Urinary Leukotriene Research Articles

Association of ambient air pollution and pesticide mixtures on respiratory inflammatory markers in agricultural communities

Air pollution exposure is associated with adverse respiratory health outcomes. Evidence from occupational and community-based studies also suggests agricultural pesticides have negative health impacts on respiratory health. Although populations are exposed to multiple inhalation hazards simultaneously, multidomain mixtures (e.g. environmental and chemical pollutants of different classes) are rarely studied. We investigated the association of ambient air pollution-pesticide exposure mixtures with urinary leukotriene E4 (LTE4), a respiratory inflammation biomarker, for 75 participants in four Central California communities over two seasons. Exposures included three criteria air pollutants estimated via the Community Multiscale Air Quality model (fine particulate matter, ozone, and nitrogen dioxide) and urinary metabolites of organophosphate (OP) pesticides (total dialkyl phosphates (DAPs), total diethyl phosphates (DE), and total dimethyl phosphates (DM)). We implemented multiple linear regression models to examine associations in single pollutant models adjusted for age, sex, asthma status, occupational status, household member occupational status, temperature, and relative humidity, and evaluated whether associations changed seasonally. We then implemented Bayesian kernel machine regression (BKMR) to analyse these criteria air pollutants, DE, and DM as a mixture. Our multiple linear regression models indicated an interquartile range (IQR) increase in total DAPs was associated with an increase in urinary LTE4 in winter (β: 0.04, 95% CI: [0.01, 0.07]). Similarly, an IQR increase in total DM was associated with an increase in urinary LTE4 in winter (β:0.03, 95% CI: [0.004, 0.06]). Confidence intervals for all criteria air pollutant effect estimates included the null value. BKMR analysis revealed potential non-linear interactions between exposures in our air pollution-pesticide mixture, but all confidence intervals contained the null value. Our analysis demonstrated a positive association between OP pesticide metabolites and urinary LTE4 in a low asthma prevalence population and adds to the limited research on the joint effects of ambient air pollution and pesticides mixtures on respiratory health.

One- versus 2-day aspirin desensitization in aspirin exacerbated respiratory disease: Aquality improvement project.

Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P= 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P= .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P= .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P= .6), 1084 vs 385 pg/mg (P= .2), 686 vs 306 cells/μL (P= .74), and 735 vs 278 kU/L (P= .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

Can we apply biomarkers in the management of non-steroidal anti-inflammatory drug exacerbated respiratory disease?

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by adult-onset asthma, chronic rhinosinusitis with nasal polyps (CRSwNPs), and aspirin/NSAID hypersensitivity, presenting recurrent asthma exacerbation and poor clinical outcomes. Patients with NERD have heterogeneous clinical phenotypes/endotypes, and the management of NERD remains challenging. Dysregulation of arachidonic acid (AA) metabolism and persistent eosinophilic airway inflammation are the major pathogenic mechanisms in the upper and lower airways of NERD. To date, increased levels of urinary leukotriene E4 (uLTE4) [a terminal metabolite of the lipoxygenase (LOX) pathway] have been the most relevant biomarker for NERD. It is demonstrated that mast cells, platelets, and epithelial cells can amplify upper and lower airway inflammation in NERD, and several potential biomarkers based on these complicated and heterogeneous mechanisms have been suggested. This review summarizes potential biomarkers for application in the management of NERD.

Effect of Dupilumab on Type 2 Biomarkers in Chronic Rhinosinusitis With Nasal Polyps: SINUS-52 Study Results.

Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab's effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study. Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks. Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings. Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab's therapeutic effects. SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454. NCT02898454.

Automated Identification of Aspirin-Exacerbated Respiratory Disease Using Natural Language Processing and Machine Learning: Algorithm Development and Evaluation Study.

