Search

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., Artificial neural network based on a set of clinical and biochemical parameters is able to stratify N‐ERD patients among asthmatic population. The sensitivity of the present artificial neural network is 94.12% and specificity is 73.08% for the prediction of N‐ERD. Artificial neural network could become a screening tool and allow to quickly identify patients with a high suspicion of N‐ERD

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 logLTE4/logPGE2 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 LTE4 in ISS and the highest logLTE4/logPGE2 ratio. Class 3 subjects had mild‐to‐moderate asthma and were also characterized by eosinophilic airway inflammation, yet increased production of pro‐ (LTE4, PGD2 and 11‐dehydro‐TBX2) was balanced by anti‐inflammatory PGE2. The value of logLTE4/logPGE2 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., Heterogeneity of NERD phenotype reflects differences in inflammatory response measured by airway cells and eicosanoids. Identifying subphenotypes provides a more insightful perception and suggests a need for more individualized approach. In aspect of logLTE4/logPGE2 ratio, latent class analysis assigned subject to different groups better than identification by disease severity or control emphasizing the heterogeneity in NERD subgroup. Abbreviations: LTE4, Leukotriene E4; NERD, NSAID‐exacerbated respiratory disease; PGE2, Prostaglandin E2

Background Aspirin desensitization (AD) is an effective and safe therapeutic option for patients with nonsteroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD). The mechanisms driving its beneficial effects remain poorly understood. Objective To investigate the effect of long-term AD on clinical, biochemical and radiological changes in N-ERD patients. Methods The study group consisted of twenty-three individuals with N-ERD who underwent AD, followed by ingestion of 325 mg aspirin twice daily. Twenty patients completed the 52 weeks of AD. The following evaluations were conducted at baseline and in the 52nd week of AD: (i) clinical: asthma exacerbations, Asthma Control Test (ACT), Visual Analogue Scale (VAS) for the assessment of nasal symptoms; (ii) blood and induced sputum supernatant (ISS) periostin, (iii) phenotypes based on induced sputum (IS) cells, (iiii) ISS and nasal lavage (NL) concentration of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), tetranor-PGD-M, tetranor-PGE-M, 8-iso-PGE2, leukotriene B4 (LTB4), LTC4, LTD4 and LTE4, and urine LTE4. Results A significant improvement was observed in ACT (P = 0.02) and VAS score (P = 0.008) in the 52nd week of AD. ISS periostin and IS eosinophil count decreased significantly in the 52nd week of AD (P = 0.04 and P = 0.01, respectively). ISS and NL eicosanoid concentrations did not change following long-term AD. Conclusion and Clinical Relevance: AD is associated with a decrease in sputum periostin biosynthesis, which may prevent the recruitment of eosinophils into respiratory tissue and be one of explanation of the clinical benefits of AD. Long-term aspirin administration does not lead to an imbalance between pro- and anti-inflammatory ISS eicosanoids.

BACKGROUND A special regulatory role for prostaglandin E2 (PGE2 ) 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 PGE2 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, PGE2 , 8-iso-PGE2 , tetranor-PGE-M, 8-iso-PGF2 α, and leukotriene C4 , D4 , and E4 , were determined using mass spectrometry. Urinary excretion of LTE4 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

A special regulatory role for prostaglandin ETo investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGEInduced 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, PGENERD 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 PGEAspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE

