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Abstract Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophil-associated disease (EAD) characterized by inflammation in small- to medium-sized blood vessels. In the REal-world inVestigation of Eosinophilic-Associated disease overLap (REVEAL) study, overlap among 11 EADs was assessed. In the present sub-study, we evaluated EGPA overlap with other EADs, all-cause EAD- and EGPA-related healthcare resource utilization (HCRU) and costs, and their relationship with blood eosinophil count and treatments received. Methods REVEAL, a retrospective study, used Optum’s de-identified Clinformatics® Data Mart Database. In this sub-study, eligibility criteria included an age of ≥ 12 years, ≥ 1 EAD, continuous health-plan eligibility, and compliance with the EGPA/GPA case definition per International Classification of Diseases Ninth/Tenth Revision diagnostic codes between 1 January 2015 and 30 June 2018. Patients were grouped based on whether they had received immunomodulators/cyclophosphamide/mepolizumab (ICM) or not (non-ICM). Results Of 701 patients with EGPA, 29.5% were in the ICM group. Overall, 72.2% had ≥ 1 overlapping EAD. The number of overlaps was similar for the ICM and non-ICM groups. In patients with blood eosinophil counts ≥ 300 cells/µL, 22.8% had ≥ 1 overlapping EAD. The mean annual all-cause cost was $98,644, 54.1% of which was from outpatients and 33.6% from inpatients. The mean annual EAD- and EGPA-related costs were $23,820 and $9,306, respectively. Patients in the non-ICM group versus the ICM group had higher all-cause ($101,560 vs $91,684) but lower EAD-related ($22,733 vs $26,412) and EGPA-related ($6,171 vs $16,786) costs. All-cause HCRU and costs increased with increasing overlap. Conclusions EGPA was associated with substantial HCRU and costs, driven by outpatient and inpatient settings. More overlapping EADs were associated with higher HCRU and costs, highlighting the need for treatment to reduce healthcare expenditure in these patients. Infographic available for this article.

Background: Eosinophil-derived neurotoxin (EDN) is an important biomarker of eosinophilic inflammation. Methods: This study evaluated Montelukast treatment response according to EDN concentration in children with perennial allergic rhinitis (PAR). Fifty-two children with PAR were recruited and took a combination of Montelukast (5mg) and Levocetirizine (5mg) "Mont/Levo Group" or only Montelukast (5mg) "Mont Group" for 4 weeks. All caregivers were instructed to record rhinitis symptoms for 4 weeks. EDN was measured before and after treatment. Results: Daytime nasal symptom scores (DNSS) significantly decreased in both the Mont/Levo (p = 0.0001; n = 20) and Mont Group (p < 0.0001; n = 20), but there were no significant differences between the two groups. EDN concentration also significantly decreased after treatment in both groups (p < 0.0001 and p < 0.001, respectively). For secondary analysis, children with a high initial EDN concentration (EDN ≥ 53 ng/mL) were placed in the "High EDN Group", while those with a lower initial EDN concentration (EDN < 53 ng/mL) were put in the "Low EDN Group". Both groups experienced significant reductions in DNSS after either treatment regimen (p < 0.0001 and p = 0.0027, respectively) but the High EDN Group had greater reductions. EDN concentrations in the High EDN Group decreased significantly from either treatment (p < 0.0001). Conclusion: We found that children with AR and a high serum EDN concentration may respond well to Montelukast treatment. A therapeutic strategy using EDN concentrations in patients with AR to evaluate therapeutic response may help improve quality of care. [ABSTRACT FROM AUTHOR]

