Recent Updates in Understanding NSAID Hypersensitivity

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• Mori F, Atanaskovic-Markovic M, Blanca-Lopez N, Gomes E, Gaeta F, Sarti L, Bergmann MM, Tmusic V, Valluzzi RL, Caubet JC. 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(3):1022-1031.e1. https://doi.org/10.1016/j.jaip.2019.10.049. (Epub 2019 Nov 27 PMID: 31785410). Retrospective data collection of 693 children with a reported history of NSAID reaction. The diagnosis of NSAID hypersensitivity was confirmed in 19.3% of the 693 children by performing OPT to culprit drug. This study highlights the importance of oral provocation tests in confirming or excluding NSAID hypersensitivity in the pediatric population.

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• Li L, Chang Y, Song S, Losina E, Costenbader KH, Laidlaw TM. Impact of reported NSAID “allergies” on opioid use disorder in back pain. J Allergy Clin Immunol. 2021;147(4):1413–9. https://doi.org/10.1016/j.jaci.2020.08.025. (Epub 2020 Sep 9 PMID: 32916184). This is a retrospective cohort study using the electronic medical record to identify patients with back pain who reported NSAID allergy. This comprised of 3620 patients or 7.7% of patients with back pain. These patients had higher odds of both documented opiate prescription and developing an opiate use disorder than the patients with an NSAID allergy label. The results emphasize the importance of allergy evaluation for potential delabeling in patients reporting NSAID allergies.

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• Kidon M, Blanca-Lopez N, Gomes E, Terreehorst I, Tanno L, Ponvert C, Chin CW, Caubet JC, Soyer O, Mori F, Blanca M, Atanaskovic-Markovic M. 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(5):469–80. https://doi.org/10.1111/pai.12915. (Epub 2018 Jun 13 PMID: 29693290). A European consensus statement summarizing diagnosis and management recommendations for pediatric and adolescent patients with NSAID hypersensitivity. For this particular patient population, data is growing, but rare.

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• Li L, Bensko J, Buchheit K, Saff RR, Laidlaw TM. Safety, outcomes, and recommendations for two-step outpatient nonsteroidal anti-inflammatory drug challenges. Allergy Clin Immunol Pract. 2022;10(5):1286-1292.e2. https://doi.org/10.1016/j.jaip.2021.11.006. (Epub 2021 Nov). A retrospective study of non-AERD patients reporting NSAID allergy in which 249 patients who underwent 262 NSAID challenges. Approximately 86% of two-step drug challenges were negative for immediate or delayed reactions allowing patients to use at least one clinically indicated NSAID. Also, challenge reactions that did occur were clinically mild. This study suggests that two-step NSAID challenges were able to delabel the majority of patients and that most positive tests had reactions which were safe to manage in an outpatient setting.

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• Blanca-Lopez N, Haroun-Diaz E, Ruano FJ, Perez-Alzate D, Somoza ML, Vasquez de la Torre Gaspar, et al. Acetyl salicylic acid challenge in children with hypersensitivity reactions to nonsteroidal anti-inflammatory drugs differentiates between cross-intolerant and selective responders. J Allergy Clin Immunol Pract. 2018;6:1226–1235. A study of 116 children (all less than 14 years old) with history of NSAID allergy who underwent a single blind oral provocation test with ASA (unless ASA was the culprit drug, then ibuprofen). If positive, cross-intolerance was confirmed. If negative, the patient was challenged with culprit drug. 26% were diagnosed with NSAID allergy. 83% of which were cross-intolerant and 17% had selective allergies. ASA challenge proved to be a safe and reasonable first step in diagnosis and management of NSAID allergy in pediatric patients.

Eser Simsek I, Cogurlu MT, Aydogan M. Two approaches for diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity in children. Ann Allergy Asthma Immunol. 2019;123(4):389–93. https://doi.org/10.1016/j.anai.2019.07.005. (Epub 2019 Jul 16 PMID: 31323315).

