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The first modern description of respiratory syndrome of aspirin hypersensitivity was published over half of the century ago, but the pathogenesis of the disease is still elusive. Just a few years after discovery how aspirin works, Andrew Szczeklik and his co‑workers described that asthmatics with aspirin hypersensitivity cross‑react to the whole class of nonsteroidal anti‑inflammatory drugs. It took rest of his life to seek for an answer on how this disease, nowadays referred to as N ‑ERD, develops and how it can be treated. In the meantime, cysteinyl leukotrienes, leukotriene modifying drugs, and novel subpopulations of lymphocytes were discovered. This review on aspirin hypersensitivity documents a progress in our understanding of mechanisms of hypersensitivity to nonsteroidal anti‑inflammatory drugs. Current concepts about origin of the disease integrate advances in the field of allergology and inflammatory mechanisms of asthma. However, pharmacological inhibition of prostaglandin biosynthesis by nonsteroidal anti‑inflammatory drugs has a pivotal role in these investigations. Presented is a central role of prostaglandin E2 , a double‑faced lipid immunoregulatory mediator whose deficiency is related to the administration of an anti‑inflammatory drug. Discussed are cysteinyl leukotrienes, the most reliable biomarkers of aspirin hypersensitivity and cells of innate immunity capable of leukotrienes production. Involvement of blood platelets and recently described mucosal basophils are areas of ongoing studies in the disease. Aspirin hypersensitivity is an acquired condition; therefore, the search for genetic predisposition using classic association studies was inconclusive. There is a new hope to explain mechanisms of aspirin hypersensitivity by studies of innate lymphoid cells, which have a central role in the regulation of respiratory mucosa function in asthma.

Background: Aspirin desensitization followed by daily aspirin use is an effective treatment for aspirin-exacerbated respiratory disease (AERD)., Objective: To assess clinical features as well as genetic, immune, cytological and biochemical biomarkers that might predict a positive response to high-dose aspirin therapy in AERD., Methods: We enrolled 34 AERD patients with severe asthma who underwent aspirin desensitization followed by 52-week aspirin treatment (650 mg/d). At baseline and at 52 weeks, clinical assessment was performed; phenotypes based on induced sputum cells were identified; eicosanoid, cytokine and chemokine levels in induced sputum supernatant were determined; and induced sputum expression of 94 genes was assessed. Responders to high-dose aspirin were defined as patients with improvement in 5-item Asthma Control Questionnaire score, 22-item Sino-Nasal Outcome Test (SNOT-22) score and forced expiratory volume in 1 second at 52 weeks., Results: There were 28 responders (82%). Positive baseline predictors of response included female sex (p = .002), higher SNOT-22 score (p = .03), higher blood eosinophil count (p = .01), lower neutrophil percentage in induced sputum (p = .003), higher expression of the hydroxyprostaglandin dehydrogenase gene, HPGD (p = .004) and lower expression of the proteoglycan 2 gene, PRG2 (p = .01). The best prediction model included Asthma Control Test and SNOT-22 scores, blood eosinophils and total serum immunoglobulin E. Responders showed a marked decrease in sputum eosinophils but no changes in eicosanoid levels., Conclusions and Clinical Relevance: Female sex, high blood eosinophil count, low sputum neutrophil percentage, severe nasal symptoms, high HPGD expression and low PRG2 expression may predict a positive response to long-term high-dose aspirin therapy in patients with AERD., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: A special regulatory role for prostaglandin E 2 (PGE 2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD)., Objective: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE 2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC)., Methods: Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE 2 , 8-iso-PGE 2 , tetranor-PGE-M, 8-iso-PGF 2 α, and leukotriene C 4 , D 4 , and E 4 , were determined using mass spectrometry. Urinary excretion of LTE 4 was measured by ELISA., Results: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA-CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE 2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE 2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE 2 as in HC resulted from 2.8 times lower dose of aspirin., Conclusion: Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE 2 biosynthesis. These results support the mechanism of PGE 2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E 4 (uLTE 4 ) levels and blood eosinophilia can improve the prediction of AERD diagnosis., Methods: Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE 4 levels were measured in urine by HPLC and ELISA, respectively., Results: Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE 4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE 4 levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE 4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE 4 and blood eosinophils were already taken into account (p = 0.57)., Conclusion: UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.