Background: Omalizumab(OMA) is the youngest medicine in asthma therapy. It is being evaluated in real-world clinical practice to provide complete understanding of the benefit of this otherwise expensive medicine. Objectives: To evaluate efficacy of OMA during one year of therapy in real-life conditions in Polish patients with severe allergic asthma. Methods: Due to the introduction of Program for Severe Allergic Asthma funded by the National Health Insurance OMA became more commonly available for Polish patients. Strict inclusion criteria should be met to enter the program. The study is one-year open-label observation lead in 15 patients qualified to the program in Pulmonary Department in Krakow. All patients have been assessed for asthma control (Asthma Control Questionnaire-ACQ), quality of life (Asthma Quality of Life Questionnaire-AQLQ), daily dose of oral corticosteroids (OCS) and asthma exacerbation rate. Results: All patients have shown good (47%,n=7,GR) or very good (53%,n=8) response (VGR) to OMA according to Global Evaluation of Treatment Effectiveness (GETE) scale after one-year therapy. OMA significantly reduced asthma exacerbation rate by 80% (by 91% in VGR and by 65% in GR group) and the dose of OCS by 62% (by 76% in VGR and by 46% in GR). ACQ declined by 34% in the group (p=0.005), by 52% in VGR (p=0,01) and by 10% in GR(p=0,2). AQLQ grew in the whole group by 34%(p=0,03) and in VGR by 40%(p=0.01). In GR group the increase by 25% was insignificant. Conclusions: Omalizumab has shown high effectiveness in real-world Polish patients in reduction of asthma exacerbations and the dose of oral corticosteroids, improvement in asthma control and quality of life indicators.

Background. Special regulatory role of eicosanoids has been postulated in aspirin-induced asthma. Objective. To investigate effects of aspirin on exhaled breath condensate (EBC) levels of eicosanoids in patients with asthma. Methods. We determined EBC eicosanoid concentrations using gas chromatography/mass spectrometry (GC-MS) and high-performance liquid chromatography/mass spectrometry (HPLC-MS2) or both. Determinations were performed at baseline and following bronchial aspirin challenge, in two well-defined phenotypes of asthma: aspirin-sensitive and aspirin-tolerant patients. Results. Aspirin precipitated bronchial reactions in all aspirin-sensitive, but in none of aspirin-tolerant patients (ATAs). At baseline, eicosanoids profile did not differ between both asthma groups except for lipoxygenation products: 5- and 15-hydroxyeicosatetraenoic acid (5-, 15-HETE) which were higher in aspirin-induced asthma (AIA) than inaspirin-tolerant subjects. Following aspirin challenge the total levels of cysteinyl-leukotrienes (cys-LTs) remained unchanged in both groups. The dose of aspirin had an effect on magnitude of the response of the exhaled cys-LTs and prostanoids levels only in AIA subjects. Conclusion. The high baseline eicosanoid profiling of lipoxygenation products 5- and 15-HETE in EBC makes it possible to detect alterations in aspirin-sensitive asthma. Cysteinyl-leukotrienes, and eoxins levels in EBC after bronchial aspirin administration in stable asthma patients cannot be used as a reliable diagnostic index for aspirin hypersensitivity.

Background: A special regulatory role for prostaglandin E 2 has been postulated in aspirin-induced asthma. A study was undertaken to investigate the effects of aspirin on the systemic production of prostaglandin E 2 and cysteinyl leucotrienes in patients with asthma. Methods: The urinary concentrations were determined of two main prostaglandin E 2 metabolites (13,14-dihydro-15keto-PGE 2 using a commercial enzyme immunoassay and 9,15-dioxo-11α-hydroxy-2,3,4,5-tetranor-prostane-1,20-dioic acid by gas chromatography/mass spectrometry) and leucotriene E 4 using an immunoassay. Determinations were performed at baseline and following oral aspirin and celecoxib challenges in two well-defined asthma phenotypes: aspirin-sensitive and aspirin-tolerant patients. Results: Aspirin precipitated bronchial reactions in all aspirin-sensitive patients but in none of the aspirin-tolerant patients. Celecoxib 400 mg was well tolerated by all patients except for one with aspirin-induced asthma. At baseline, the mean levels of prostaglandin E 2 metabolites did not differ between the groups. Following different aspirin provocation doses, the mean levels of the two main prostaglandin E 2 metabolites were decreased in the aspirin-tolerant group but remained unchanged in the aspirin-sensitive group. The dose of aspirin had no effect on the magnitude of the response on the prostaglandin E 2 metabolites and its duration. In both groups, urinary prostaglandin E 2 metabolites decreased following celecoxib challenge. No correlation was found between prostaglandin E 2 metabolites and leucotriene E 4 . Conclusions: Aspirin-precipitated asthmatic attacks are not associated with changes in the systemic production of prostaglandin E 2 . In contrast, the systemic production of prostaglandin E 2 becomes depressed by aspirin in non-sensitive patients. This different response might indicate COX-1-dependent prostaglandin E 2 control of inflammatory cells in aspirin-induced asthma. Thus, PGE 2 is released during the clinical reactions to aspirin through an alternative COX-2 pathway. The clinical implications of this finding are in line with current observations of good tolerance of the selective COX-2 inhibitors in aspirin-sensitive patients.

