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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: Arachidonic acid metabolites regulate several aspects of airway function including inflammation, muscle contraction and mucous secretion., Objective: The aim of this study was to evaluate concentration of selected 5-lipoxygenase- and cyclooxygenase-derived eicosanoids in exhaled breath condensate (EBC) during allergen-induced bronchoconstriction., Methods: The study was performed on 24 allergic rhinitis/asthma patients sensitized to a house dust mite (HDM) Dermatophagoides pteronyssinus (Dp) and 13 healthy controls (HCs). Bronchial challenge with Dp extract was performed only in the allergic patients. EBC samples were collected before (T 0 ) and during Dp-induced bronchoconstriction (T EAR ). Eicosanoid concentration was measured using HPLC-tandem mass spectrometry., Results: Significant bronchoconstriction after Dp challenge was demonstrated in 15 patients (Rs), while in 9 patients (NRs) no asthmatic response could be detected. At T 0 the most abundant eicosanoids in EBC of HDM-allergic patients were LTB 4 and 5-oxo-ETE, while in HCs EBC concentration of LTB 4 was significantly greater than that of 5-oxo-ETE. Allergen challenge resulted in significant increase in EBC concentration of 5-oxo-ETE, LTD 4 and 8-iso-PGE 2 only in Rs. At T EAR , the relative change of 5-oxo-ETE concentration in EBC correlated with decrease of peripheral blood eosinophilia (R = -0.774; P = .0012). Moreover, the relative increase of 5-oxo-ETE in EBC at T EAR significantly correlated with the severity of the subsequent late asthmatic response (R = 0.683, P = .007)., Conclusion: Our study demonstrates significant up-regulation of 5-oxo-ETE synthesis in HDM-allergic patients and indicates possible involvement of that mediator in the pathogenesis of allergic asthma., (© 2017 John Wiley & Sons Ltd.)

Background: Induced sputum (IS) allows to measure mediators of asthmatic inflammation in bronchial secretions. The specific role of induced sputum supernatant (ISS) endogenous bioactive lipid mediators in subtypes of asthma is not well understood., Objective: To investigate the interactions between airway inflammation and clinical phenotypes of asthma, we integrated induced sputum supernatant (ISS) eicosanoids and quantitative assessment of infiltrating cells into new subtypes with the means of latent class analysis (LCA)., Methods: One hundred and thirty-nine asthmatics with and without aspirin hypersensitivity underwent sputum induction. High-performance liquid chromatography or gas chromatography coupled with mass spectrometry was used to profile eicosanoids. Nineteen variables covering clinical characteristics, IS inflammatory cells and eicosanoids were considered in the LCA., Results: Four phenotypic asthma classes were distinguished. Class 1 with mild-to-moderate asthma, chronic rhinosinusitis (CRS), high PGA2 in ISS and almost equal distribution of inflammation cell patterns. Class 3 subjects also had mild-to-moderate asthma but without upper airway symptoms. Induced sputum was often paucigranulocytic with low levels of lipid mediators. Classes 2 and 4 represented severe asthma with CRS and impaired lung function despite high doses of steroids. High blood and sputum eosinophilia was in line with high cysteinyl leukotrienes and PGD2 in ISS only in class 2. Class 4 subjects tended to have increased sputum neutrophilia and PGE2 in ISS. Aspirin hypersensitivity was most frequent among class 2 subjects., Conclusions & Clinical Relevance: The LCA revealed four distinct asthma classes differing in eicosanoid pathways., (© 2015 John Wiley & Sons Ltd.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the medications most frequently involved in hypersensitivity drug reactions. Because NSAIDs are prescribed for many conditions, this is a world-wide problem affecting patients of all ages. Various hypersensitivity reactions have been reported, mainly affecting the skin and/or the respiratory airways. The most frequent of these is acute urticaria, which can be induced by several different NSAIDs. Both specific and non-specific immunological pathways have been proposed as underlying mechanisms. This review presents the clinical phenotypes and the drugs involved in NSAID hypersensitivity. Five major clinical syndromes can be distinguished: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated cutaneous disease (AECD), multiple NSAID-induced urticaria/angioedema (MNSAID-UA), single NSAID-IgE reactions and single NSAID T cell responses. However, further classification is possible within these five major entities, by detailed descriptions of the clinical characteristics enabling more phenotypes to be defined. This detailed differentiation now seems required in order to undertake appropriate pharmacogenetic studies., (© 2013 John Wiley & Sons Ltd.)

