Eosinophil-derived Neurotoxin Levels Research Articles

Evaluation of Eosinophil-Derived Neurotoxin Level and Asthma Severity in Isolated Asthma in Comparison to Asthma with Allergic Comorbidity

Abstract Background Asthma and associated type 2 inflammation are observed in 50–70% of patients with asthma and eosinophilic inflammation is a common feature in many asthma patients, and is associated with a higher risk of a more severe disease. Esinophilic Derived Neurotoxin (EDN) it’s useful as a clinical biomarker for the diagnosis and monitoring of asthma. High levels of EDN have been observed in patients with asthma, with higher levels measured during asthma exacerbations than in those with stable asthma. Objective To compare the association of the level of Esinophilic Derived Neurotoxin and burden of asthma in patients with asthma with Allergic comorbidities such as rhinitis and / or eczema compared to patients with asthma alone. Methods A cross sectional study included 100 adult patients, 50 patients diagnosed as asthma according to GINA guidelines and 50 patients diagnosed as asthma with allergic comorbidity such as Allergic rhinitis and/or eczema were selected from those who presented to the Allergy and clinical immunology clinics at Ain Shams University Hospitals during the period between January to July 2022. Results 50% of the studied population had bronchial asthma alone while the remaining had asthma with allergic comorbidities with most of them had asthma with allergic rhinitis and Most of the patients with allergic rhinitis had mod/severe persistent AR. 77% of total patients had positive SPT and 23% had negative SPT. Most of the patients had positive result for dust mites (Dermatophagoides farina 35% and Dermatophagoides pteronyssinus 30%) followed by pollens (mugwort 27%, rye grass 26% and tobacco 13%) and Animal dander (horse hair 15%, sheep wool 14%, cat hair 13% and dog hair 12%). The Median (IQR) of absolute eosinophil count and total IgE were higher in patients with asthma with Allergic comorbidities [0.68 (0.58 – 0.83) cells/mm3 and 155 (120 – 350) IU/ml respectively] while patients with asthma alone were 0.25 (0.12 – 0.45) cells/mm3 and 68.5 (29 – 123) IU/ml respectively. Our study showed the Median (IQR) of Serum EDN level was higher in patients with asthma with Allergic comorbidities [34 (28 – 40) ng/ml] compared to the patients with asthma alone [15(11 – 18) ng/m]. The quality of life and asthma control test was poor in asthmatic patients with allergic comorbidities compared to patients with asthma alone. Conclusion Serum EDN, Absolute Eosinophilis and total IgE can be used as a marker of T2 inflammation of air ways as their levels were higher in asthma with Allergic comorbidities. Asthma with comorbidities has more symptom burden with poorer quality of life and lower asthma control test than asthma alone; with more concern to be taken for those patients with asthma comorbidities as they have more severe asthma and poorer quality of life

Association of mucus eosinophil-derived neurotoxin levels with disease control status in patients with chronic rhinosinusitis.

Identifying the biomarkers for uncontrolled chronic rhinosinusitis (CRS) is important for directing treatment decisions. Eosinophilia has been reported to be involved in the poor disease control of CRS and mucus eosinophil-derived neurotoxin (EDN) is potentially a biomarker of intense eosinophil activation. This study aimed to assess the relationship between mucus EDN levels, disease severity, and degree of CRS control. A total of 150 adult patients with CRS and 25 healthy controls were prospectively enrolled. The nasal mucus and tissue specimens were collected to analyze EDN levels. Disease severity was assessed by Lund-Mackay score and 22-item Sino-Nasal Outcome Test (SNOT-22) score. Five CRS symptom severities during the prior month (nasal blockage, rhinorrhoea/postnasal drip, facial pain/pressure, smell, sleep disturbance or fatigue), use of rescue medications in the last six months, and the presence of diseased mucosa on nasal endoscopy were obtained. Consistent with the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 CRS control criteria, uncontrolled CRS was defined as meeting at least three items. 40% of patients with CRS presented with uncontrolled status. Patients with uncontrolled CRS had significantly higher nasal mucus EDN levels (P = 0.010), percentage of blood eosinophil (P = 0.015), SNOT-22 score (P < 0.001), Lund-Mackay score (P = 0.008), and a more eosinophilic dominant phenotype of CRS (P < 0.001) than patients with controlled CRS. Furthermore, mucus EDN levels were positively correlated with blood eosinophils (r = 0.541, P = 0.005), SNOT-22 score (r = 0.460, P = 0.021), and Lund-Mackay score (r = 0.387, P = 0.039). Mucus EDN levels were the significant parameter related to uncontrolled CRS in multivariable analysis after adjusting for patient demographics and comorbidities (odds ratio = 1.323; P = 0.004). Mucus EDN levels may be a potential biomarker for identifying the CRS control status.