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophil-associated disease (EAD) characterized by inflammation in small- to medium-sized blood vessels. In the REal-world inVestigation of Eosinophilic-Associated disease overLap (REVEAL) study, overlap among 11 EADs was assessed. In the present sub-study, we evaluated EGPA overlap with other EADs, all-cause EAD- and EGPA-related healthcare resource utilization (HCRU) and costs, and their relationship with blood eosinophil count and treatments received. Methods: REVEAL, a retrospective study, used Optum's de-identified Clinformatics® Data Mart Database. In this sub-study, eligibility criteria included an age of ≥ 12 years, ≥ 1 EAD, continuous health-plan eligibility, and compliance with the EGPA/GPA case definition per International Classification of Diseases Ninth/Tenth Revision diagnostic codes between 1 January 2015 and 30 June 2018. Patients were grouped based on whether they had received immunomodulators/cyclophosphamide/mepolizumab (ICM) or not (non-ICM). Results: Of 701 patients with EGPA, 29.5% were in the ICM group. Overall, 72.2% had ≥ 1 overlapping EAD. The number of overlaps was similar for the ICM and non-ICM groups. In patients with blood eosinophil counts ≥ 300 cells/µL, 22.8% had ≥ 1 overlapping EAD. The mean annual all-cause cost was $98,644, 54.1% of which was from outpatients and 33.6% from inpatients. The mean annual EAD- and EGPA-related costs were $23,820 and $9,306, respectively. Patients in the non-ICM group versus the ICM group had higher all-cause ($101,560 vs $91,684) but lower EAD-related ($22,733 vs $26,412) and EGPA-related ($6,171 vs $16,786) costs. All-cause HCRU and costs increased with increasing overlap. Conclusions: EGPA was associated with substantial HCRU and costs, driven by outpatient and inpatient settings. More overlapping EADs were associated with higher HCRU and costs, highlighting the need for treatment to reduce healthcare expenditure in these patients. Infographic available for this article. [ABSTRACT FROM AUTHOR]

Certain environmental allergen exposures are more common in disadvantaged communities and may contribute to differences in susceptibility to upper respiratory infections (URIs). We examined associations between indoor allergens and: (1) URI; (2) URI + cold symptoms; (3) URI + cold symptoms + pulmonary eosinophilic inflammation (fraction of exhaled nitric oxide ≥20 ppb); and (4) URI + cold symptoms + reduced lung function (percent predicted forced expiratory volume in 1 second of <80%). We used data from the Environmental Control as Add-on Therapy for Childhood Asthma (ECATCh) study. Allergen concentrations were measured in air (mouse) and settled dust (mouse, cockroach, dog, and cat). URI was determined by testing nasal mucus for upper respiratory viruses. We evaluated associations between allergen concentrations and URI-associated outcomes accounting for age, sex, study month, season, health insurance, and household size. Ninety participants (92% Black, 92% public insurance) with 192 observations were included; 52 (27%) of observations were positive for URI. A doubling in cockroach allergen concentration increased the odds of a URI with cold symptoms by 18% (odds ratio [OR] = 1.18, 95% confidence interval [CI], 0.99-1.40), the odds of a URI + cold symptoms + pulmonary eosinophilic inflammation by 31% (OR = 1.31, 95% CI, 1.10-1.57), and the odds of a URI + cold symptoms + reduced lung function by 45% (OR = 1.45, 95% CI, 1.13-1.85). Mouse allergen concentrations were positively associated with all outcomes. Associations were suggestively stronger among children sensitized to pest allergens. Cockroach and mouse, but not dog or cat, allergen exposure may predispose children with asthma to URIs with colds and lower respiratory outcomes. [ABSTRACT FROM AUTHOR]

Background: Clustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi‐omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development. Objectives: To determine whether multi‐omics integration of sputum leads to improved granularity of the molecular classification of severe asthma. Methods: We analyzed six ‐omics data blocks–microarray transcriptomics, gene set variation analysis of microarray transcriptomics, SomaSCAN proteomics assay, shotgun proteomics, 16S microbiome sequencing, and shotgun metagenomic sequencing–from induced sputum samples of 57 severe asthma patients, 15 mild‐moderate asthma patients, and 13 healthy volunteers in the U‐BIOPRED European cohort. We used Monti consensus clustering algorithm for aggregation of clustering results and Similarity Network Fusion to integrate the 6 multi‐omics datasets of the 72 asthmatics. Results: Five stable omics‐associated clusters were identified (OACs). OAC1 had the best lung function with the least number of severe asthmatics with sputum paucigranulocytic inflammation. OAC5 also had fewer severe asthma patients but the highest incidence of atopy and allergic rhinitis, with paucigranulocytic inflammation. OAC3 comprised only severe asthmatics with the highest sputum eosinophilia. OAC2 had the highest sputum neutrophilia followed by OAC4 with both clusters consisting of mostly severe asthma but with more ex/current smokers in OAC4. Compared to OAC4, there was higher incidence of nasal polyps, allergic rhinitis, and eczema in OAC2. OAC2 had microbial dysbiosis with abundant Moraxella catarrhalis and Haemophilus influenzae. OAC4 was associated with pathways linked to IL‐22 cytokine activation, with the prediction of therapeutic response to anti‐IL22 antibody therapy. Conclusion: Multi‐omics analysis of sputum in asthma has defined with greater granularity the asthma endotypes linked to neutrophilic and eosinophilic inflammation. Modelling diverse types of high‐dimensional interactions will contribute to a more comprehensive understanding of complex endotypes. Key Points: Unsupervised clustering on sputum multi‐omics of asthma subjects identified 3 out of 5 clusters with predominantly severe asthma.One severe asthma cluster was linked to type 2 inflammation and sputum eosinophilia while the other 2 clusters to sputum neutrophilia.One severe neutrophilic asthma cluster was linked to Moraxella catarrhalis and to a lesser extent Haemophilus influenzae while the second cluster to activation of IL‐22. [ABSTRACT FROM AUTHOR]