Introduction While spirometry plays a key role in diagnosing chronic obstructive pulmonary disease (COPD), imaging methods including endobronchial ultrasound (EBUS) and chest computed tomography (CT) appear to be useful for investigating structural changes in the lungs. Objectives The aim of this study was to evaluate remodeling in COPD patients using EBUS and chest CT. Patients and methods The study included 33 patients with COPD, 15 patients with severe asthma, and 15 control subjects. All subjects underwent pulmonary function tests and bronchoscopy with EBUS to measure the total thickness of the bronchial wall and its layers. Additionally, in COPD patients, a chest CT was performed to measure total bronchial wall thickness. Results The total bronchial wall thickness measured by EBUS in patients with COPD (1.192 ±0.079 mm) was significantly smaller than that in asthmatic patients (1.433 ±0.230 mm, P = 0.001) and significantly greater than in control subjects (1.099 ±0.095 mm, P = 0.04), and was positively correlated with residual volume (RV) / total lung capacity (r = 0.5, P = 0.02), RV (r = 0.6, P = 0.007), and RV (%) (r = 0.5, P = 0.05). The thickness of the bronchial wall layers in patients with COPD were as follows: L1 = 0.135 ±0.018 mm, L2 = 0.151 ±0.026 mm, and L3-5 = 0.906 ±0.065 mm. There was no correlation between the thickness of the bronchial wall layers and forced expiratory volume in 1 second. Conclusions The results of this study show that EBUS is a useful method for evaluating bronchial wall layers not only in asthma but also in COPD, and suggest that the pattern of remodeling differs in each of these diseases.

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.

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 (LTC4S) mRNA in eosinophils. There was a trend toward a better response in carriers of LTC4S 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.

Summary Background Montelukast, a cysteinyl-leukotriene receptor antagonist, was reported to have a protective effect against exercise-induced bronchoconstriction (EIB). Aspirin-induced asthma (AIA) is characterized by overproduction of cysteinyl-leukotrienes. Objective The aim of the study was to compare the response to exercise and the effect of montelukast on EIB in AIA as compared to aspirin-tolerant asthma (ATA). Methods A placebo-controlled, double blind, cross-over randomized study was performed in 19 AIA and 21 ATA patients with stable asthma. A single dose of montelukast (10 mg) or placebo (PL), was given orally one hour prior to exercise challenge. FEV1 was measured before and 5, 10, 15 min after exercise and then at 15-minute intervals for 4 h. Urinary LTE4 excretion and blood eosinophil count were measured at baseline, 2 h and 4 h following exercise challenge. Results Positive bronchial response to exercise was observed in 47.5% of all patients studied. Exercise led to almost identical maximal fall in FEV1 in AIA and ATA patients (23.5% ± 6.8% vs. 21.8% ± 12.0%, respectively; P = 0.7). Montelukast, as compared to PL, significantly attenuated EIB in 63.2% of 19 patients with positive exercise test preceded by PL. The mean of maximum fall in FEV1 from the pre-exercise value was 10.2% ± 13.8 after montelukast as compared to 22.5% ± 10.2 after placebo (P

