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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 ( T0) and during Dp-induced bronchoconstriction ( TEAR). 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 T0 the most abundant eicosanoids in EBC of HDM-allergic patients were LTB4 and 5-oxo-ETE, while in HCs EBC concentration of LTB4 was significantly greater than that of 5-oxo-ETE. Allergen challenge resulted in significant increase in EBC concentration of 5-oxo-ETE, LTD4 and 8-iso-PGE2 only in Rs. At TEAR, 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 TEAR 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Multiple NSAID-induced urticaria/angioedema ( MNSAID- UA) is an entity well differentiated from aspirin-exacerbated respiratory disease ( AERD), although no detailed phenotype analysis has yet been performed. The objective was to evaluate the functional characteristics of MNSAID- UA subjects by analyzing the response to nasal lysine-aspirin challenge and measurement of nasal inflammatory mediator release compared with AERD subjects and controls. Methods The study included 85 subjects with confirmed hypersensitivity to NSAIDs (≥3 episodes with >2 different NSAIDs or positive drug provocation) with either cutaneous ( MNSAID- UA, n = 25) or respiratory manifestations ( AERD, n = 60) and 30 tolerant controls (15 aspirin-tolerant asthmatic patients and 15 healthy controls). Nasal lavages at 0, 15, 60, and 120 min after lysine-aspirin challenge were analyzed for ECP, tryptase, PGE2, PGD2, LTD4, and LTE4. Results Lysine nasal challenge was positive in 80% of the AERD cases but positive only in 12% of the MNSAID- UA group. MNSAID- UA subjects showed no changes in nasal ECP, whereas subjects with AERD had increased levels of ECP, with the highest peak at 15 min after challenge ( P < 0.05). Tryptase levels were higher in AERD compared with MNSAID- UA and controls with the highest release of tryptase at 60 min ( P < 0.05). Significant increases in PGD2, LTD4, and LTE4 were observed in AERD (at 60 min for PGD2, LTD4, and LTE4) but not in MNSAID- UA or control subjects ( P < 0.05). Conclusions Data support the observation that MNSAID- UA, although sharing a common response with AERD to COX inhibitors, seems to have a distinctive phenotype, based on the response to nasal challenge and the release of inflammatory mediators. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

Cite this as: M. Sanak, Clinical & Experimental Allergy, 2011 (41) 2-5. [ABSTRACT FROM AUTHOR]

Low-affinity IgE receptor gene ( FCER2) rs3760687 polymorphism was found to be associated with differential binding affinity of transcription factors Sp1 and Sp3 leading to altered transcriptional activity. Haplotypic interaction of functional FCER2 polymorphisms (rs28364072, rs2228137 and rs3760687) might potentially provide a background for genotype–phenotype associations previously observed for some rather non-functional FCER2 variants. [ABSTRACT FROM AUTHOR]

Background: The high-affinity receptor for immunoglobulin-E (IgE) (Fc ℇRI) plays a major role in the pathogenesis of allergy, but there are only two published studies on its α subunit (Fc ℇRI α) genetic variability in allergic diseases. Aims of the study: Mutational screening in the region of the Fc ℇRIα gene promoter and the first exon with subsequent genetic variability assessment in allergic patients and a random population sample. Methods: Allergic subjects were individuals with asthma or urticaria. Age- and sex-matched controls were randomly selected from a large population sample. Mutational screening was performed using a single-stranded conformational polymorphism and subsequent sequencing. Detected polymorphisms were genotyped by restriction fragment length polymorphism. Total serum IgE was measured in allergic subjects and controls. Skin prick tests, blood eosinophil count and aspirin challenge test were performed only in the subjects. A subgroup of the subjects was further characterized by autologous serum skin test, histamine release test, Phadiatop and IgE antibodies against staphylococcal enterotoxins. Results: Two linked polymorphisms −344 C>T and −95 T>C were found within the Fc ℇRI α gene. The allele −344 T frequency was 0.45 vs 0.37 ( P = 0.33), and the allele −95 C frequency was 0.26 in subjects vs 0.30 in controls ( P = 0.62). Serum IgE was significantly higher in subjects homozygous for the −344T allele (TT genotype) than in those carrying the −344 C allele (CT or CC genotype; P = 0.003), but this association was not detectable in controls. Conclusions: Our findings of genotype-related differences in IgE levels in allergic patients suggest an impact of −344 C>T but not −95 T>C gene polymorphism of Fc ℇRI α on total levels of IgE. The genetic variability in Fc ℇRI α at the −344 nucleotide of its regulatory sequence, though not related to atopy, predicts higher levels of the immunoglobulin. [ABSTRACT FROM AUTHOR]