Monitoring pediatric eosinophilic esophagitis disease activity using an unsedated blind esophageal brushing model: A pilot study.

Recurrent upper endoscopies are essential for monitoring therapy response and disease activity in patients with eosinophilic esophagitis (EoE), leading to increased costs, procedural complications, and anesthesia exposure. The aim of this study was to examine an office-based model using serial sedation-free blind esophageal epithelial brushing (BEEB) to monitor therapy response through eosinophil-derived neurotoxin (EDN) levels and guide therapy plans in pediatric EoE patients. EoE patients (≤21 years of age) were enrolled in this prospective study. Subjects were placed on dietary, pharmacologic, or combination therapy with the goal of inducing or maintaining remission. To assess response to sequential interventions, subjects underwent sequential sedation-free BEEBs through nasogastric tubesto measure EDN levels. Based on serial brushings, an individual plan of diet, medications, or a combination of both was created for each subject, and a final endoscopy was then performed to validate the accuracy of the individual plans. Twenty-four subjects completed the study. The average peak eosinophil countin patients with active EoE was 58.1 ± 30.8 eosinophils per high-power field and mean EDN level was 165.2 ± 191.3 μg/mL. A total of 42 BEEBs were completed. Individual therapy plans based on sequential BEEB were accurate in 19 out of the 24 patients (79%) and specifically nine out of 10 patients (90%) treated with elimination diets. This study suggests that office-based sedation-free BEEBs can be used to monitor therapy response and disease activity in pediatric EoE patients.

Serum microRNA-223 as a potential biomarker for allergic rhinitis and its correlation to eosinophil-derived neurotoxin

Allergic rhinitis (AR) is a global health problem. It is an inflammatory condition defined by a malfunction of the immune system's regulatory mechanism. MicroRNA-223 (miRNA-223) has been linked to the modulation of AR in the last few years. The goal of this study was to determine whether miR-223 can be utilized as a potential biomarker for diagnosis of AR, and whether it correlates with the total nasal symptom score (TNSS) along with serum interleukin-17 (IL-17), interleukin-4 levels (IL-4) and eosinophil-derived neurotoxin (EDN). This study included 76 adult participants, consisted of 38 AR patients and 38 apparently healthy controls. Serum levels of miR-223 were assayed using real-time PCR. The levels of EDN, IL-17 and IL-4 in the serum were determined using an enzyme-linked immunosorbent assay. The optimal cutoff value for the analyzed factors to diagnose AR was determined using a receiver operating characteristic curve analysis (ROC). The demographic features (age and gender) of the two study groups were matched. Patients with pollen-induced AR had significantly higher levels of miR-223 in their serum compared to the controls (median = 3.82; median = 1.03, respectively, p &lt; 0.001). In AR cases, a significant positive association was observed between miR-223 expression level and TNSS (r = 0.492, p = 0.002), EDN serum level (r = 0.427, p = 0.008), IL-4 serum level (r = 0.341, p = 0.036) and IL-17 serum level (r = 0.324, p = 0.047). MiR-223, at a cutoff value of 1.18, had a sensitivity and specificity of 94.9 % and 92.5%, respectively. In conclusion, miR-223 expression is significantly greater in blood of AR patients. There is a significant association between miR-223 and clinical severity of AR, each of IL-17 and IL-4 as well as EDN. Therefore, miR-223 may be employed as an effective biomarker for AR diagnosis.

Antiviral effect of high-pressure nasal stimulation.

