Abstract

Althoug many hypersensitivity diseases have been extensively investigated, little information is available in the literature about possible cofactors contributing to those reactions and the comorbidities that should be taken into account when assessing a patient complaining of adverse reactions triggered by exposure to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs can be cofactors for many clinically relevant conditions, especially food-dependent exercise-induced anaphylaxis, chronic urticaria, uncontrolled asthma, angioedema induced by angiotensin-converting enzyme inhibitors, and oral mite anaphylaxis. Although the role of NSAID use as cofactors has not been fully evaluated in children and adolescents, awareness on these relationships is required for the correct diagnosis, classification, and treatment of affected patients.

References

  1. Neubert A, Verhamme K, Murray ML, et al. The prescribing of analgesics and non-steroidal anti-inflammatory drugs in paediatric primary care in the UK, Italy and the Netherlands. Pharmacol Res 2010;62:243-248. https://doi.org/10.1016/j.phrs.2010.04.006
  2. Kidon M, Blanca-Lopez N, Gomes E, et al. EAACI/ENDA Position Paper: diagnosis and management of hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in children and adolescents. Pediatr Allergy Immunol 2018;29:469-480. https://doi.org/10.1111/pai.12915
  3. Mori F, Atanaskovic-Markovic M, Blanca-Lopez N, et al. A multicenter retrospective study on hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children: a report from the european network on drug allergy (ENDA) group. J Allergy Clin Immunol Pract 2020;8:1022-1031. https://doi.org/10.1016/j.jaip.2019.10.049.
  4. Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs 2007;9:195-204. https://doi.org/10.2165/00148581-200709030-00008.
  5. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999;104:5-13. https://doi.org/10.1016/s0091-6749(99)70106-5.
  6. Kanabar D, Dale S, Rawat M. A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms. Clin Ther 2007;29:2716-2723. https://doi.org/10.1016/j.clinthera.2007.12.021.
  7. Kauffman RE, Lieh-Lai M. Ibuprofen and increased morbidity in children with asthma: fact or fiction? Paediatr Drugs 2004;6:267-272. https://doi.org/10.2165/00148581-200406050-00001.
  8. Tan E, Braithwaite I, McKinlay CJD, et al. Comparison of Acetaminophen (paracetamol) with Ibuprofen for Treatment of Fever or Pain in children younger than 2 years: a systematic review and Meta-analysis. JAMA Netw Open 2020;3:e2022398. https://doi.org/10.1001/jamanetworkopen.2020.22398.
  9. McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011;128:1181-1185. https://doi.org/10.1542/peds.2011-1106.
  10. Sherbash M, Furuya-Kanamori L, Nader JD et al. Risk of wheezing and asthma exacerbation in children treated with Paracetamol versus Ibuprofen: a systematic review and meta-analysis of randomised controlled trials. BMC Pulm Med 2020;20:72. https://doi.org/10.1186/s12890-020-1102-5.
  11. Eneli I, Sadri K, Camargo C Jr, et al. Acetaminophen and the risk of asthma: the epidemiologic and pathophysiologic evidence. Chest 2005;127:604-612. https://doi.org/10.1378/chest.127.2.604.
  12. Sheehan WJ, Mauger DT, Paul IM et al. Acetaminophen versus Ibuprofen in young children with mild persistent asthma. N Engl J Med 2016;375:619-630. https://doi.org/10.1056/NEJMoa1515990.
  13. Fu LS, Lin CC, Wei CY, et al. Risk of acute exacerbation between acetaminophen and ibuprofen in children with asthma. Peer J 2019;16:7. https://doi.org/10.7717/peerj.6760.
  14. Baxter L, Cobo MR, Bhatt A, et al. The association between ibuprofen administration in children and the risk of developing or exacerbating asthma: a systematic review and meta-analysis. BMC Pulm Med 2024;24:412. https://doi.org/10.1186/s12890-024-03179-3.
  15. Chung RS, Huang YC, Chen YH et al. Impact of antipyretics on acute asthma exacerbation during respiratory infection - A nationwide population-based study. Pediatr Neonatol 2020;61:475-480. https://doi.org/10.1016/j.pedneo.2020.03.018.
  16. Zuberbier T, Abdul Hameed Ansari Z, Abdul Latiff AH, et al. The International Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. Allergy 2026 Feb 6. https://doi.org/10.1111/all.70210.