Biochemical analysis of expiratory breath condensate is an emerging non-invasive technique for assessment of airway inflammation.We wondered whether application of expiratory breath condensate could facilitate diagnosis of aspirin-intolerant asthma and reproduce eicosanoids mediators' abnormalities described in this disease.We measured prostaglandins (PGs) E2, F2α, 9α11βF2 and iso-F2 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 9α11βPGF2, the metabolite of PGD2 and urinary leukotriene (LT) E4 were measured before and following the challenge.At baseline, PG did not differ between the groups, except for lower 9α11βPGF2 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 LTE4 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 LTE4.In asthmatic patients on chronic corticotherapy measurement of urinary LTE4 excretion rather than cys-LTs in breath condensate is of greater value for diagnosis of aspirin hypersensitivity. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment with antileukotriene drugs results in clinical improvement in many, though not all, patients with asthma. It can be hypothesized that the subpopulation of asthmatic patients, characterized by aspirin intolerance and cysteinyl-leukotriene overproduction, might profit most from antileukotriene treatment. Materials and methods We compared the clinical response to montelukast in two well-matched groups of patients with mild asthma: 26 aspirin-intolerant asthmatics (AIAs) and 33 aspirin-tolerant asthmatics (ATAs). We also searched for possible predictors of the clinical response among the parameters reflecting the expression and production of cysteinyl-leukotrienes (cys-LTs). This was an 8-week, single-blind, placebo-controlled trial. Results Following a 3-week montelukast 10 mg day-1 treatment compared with placebo, there was a statistically significant reduction in the mean daytime and nocturnal asthma symptoms and β2 -agonist use, as well as a significant improvement in the morning and evening peak expiratory flows and quality of life. Both groups showed a similar significant improvement in the parameters studied. Clinical response did not correlate with the baseline urinary LTE4 excretion level. Improvement of asthma was observed mostly in patients with a low baseline and non-IL-5 inducible expression of LTC4 synthase (LTC4 S) mRNA in eosinophils. There was a trend toward a better response in carriers of LTC4 S allele C, but no relationship to the CC10 genetic polymorphism. Conclusions No difference in the clinical response to the montelukast treatment was observed between the AIAs and the ATAs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Evaluates whether measurement in vitro of cysteinyl leukotrienes (Cys-LTs) release by isolated peripheral blood leucocytes, stimulated with acetyl salicylic acid, can be of use for aspirin-induced asthma (AIA) diagnosis. Administration of a cellular allergen stimulation test; Enzyme-linked immunosorbent assay of Cys-LTs; Differences between cys-LTs release by leucocytes from AIA and aspirin-tolerant asthma.

The article offers information on urinary leukotriene E4 (uLTE4) excretion in asthma for which a comparison of HPLC mass spectrometry and enzymatic immunoassay (ELISA) is mentioned. It states that the purification of urine, by affinity extraction with monoclonal antibody can improve specificity. It discusses asthmatic tests of patients on which it reports that through the use of ELISA method, no difference between healthy subjects and asthmatics, who tolerated aspirin well, is noted.