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• Martínez Antón MD, Galán Gimeno C, Sánchez de Vicente J, Jáuregui Presa I, Gamboa Setién PM. Etoricoxib-induced fixed drug eruption: report of seven cases. Contact Dermatitis. 2021;84(3):192–195. https://doi.org/10.1111/cod.13659. Epub 2020 Aug 18. PMID: 32666601. A report of seven cases of fixed drug eruption (FDE) induced by etoricoxib (a selective COX-2 inhibitor) diagnosed on clinical presentation. In six of the cases, the diagnosis was confirmed with positive patch testing, and the other case had positive low-dose oral challenge. NSAIDs are suspected to be a common cause of FDE.

• Doña I, Barrionuevo E, Salas M, Cornejo-García JA, Perkins JR, Bogas G, Prieto A, Torres MJ. Natural evolution in patients with nonsteroidal anti-inflammatory drug-induced urticaria/angioedema. Allergy. 2017;72(9):1346–55. https://doi.org/10.1111/all.13147. (Epub 2017 Mar 20 PMID: 28226401). This study identified 38 patients with history of NIUA and positive oral challenge to ASA and prospectively re-evaluated them with both ASA and other NSAIDs after 60 months and then 78 months from initial evaluation. The majority of patients approximately 63% tolerated ASA and other NSAIDs at 60 months, and this number remained similar at 78 months. A shorter time interval to tolerance was noted in patients with isolated urticarial, non-atopic patients, and those who experienced reactions over 1 h after exposure. This study suggests that patients with NIUA may develop tolerance and repeat evaluation at least three 3 years out from initial reaction may be reasonably considered.

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• Li L, Laidlaw T. Cross-reactivity and tolerability of celecoxib in adult patients with NSAID hypersensitivity. J Allergy Clin Immunol Pract. 2019;7(8):2891–2893.e4. https://doi.org/10.1016/j.jaip.2019.04.042. Epub 2019 May 14. PMID: 31100553. Meta-analysis of blinded, placebo-controlled trials prior to November of 2018 in which patients with NSAID allergies were challenged with selective COX-2 inhibitors. Sixty-two62 studies were identified. Celecoxib and rofecoxib were the most commonly used. A reaction rate of 3.29% was calculated with the majority of reactions being isolated cutaneous reactions. Although selective COX-2 inhibitors are generally well tolerated in patients with NSAID hypersensitivity, a history of urticarial and/or angioedema or anaphylaxis due to small risk of cross-reactivity OPT was recommended prior to use. AERD patients may use selective COX-2 inhibitors without prior challenge.

• 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(10):3577–3583.e1. https://doi.org/10.1016/j.jaip.2020.06.057. Epub 2020 Jul 14. PMID: 32673879. A total of 121 patients with CSU and a history of NSAID-induced exacerbation were evaluated with two challenges—without the use of anti-histamines and with pre-treatment using anti-histamines. Ninety-sixsix patients tested positive without anti-histamine pretreatment; however, 72 of these patients had a negative challenge with anti-histamine pretreatment. These results indicate that clinical control of underlying CSU with anti-histamines may allow for unnecessary avoidance of NSAIDS by decreasing NSAID-induced exacerbations of disease.

• Rossini R, Iorio A, Pozzi R, Bianco M, Musumeci G, Leonardi S, Lettieri C, Bossi I, Colombo P, Rigattieri S, Dossena C, Anzuini A, Capodanno D, Senni M, Angiolillo DJ. Aspirin desensitization in patients with coronary artery disease: results of the multicenter ADAPTED Registry (Aspirin Desensitization in Patients With Coronary Artery Disease). Circ Cardiovasc Interv. 2017;10(2):e004368. https://doi.org/10.1161/CIRCINTERVENTIONS.116.004368. PMID: 28193678. A prospective, multicenter study of 330 patients with both a history of ASA hypersensitivity and coronary artery disease underwent rapid ASA desensitization and was successful in 315 of the patients. The 15 patients without successful desensitization had minor reactions that responded to treatment with steroids and antihistamines. A total of 253 of the patients continued aspirin for 12 months. The other 62 stopped aspirin due to medical recommendation, not because of a hypersensitivity reaction. A rapid desensitization protocol was with both effective and safe in a variety of patients regardless of initial aspirin reaction which allows for appropriate treatment of coronary artery disease.

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