Li D, et al. Efficacy and safety of Sublingual immunotherapy for allergic rhinitis: an overview of systematic reviews and meta analyses. Eur Arch Otorhinolaryngol. 2025;[Epub ahead of print].

[34] Buta F, Paoletti G, Bragato MC, Giovannini M, Canonica GW, Heffler E. Real-world evidence of allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2024; 24: 529-35.

[35] Dwivedi V, Kopanja S, Schmidthaler K, Sieber J, Bannert C, Szépfalusi Z. Preventive allergen immunotherapy with inhalant allergens in children. Allergy. 2024; 79: 2065-87.

[36] Nakagome K, Nagata M. Allergen immunotherapy in asthma. Allergol Int. 2024; 73: 487-93.

[37] Harintajinda S, Klangkalya N, Kanchongkittiphon W, Rerkpattanapipat T, Kerddonfak S, Manuyakorn W. Allergic rhinitis in remission with house dust mite subcutaneous immunotherapy. Asian Pac J Allergy Immunol. 2025; 43: 189-97.

[38] Jesenak M, Bobcakova A, Djukanovic R, Gaga M, Hanania NA, Heaney LG, et al. Promoting Prevention and Targeting Remission of Asthma: A EUFOREA Consensus Statement on Raising the Bar in Asthma Care. Chest. 2025; 167: 956-74.

[39] Yuta A, Ogawa Y, Kozaki H, Shimizu T. Clinical Efficasy of House Dust Mite Sublingual Immunotherapy with Miticure^® Tablets in 115 Paitents for 3 Years . Arerugi. 2023; 72: 273-80. Japanese.

[40] Sakurai D, Ishii H, Shimamura A, Watanabe D, Yonaga T, Matsuoka T. Sublingual Immunotherapy for Japanese Cedar Pollinosis: Current Clinical and Research Status. Pathogens. 2022; 11: 1313.

[41] Erlewyn-Lajeunesse M, Villa LP, Shaikh S, Smith M, Balodima V, Baker S, et al. ; BRIT Practitioners Group. Inequalities in Access to Specialist Allergy Services in the United Kingdom: A Report From the BSACI Registry for Immunotherapy (BRIT). Clin Exp Allergy. 2025; 55: 458-68.

[42] Cabrera M, Ryan D, Erlewyn-Lajeunesse M, Levin M, Martínez-Cañavate A, Villaizán Pérez C, et al. Global assessment of the knowledge and confidence in managing allergic disorders among primary care pediatricians across Europe: An EAACI task force report. Pediatr Allergy Immunol. 2024; 35: e14116.

[43] Cabrera M, Ryan D, Angier E, Losappio L, Flokstra-de Blok BMJ, Gawlik R, et al. Current allergy educational needs in primary care. Results of the EAACI working group on primary care survey exploring the confidence to manage and the opportunity to refer patients with allergy. Allergy. 2022; 77: 378-87.

[44] Schädlich PK, Brecht JG. Economic evaluation of specific immunotherapy versus symptomatic treatment of allergic rhinitis in Germany. Pharmacoeconomics. 2000; 17: 37-52.

[45] Petersen KD, Gyrd-Hansen D, Dahl R. Health-economic analyses of subcutaneous specific immunotherapy for grass pollen and mite allergy. Allergol Immunopathol (Madr). 2005; 33: 296-302.

[46] Berto P, Passalacqua G, Crimi N, Frati F, Ortolani C, Senna G, et al. ; Italian SPAI Study Group. Economic evaluation of sublingual immunotherapy vs symptomatic treatment in adults with pollen-induced respiratory allergy: the Sublingual Immunotherapy Pollen Allergy Italy (SPAI) study. Ann Allergy Asthma Immunol. 2006; 97: 615-21.

[47] Bachert C, Vestenbaek U, Christensen J, Griffiths UK, Poulsen PB. Cost-effectiveness of grass allergen tablet (GRAZAX) for the prevention of seasonal grass pollen induced rhinoconjunctivitis - a Northern European perspective. Clin Exp Allergy. 2007; 37: 772-9.

[48] Rodríguez-Otero N, Ramírez-Mateo E, Plana MN, Heffler E, Antolín-Amérigo D. Cost-effectiveness of allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2024; 24: 496-503.

[49] Hu Q, Li L, Long Z, Huo B, Hao Y, Cheng X, et al. Current status and progress of health economics research on allergen specific immunotherapy. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2025; 39: 894-8. Chinese.