Two FCER1A gene proximal promoter polymorphisms, –344C > T and –95T > C, both associated with total serum IgE and/or allergic disorders in Caucasians and East Asians, were shown to influence the gene expression in additive manner. In face of the rarity of other proximal promoter variants in Caucasians or their lack in East Asians, future investigations of the FCER1A locus in these ethnic groups should probably focus on three common haplotypes of the common –344C > T and –95T > C polymorphisms. [ABSTRACT FROM AUTHOR]

An abstract of the article "Aspirin tolerance and leukotriene biosynthesis in Churg-Strauss syndrome," by W. Szczeklik, L. Mastalerz, B. Sokolowska, M. Sanak and E. Nizankowska-Mogilnicka is presented.

The article presents a comparative study of FCER1A gene exon 1A polymorphisms in Japanese and Polish subjects. FCER1A stands for polymorphisms of the gene encoding α-subunit of the high affinity immunoglobulin E receptor. It was suggested that FCER1A was involved in the pathogenesis of allergic disorders.

A letter to the editor is presented in response to the article "Association and functional relevance of E237G, a polymorphism of the high-affinity immunoglobulin E-receptor ß chain gene, to airway hyper-responsiveness," by Y. K. Kim, H. W. Park, and J. S. Yang in the previous issue.

The article discusses a study that reveals that FCER1A and FCER1B polymorphism demonstrated an additive association with total serum immunoglobulin E (IgE) in allergic patients. FCER1A and FCER1B are the genes encoding subunits of the high-affinity IgE receptor. FCER1B -109TT controls tended to have higher serum IgE levels than subjects carrying the variant -109C allele.

Editorial. Focuses on the role of cyclooxygenase-1 and cyclooxygenase-2 in asthma pathogenesis. Use of selective inhibitors; Possibilities for anti-inflammatory treatment in patients with urticaria; Differences between aspirin and other non-steroid anti-inflammatory drugs.

