A new classification option for NSAID hypersensitivity: Kalyoncu classification

Main Article Content

Ebru Özdemir
Ebru Damadoğlu
Gül Karakaya
A. Fuat Kalyoncu


drug hypersensitivity, European Network for Drug Allergy, Kalyoncu classification, nonsteroidal -anti--inflammatory drugs


Background: The European Network for Drug Allergy (ENDA) proposed a consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in 2011. A subgroup of patients with NSAIDs-exacerbated respiratory disease (NERD) develop urticaria/angioedema type reactions in response to NSAIDs. The Kalyoncu classification might be a novel option to classify patients with NSAID hypersensitivity (NH). In this study, we compare the ENDA and the Kalyoncu classifications.

Methods: This study enrolled a total of 196 patients. NH reaction types were categorized as asthma, rhinitis, urticaria/angioedema and anaphylaxis. Based on the reaction history and oral provocation test findings, patients were grouped according to ENDA and Kalyoncu classifications.

Results: The mean age of the 196 patients was 40.32±13.28 years, and 130 (66.3%) of them were female. Under the ENDA and Kalyoncu classifications, the most common NH subgroups were NERD (32%), and isolated NH (34.2%), the least prevalent NH subgroups were single NSAID-induced delayed reactions (SNIDR) (1.5%), and pseudo Samter’s syndrome (11.7%).

Conclusions: Our research revealed that the Kalyoncu classification is more descriptive of patients with NERD exhibiting urticaria/angioedema-type reactions. It also provides future risk assessment for development of NERD. For controversial cases, the Kalyoncu classification can be utilized as a new complimentary option alone or in conjunction with ENDA classification.

Abstract 169 | PDF Downloads 200 HTML Downloads 13 XML Downloads 9


1. Doña I, Blanca-López N, Torres MJ, García-Campos J, -García-Núñez I, Gómez F, et al. Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients. J Investig Allergol Clin Immunol. 2012;22(5):363–71.

2. Blanca-López N, Pérez-Alzate D, Canto G, Blanca M. Practical approach to the treatment of NSAID hypersensitivity. Expert Rev Clin Immunol. 2017;13(11):1017–27. 10.1080/1744666X.2017.1377072

3. Doña I, Blanca-López N, Cornejo-García JA, Torres MJ, Laguna JJ, Fernández J, et al. Characteristics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs: patterns of response. Clin Exp Allergy. 2011;41(1):86–95. 10.1111/j.1365-2222.2010.03651.x

4. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56(9):813–24.

5. Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. Hypersensitivity to nonsteroidal anti--inflammatory drugs (NSAIDs)-classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA. Allergy. 2011;66(7):818–29. 10.1111/j.1398-9995.2011.02557.x

6. Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy. 2013;68(10):1219–32. 10.1111/all.12260

7. Caimmi S, Caimmi D, Bousquet PJ, Demoly P. How can we-better classify NSAID hypersensitivity reactions? validation from a large database. Int Arch Allergy Immunol. 2012;159(3):306–12. 10.1159/000337660

8. Demir S, Olgac M, Unal D, Gelincik A, Colakoglu B, Buyukozturk S. Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification. Allergy. 2015;70(11):1461–7. 10.1111/all.12689

9. Kim YJ, Lim KH, Kim MY, Jo EJ, Lee SY, Lee SE, et al. Cross-reactivity to acetaminophen and celecoxib according to the type of nonsteroidal anti-inflammatory drug hypersensitivity. Allergy Asthma Immunol Res. 2014;6(2):156–62. 10.4168/aair.2014.6.2.156

10. Pérez-Alzate D, Blanca-López N, Doña I, Agúndez JA, García-Martín E, Cornejo-García JA, et al. Asthma and rhinitis ınduced by selective ımmediate reactions to paracetamol and non-steroidal anti-inflammatory drugs in aspirin tolerant subjects. Front Pharmacol. 2016;20(7):215. 10.3389/fphar.2016.00215

11. Cavkaytar O, Yilmaz EA, Karaatmaca B, Buyuktiryaki B, Sackesen C, Sekerel BE, et al. Different phenotypes of non-steroidal anti-ınflammatory drug hypersensitivity during childhood. Int Arch Allergy Immunol. 2015;167(3):211–21. 10.1159/000438992

12. Blanca-Lopez N, Soriano V, Garcia-Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. J Asthma Allergy. 2019;8(12):217–33. 10.2147/JAA.S164806

13. Vásquez LDM, Silva DL, Ramírez LF, Olaya M, Serrano CD. Descriptive analysis of cross-reactive anaphylaxis as a different clinical subtype of nonsteroidal anti-ınflammatory drug (NSAID) hypersensitivity. Int Arch Allergy Immunol. 2021;182(2):131–8. 10.1159/000510335

14. Doña I, Barrionuevo E, Salas M, Laguna JJ, Agúndez J, García-Martín E, et al. NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs. Sci Rep. 2018;12;8(1):16710. 10.1038/s41598-018-34668-1

15. Oropeza AR, Bindslev-Jensen C, Broesby-Olsen S, Kristensen T, Møller MB, Vestergaard H, et al. Patterns of anaphylaxis after diagnostic workup: a follow-up study of 226 patients with suspected anaphylaxis. Allergy. 2017;72(12):1944–52. 10.1111/all.13207

16. Skypala IJ, Cecchi L, Shamji MH, Scala E, Till S. Lipid transfer protein allergy in the United Kingdom: characterization and comparison with a matched Italian cohort. Allergy. 2019;74(7):1340–51. 10.1111/all.13747

17. Pouessel G, Beaudouin E, Tanno LK, Drouet M, Deschildre A, Labreuche J, et al. Food-related anaphylaxis fatalities: analysis of the allergy vigilance network® database. Allergy. 2019;74(6):1193–6. 10.1111/all.13717