Aspirin-exacerbated respiratory disease (AERD) is an acquired inflammatory condition characterized by the presence of asthma, chronic rhinosinusitis with nasal polyposis, and respiratory hypersensitivity reactions on ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Despite AERD having a classic constellation of symptoms, the diagnosis is often overlooked, with an average of greater than 10 years between the onset of symptoms and diagnosis of AERD. Without a diagnosis, individuals will lack opportunities to receive effective treatments, such as aspirin desensitization or biologic medications. Our aim was to develop a combined algorithm that integrates both natural language processing (NLP) and machine learning (ML) techniques to identify patients with AERD from an electronic health record (EHR). A rule-based decision tree algorithm incorporating NLP-based features was developed using clinical documents from the EHR at Mayo Clinic. From clinical notes, using NLP techniques, 7 features were extracted that included the following: AERD, asthma, NSAID allergy, nasal polyps, chronic sinusitis, elevated urine leukotriene E4 level, and documented no-NSAID allergy. MedTagger was used to extract these 7 features from the unstructured clinical text given a set of keywords and patterns based on the chart review of 2 allergy and immunology experts for AERD. The status of each extracted feature was quantified by assigning the frequency of its occurrence in clinical documents per subject. We optimized the decision tree classifier's hyperparameters cutoff threshold on the training set to determine the representative feature combination to discriminate AERD. We then evaluated the resulting model on the test set. The AERD algorithm, which combines NLP and ML techniques, achieved an area under the receiver operating characteristic curve score, sensitivity, and specificity of 0.86 (95% CI 0.78-0.94), 80.00 (95% CI 70.82-87.33), and 88.00 (95% CI 79.98-93.64) for the test set, respectively. We developed a promising AERD algorithm that needs further refinement to improve AERD diagnosis. Continued development of NLP and ML technologies has the potential to reduce diagnostic delays for AERD and improve the health of our patients.

Vascular Inflammatory Markers as Predictors of Peripheral Arterial Disease Patients' Quality-of-Life Changes after Endovascular Treatment.

The association between chronic inflammation and depression, anxiety, anhedonia, and quality of life (QoL) has been recently emphasized. However, the pathophysiology of this relationship remains unsolved. This study aims to assess the dependence between vascular inflammation represented by eicosanoid concentration and quality of life in patients with peripheral arterial disease (PAD). A total of 175 patients undergoing endovascular treatment due to lower limbs ischemia were covered with eight years of observation after the endovascular procedure, including ankle-brachial index (ABI), color Doppler ultrasound examination, urinary leukotriene E4 (LTE4), thromboxane B2 (TXB2) and 5-Hydroxyeicosatetraenoic acid (5-HETE) measurement and quality-of-life assessment with VascuQol-6. The baseline concentrations of LTE4 and TXB2 reversely correlated with preoperative VascuQol-6 and were predictive of the postoperative values of VascuQol-6 at each follow-up. At every follow-up timepoint, the results of VascuQol-6 reflected the LTE4 and TXB2 concentrations. Higher concentrations of LTE4 and TXB2 were correlated with lower life quality during the next follow-up meeting. Changes in VascuQol-6 at eight years vs. preoperative values were reversely related to the preoperative concentrations of LTE4 and TXB2. This is the first study to confirm that changes in life quality in PAD patients undergoing endovascular treatment are highly dependent on eicosanoid-based vascular inflammation.

Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. Amouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P= .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8%± 3.6% with ifetroban vs -8.4%± 2.1% with placebo [P= .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

Association of eosinophil-derived neurotoxin levels with asthma control status in patients with aspirin-exacerbated respiratory disease.

The long-term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil-derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin-exacerbated respiratory disease (AERD), and aspirin-tolerant asthma (ATA). A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K-EDN ELISA kit. Urinary leukotriene E4 (LTE4 ) level was measured using liquid chromatography-mass spectrometry (LC-MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well-controlled or partly-controlled asthma (ANOVA, p<0.001); in patients with AERD, the sputum EDN levels showed significant correlations with ACT, ACQ, and AQLQ scores (p=0.010, r=-0.536, p=0.001, r=0.665, and p<0.001, r=-0.691, respectively), while no differences were noted in patients with ATA. Sputum EDN level was the only significant factor for ACT, ACQ, and AQLQ scores in patients with AERD (p=0.001, p<0.001, and p<0.001, respectively) in the multivariate analysis adjusting for age, sex, peripheral eosinophil count, and urine LTE4 . The ROC curve analysis demonstrated that sputum EDN can predict uncontrolled asthma with 80% sensitivity and 88.2% specificity for ACT≤19 (area under the ROC curve [AUC]=0.824, p=0.019); 71.4% sensitivity and 86.7% specificity for ACQ≥1.5 (AUC=0.752, p=0.049) only in AERD patients. The level of sputum EDN may be a potential biomarker for identifying the asthma control status in patients with AERD.

Allergic Rhinitis in Preschoolers: A Systematic Review of Diagnostics.