Background: 15-oxo-eicosatetraenoic acid (15-oxo-ETE), is a product of arachidonic acid (AA) metabolism in the 15-lipoxygenase-1 (15-LOX-1) pathway. 15-oxo-ETE was overproduced in the nasal polyps of patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). In this study we investigated the systemic biosynthesis of 15-oxo-ETE and leukotriene E 4 (LTE 4 ) and assessed their diagnostic value to identify patients with N-ERD., Methods: The study included 64 patients with N-ERD, 59 asthmatics who tolerated aspirin well (ATA), and 51 healthy controls. A thorough clinical characteristics of asthmatics included computed tomography of paranasal sinuses. Plasma and urinary 15-oxo-ETE levels, and urinary LTE 4 excretion were measured using high-performance liquid chromatography and tandem mass spectrometry. Repeatability and precision of the measurements were tested., Results: Plasma 15-oxo-ETE levels were the highest in N-ERD (p < .001). A receiver operator characteristic (ROC) revealed that 15-oxo-ETE had certain sensitivity (64.06% in plasma, or 88.24% in urine) for N-ERD discrimination, while the specificity was rather limited. Modeling of variables allowed to construct the Aspirin Hypersensitivity Diagnostic Index (AHDI) based on urinary LTE 4 -to-15-oxo-ETE excretion corrected for sex and the Lund-Mackay score of chronic rhinosinusitis. AHDI outperformed single measurements in discrimination of N-ERD among asthmatics with an area under ROC curve of 0.889, sensitivity of 81.97%, specificity of 87.23%, and accuracy of 86.87%., Conclusions: We confirmed 15-oxo-ETE as a second to cysteinyl leukotrienes biomarker of N-ERD. An index based on these eicosanoids corrected for sex and Lund-Mackay score has a similar diagnostic value as gold standard oral aspirin challenge in the studied group of patients with asthma., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: To evaluate plasma levels of selected cytokines and investigate their correlation with choroidal thickness (CT) in patients with acute and chronic central serous chorioretinopathy (CSC)., Methods: We enrolled 30 patients with acute CSC, 30 patients with chronic CSC and 20 controls. Plasma concentrations of 12 cytokines, interleukins IL-8, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10 and IL-12 p70, granulocyte-macrophage colony-stimulating factor, interferon-γ, tumour necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF), were measured using multiplex immunoassays. Differences in cytokine levels between groups were assessed. We also investigated correlations between cytokine levels and CT using swept-source optical coherence tomography, as well as an association between plasma cytokine profile and systemic hypertension., Results: We noted differences in IL-6 (p = 0.005), IL-10 (p = 0.03), IL-12 p70 (p = 0.028) and VEGF (p = 0.029) levels between groups. Pro-inflammatory IL-12 p70 and multidirectional IL-10 cytokines were upregulated, while pro-angiogenic VEGF was downregulated in chronic CSC as compared with controls (p = 0.005, p = 0.025 and p = 0.027, respectively). Interleukin-6 (IL-6) was upregulated in acute and chronic CSC (p = 0.030 and p = 0.005, respectively). Interleukin-5 (IL-5), IL-6 and IL-12 levels correlated with mean CT in acute CSC (p = 0.008, p = 0.003 and p = 0.044, respectively), while IL-8, IL-6 and TNF-α plasma levels correlated with hypertension in chronic CSC (p = 0.005, p = 0.033 and p = 0.001, respectively)., Conclusion: We provided new evidence for the possible role of plasma cytokines in the pathogenesis of CSC. Our results suggest that IL-6 may be important in the pathophysiology of acute and chronic CSC. The association between inflammatory response and hypertension in patients with CSC was also confirmed., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D 2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date, it has resulted in ~9 million confirmed cases and caused almost 500 000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a "cytokine storm" leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: To date, there has been no reliable in vitro test to either diagnose or differentiate nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD). The aim of the present study was to develop and validate an artificial neural network (ANN) for the prediction of N-ERD in patients with asthma., Methods: This study used a prospective database of patients with N-ERD (n = 121) and aspirin-tolerant (n = 82) who underwent aspirin challenge from May 2014 to May 2018. Eighteen parameters, including clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant (ISS) and urine were extracted for the ANN., Results: The validation sensitivity of ANN was 94.12% (80.32%-99.28%), specificity was 73.08% (52.21%-88.43%), and accuracy was 85.00% (77.43%-92.90%) for the prediction of N-ERD. The area under the receiver operating curve was 0.83 (0.71-0.90)., Conclusions: The designed ANN model seems to have powerful prediction capabilities to provide diagnosis of N-ERD. Although it cannot replace the gold-standard aspirin challenge test, the implementation of the ANN might provide an added value for identification of patients with N-ERD. External validation in a large cohort is needed to confirm our results., (© 2020 The Authors. Allergy published by John Wiley & Sons Ltd.)

Background: Induced sputum (IS) allows to measure mediators of asthmatic inflammation in bronchial secretions. NSAID-exacerbated respiratory disease (NERD) is recognized as a distinct asthma phenotype, usually with a severe course, eosinophilic airway inflammation, and increased production of pro-inflammatory eicosanoids. A more insightful analysis of NERD patients has shown this phenotype to be nonhomogeneous., Objective: We aimed to identify possible subphenotypes in a cohort of NERD patients with the means of latent class analysis (LCA)., Methods: A total of 95 asthma patients with aspirin hypersensitivity underwent sputum induction. High-performance liquid chromatography or gas chromatography coupled with mass spectrometry was used to profile eicosanoids in induced sputum supernatant (ISS). Sixteen variables covering clinical characteristics, IS inflammatory cells, and eicosanoids were considered in the LCA., Results: Three classes (subphenotypes) were distinguished within the NERD cohort. Class 1 subjects had mild-to-moderate asthma, an almost equal distribution of inflammatory cell patterns, the lowest concentrations of eicosanoids, and logLTE 4 /logPGE 2 ratio. Class 2 represented severe asthma with impaired lung function despite high doses of steroids. High sputum eosinophilia was in line with higher pro-inflammatory LTE 4 in ISS and the highest logLTE 4 /logPGE 2 ratio. Class 3 subjects had mild-to-moderate asthma and were also characterized by eosinophilic airway inflammation, yet increased production of pro- (LTE 4 , PGD 2 and 11-dehydro-TBX 2 ) was balanced by anti-inflammatory PGE 2 . The value of logLTE 4 /logPGE 2 was between values calculated for classes 1 and 3, similarly to disease control and severity., Conclusions: LCA revealed three distinct NERD subphenotypes. Our results support a more complex pathobiology of aspirin hypersensitivity. Considering NERD heterogeneity, the relationship between inflammatory pathways and clinical manifestations of asthma may lead to more individualized treatment in difficult to treat patients in the future., (© 2019 The Authors. Allergy published by John Wiley & Sons Ltd.)