  17. Fricke J, Ávila G, Keller T, et al. Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta-analysis. Allergy 2020;75:423-432. https://doi.org/10.1111/all.14037.
  18. Votto M, Achilli G, De Filippo M, et al. Pediatric chronic spontaneous urticaria: a brief clinician’s guide. Expert Rev Clin Immunol 2022;18:889-899. https://doi.org/10.1080/1744666X.2022.2101999.
  19. Balp MM, Weller K, Carboni V, et al. Prevalence and clinical characteristics of chronic spontaneous urticaria in pediatric patients. Pediatr Allergy Immunol 2018;29:630-636. https://doi.org/10.1111/pai.12910.
  20. Franceschini F, Bianchi A, Bottau P, et al. L’ipersensibilità a farmaci nel bambino: come comportarsi. RIAP. 2023;37:22-42.
  21. Romano A, Valluzzi RL, Alvarez-Cuesta E, et al. Updating the classification and routine diagnosis of NSAID hypersensitivity reactions: a WAO Statement. World Allergy Organ J 2025;18:101086. https//doi.org/ 10.1016/j.waojou.2025.101086.
  22. Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A. Subtypes of chronic urticaria in patients attending allergy clinics in Venezuela. Eur Ann Allergy Clin Immunol 2014;46:210-215.
  23. Sánchez J, Sánchez A, Cardona R. Prevalence of Drugs as Triggers of Exacerbations in Chronic Urticaria. J Investig Allergol Clin Immunol 2019;29:112-117. https//doi.org/10.18176/jiaci.0287.
  24. Cavkaytar O, Arik Yilmaz E, Buyuktiryaki B et al. Challenge-proven aspirin hypersensitivity in children with chronic spontaneous urticaria. Allergy 2015;70:153-160. https//doi.org/ 10.1111/all.12539.
  25. Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A, et al. Aspirin-exacerbated cutaneous disease (AECD) is a distinct subphenotype of chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2015;29:698-701. https//doi.org/ 10.1111/jdv.12658.
  26. Doña I, Blanca-López N, Torres MJ, et al. NSAID-induced urticaria/angioedema does not evolve into chronic urticaria: a 12-year follow-up study. Allergy 2014;69:438-444. https//doi.org/10.1111/all.12335.
  27. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol 2003;111:1095-1098. https//doi.org/10.1067/mai.2003.1444.
  28. Doña I, Pérez-Sánchez N, Eguiluz-Gracia I, et al. Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Allergy 2020;75:561-575. https//doi.org/10.1111/all.14032.
  29. Saretta F, Tomei L, Mori F, et al. In vitro diagnostic testing for drug allergy in children. Pediatr Allergy Immunol 2023;34:e13955. https//doi.org/10.1111/pai.13955.
  30. Mastrorilli C, Bernardini R, Liotti L, et al. Chronic urticaria and drug hypersensitivity in children. Acta Biomed 2019;29:61-65. https//doi.org/10.23750/abm.v90i3-S.8166.
  31. Berges-Gimeno MP, Alvarez-Cuesta E, Atanaskovic-Markovic M, et al. Drug hypersensitivity reactions in children in clinical practice: a WAO Statement. World Allergy Organ J 2025;18:101087. https//doi.org/10.1016/j.waojou.2025.101087.
  32. Güvenir F, Turgay Yağmur İ, Dibek Mısırlıoğlu E. Alternative Drug Safety in Children with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity. Int Arch Allergy Immunol 2024;185:921-927. https//doi.org/10.1159/000538877.
  33. Sánchez J, Diez S, Cardona R. Clinical control of CSU with antihistamines allows for tolerance of NSAID-Exacerbated Cutaneous Disease. J Allergy Clin Immunol Pract 2020;8:3577-3583. https//doi.org/10.1016/j.jaip.2020.06.057.
  34. Romano A, Gaeta F, Caruso C et al. Evaluation and updated classification of acute hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs): NSAID-exacerbated or -Induced food allergy. J Allergy Clin Immunol Pract 2023;11:1843-1853. https//doi.org/10.1016/j.jaip.2023.03.036.
  35. Ruano-Zaragoza M, Casas-Saucedo R, De la Cruz Martinez CA, et al. Advances in the understanding of the cofactor effect in lipid transfer protein food allergy: from phenotype description to clinical management. Allergy 2022;77:1924-1926. https//doi.org/ 10.1111/all.15291.
  36. Sánchez-López J, Araujo G, Cardona V, et al. Food dependent NSAID-induced hypersensitivity (FDNIH) reactions: unraveling the clinical features and risk factors. Allergy 2021;76:1480-1492. https//doi.org/10.1111/all.14689.