We determined the effect of a long acting beta2-agonist, salmeterol, on aspirin-induced asthma (AIA) attacks and urinary release of eicosanoids in a double-blind, placebo-controlled, crossover study in 10 asthmatics sensitive to aspirin. The patients inhaled 50 microgram of salmeterol or placebo 15 min prior to a cumulative challenge with increasing doses of lysine-aspirin (L-ASA) (Part I), and before a single, predetermined dose of L-ASA that caused a 20% fall in FEV1 (PD20) (Part II). Salmeterol significantly attenuated aspirin-precipitated bronchoconstriction and the increase in urinary LTE4. Salmeterol also prevented the decrease in blood eosinophils, and abolished the correlation between the urinary levels of LTE4 and provocative doses of aspirin. In addition, PGD-M, the major urinary metabolite of PGD2, increased after L-ASA inhalation in six of nine subjects; this increase was blocked in all six by salmeterol. The protective effect of salmeterol on aspirin-induced attacks and mediator release suggests that it may be efficacious in aspirin-sensitive asthma.

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 E 4 and the stable plasma prostaglandin (PG) D 2 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.

The value of measurements of eicosanoids in exhaled breath condensate (EBC) for the evaluation of childhood asthma is still inconclusive most likely because of the limited value of the methods used. In this case-control study in 48 asthmatic and 20 healthy children, we aimed to characterize the baseline profile of the inflammatory mediators cysteinyl leukotrienes (cysLTs), 9(alpha)11(beta)PGF(2), PGE(2), PGF(2alpha), 8-isoprostane (8-iso-PGF(2alpha)) within EBC in asthmatic compared with healthy children using new methods. In addition, we investigated their relation to other inflammatory markers. The assessment included collection of EBC, measurement of fractional exhaled nitric oxide (FE(NO)) and evaluation of urinary excretion of leukotriene E(4.) cysLTs were measured directly in EBC by radioimmunoassay and prostanoids were measured using gas chromatography negative-ion chemical ionization mass spectrometry. Only cysLT levels were significantly higher in asthmatic compared with healthy children (p = 0.002). No significant differences in cysLTs were found between steroid naive and patients receiving inhaled corticosteroids. In contrast, FE(NO) was significantly higher in steroid naive compared with steroid-treated asthmatic and healthy children (p = 0.04 and 0.024, respectively). The diagnostic accuracy of cysLTs in EBC for asthma was 73.6% for the whole group and 78.2% for steroid-naive asthmatic children. The accuracy to classify asthmatic for FE(NO) was poor (62.9%) for the whole group, but improved to 79.9% when only steroid-naive asthmatic children were taken into consideration. cysLTs in EBC is an inflammatory marker which distinguishes asthmatics, as a whole group, from healthy children.

We performed a double-blind, two-phase study on protective and bronchodilator effects of prostaglandins E2 and E1 (PGE2, PGE1) and salbutamol in patients with aspirin-induced asthma (AIA). In phase 1 we assessed the effects of pretreatment with PGE2, salbutamol, or the PGE1-analogue, misoprostol, on bronchoconstriction precipitated by inhalation of L-lysine aspirin in 11 patients with AIA. PGE2 and salbutamol were inhaled at equimolar concentrations of 0.25 mumol, 5 min before the aspirin challenge, while 400 micrograms misoprostol was administered orally 1 h before challenge. PGE2 attenuated the bronchoconstrictive reactions in 10 patients, salbutamol in eight, and misoprostol in seven. The mean provocative dose of aspirin causing a 20% fall in FEV1 (PD20) decreased after PGE2 (p = 0.04) and salbutamol (p = 0.06), but only marginally after misoprostol (p = 0.25). There was a positive correlation between magnitude of the protection offered by the three compounds in individual subjects. In phase 2, we examined bronchial response to inhaled PGE2, PGE1, salbutamol, and 2% ethanol in 12 AIA patients compared with 10 aspirin-tolerant patients with asthma. AIA subjects were characterized by less pronounced and shorter bronchodilator responses. There was no correlation between the protective and bronchodilator actions of the compounds used in individual patients. Thus, inhaled PGE2 and salbutamol protect against aspirin-induced attacks of asthma through mechanisms unrelated to their bronchodilator properties. Airways of aspirin-sensitive patients with asthma demonstrate distinct bronchial reactivity.