In a previous study, we reported an increase of nasal nerve growth factor (NGF) in patients treated with high-pressure administration of sterile saline isotonic solution (HPpSIS). Herein we characterized the nasal mucosa in terms of innate immune response and cytokine signature, including antiviral properties. Potential NGF and antiviral benefits of HPpSIS were also discussed. Twenty (20) patients (11 males, 9 females; age range 30-75 years old) underwent HPpSIS and nasal samples were collected before and after treatment. Nasal scraping was used for morphological (smears and Quick May-Grunwald Giemsa staining, MGG), biochemical (Histamine, Serotonin; ELISA) and molecular (messenger RNA, mRNA) analyses. Amplification of transcripts specific for Toll-like receptor (TLR) 3 (TLR3), TLR7, TLR9, Interleukin-(IL) 18 (IL18), IL13, IL12, eosinophil-derived neurotoxin (EDN), Eosinophil Cationic Protein (ECP), γ Interferon (γIFN), tryptase and serotonin was performed using the 2-step real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR). Clinical and laboratory data were analyzed and compared. The clinical evaluation showed a protective effect of our therapy. Smears showed the presence of leucocytes, eosinophils (EOs) and mast cells (MCs), and increased immunoreactivity for ECP/RNase3 and EDN after HPpSIS. ELISA showed increased levels of Serotonin and EDN associated with unchanged levels of substance P(SP) and histamine. Increased eosinophil-derived neurotoxin eosinophil-derived neurotoxin (EDN) levels were confirmed by in situ fluorescent analysis. HPpSIS induced the upregulation of TLR3, TLR7 and TLR9 transcripts, while no changes were observed for Intercellular Adhesion Molecule 1 (ICAM1), IL18, Interleukin-15 (IL15) and IL12 transcripts nor for Interleukin-6 (IL6) and IL13. No changes were also observed for γIFN and EDN/RNase2 transcripts, while ECP/RNase3 transcripts were significantly upregulated after HPpSIS. Finally, tryptase transcripts were unchanged while serotonin transcripts were significantly increased after HPpSIS. The clinical and biomolecular changes observed at the nasal mucosa due to HpSS treatment suggest the activation of an innate surveillance, by means of TLR transcription, and a possible anti-viral response due to EDN upregulation. It remains to be verified if NGF, known to be released locally upon HpSIS treatment, might in part be responsible for this local activation.

Tezepelumab and Mucus Plugs in Patients with Moderate-to-Severe Asthma

BackgroundMucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo.MethodsCASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores.ResultsAbsolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation.ConclusionsTezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.