  37. Asero R, Pravettoni V, Scala E, Villalta D. Lipid transfer protein allergy: a review of current controversies. Clin Exp Allergy 2022;52: 222-230. https//doi.org/10.1111/cea.14049.
  38. Christensen MJ, Eller E, Mortz CG, et al. Wheat-dependent cofactor-augmented anaphylaxis: a prospective study of exercise, aspirin,and alcohol efficacy as cofactors. J Allergy Clin Immunol Pract.2019;7:114-121. https//doi.org/ 10.1016/j.jaip.2018.06.018.
  39. Aihara M, Miyazawa M, Osuna H et al. Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation. Br J Dermatol 2002;146:466-472.https//doi.org/10.1046/j.1365-2133.2002.04601.
  40. Gomułka K, Wolańczyk-Mędrala A, Barg W et al. Food-dependent, exercise-induced anaphylaxis triggered by co-incidence of culprit food, physical effort and a very high dose of ibuprofen or menstruation: a case report. Postepy Dermatol Alergol 2017;34:87-88. https//doi.org/10.5114/ada.2017.65629.
  41. Carucci, L. Bova, M. Petraroli, A. et al. Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema: From Bed to Bench. J. Investig. Allergol. Clin. Immunol 2020;30:272-280. https//doi.org/10.18176/jiaci.0458.
  42. Mathey M, Maj C., Eriksson N et al. Meta analysis of ACE inhibitor induced angioedema identifies novel risk locus. J Allergy Clin Immunol 2024;153:1073-1082 https://doi.org/10.1016/j.jaci.2023.11.921.
  43. Smolinska S, Antolin-Amerigo D, Popescu FD. Bradykinin metabolism and drug induced angioedema. Int J Mol Sci 2023;24:11649 https://doi.org/10.3390/ijms241411649.
  44. Landry L, Witten T, Anwar AI et al. Angiotensin-Converting Enzyme Inhibitors and Other Medications Associated With Angioedema. Cureus 2023;15:e49306. https://doi.org/10.7759/cureus.49306.
  45. Montinaro V, Cicardi M. ACE inhibitor mediated angioedema. International Immunopharmacology 2020;78:106081. https://doi.org/10.1016/j.intimp.2019.106081.
  46. Banerji A, Blumenthal K, Lai K, et al. Epidemiology of ACE inhibitor angioedema utilizing a large electronic health record. J Allergy Clin Immunol Pract. 2017;5:744-749. https//doi.org/10.1016/j.jaip.2017.02.018.
  47. Davin L, Marechal P, Lancellotti P, et al. Angioedema: a rare and sometimes delayed side effect of angiotensing converting enzyme inhibitors. Acta Cardiol 2018. https//doi.org/10.1080/00015385.2018.1507477.
  48. Harezlak T, Religioni U, Szymanski F et al. Drug interactions affecting kidney function: beware of health threats from triple whammy Adv Ther 2022;39:140-147. https://doi.org/10.1007/s12325-021-01939-9.
  49. Calvo DM, Saiz LC, Leache L et al. Acute kidney injury and morbi-mortality associated with “triple whammy” combination. Systematic review and meta-analysis. J Clin Pharmacol 2025;91:3031-3041 https://doi.org/10.1002/bcp.70263.
  50. Preiser Funke T, Bergmann KC. Oral mite anaphylaxis (pancake syndrome) caused by storage mites Acarus siro and its treatment with allergen immunotherapy. Allergologie select 2023;7:113-115. https://doi.org/10.5414/ALX02415E.
  51. Sanchez Borges M, Fernandez Caldas E Hidden allergens and oral mite anaphylaxis: the pancake syndrome revisited. Curr Opin Allergy Clin Immunol 2015;15:337-343. http//doi.org/10.1097/ACI.0000000000000175.
  52. Sompornrattanaphan M, Jitvanitchakul J, Malainual M et al. Dust mite ingestion associated, exercise induced anaphylaxis: a case report and literature review. Allergy Asthma Clin Immunol 2020;16:2-5. https://doi.org/10.1186/s13223-019-0399-1.
  53. Kymioni VM, Karatsoli I, Koronas N et al. Oral mite anaphylaxis after pizza consumption in a child: a case report and review of literature. Allergol Immunopathol 2025;53:149-152. https://doi.org/10.15586/aei.v53i6.1460.
  54. Sanchez-Borges M, Suarez Chacon R, Capriles Hulette A et al. Anaphylaxis from ingestion of mites: Pancake anaphylaxis. J Allergy Clin Immunol 2013;131:31-35. https://doi.org/10.1016/j.jaci.2012.09.026.
  55. Sanchez-Borges M, Fernandez-Caldas E, Capriles-Hulett A et al. Mite-induced inflammation: More than allergy. Allergy and Rhinology 2012;3:e25-e29. https//doi.org/10.2500/ar.2012.3.0025.
  56. Van Wijk G, de Groot H, Bogaard JM. Drug-dependent exercise-induced anaphylaxis. Allergy 1995;50:992-994. https//doi.org/10.1111/j.1398-9995.1995.tb02514.