Background: The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison., Methods: Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry., Results: No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11β-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups., Conclusions: We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and 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.)

Purpose: To analyse the prevalence and changes in circulating anti-endothelial cell antibodies (AECA) during anti-vascular endothelial growth factor (anti-VEGF) therapy., Methods: Ninety-eight patients with exudative age-related macular degeneration (AMD) were treated with intravitreal bevacizumab. Fifty sex- and age-matched healthy subjects were used as controls. Serum AECA were detected using indirect immunofluorescence on primate skeletal muscle and cultivated human umbilical vein endothelial cells (HUVEC). These investigations were repeated at 4-week intervals within 8 months of follow-up., Results: At baseline examination, 30 of the 98 patients (30.6%) were positive for AECA. The titres of AECA ranged from 1:10 to 1:320. In the control group, AECA were present in only nine sera (18%) with titres ranging between 1:20 and 1:80 (p = 0.0000). The greatest rates of reduction of AECA titres were observed during the 'loading' phase of therapy. During the 'maintenance' phase, the rates of changes in serum AECA levels were less significant and remained constant. In follow-up period in 13 patients (13.3%), serum AECA were detected de novo in titres of 1:10 to 1:80. Statistical analysis did not show any significant correlation between the presence of AECA and activity of the disease., Conclusions: There is growing evidence that AMD is an immune-mediated disease, and thus it cannot be excluded that AECA may be involved in its pathogenesis and progression. We also speculate that AECA develop in response to retinal damage and anti-VEGF therapy., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Urinary 11-dehydro-thromboxane (TX)B2 has been described as a potential predictive biomarker of major adverse cardiovascular events (MACEs) in high cardiac risk patients. This part of LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) study aimed to evaluate the relationship between 11-dehydro-TXB2 and MACEs in patients with acute myocardial infarction (AMI)., Methods and Results: LTIMI was an observational, prospective study in 180 consecutive patients with AMI type 1 referred for primary percutaneous coronary intervention. On admission and at follow-up visits (1 month, 1 year), 11-dehydro-TXB2 was measured in urinary samples by using high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was occurrence of composite MACEs during 1-year after AMI. Left ventricular ejection fraction was assessed in echocardiography on admission and at 1-year follow-up. Analyses of 11-dehydro-TXB2 (pg/mg creatinine) were performed on log-transformed data and expressed as median with IQR (Q1-Q3). 11-Dehydro-TXB2 level on admission was 7.39 (6.85-8.01) and decreased at 1 month (6.73, 6.27-7.12; P<0.001) and 1-year follow-up (6.37, 5.91-6.94; P<0.001). In univariate analysis, baseline 11-dehydro-TXB2 was higher in patients with MACEs (n=60; 7.73, 7.07-8.60) compared with those without MACEs (n=119; 7.28, 6.68-7.79; P=0.002). In multivariate regression model, 11-dehydro-TXB2 and 3 other variables (diabetes, multivessel disease, and left ventricular ejection fraction) were found to be best 1-year cumulative MACE predictors with odds ratio for 11-dehydro-TXB2 of 1.58 (95% CI 1.095-2.33; P=0.017) and area under the curve (in receiver operating characteristic analysis of 0.8). Baseline 11-dehydro-TXB2 negatively correlated with both left ventricular ejection fraction on admission (R=-0.21; P=0.006) and after 1 year (R=-0.346; P<0.001)., Conclusions: 11-Dehydro-TXB2 predicts 1-year cumulative MACEs in AMI patients and provides prognostic information on the left ventricular performance., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Purpose: To determine changes in anti-retinal antibodies (ARAs) during anti-VEGF therapy in patients with exudative age-related macular degeneration (AMD) and to assess the correlations between ARAs and disease activity., Methods: The study comprised 98 patients treated with intravitreal bevacizumab. The ophthalmic examination included best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundoscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). Serum ARAs levels were assessed by indirect immunofluorescence (IIF) on normal monkey retina substrate. These studies were repeated at 4 week intervals within 8 months of a follow-up. The sera of 50 sex- and age-matched healthy subjects were used as controls., Results: At baseline examination, 94 (95.5%) of the 98 patients were positive for ARAs. The ARAs titres were significantly higher (p = 0.0000) than in controls. A positive correlation was found between titres of ARAs and the diameter of choroidal neovascularization (CNV) as measured by FA (p = 0.0000), and central retinal thickness (CRT) assessed by OCT (p = 0.0000). A positive correlation was also found between the diameter of CNV, CRT and the complexity of circulating ARAs. Following treatment all patients demonstrated significant decrease in ARAs levels as well as improvement of BCVA, reduction of subretinal fluid on OCT and decreased leakage on FA., Conclusion: Changes in serum ARAs levels occurred in parallel with clinical outcomes of anti-VEGF therapy. Treatment reduced serum levels of ARAs, with the greatest reduction occurring during the 'loading' phase. This study demonstrated that ARAs may act as a serum biomarker of the efficacy of anti-VEGF therapy., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.)