ANALYSIS OF THE RISK OF RECURRENT WHEEZING IN CHILDREN WITH BRONCHIOLITIS BASED ON THE WEIBULL MATHEMATICAL MODEL

Given the frequency of recurrent wheezing (up to 50 % of cases) in young children during the first year after bronchiolitis, the assessment of the prognostic value of diagnostic biological markers of bronchiolitis requires special attention.According to modern concepts, mast cells, eosinophils, play a significant role in the pathogenesis of bronchiolitis, with degranulation of which the release of cationic proteins (eosinophilic cationic protein (ECP), eosinophil-derived neurotoxin (EDN)) and molecular mediators, namely vascular cell adhesion molecule-1 (VCAM-1), which is a regulator of leukocyte adhesion and transendothelial migration. That is why VCAM-1, ECP and EDN are discussed as important prognostic markers in assessing the risk of recurrent wheezing in children with bronchiolitis.The aim of the study. To analyze the risk factors for recurrent wheezing in children with bronchiolitis, considering allergic history, the influence of external factors (passive smoking, place of residence), levels of VCAM-1, ECP, EDN in the blood serum.Material and Methods. This article is a part of the research work of the Department of Paediatrics No. 1 of Vinnytsia National Medical University named after M.I. Pyrohov on the topic "Optimization of diagnosis and treatment of somatic pathology in children", state registration No. 0115U007075.A clinical examination of 67 infants was carried out. The main group consisted of 34 children with bronchiolitis without a complicated allergic history. The comparison group consisted of 33 children with bronchiolitis who had a burdened allergic history. The average age of the children in the main group was 8.4±1.6 months, and 6.2±1.4 months in the comparison group. The analytical component of the study was based on parametric survival models (Weibull and generalized Gamma models). The analysis of Weibull models was performed in the statistical packages of analytical system R for Mac OS X FAQ, Version 3.1.0 2014-04-10, R. app 1.64 based on the Mac OS X 10.9 platform, 64-bit Intel Core i7 architecture.The study was approved by the Commission on Biomedical Ethics for compliance with the moral and legal rules for conducting medical research at Vinnytsia National Medical University named after M.I. Pyrohov. It was established that the research does not contradict the basic bioethical norms and meets the principles of compliance with the basic provisions of the GCP (1996), the Council of Europe Convention on Human Rights and Biomedicine (04.04.1997), WMA Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects (1964-2008) and Order of the Ministry of Health of Ukraine No. 690 of 23.09.2009 (as amended by Order of the Ministry of Health of Ukraine No. 523 of 12.07.2012). All patients were informed about the purpose and possible consequences of the research procedures. All patients signed an informed written consent to participate in the study prior to the procedure.Results of the study. The risks of recurrent wheezing in children with bronchiolitis according to the Weibull model were allergic history ( β=1,996) mixed feeding, and to an even greater extent artificial feeding ( β=7,832 and β=8,337). High serum levels of ECP β=5,03, EDN β=0,182 and VCAM-1 β=0,0254 are reliable markers of increased risk of recurrent wheezing in children with bronchiolitis. Living in rural areas ( β=-5,8) significantly reduces the risk of recurrent wheezing in children with bronchiolitis compared to children living in urban areas β=0.0162).Conclusions. 1. The levels of VCAM-1, ECP and EDN in the blood serum were recognized as reliable markers for the prognosis of recurrent vesicitis in children with bronchiolitis. The level of EDN ≤ 7 ng/ml in the blood serum is a prognostic marker for the risk of recurrent wheezing in children with bronchiolitis.2. The hypothesis that artificial feeding in children with bronchiolitis with a complicated allergic history confirms and significantly increases the risk of recurrent vesicitis in children with bronchiolitis. The hypothesis about the role of passive smoking exposure in a significant increase in the risk of recurrent wheezing in children with bronchiolitis was confirmed only for patients with EDN levels not exceeding 7 ng/ml in the blood serum.

Association of EDN levels in patients with asthma and correlation with FEV1%: A meta-analysis.

Background: Eosinophil-derived neurotoxin (EDN), an eosinophil degranulation product, is a good biomarker for eosinophilic inflammation of the airway. Several articles have shown that EDN levels are higher in patients with asthma than in controls, and EDN levels are correlated with the percentage of predicted forced expiratory volume in the first second (FEV1%) in patients with asthma. Their results were inconclusive. Methods: A comprehensive meta-analysis was performed to assess EDN levels between patients with asthma and controls, and the correlations between EDN and FEV1% in the patients with asthma. Fourteen relevant articles were identified from electronic data bases. Pooled standardized mean difference (SMD) with a 95% confidence interval (CI) for the difference of EDN levels between the patients with asthma and controls, and pooled coefficient (r) values with 95% CI for the correlations between EDN and FEV1%, respectively, were calculated. Results: A total of 14 articles were selected. Among the included reports, six articles related to the difference and eight essays on the correlation. Pooled effect size showed that EDN levels were higher in patients with asthma than in controls (SMD 2.85 [95% CI, 1.92-3.78]). Furthermore, the pooled effect size showed that EDN levels were negatively correlated with FEV1% in patients with asthma (r -0.21 [95% CI, -0.28 to -0.14]). Conclusion: EDN levels increased in the patients with asthma compared with in the controls. They were correlated with FEV1% in the patients with asthma, which indicated that EDN could be a reliable marker to monitor asthma's therapeutic effects.

Olfactory cleft mucus eosinophil-derived neurotoxin better reflects olfactory loss than blood eosinophil counts in patients with chronic rhinosinusitis.