Most studies that seek to analyze the prevalence of allergic rhinitis do not include preschool children and the diagnosis in this age group is difficult. Identify complementary tests to the diagnosis of allergic rhinitis in preschool children and verify if there is scientific robustness to propose a diagnostic algorithm for this condition in this age group. Systematic review of the literature in four databases: SCIELO, PubMed/MEDLINE, LILACS and SCOPUS. Each article was initially chosen by title, abstract and by the keywords "allergic rhinitis," "diagnosis" and "preschool." Those articles selected entered the complete reading and data extraction phase. The study was registered in the International Prospective Register of Systematic Reviews under number CRD42020207053. Fourteen articles were suitable for analysis. In the assessment using Quality Assessment of Diagnostic Accuracy Studies - 2, all studies had at least one domain considered "high risk" or "undetermined risk." Seven reports of nasal cytology, seven of specific IgE, four of immediate hypersensitivity skin test, one of nasal nitric oxide, three of total IgE and one of urinary leukotriene E4 were found. Eight articles evaluated more than one diagnostic test. There are no defined criteria for the diagnosis of allergic rhinitis in preschool children. Nasal cytology, serum specific IgE and immediate hypersensitivity skin test were the most used tests. A reliable diagnostic criterion in this age group is necessary so that in the future it is possible to propose a diagnostic algorithm for allergic rhinitis in preschool children.

Blow Me Away: Change in Exhaled Fractional Nitric Oxide (FeNO) Levels May Help to Identify Aspirin Exacerbated Respiratory Disease (AERD)

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a heterogenous disease. Aspirin-exacerbated respiratory disease (AERD) is a distinct CRSwNP phenotype with a unique therapeutic approach. Our study aimed to compare fractional exhaled nitric oxide (FeNO) and urinary leukotriene E4 (LTE4), before and after endoscopic sinus surgery (ESS) among CRSwNP patients with and without AERD.

Periostin as an important biomarker of inflammatory phenotype T2 in Brazilian asthma patients.

The aim of this study was to assess the laboratory performance of periostin associated with a panel of biomarkers to identify the inflammatory phenotype of Brazilian asthma patients. We evaluated 103 Brazilian individuals, including 37 asthmatics and 66 nonasthmatic controls. Both groups underwent analyses for serum periostin, eosinophil levels in the peripheral blood, the fraction of exhaled nitric oxide (FeNO), total serum IgE, urinary leukotriene E4, and serum cytokines. Higher levels of periostin (p = 0.005), blood eosinophils (p = 0.012), FeNO (p = 0.001), total IgE (p < 0.001), and IL-6 (p ≤ 0.001) were found in the asthmatic patients than the controls. Biomarker analyses by the ROC curve showed an AUC greater than 65%. Periostin (OR: 12,550; 95% CI: 2,498-63,063) and IL-6 (OR: 7,249; 95% CI: 1,737-30,262) revealed to be suitable asthma inflammation biomarkers. Blood eosinophils, FeNO, total IgE, IL-6, TNF, and IFN-g showed correlations with clinical severity characteristics in asthmatic patients. Periostin showed higher values in T2 asthma (p = 0.006) and TNF in non-T2 asthma (p = 0.029). The panel of biomarkers proposed for the identification of the inflammatory phenotype of asthmatic patients demonstrated good performance. Periostin proved to be an important biomarker for the identification of T2 asthma.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients

BackgroundCysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed.MethodsBlood and spot urine were collected in “severe” (n = 26), “critically ill” (n = 17) and “critically ill on VV-ECMO” (n = 17) patients with COVID-19 at days 1–2 (admission), 3–4, 5–8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated.ResultsU-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients.ConclusionsU-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Phenotype characterization and biomarker evaluation in moderate to severe type 2-high asthma.