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a serious inflammatory condition. Nasal fluids (NFs) present a noninvasive alternative to nasal biopsy for studying CRSwNP pathogenesis. We aimed to compare the protein and mRNA inflammation signature between nasal polyps (NPs) and NFs. Method: The performance of polyvinyl alcohol (PVA) sponges and NFs absorbable device (NFAD) for collecting NFs from 20 patients with CRSwNP was compared using the Luminex assay. The other group consisted of four healthy controls and an additional 21 CRSwNP patients (including eosinophilic CRSwNP [ECRSwNP] and non-eosinophilic CRSwNP [NECRSwNP]) for protein quantification by Olink platform and gene expression evaluation by RNA-sequencing. Spearman's analysis was performed to detect correlations between protein expression levels in NFs and clinical assessment variables. Results: NFAD-collected NFs contained at least a 2-fold higher concentration of cytokines than that obtained using PVA sponge, and these cytokines levels are significantly associated with NPs (ρ > 0.45, p < 0.05). Differentially expressed proteins between NFs and NPs were significantly correlated in the ECRSwNP subgroup compared with controls (ρ = 0.41, p < 0.01). Levels of Th2/IL-13, MCP4, and CCL4, characteristic of eosinophilic infiltration, were increased in ECRSwNP patients. A significant correlation between gene and protein expression was observed (ρ = 0.34, p < 0.01). PDL2 levels in NFs were positively correlated with ECRSwNP postoperative recurrence, the nasal VAS, and SNOT-22 scores (ρ > 0.68, p < 0.05 for all). Conclusion: Our study revealed similarities and discrepancies in inflammatory signatures between NPs and NFs in the same CRSwNP patient. [ABSTRACT FROM AUTHOR]

Abstract Background Clustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi‐omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development. Objectives To determine whether multi‐omics integration of sputum leads to improved granularity of the molecular classification of severe asthma. Methods We analyzed six ‐omics data blocks–microarray transcriptomics, gene set variation analysis of microarray transcriptomics, SomaSCAN proteomics assay, shotgun proteomics, 16S microbiome sequencing, and shotgun metagenomic sequencing–from induced sputum samples of 57 severe asthma patients, 15 mild‐moderate asthma patients, and 13 healthy volunteers in the U‐BIOPRED European cohort. We used Monti consensus clustering algorithm for aggregation of clustering results and Similarity Network Fusion to integrate the 6 multi‐omics datasets of the 72 asthmatics. Results Five stable omics‐associated clusters were identified (OACs). OAC1 had the best lung function with the least number of severe asthmatics with sputum paucigranulocytic inflammation. OAC5 also had fewer severe asthma patients but the highest incidence of atopy and allergic rhinitis, with paucigranulocytic inflammation. OAC3 comprised only severe asthmatics with the highest sputum eosinophilia. OAC2 had the highest sputum neutrophilia followed by OAC4 with both clusters consisting of mostly severe asthma but with more ex/current smokers in OAC4. Compared to OAC4, there was higher incidence of nasal polyps, allergic rhinitis, and eczema in OAC2. OAC2 had microbial dysbiosis with abundant Moraxella catarrhalis and Haemophilus influenzae. OAC4 was associated with pathways linked to IL‐22 cytokine activation, with the prediction of therapeutic response to anti‐IL22 antibody therapy. Conclusion Multi‐omics analysis of sputum in asthma has defined with greater granularity the asthma endotypes linked to neutrophilic and eosinophilic inflammation. Modelling diverse types of high‐dimensional interactions will contribute to a more comprehensive understanding of complex endotypes. Key Points Unsupervised clustering on sputum multi‐omics of asthma subjects identified 3 out of 5 clusters with predominantly severe asthma. One severe asthma cluster was linked to type 2 inflammation and sputum eosinophilia while the other 2 clusters to sputum neutrophilia. One severe neutrophilic asthma cluster was linked to Moraxella catarrhalis and to a lesser extent Haemophilus influenzae while the second cluster to activation of IL‐22.