Eosinophils are associated with olfactory dysfunction in chronic rhinosinusitis (CRS) and eosinophil-derived neurotoxin (EDN) is a sensitive marker of intense eosinophil activation. This study aimed to analyze olfactory cleft mucus and olfactory mucosa EDN levels and their association with olfactory dysfunction in CRS. We prospectively recruited 150 patients with CRS electing endoscopic sinus surgery and 25 healthy controls. Both superior turbinate biopsy specimens and olfactory cleft mucus were collected to analyze EDN levels. Sniffin' Sticks test scores, olfactory cleft computed tomography (CT) scores, and olfactory cleft endoscopy scale (OCES) were obtained. Multivariable logistic regression analysis was applied to analyze the predictability of EDN levels for olfactory dysfunction in CRS. Chronic rhinosinusitis with olfactory dysfunction presented significantly higher olfactory mucosa (p=0.016) and olfactory cleft mucus (p<0.001) EDN levels than CRS without olfactory dysfunction. Mucus EDN levels were positively correlated with blood eosinophils (r=0.625, p=0.002), olfactory cleft CT scores (r=0.738, p<0.001), and OCES (r=0.605, p=0.004) in CRS. Furthermore, mucus EDN levels were significantly negatively correlated with threshold, discrimination, and identification (TDI) (r=-0.688), olfactory threshold (r=-0.606), olfactory discrimination (r=-0.608), and olfactory identification (r=-0.697) scores. After adjusting for patient demographics and comorbidities, mucus EDN levels were significantly associated with olfactory dysfunction in CRS (odds ratio=2.162; p=0.027). Mucus EDN levels showed a significantly better performance for predicting olfactory dysfunction than blood eosinophil counts (area under the curve, 0.873vs. 0.764, p=0.024). Olfactory cleft mucus EDN level may be a better biomarker for predicting olfactory dysfunction in CRS than blood eosinophil counts.

Eosinophil Granule Proteins Involvement in Acute Appendicitis-An Allergic Disease?

Several pieces of evidence point to an allergic component as a trigger of acute appendicitis. As the Th2 immune response is characterized by eosinophil mobilization to the target organ and release of their cationic granule proteins, it is reasonable to investigate if the degranulation of eosinophils could be associated with the local injury. The primary aim of this study is to evaluate the participation of eosinophils granules proteins in acute appendicitis, both at local and systemic levels and the secondary aim is to evaluate the diagnostic accuracy of eosinophils granules proteins for the detection of acute appendicitis, as well as for distinguishing between complicated and uncomplicated acute appendicitis. Eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP) and eosinophil peroxidase (EP) are the most well-known eosinophil granule proteins. From August 2021 to April 2022, we present a prospective single-center study to evaluate the EDN, ECP, and EP concentrations simultaneously in appendicular lavage fluid (ALF) and the serum of 22 patients with acute phlegmonous appendicitis (APA), 24 with acute gangrenous appendicitis (AGA), and 14 normal controls. Concerning EDN, no differences were found between groups. ECP concentrations in ALF and serum were significantly higher in the histologically confirmed acute appendicitis compared to the control groups (p < 0.0001 and p < 0.0001, respectively). In ALF, no differences were found between ECP levels in APA: 38.85 ng/mL (IQR 26.50-51.77) and AGA 51.55 ng/mL (IQR 39.55-70.09) groups (p = 0.176). In the serum, no difference was found between ECP levels at APA: 39 ng/mL (IQR 21.30-56.90) and AGA: 51.30 ng/mL (IQR 20.25-62.59) (p = 0.100). For EP, the concentrations in ALF (p < 0.001) and serum (p < 0.001) were both higher in acute appendicitis compared to the control. In ALF, no difference was found between APA: 240.28 ng/mL (IQR 191.2-341.3) and AGA: 302.5 (IQR 227.7-535.85) (p = 0.236). In the serum, no differences were found between APA: 158.4 ng/mL (IQR 111.09-222.1) and AGA: 235.27 (IQR 192.33-262.51) (p = 0.179). Globally, the ALF concentrations were higher than serum concentrations, reflecting an intense inflammatory local reaction in AA. The optimal ECP cut-off for discriminating between acute appendicitis and the controls was >11.41 ng/mL, with a sensitivity of 93.5%, but with a specificity for identifying appendicitis of 21.4%, good discriminative power (AUC = 0.880). For EP, the optimal cut-off was >93.20 ng/mL, with a sensitivity of 87%, but with a specificity of 14.3% (AUC = 0.901), excellent discriminative power. For the diagnosis of perforated AA, the discriminative power of ECP and EP serum concentrations are weak (AUC = 0.562 and AUC = 0.664, respectively). Concerning the presence of peritonitis, the discriminative power of ECP and EP serum concentrations is acceptable, respectively: AUC = 0.724 and AUC = 0.735. Serum levels of EDN (p = 0.119), ECP (p = 0.586) and EP (p = 0.08) in complicated appendicitis were similar to uncomplicated appendicitis. Serum concentrations of ECP and EP can be added to decision-making AA diagnosis. A Th2-type immune response is present in AA. These data bring forward the role of an allergic reaction in the pathogenesis of acute appendicitis.