Purpose: To determine serum antiretinal antibody (ARA) levels in response to treatment with intravitreal bevacizumab of exudative age-related macular degeneration (AMD)., Methods: The study comprised 22 patients treated with intravitreal bevacizumab (Avastin) 1.25mg. In all patients, serum ARA levels were assessed by indirect immunofluorescence on normal monkey retina substrate. The ophthalmic examination including best corrected visual acuity (BCVA), fundoscopy, fluorescein angiography, optical coherence tomography (OCT) and immunohistochemical investigations. These were repeated at 4-week intervals during a loading phase of antiangiogenic therapy. Sera of 22 sex- and age-matched healthy subjects were used as controls for immunohistochemical studies., Results: Before bevacizumab therapy, ARAs were detected in the sera of all patients at titres ranging from 1:40 to 1:1280. The titres were significantly higher (p < 0.01) than in controls (1:10-1:40). There was no significant correlation between serum ARA titres and neither the type nor the dimensions of choroidal neovascularization, as well as central retinal thickness. Following treatment, all patients demonstrated significant decrease in ARA levels. This correlated with improvement of BCVA, decreased leakage of fluorescein and reduction of subretinal fluid on OCT., Conclusion: Serum ARA levels demonstrate a dynamic change which occurs in parallel with clinical outcomes of antiangiogenic therapy. They also may act as markers of the therapeutic benefits of vascular endothelial growth factor inhibition., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

A single nucleotide T to C transition of the gene encoding glycoprotein IIIa leads to a common diallelic polymorphism Leu-33-->Pro (PLA1/A2). We studied the relationship between the PlA1/A2 polymorphism and platelet function in 80 healthy men, aged 20-25 years. Before aspirin ingestion, bleeding time (BT) was shorter in carriers of the PlA2 than in carriers of the PlA1/A1 allele. At 4 h after ingestion of 300 mg of aspirin, BT became prolonged, and the intergroup difference was enhanced. In seven out of 26 PLA2 allele carriers, aspirin shortened BT on average by 30 s, compared with only one among 54 subjects with the PlA1/A1 genotype. Thus, BT both at baseline and after aspirin depends on the PlA1/A2 polymorphism of glycoprotein IIIa. Carriers of the PlA2 allele appear to be more resistant to the antithrombotic action of aspirin.