There are two major pathological phenotypes of asthma, type 2 (T2)-high and T2-low asthma, which are important in determining treatment strategies. However, the characteristics and phenotypes of T2-high asthma have not yet been fully identified. This study aimed to identify the clinical characteristics and phenotypes of patients with T2-high asthma. This study used data from a nationwide asthma cohort study in Japan, NHOM Asthma Study. T2-high asthma was defined as a blood eosinophils count ≥ 300 /μL and/or fractional exhaled nitric oxide level ≥ 25 ppb, and the clinical characteristics and biomarkers were compared between T2-high and T2-low asthma. Furthermore, T2-high asthma was phenotyped via hierarchical cluster analysis using Ward's method. Patients with T2-high asthma were older, less likely to be female, had longer asthma duration, had lower pulmonary function, and had more comorbidities, including sinusitis and SAS. Patients with T2-high asthma showed higher serum thymus and activation-regulated chemokine and urinary leukotriene E4 levels and lower serum ST2 levels than those with T2-low asthma. There were four phenotypes among patients with T2-high asthma: Cluster 1 (youngest, early-onset, and atopic), Cluster 2 (long duration, eosinophilic, and low lung function), Cluster 3 (elderly, female-dominant, and late-onset), and Cluster 4 (elderly, late-onset, and asthma-COPD overlap-dominant). Patients with T2-high asthma have distinct characteristics and four distinct phenotypes, in which eosinophil-dominant Cluster 2 is the most severe phenotype. The present findings may be useful in precision medicine for asthma treatment in the future.

Stratification of clinical and inflammatory phenotypes according to the urinary leukotriene E4 level in adult asthmatics

Stratification of clinical and inflammatory phenotypes according to the urinary leukotriene E4 level in adult asthmatics

Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) comprises the triad of chronic rhinosinusitis with nasal polyps, asthma and intolerance to NSAIDs. Dupilumab treatment, targeting the interleukin-4 (IL-4) receptor α, significantly reduces polyp burden as well as asthma symptoms. Here we aimed to investigate the effect of dupilumab on aspirin intolerance, burden of disease and nasal cytokine profiles in patients with N-ERD. In this open-label trial, adult patients with confirmed N-ERD were treated with dupilumab for 6 months. Clinical parameters (e.g. total polyp scores, quality of life questionnaires, smell test, spirometry), oral aspirin provocation testing and blood, nasal and urine sampling were monitored at regular intervals for up to 6 months after starting dupilumab therapy. Of the 31 patients included in the study, 30 completed both aspirin provocation tests. After 6 months of treatment with dupilumab, 23% of patients (n=7 of 30) developed complete aspirin tolerance and an additional 33% of patients (n=10 of 30) tolerated higher doses. Polyp burden was significantly reduced (total polyp score: -2.68±1.84, p<0.001), while pulmonary symptoms (asthma control test: +2.34±3.67, p<0.001) and olfactory performance improved (University of Pennsylvania Smell Identification Test: +11.16±9.54, p<0.001) in all patients after therapy. Patients with increased aspirin tolerance showed a significant decrease in urinary leukotriene E4 levels and their improvement in clinical parameters was associated with a reduction of eotaxin-1, C-C motif chemokine ligand 17, IL-5, IL-17A and IL-6. In this study, 57% of N-ERD patients tolerated higher doses of aspirin under dupilumab therapy.

Urinary Leukotriene E4 as a Biomarker in NSAID-Exacerbated Respiratory Disease (N-ERD): a Systematic Review and Meta-analysis.

Non-steroidal exacerbated respiratory disease (N-ERD) currently requires aspirin challenge testing for diagnosis. Urinary leukotriene E4 (uLTE4) has been extensively investigated as potential biomarker in N-ERD. We aimed to assess the usefulness of uLTE4 as a biomarker in the diagnosis of N-ERD. N-ERD, formerly known as aspirin-intolerant asthma (AIA), is characterised by increased leukotriene production. uLTE4 indicates cysteinyl leukotriene production, and a potential biomarker in N-ERD. Although several studies and have examined the relationship between uLTE4 and N-ERD, the usefulness of uLTE4 as a biomarker in a clinical setting remains unclear. Our literature search identified 38 unique eligible studies, 35 were included in the meta-analysis. Meta-analysis was performed (i.e. pooled standardised mean difference (SMD) with 95% confidence intervals (95% CI)) and risk of bias assessed (implementing Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Cochrane DTA)). Data from 3376 subjects was analysed (1354N-ERD, 1420 ATA, and 602 HC). uLTE4 was higher in N-ERD vs ATA (n = 35, SMD 0.80; 95% CI 0.72-0.89). uLTE4 increased following aspirin challenge in N-ERD (n = 12, SMD 0.56; 95% CI 0.26-0.85) but not ATA (n = 8, SMD 0.12; CI - 0.08-0.33). This systematic review and meta-analysis showed that uLTE4 is higher in N-ERD than ATA or HC. Likewise, people with N-ERD have greater increases in uLTE4 following aspirin challenge. However, due to the varied uLTE4 measurement and result reporting practice, clinical utility of these findings is limited. Future studies should be standardised to increase clinical significance and interpretability of the results.