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.

Multiplex Specific IgE Profiling in Neonatal Stool of Preterms Predicts IgE-Mediated Disease

Background: The natural history of immunoglobulin (Ig) E-mediated diseases in preterm infants is still elusive. We aimed at developing a non-invasive tool for detecting specific IgE (sIgE) and eosinophil-derived neurotoxin (EDN) in neonatal fecal samples and evaluating its predictive value for the development of IgE-mediated diseases during the first year of life. Methods: We developed a stool extraction protocol, followed by freeze-drying and solubilization. The sIgEs were investigated in neonatal fecal samples from 21 preterm infants with a 300-allergen multiplex and confirmed by a capillary Western blot with a nano-immunoassay. EDN concentration was used to investigate the local eosinophilic component. Results: The multiplexed allergen assay detected sIgE in all of the samples. A Western blot was used to confirm the results. The frequency and levels of sIgE in the neonatal fecal samples differed between the infants who developed IgE-mediated diseases and the controls. Allergen specificity was associated with the development of cow’s milk allergy (CMA) and asthma. The development of CMA was predicted by the sIgE response to milk proteins (sensitivity was 88%; specificity was 78%). The EDN levels predicted the development of IgE-mediated diseases (sensitivity was 100%; specificity was 75%). Conclusion: The non-invasive investigation of neonatal fecal sIgE is a promising tool for predicting the subsequent development of IgE-mediated diseases. Clinical Implications: The non-invasive sIgE and EDN profiling of neonatal fecal samples from preterm infants can predict the development of IgE-mediated diseases.

Atopic march Eosinophil-Derived Neurotoxin levels and the onset of allergic airway disease in preschool children

“Atopic march” is the progression of allergic conditions through infancy and childhood. We investigated the association between blood eosinophil-derived neurotoxin (EDN) levels in preschool children with food allergy (FA) or atopic dermatitis (AD) and the onset of allergic airway disease [bronchial asthma (BA), allergic rhinitis (AR)].

Serum Levels of Eosinophil-Derived Neurotoxin, Platelet-Activating Factor and Vascular Endothelial Growth Factor in Adult Patients with Atopic Dermatitis-A Pilot Study.

Atopic dermatitis (AD) is a chronic, highly pruritic, relapsing-remitting inflammatory skin disease. The etiology of AD has not been fully explained yet and complex interactions of various small molecules are still being taken into account. The aim of this research was to investigate the serum eosinophil-derived neurotoxin (EDN), platelet activating factor (PAF) and vascular endothelial growth factor (VEGF) concentrations in relation to the disease severity and pruritus intensity in adult patients with AD. This pilot study was performed on 30 participants (15 patients with AD and 15 healthy controls). Blood samples were taken to examine the serum levels of EDN, PAF and VEGF using the enzyme-linked immunosorbent assay (ELISA) test. The severity of disease was assessed by the Scoring Atopic Dermatitis (SCORAD) index. The intensity of pruritus, as a subjective symptom, was determined by the Visual Analogue Scale (VAS). Obtained results revealed that the EDN (p = 0.016) and VEGF (p = 0.032), but not PAF (p = 0.841) concentrations were significantly higher in patients with AD compared with those of the control group. There was positive correlation between the EDN level and the SCORAD index in patients with AD (r = -0.9, p = 0.037) which was not found for the PAF and VEGF levels. Circulating EDN, PAF and VEGF levels were not significantly correlated with the severity of pruritus. Our results suggest that the END and VEGF serum levels are significantly increased in patients with AD compared to control group. Moreover, EDN might be useful to reflect the severity of symptoms.