[50] Reineke U, Cappello C. Is AIT worth your while? Economic evaluation of allergen-specific immunotherapy (AIT) for otorhinolaryngologists in private practice. HNO. 2025; 73: 225-32. German.

[51] Hankin CS, Cox L, Bronstone A. The health economics of allergen immunotherapy. Immunol Allergy Clin North Am. 2011; 31: 325-41, x.

[52] Ciprandi G, Tosca MA. Under-prescription of allergen-immunotherapy: why is it important to prescribe it in childhood instead? Immunotherapy. 2021; 13: 359-61.

[53] Calderón MA, Frankland AW, Demoly P. Allergen immunotherapy and allergic rhinitis: false beliefs. BMC Med. 2013; 11: 255.

[54] Ridolo E, Montagni M, Bonzano L, Senna G, Incorvaia C. Arguing the misconceptions in allergen-specific immunotherapy. Immunotherapy. 2014; 6: 587-95.

[55] Recommendations on common regulatory approaches for allergen products [Internet]. Co-ordination Group for Mutual Recognition and Decentralised Procedures - Human; [cited 2025 Sep 25]. Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/01_General_Info/CMDh_399_2019_clean_Rev0_2020_07.pdf

[56] Bonertz A, Mahler V, Vieths S. New guidance on the regulation of allergen products: key aspects and outcomes. Curr Opin Allergy Clin Immunol. 2020; 20: 624-30.

[57] Bonertz A, Roberts GC, Hoefnagel M, Timon M, Slater JE, Rabin RL, et al. Challenges in the implementation of EAACI guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products. Allergy. 2018; 73: 64-76.

[58] Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases [Internet]. European Medicines Agency; [cited 2025 Sep 25]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-development-products-specific-immunotherapy-treatment-allergic-diseases_en.pdf

[59] Bonini S, Pfaar O. Novel adaptive design for allergen immunotherapy clinical trials. Allergy. 2022; 77: 1950-51.

[60] Tang X, Rabin RL, Yan LK. A three-stage design for allergen immunotherapy trials. Allergy. 2022; 77: 1835-42.

[61] Gerth van Wijk R, van Daele P. Moving forward with allergen immunotherapy: The significance of real-world studies. J Allergy Clin Immunol. 2023; 152: 362-4.

[62] Bakker E, Plueschke K, Jonker CJ, Kurz X, Starokozhko V, Mol PGM. Contribution of Real-World Evidence in European Medicines Agency's Regulatory Decision Making. Clin Pharmacol Ther. 2023; 113: 135-51.

[63] Vogelberg C, Klimek L, Brüggenjürgen B, Jutel M. Real-world evidence for the long-term effect of allergen immunotherapy: Current status on database-derived European studies. Allergy. 2022; 77: 3584-92.

[64] Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry [Internet]. U.S. Department of Health and Human Services Food and Drug Administration; [cited 2025 Sep 25]. Available from: https://www.fda.gov/media/154449/download#:~:text=A.-,Using%20Registry%20Data%20to%20Support%20Regulatory%20Decisions,or%20designed%20by%20the%20sponsor

[65] Del Giacco S, Canonica GW, Agache I, Price D, Roche N, Schunemann H, et al. Expert Perspectives on Next Generation Health Guidelines: How to Integrate RWE in EBM. Pragmat Obs Res. 2025; 16: 169-77.

[66] Canonica GW, Agache I, Schünemann HJ, Roche N, Price D, Del Giacco S. Next generation health guidelines: The role of real-life data in evidence-based medicine. Allergy. 2024; 79: 12-4.

[67] Real-world evidence framework to support EU regulatory decision-making [Internet]. European Medicines Agency; [cited 2025 Sep 26]. Available from: https://www.ema.europa.eu/en/documents/report/real-world-evidence-framework-support-eu-regulatory-decision-making-3rd-report-experience-gained-regulator-led-studies-february-2024-february-2025_en.pdf

[68] Parums DV. A Review of the Importance and Relevance of Real-World Data and Real-World Evidence. Med Sci Monit. 2025; 31: e951118.

[69] Costanzo G, Caruso C, Paoletti G, Baglivo I, Colantuono S, Bagnasco D, et al. RIAIT (Italian Registry of Allergen Immunotherapy): Protocol for a New Tool in a New Vision of Disease-Modifying Therapy for Allergists. J Pers Med. 2024; 14: 854.