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Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyp formation, adult-onset asthma, and hypersensitivity to all cyclooxygenase-1 (COX-1) inhibitors. Oxygenated lipids are collectively known as oxylipins and are polyunsaturated fatty acids (PUFA) oxidation products. The most extensively researched oxylipins being the eicosanoids formed from arachidonic acid (AA). There are four major classes of eicosanoids including leukotrienes, prostaglandins, thromboxanes, and lipoxins. In N-ERD, the underlying inflammatory process of the upper and lower respiratory systems begins and occurs independently of NSAID consumption and is due to the overproduction of cysteinyl leukotrienes. Leukotriene mediators all induce edema, bronchoconstriction, and airway mucous secretion. Thromboxane A 2 is a potent bronchoconstrictor and induces endothelial adhesion molecule expression. Elevated Prostaglandin D 2 metabolites lead to vasoconstriction, additionally impaired up-regulation of prostaglandin E 2 leads to symptoms seen in N-ERD as it is essential for maintaining homeostasis of inflammatory responses in the airway and has bronchoprotective and anti-inflammatory effects. A characteristic feature of N-ERD is diminished lipoxin levels, this decreased capacity to form endogenous mediators with anti-inflammatory properties could facilitate local inflammatory response and expose bronchial smooth muscle to relatively unopposed actions of broncho-constricting substances. Treatment options, such as leukotriene modifying agents, aspirin desensitization, biologic agents and ESS, appear to influence eicosanoid pathways, however more studies need to be done to further understand the role of oxylipins. Besides AA-derived eicosanoids, other oxylipins may also pay a role but have not been sufficiently studied. Identifying pathogenic N-ERD mechanism is likely to define more effective treatment targets., Competing Interests: Conflict of interest Elina Jerschow: Advisory Board—GlaxoSmithKline, Regeneron/Sanofi. Consultant—GlaxoSmithKline. AstraZeneca, Regeneron. Research grants: AstraZeneca, Regeneron., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD., Competing Interests: EJ served on the Advisory Board for GSK, Sanofi/Regeneron, and Novartis/Genentech; she is a consultant for GSK and has research support from AstraZeneca and from Cumberland Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sehanobish, Asad, Barbi, Porcelli and Jerschow.)

Background: Aspirin desensitization and treatment benefits most patients with aspirin-exacerbated respiratory disease (AERD), although some patients fail therapy. Our objective was to assess whether recent endoscopic sinus surgery (ESS) improved aspirin treatment outcomes in AERD patients who initially failed aspirin therapy., Methods: Outcomes of aspirin desensitization and treatment in AERD patients prospectively enrolled were assessed preoperatively and at 4, 12, and 24 weeks after ESS by determining changes in Asthma Control Test (ACT) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores and respiratory function. Biomarkers, including fractional excretion of nitric oxide (FeNO), spirometry, nasal inspiratory peak flow (NPF), immunoglobulin E (IgE), and eosinophil count, were measured., Results: Nineteen patients who benefited (responders) and 21 patients who failed (nonresponders) preoperative aspirin treatment with a distant history of ESS (mean, 48 months) were identified. Nonresponders were more likely to be African American (71%, p < 0.01) and have higher baseline IgE levels (252 kU/L vs 87 kU/L in responders, p < 0.01). 24 of the 40 patients (nine responders and 15 non-responders) required subsequent ESS and underwent another aspirin desensitization 3-4 weeks after ESS. All 24 patients tolerated a second round of aspirin desensitization and treatment. The primary aspirin therapy was associated with a significant increase in IgE in nonresponders, but there was no significant increase in IgE after the second aspirin desensitization and treatment., Conclusion: Antecedent ESS enhances aspirin treatment responses in AERD patients and may convert patients who failed aspirin treatment before surgery to a more responsive phenotype after ESS. Patients with higher baseline serum IgE levels may benefit from ESS performed shortly before aspirin desensitization and therapy., (© 2019 ARS-AAOA, LLC.)

Background: Graded challenges are performed to exclude hypersensitivity reactions in patients with a low likelihood of drug allergy. Literature regarding optimal protocols with a defined number of steps and use of placebo is lacking., Objective: To identify allergic drug reactions (ADRs) through a 3-step protocol composed of placebo followed by a 2-step graded drug challenge., Methods: We performed a 5-year retrospective chart review of all patients with historical ADRs who underwent single-blind, placebo-controlled graded drug challenges between October 2010 and November 2015 at an outpatient drug allergy clinic. Patients' demographic characteristics and description of historical reaction were obtained. Outcomes of challenges to drug versus placebo were compared by drug class., Results: Two hundred twenty-nine patients underwent at least 1 single-blind placebo-controlled graded challenge. The most commonly challenged drug class was beta-lactams (70.8%) followed by nonsteroidal anti-inflammatory drugs (17.5%). The reaction rate to drug and placebo was similar during beta-lactam challenges (9.4% vs 8.2%; P = .9) and during nonsteroidal anti-inflammatory drug challenges (14% vs 7%, P = .5), respectively. Only 10 patients (4.4%) had objective findings during drug challenges. Patients who reacted to placebo before beta-lactam challenges had an increased number of drug allergies (4.3 ± 1.0) compared with nonreactors (2.4 ± 0.1) and to beta-lactam reactors (3.3 ± 0.7) (P = .002). All placebo reactors were female (20 of 183 vs 0 of 46 males; P = .02)., Conclusions: Two-step graded challenges are safe in appropriately selected patients with a low risk of reaction. Placebo should be considered to reduce false-positive results, especially in females and in patients with multiple drug allergies., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)