Background: Aspirin-exacerbated respiratory disease (AERD) is diagnosed through graded aspirin challenges that induce hypersensitivity reactions and eicosanoid level changes. It is not known whether diagnostically useful changes also occur after low-dose aspirin challenges that do not induce hypersensitivity reactions., Objective: To investigate the utility of low-dose oral aspirin challenges for diagnosing AERD by measuring different clinical parameters and eicosanoid changes., Methods: Sixteen patients with AERD and 13 patients with aspirin-tolerant asthma underwent oral challenges with low-dose (20 or 40 mg) aspirin and diagnostic oral graded aspirin challenges (up to 325 mg of aspirin). Forced expiratory volume in 1 second, nasal peak flow, the fraction of exhaled nitric oxide (FeNO), and eicosanoid levels in plasma and urine were analyzed., Results: In patients with AERD but not in those with aspirin-tolerant asthma, 40-mg aspirin challenges induced a significant mean (SEM) decrease from baseline in FeNO (19% [5.1%]; P = .001) without causing any hypersensitivity reaction. The FeNO decrease also occurred after higher-dose aspirin challenges (27.8% [4.9%]; P < .001). The sensitivity and specificity of 40-mg aspirin-induced FeNO changes for identifying AERD were 90% and 100% with an area under the curve of 0.98 (95% CI, 0.92-1.00). The low-dose challenge also induced a significant leukotriene E4 urine increase in patients with AERD (from 6.32 [0.08] to 6.91 [0.15] log-pg/mg creatinine; P < .001), but the sensitivity and specificity of these changes were less than for the FeNO changes., Conclusion: The low-dose aspirin-induced decrease in FeNO in patients with AERD may be useful for the diagnosis of aspirin allergy without inducing a hypersensitivity reaction., Trial Registration: clinicaltrials.gov Identifier: NCT01320072., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD., Methods: Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges., Results: AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF-β1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal)., Conclusions: AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of this pilot study was to evaluate changes in the concentration of prostaglandin E2 (PGE2) in induced sputum supernatant in 3 groups: sub- jects with NSAID-exacerbated respira- tory disease (NERD), aspirin tolerant asthma (ATA) and healthy controls (HC), before and after oral aspirin chal- lenge test. The study was conducted in the years 2014-2015 at the Clinical Department of the Pulmonology Clinic at the University Hospital in Cracow. 43 patients were enrolled in the study (NERD - n = 15, ATA - n = 15 and HC - n = 13). All of them underwent a placebo-controlled oral aspirin challenge. Sputum was induced 24 hours before the challenge and immediately after the test. Induced sputum was processed in order to obtain cystospin slides to depict inflammatory cell patterns and supernatants, in which PGE2 was measured. The concentration of PGE2 was determined using mass spectrometry coupled with gas chromatography (gas chromatography/mass spectrometry - GC/MS). After aspirin challenge, the concentration of PGE2 in induced sputum supernatant decreased in both asthmatics hypersensitive to aspirin (p = 0.01) and those who tolerated aspirin well (p = 0.17). The change in the healthy control group was not statistically significant. These results support the cyclooxygenase theory of PGE2 inhibition by aspirin. However, the mechanism of bronchoconstriction after aspirin administration alone in patients with NSAID-exacerbated respiratory disease remains unclear.