Downloads

PDF
Authors

Fabrizio Franceschini - Private Practice in Allergy, Ancona, Italy

Giuseppe Crisafulli - Allergology Unit, Pediatric Department, University of Messina, Messina, Italy

Francesca Saretta - Primary Care Pediatrician, Azienda Sanitaria, Universitaria Friuli Centrale, Udine, Italy

Paolo Bottau - Pediatric and Neonatology Unit, Imola Hospital, Imola, Italy

Silvia Caimmi - Clinica Pediatrica Unit, San Matteo Hospital, University di Pavia, Pavia, Italy

Annamaria Bianchi - Pediatric Unit, San Camillo Forlanini Hospital, Roma, Italy

Lucia Liotti - Pediatric Unit, Salesi Hospital, Ancona, Italy

Francesca Mori - Allergy Unit, Meyer Children’s Hospital IRCCS, Florence, Italy

Sara Riscassi - Pediatric Department, Bolzano Hospital, Bolzano, Italy

Rocco Luigi Valluzzi - Allergology Unit, Pediatric Department, Bambino Gesù Pediatric Hospital, Roma, Italy

Benedetta Neri - Specialty School of Paediatrics, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Carlo Caffarelli - Clinica Pediatrica Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy

License

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Copyright

Copyright (c) 2026 Italian Journal of Pediatric Allergy and Immunology

How to Cite
Franceschini, F., Crisafulli, G. ., Saretta, F., Bottau, P., Caimmi, S. ., Bianchi, A., Liotti, L. ., Mori, F., Riscassi, S., Valluzzi, R. L., Neri, B. ., & Caffarelli, C. (2026). Non-steroidal antinflammatory drugs as cofactors in hypersensitivity diseases. Italian Journal of Pediatric Allergy and Immunology, 40(1), 25–30. https://doi.org/10.53151/2531-3916/2026-2255
  • Abstract viewed - 0 times
  • PDF downloaded - 0 times