Serum Levels of Vascular Endothelial Growth Factor, Platelet Activating Factor and Eosinophil-Derived Neurotoxin in Chronic Spontaneous Urticaria-A Pilot Study in Adult Patients.

Chronic spontaneous urticaria (CSU) is a skin disease characterized by the presence of wheals, angioedema, or both for at least 6 weeks. Although, CSU is often regarded as autoimmune in nature, its etiology is not fully explained and interactions between various small molecules are still taken under account. The aim of this research was to investigate the mean serum concentration of vascular endothelial growth factor (VEGF), platelet activating factor (PAF), and eosinophil-derived neurotoxin (EDN) in relation to the disease activity and pruritus intensity in adult patients with CSU. Fifteen patients with CSU and 15 healthy subjects participated in this pilot study. Blood samples were taken to examine the mean serum levels of VEGF, PAF, and EDN by the enzyme-linked immunosorbent assay test (ELISA). The Urticaria Activity Score (UAS7) and The Visual Analogue Scale (VAS) were used to assess the disease activity and the pruritus intensity, respectively. Obtained results revealed that VEGF, PAF, and EDN concentrations were higher in patients with CSU compared with those of the control group, but only for VEGF it was statistically significant (p = 0.008). However, levels of all investigated cytokines were not significantly correlated neither with the disease activity nor with the pruritus intensity. Our results showed higher serum levels of VEGF, PAF, and EDN among CSU patients which may highlight a functional role of these cytokines in the disease’s pathogenesis. In contrast, VEGF, PAF, or EDN might not be useful to reflect the severity of symptoms.

Identification of novel genes influencing eosinophil-specific protein levels in asthma families

Eosinophils play a key role in the asthma allergic response by releasing cytotoxic molecules such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) that generate epithelium damages. We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families. We performed univariate and bivariate genome-wide association analyses of ECP and EDN levels in 1018 subjects from the EGEA study with follow-up in 153 subjects from the Saguenay-Lac-Saint-Jean study and combined the results of these 2 studies through meta-analysis. We then conducted Bayesian statistical fine mapping together with quantitative trait locus and functional annotation analyses to identify the most likely functional genetic variants and candidate genes. We identified 5 genome-wide significant loci (P&amp;lt; 5×10&lt;sup&gt;-8&lt;/sup&gt;) including 7 distinct signals associated with ECP and/or EDN levels. The genes targeted by our fine mapping and functional search include RNASE2 and RNASE3 (14q11), which encode EDN and ECP, respectively, and 4 other genes that regulate ECP and EDN levels. These 4 genes were JAK1 (1p31), a transcription factor that plays a key role in the immune response and acts as a potential therapeutic target for eosinophilic asthma; ARHGAP25 (2p13), which is involved in leukocyte recruitment to inflammatory sites; NDUFA4 (7p21), which encodes a component of the mitochondrial respiratory chain and is involved in cellular response to stress; and CTSL (9q22), which is involved in immune response, extracellular remodeling, and allergic inflammation. Analysis of specific phenotypes produced by eosinophils allows the identification of genes that play a major role in allergic response and inflammation, and offers potential therapeutic targets for asthma.

Esophageal epithelial immunoglobulin G is an important marker for the diagnosis and management of pediatric eosinophilic esophagitis

Background and AimOur primary aim was to describe the prevalence of immunoglobulin G (IgG) and its subclass IgG4 in immunohistochemistry staining in esophageal biopsy specimens of children with eosinophilic esophagitis (EoE) compared with that of specimens from children with gastroesophageal reflux disease (GERD).MethodsEsophageal biopsy specimens from children with EoE or GERD were stained prospectively for IgG and IgG4 antibodies. Subjects with EoE were divided into cohorts with either active EoE or EoE in remission. Active EoE cases were further divided into proton pump inhibitor responsive (PPI‐r) and PPI‐nonresponsive (PPI‐nr) subgroups. Demographic, clinical, and histologic data were compared among groups, including quantified IgG and IgG4 staining, peak eosinophil count, eosinophil‐derived neurotoxin levels, and EoE endoscopic reference score.ResultsSeventy‐nine children (aged 10.6 ± 5.6 years; 68% male) were enrolled. IgG‐positive cell counts were significantly elevated in those with active EoE (n = 29, 3 [interquartile range, IQR: 2–6]/high‐powered field [HPF]), compared with those having EoE remission (n = 25, 1 [IQR: 0–2]/HPF; P = 0.002) and those with GERD (n = 25, 0 [IQR: 0–0.25]/HPF, P = <0.0001). IgG‐positive cell counts were significantly higher in the PPI‐r (n = 15, 5 [IQR: 2.5–11]/HPF) subgroup, compared with the PPI‐nr subgroup (n = 11, 3 [IQR: 1.5–3.5]/HPF; P = 0.041) at baseline endoscopy.ConclusionInitial esophageal tissue biopsy specimens from pediatric subjects with active EoE showed a significant increase in IgG‐positive staining compared with tissue from subjects in EoE remission or with GERD. There was higher positivity of IgG‐stained cells in the PPI‐r subgroup compared with the PPI‐nr subgroup.