Urinary Cysteinyl Leukotrienes as Biomarkers of Endothelial Activation, Inflammation and Oxidative Stress and Their Relationship with Organ Dysfunction in Human Septic Shock.

Cysteinyl leukotrienes (CysLT) are potent vascular leakage-promoting agents but have been scarcely explored in human septic shock (SS). We evaluated CysLT at admission and during hospitalization and their correlation with endothelial dysfunction, inflammation, oxidative stress, the renin-angiotensin-aldosterone system, and cardiac, renal, respiratory, and hepatic parameters in SS patients. Blood and spot-urine samples were collected at days 1-2 (admission), 3-4, and 5-8 in SS patients (n = 13) and at a single time point in controls (n = 22). Urinary CysLT (u-CysLT) and isoprostanes, plasma, and urinary angiotensinogen, serum myeloperoxidase, and IL-10 were quantified by ELISA. Serum intercellular-adhesion molecule-1, vascular cell-adhesion molecule-1, E-selectin, tumor necrosis factor-α, IL-1β, and IL-6 were measured by multiplex immunoassays. Routine markers were evaluated using automated analyzers. At admission, SS patients had increased u-CysLT, endothelial activation, inflammation, oxidative stress, and plasma and urinary angiotensinogen, as well as cardiac, respiratory, hepatic, and renal injury/dysfunction. There were no changes in u-CysLT during hospitalization. Both correlation and multivariate analyses showed positive relationships of u-CysLT with endothelial activation, inflammation, oxidative stress, proteinuria, and hepatic injury/dysfunction markers. These results suggest that u-CysLT may be potential non-invasive biomarkers for monitoring the pathophysiological mechanisms underlying SS, as well as putative therapeutic targets.

SNIFFING AROUND FOR CLINICAL SCREENING MARKERS TO PREDICT AERD IN CRSWNP PATIENTS

<h3>Introduction</h3> Aspirin-exacerbated respiratory disease(AERD) is a sub-group of chronic rhinosinusitis with nasal polyps(CRSwNP) associated with asthma and cyclooxygenase-1 inhibitor sensitivity. AERD pathogenesis involves dysregulation of arachidonic acid metabolism which favors pro-inflammatory mediator overproduction. A significant proportion of AERD patients are suspected to be undiagnosed, as aspirin sensitivity is frequently unreported. There are no standard AERD screening modalities but aspirin challenge(AC) is an effective diagnostic tool. <h3>Methods</h3> A retrospective, observational study was conducted from 1/1/2016-12/29/2021. 210 subjects met inclusion criteria of CRSwNP patients who underwent AC, desensitization or had clinically diagnosed AERD. Baseline level of serum eosinophils(EOS), basophils, immunoglobulins, complements, tryptase, spot urine leukotriene E4(LTE4), fractional exhaled nitric oxide(FeNO) and Lund-Mackay CT-sinus score(LMCT) were evaluated. 33 subjects on biologic therapy were excluded. <h3>Results</h3> AERD was diagnosed in 74/177(41.80%) subjects. 61 subjects denied NSAID sensitivity and then completed AC, from which 14/61(22.95%) were positive. Several markers showed significant correlation with positive AC including LMCT, EOS and LTE4. Total complement(CH50) showed a slight but significant negative trend with positive AC but values remained within normal range. Other markers showed no correlation. <h3>Conclusion</h3> Contemporary literature reports different AERD endotypes which may obscure clinical phenotypes and hamper diagnosis. Clinical markers could prove valuable screening tools for atypical phenotypes. Prior studies have correlated AERD with serum basophils, EOS, IgE, LTE4 and LMCT. Our data correlates AERD diagnosis with LMCT, EOS, LTE4 and CH50. Further studies are needed to confirm our CH50 results. These clinical, laboratory and radiologic markers could prove useful screening tools for identifying candidates for AC.

Safety and efficacy of the 5-lipoxygenase-activating protein inhibitor AZD5718 in patients with recent myocardial infarction: The phase 2a FLAVOUR study

BackgroundLeukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. MethodsPatients 7–28 days after myocardial infarction (±ST elevation), with <50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4- and 12-week cohorts. Change in urine leukotriene E4 (uLTE4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. ResultsOf 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE4 levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths. ConclusionsIn patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected. ClinicalTrials.gov identifier: NCT03317002.

Clinical Study of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers.

Simple SummaryAspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts.The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.