18. Dubois AEJ, Turner PJ, Hourihane J, Ballmer-Weber B, Beyer K, Chan CH, et al. How does dose impact on the severity of food-induced allergic reactions, and can this improve risk assessment for allergenic foods?: Report from an ILSI Europe Food Allergy Task Force Expert Group and Workshop. Allergy. 2018;73(7):1383–92. 10.1111/all.13405

19. Pérez-Sánchez N, Bogas G, Cornejo-García JA, Andreu I, Doña I, Pérez-Alzate D, et al. Multiple nonsteroidal anti-inflammatory drug hypersensitivity without hypersensitivity to aspirin. J Allergy Clin Immunol Pract. 2016;4(3):524–5. 10.1016/j.jaip.2015.11.017

20. Bogas G, Pérez-Sánchez N, Andreu I, Doña I, Perkins JR, Blanca M, et al. Anaphylaxis to 2 NSAIDs in a patient who tolerated ASA. J Investig Allergol Clin Immunol. 2016;26(4):266–8. 10.18176/jiaci.0066

21. Kowalski ML, Agache I, Bavbek S, Bakirtas A, Blanca M, Bochenek G, et al. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy. 2019;74(1):28–39. 10.1111/all.13599

22. Bochenek G, Kuschill-Dziurda J, Szafraniec K, Plutecka H, Szczeklik A, Nizankowska-Mogilnicka E. Certain subphenotypes of aspirin-exacerbated respiratory disease distinguished by latent class analysis. J Allergy Clin Immunol. 2014;133(1):98–103. 10.1016/j.jaci.2013.07.004

23. Lee HY, Ye YM, Kim SH, Ban GY, Kim SC, Kim JH, et al. Identification of phenotypic clusters of nonsteroidal anti-inflammatory drugs exacerbated respiratory disease. Allergy. 2017;72(4):616–26. 10.1111/all.13075

24. Blanca-López N, Haroun-Diaz E, Ruano FJ, Pérez-Alzate D, Somoza ML, Vázquez de la Torre Gaspar M, et al. Acetyl salicylic acid challenge in children with hypersensitivity reactions to nonsteroidal anti-ınflammatory drugs differentiates between cross-ıntolerant and selective responders. J Allergy Clin Immunol Pract. 2018;6(4):1226–35. 10.1016/j.jaip.2017.08.029

25. Karakaya G, Celebioglu E, Kalyoncu AF. Non-steroidal anti-inflammatory drug hypersensitivity in adults and the factors associated with asthma. Respir Med. 2013;107(7):967–74. 10.1016/j.rmed.2013.03.014

26. Global Initiative for Asthma Global strategy for asthma management and prevention. Fontana, WI: Global Initiative for Asthma; 2021 [Accessed 2021 Sep]. Available from: https://www.ginasthma.org/reports

27. Bousquet J, Schünemann HJ, Togias A, Bachert C, Erhola M, Hellings PW, et al. Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on grading of recommendations assessment, development and evaluation (GRADE) and real-world evidence. J Allergy Clin Immunol. 2020;145(1):70–80. 10.1016/j.jaci.2019.06.049

28. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393–414. 10.1111/all.13397

29. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Rivas MF, Fineman S, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. 2020;13(10):100472. 10.1016/j.waojou.2020.100472

30. Kowalski ML, Stevenson DD. Classification of reactions to non-steroidal antiinflammatory drugs. Immunol Allergy Clin North Am. 2013;33(2):135–45. 10.1016/j.iac.2012.10.008

31. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol. 2005;5(4):309–16. 10.1097/01.all.0000173785.81024.33

32. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclooxygenase enzymes. Ann Allergy Asthma Immunol. 2001;87(3):177–80. 10.1016/S1081-1206(10)62221-1

33. Kalyoncu AF. Aspirin-induced asthma needs a classification. Allergol Immunopathol. 2000;28(6):334–5.

34. Hamera-Slynarska M, Slynarski K. The undesirable side effects of non-steroidal antiinflammatory drugs. Ortop Traumatol Rehabil. 2001;3(1):126–8.

35. Dursun AB, Woessner KA, Simon RA, Karasoy D, Stevenson DD. Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis. Ann Allergy Asthma Immunol. 2008;100(5):420–5. 10.1016/S1081-1206(10)60465-6

36. Stevens W, Buchheit K, Cahill KN. Aspirin-exacerbated diseases: advances in asthma with nasal polyposis, urticaria, angioedema, and anaphylaxis. Curr Allergy Asthma Rep. 2015;15(12):69. 10.1007/s11882-015-0569-2

37. Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2002;89(5):474–8. 10.1016/S1081-1206(10)62084-4

38. Karakaya G, Kalyoncu AF. Nasal polyp, analgesic intolerance, and bronchial hyperreactivity. In: Önerci TM, Ferguson BJ, (Eds). Nasal polyposis. 1st ed. Berlin Heidelberg: Springer-Verlag; 2010. p. 119–26.

39. Cahill KN, Bensko JC, Boyce JA, Laidlaw TM. Prostaglandin D2: a dominant mediator of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2015;135(1):245–52. 10.1016/j.jaci.2014.07.031

40. Bavbek S, Yilmaz I, Celik G, Aydin O, Erkekol FÖ, Orman A, et al. Prevalence of aspirin-exacerbated respiratory disease in patients with asthma in Turkey: a cross-sectional survey. Allergol Immunopathol. 2012;40(4):225–30. 10.1016/j.aller.2011.05.015

41. Vally H, Taylor ML, Thompson PJ. The prevalence of aspirin intolerant asthma (AIA) in Australian asthmatic patients. Thorax. 2002;57(7):569–74. 10.1136/thorax.57.7.569