Eosinophil-derived neurotoxin: An asthma exacerbation biomarker in children.

Background: Asthma is a heterogeneous disease, characterized by chronic airway inflammation. Asthma exacerbations (AE) are episodes characterized by a progressive increase in symptoms of shortness of breath, cough, wheezing, or chest tightness with a decrease in lung function. There have been previous studies that examined the role of eosinophil-derived neurotoxin (EDN) in asthma, but there have been no studies of the role of EDN in children experiencing AE. Objective: In this study, we aimed to examine the association of EDN with lung function and prognosis in children admitted for severe AE. Methods: We enrolled 82 children who were admitted for severe AE at two different university hospitals in South Korea between January 2018 and December 2019. Blood tests, including white blood cell count, myeloperoxidase (MPO), total eosinophil count, EDN, C-reactive protein (CRP) level, and interleukin (IL) 4, IL-5, IL-10 values, and lung function were measured on admission and at discharge in each patient. Results: We observed significant decreases in the levels of MPO, EDN, CRP, and IL-4, with significant improvement in lung function after treatment. We then classified the subjects into two groups of different clinical phenotypes: eosinophilic asthma exacerbation (EAE) group and non-EAE group. EDN levels were higher and lung functions were lower in the EAE group. Also, we found that the EDN level was a significant biomarker useful for predicting the number of days for hospital stay. Conclusion: We found that EDN can act as a biomarker that reflects lung function, and that EDN could act as a prognostic biomarker, which demonstrated the complex role of EDN in children experiencing AE.

Role of Thymus and Activation-Regulated Chemokine in Allergic Asthma.

BackgroundAsthma is a chronic inflammatory airway disease characterized by the predominant infiltration of inflammatory cells in the airways. Thymus and activation-regulated chemokine/C–C motif chemokine 17 (TARC/CCL17) is a chemokine responsible for trafficking T helper 2 cells into sites of allergic inflammation.ObjectiveTo validate the role of TARC in association with clinical and inflammatory parameters in adult asthmatics.MethodsWe enrolled 128 asthmatic patients and 70 healthy controls (HCs). Asthma-related clinical and laboratory parameters, including lung function and eosinophil counts, were measured. Serum levels of TARC, free immunoglobulin E (IgE), and eosinophil-derived neurotoxin (EDN) were determined by using enzyme-linked immunosorbent assay; serum total IgE level was measured using ImmunoCAP. The levels of inflammatory lipid mediators, such as leukotriene E4 (LTE4), 15-hydroxyeicosatetraenoic acid (15-HETE), thromboxane B2 (TXB2), and prostaglandin F2α (PGF2α), were measured by liquid chromatography-tandem mass spectrometry.ResultsSerum TARC levels are significantly higher in asthmatics than in HCs and in allergic asthmatics than in HCs (P < 0.010 for all), with significantly negative correlations between serum TARC levels and FEV1%/MMEF% values (r = −0.314, r = −0.268, P < 0.050 for both). The patients with higher serum TARC levels had higher levels of serum total and free IgE levels (P < 0.050 for both) with positive correlations to serum levels of EDN, TXB2, and 15-HETE (r = 0.233, r = 0.264, and r = 0.223, respectively, P < 0.050 for all).ConclusionWe suggest the role of TARC in allergic asthma via contributing to mast cell and eosinophilic inflammation.