Background: Churg-Strauss syndrome (CSS) shares similarities with asthma and hypereosinophilic syndrome (HES). Eicosanoids--important inflammatory and signaling molecules--are present in exhaled breath condensate (EBC) and broncho-alveolar lavage fluid (BALF)., Objectives: To assess eicosanoid profile both in EBC and BALF of CSS subjects searching for a pattern characteristic of this syndrome., Methods: EBCs from 23 CSS patients, 30 asthmatics, 12 HES patients and 54 healthy controls (HC) were assessed quantitatively for 19 eicosanoids by a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). In addition, in 21 of 23 CSS subjects and in nine asthmatics, eicosanoids were determined in BALF., Results: EBC from CSS patients showed markedly elevated levels of 12-HETE as compared with other studied groups. BALF was characterized by a significant elevation of 12-HETE and its metabolite 12-tetranor HETE in CSS as compared with asthma. Clinical activity of CSS correlated with 12-HETE and its metabolites levels in BALF, but not in EBC., Conclusion and Clinical Relevance: CSS is clearly distinguished from bronchial asthma, and HES by a marked increase in 12-HETE concentration in both EBC and BALF. This points to a possible new pathogenic mechanism in CSS and may help in future in establishing the diagnosis of CSS., (© 2011 Blackwell Publishing Ltd.)

Background: Biochemical analysis of expiratory breath condensate is an emerging non-invasive technique for assessment of airway inflammation., Objective: We wondered whether application of expiratory breath condensate could facilitate diagnosis of aspirin-intolerant asthma and reproduce eicosanoids mediators' abnormalities described in this disease., Methods: We measured prostaglandins (PGs) E(2), F(2 alpha), 9 alpha 11 beta F(2) and iso-F(2) by gas-chromatography/mass-spectrometry and cysteinyl leukotrienes (cys-LTs) by radioimmunoassay in breath condensates of asthmatic patients undergoing oral aspirin challenge. Fourteen patients with aspirin-induced asthma and 20 aspirin-tolerating asthmatics, most of them on chronic inhaled corticotherapy, were studied and compared with 10 healthy subjects. Additionally, plasma 9 alpha 11 beta PGF(2), the metabolite of PGD(2) and urinary leukotriene (LT) E(4) were measured before and following the challenge., Results: At baseline, PG did not differ between the groups, except for lower 9 alpha 11 beta PGF(2) in aspirin-intolerant asthma. Their concentrations were not changed by the challenge. Breath condensate cys-LTs were similar in the groups studied at base, and after aspirin challenge increased only in aspirin-intolerant patients. Elevated baseline urinary LTE(4) and its further increase following aspirin challenge was highly diagnostic for aspirin-intolerant asthma. The discriminatory value of cys-LTs increase in breath condensates was lower (72.8%) than either basal (99%) or post-challenge increase (94%) of urinary LTE(4)., Conclusions: In asthmatic patients on chronic corticotherapy measurement of urinary LTE(4) excretion rather than cys-LTs in breath condensate is of greater value for diagnosis of aspirin hypersensitivity.

Background: Eosinophilopoetic cytokine IL-5 enhances cysteinyl-leukotriene (cys-LT) synthesis in eosinophils in vitro. In patients with aspirin-induced asthma (AIA) bronchial biopsies revealed eosinophil infiltration and a marked increase in IL-5 positive cells., Objective: We wondered whether in AIA patients the bronchial IL-5 increase is reflected in peripheral blood, and if so, whether it is related to overproduction of cys-LT., Methods: In 11 stable patients with AIA, 32 with ATA (aspirin-tolerant asthma) and in 16 controls we measured serum IL-5 concentrations and urinary LTE4, believed to reflect global cys-LT production., Results: Serum IL-5 was detectable in 12 of 43 asthmatics, but in none of the control subjects. It was highest in the ATA group and differed significantly from the controls. There was no significant difference in IL-5 levels between: (i) the asthmatic groups studied, and (ii) AIA patients and controls. No relationship was found between serum IL-5 and urinary cys-LT., Conclusion: Overexpression of IL-5 reported in the airways of aspirin-sensitive patients with asthma was not reflected in their blood. If IL-5 affects cys-LT production, it is rather in the bronchi of the patients than in the blood.

Aspirin-induced asthma (AIA) is a clinical syndrome related to cysteinyl leukotriene overproduction in airways. The confirmation of the diagnosis requires inconvenient provocation tests with acetyl salicylic acid (ASA). A study was performed to evaluate whether measurement in vitro of cysteinyl leukotrienes (cys-LTs) release by isolated peripheral blood leucocytes, stimulated with ASA, can be of use for diagnosis of AIA. A cellular allergen stimulation test, CAST, was adapted to measure leukotriene release from leucocytes of 32 aspirin-tolerant and 26 aspirin-intolerant asthmatics. The cells were stimulated with Lys-ASA, N-formyl-methionyl-leucyl-phenylalanine (fMLP), or both fMLP and Lys-ASA, in a buffer containing IL-3, and results compared with human leukaemia cell line (Hl-60) response to Lys-ASA. Cys-LTs were measured in cell supernatant fluids by ELISA. ASA had a rather week stimulatory effect on cys-LTs release in both groups of patients. Contrary to some previous studies, no significant differences were found between cys-LTs release by leucocytes from AIA and ATA, or by differentiated Hl-60 cells. Measurement of cysteinyl-leukotriene release by peripheral blood leucocytes pre-treated with aspirin has no value for diagnosis of AIA.