Background: Isoprostanes are bioactive compounds formed by non-enzymatic oxidation of polyunsaturated fatty acids, mostly arachidonic, and markers of free radical generation during inflammation. In aspirin exacerbated respiratory disease (AERD), asthmatic symptoms are precipitated by ingestion of non-steroid anti-inflammatory drugs capable for pharmacologic inhibition of cyclooxygenase-1 isoenzyme. We investigated whether aspirin-provoked bronchoconstriction is accompanied by changes of isoprostanes in exhaled breath condensate (EBC)., Methods: EBC was collected from 28 AERD subjects and 25 aspirin-tolerant asthmatics before and after inhalatory aspirin challenge. Concentrations of 8-iso-PGF2α, 8-iso-PGE2, and prostaglandin E2 were measured using gas chromatography/mass spectrometry. Leukotriene E4 was measured by immunoassay in urine samples collected before and after the challenge., Results: Before the challenge, exhaled 8-iso-PGF2α, 8-iso-PGE2, and PGE2 levels did not differ between the study groups. 8-iso-PGE2 level increased in AERD group only (p=0.014) as a result of the aspirin challenge. Urinary LTE4 was elevated in AERD, both in baseline and post-challenge samples. Post-challenge airways 8-iso-PGE2 correlated positively with urinary LTE4 level (p=0.046), whereas it correlated negatively with the provocative dose of aspirin (p=0.027)., Conclusion: A significant increase of exhaled 8-iso-PGE2 after inhalatory challenge with aspirin was selective and not present for the other isoprostane measured. This is a novel finding in AERD, suggesting that inhibition of cyclooxygenase may elicit 8-iso-PGE2 production in a specific mechanism, contributing to bronchoconstriction and systemic overproduction of cysteinyl leukotrienes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Altered metabolism of eicosanoids is a characteristic finding in aspirin-exacerbated respiratory disease (AERD). Bronchial challenge with lysyl-aspirin can be used as a confirmatory diagnostic test for this clinical condition. Induced sputum allows to measure mediators of asthmatic inflammation in bronchial secretions., Objectives: To investigate the influence of inhaled lysyl-aspirin on sputum supernatant concentration of eicosanoids during the bronchial challenge test. Subjects with asthma hypersensitive to nonsteroidal anti-inflammatory drugs were compared with aspirin-tolerant asthmatic controls., Methods: Induced sputum was collected before and following bronchial challenge with lysyl-aspirin. Sputum differential cell count and sputum supernatant concentrations of selected lipoxygenases products: 5-,12-,15-hydroxyeicosatetraenoic acid, cysteinyl leukotrienes, leukotriene B4 , 11-dehydro-thromboxane B2 , and prostaglandins E2 , D2 , and F2α and their metabolites, were measured using validated methods of chromatography-mass spectrometry., Results: Aspirin precipitated bronchoconstriction in all AERD subjects, but in none of the aspirin-tolerant asthmatics. Phenotypes of asthma based on the sputum cytology did not differ between the groups. Baseline sputum eosinophilia correlated with a higher leukotriene D4 (LTD4 ) and leukotriene E4 (LTE4 ) concentrations. LTC4 , PGE2 , and 11-dehydro-TXB2 did not differ between the groups, but levels of LTD4 , LTE4 , and PGD2 were significantly higher in AERD group. Following the challenge, LTD4 and LTE4 increased, while PGE2 and LTB4 decreased in AERD subjects only., Conclusions: During the bronchial challenge, decrease in PGE2 and its metabolite is accompanied by a surge in bronchoconstrictory cysteinyl leukotrienes produced at the expense of LTB4 in AERD subjects. Bronchial PGE2 inhibition in AERD seems specific and sensitive to a low dose of aspirin., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with aspirin-induced asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti-inflammatory properties, but that supposition requires further corroboration., Objective: We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study., Methods: Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E4 and the stable plasma prostaglandin (PG) D2 metabolite 9α,11β-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months., Results: Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E(4) or 9α,11β-PGF(2) levels after AD., Conclusion: The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA., (Copyright © 2014. Published by Elsevier Inc.)

Our knowledge on the variability of FCER1A gene encoding for alpha-subunit of the high-affinity immunoglobulin E receptor (FcepsilonRI) that plays a central role in the pathogenesis of allergy and related disorders, has been recently much extended. Last findings from FCER1A mutational screening and genetic association studies, followed by functional analyses of the polymorphisms, are briefly summarized in this mini-review. The association between FCER1A gene variants and total serum IgE levels seems especially interesting and, supported by functional analyses of polymorphisms, may provide a rationale for pharmacogenetic studies on anti-IgE therapy that indirectly suppresses FcepsilonRI expression.