Danuta Kielar,1 Andrew M Jones,2 Xia Wang,3 Heide Stirnadel-Farrant,1 Rohit K Katial,4 Abhinav Bansal,5 Manu Garg,5 Chandrakant Sharma,5 Shubhankar Thakar,5 Qin Ye5 1BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 2Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 3Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 4BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 5ZS, Philadelphia, PA, USACorrespondence: Danuta Kielar, AstraZeneca, Academy House, 136 Hills Road, Cambridge, CB2 8PA, UK, Tel +44 7384905053, Email danuta.kielar@astrazeneca.comBackground: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting.Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] < 60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3– 4. The primary outcomes were CKD progression and all-cause mortality.Results: We found that high eosinophilic levels (bEOS ≥ 300 cells/μL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥ 300 cells/μL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with < 300 cells/μL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression.Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.Keywords: eosinophilic inflammation, renal insufficiency, glomerular filtration rate

Chronic obstructive pulmonary disease (COPD) and asthma are chronic inflammatory diseases of the airways. Galectin-13 has recently been forwarded as a biomarker for airway eosinophilic inflammation in asthma. However, the association between galectin-13 and COPD remains unknown. To examine the changes in galectin-13 expression in acute exacerbations of COPD (AECOPD) and the stable phase of COPD and unveil the association between galectin-13 expression and eosinophilic inflammation in COPD, we measured plasma galectin-13 expression in different phases of COPD patients (n = 60, 44 AECOPD patients, and 16 stable COPD patients) and healthy controls (n = 15). Plasma levels of galectin-13 in 60 COPD patients were further analyzed and compared to systemic inflammation, airway eosinophilic inflammation, and lung function. The plasma galectin-13 level was markedly increased in subjects with AECOPD compared to stable COPD patients and healthy controls. Plasma galectin-13 levels in COPD subjects were positively correlated with serum CRP (rs = 0.46, p = 0.0003), peripheral blood eosinophilia count (rs = 0.57, p

Jiachen Li,1 Lirong Liang,1 Lin Feng,1 Siyu Cao,2 Yutong Samuel Cai,3 Xiaobo Li,4 Zhenbei Qian,2 Christopher E Brightling,5 Zhaohui Tong2 1Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Centre for Environmental Health and Sustainability, Department of Population Health Sciences, University of Leicester, Leicester, UK; 4Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 5Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UKCorrespondence: Lirong Liang, Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 010-85231547, Email llrcruie@163.comPurpose: Blood eosinophil is a promising biomarker for phenotyping patients with acute exacerbation of COPD (AECOPD). We aimed to evaluate the prognostic value of eosinophil on short- and long-term outcomes stratified by corticosteroid treatment among AECOPD inpatients.Patients and Methods: In this retrospective cohort study, we included patients hospitalized for AECOPD from July 2013 to June 2021 in Beijing, China. Clinical data were collected from electronic medical records. The blood eosinophil count was measured within 24h after admission. Eosinophilic AECOPD was defined as having an eosinophil percentage ≥ 2%. The study outcomes were length of stay (LOS), treatment failure, and AECOPD readmission risk within 3 years of discharge. Multivariable models were used to analyze the associations between blood eosinophil count and outcomes stratified by corticosteroid treatment during hospitalization.Results: A total of 2406 AECOPD patients were included. The median LOS of AECOPD patients was 10 (interquartile range: 8– 14) days. The eosinophil percentage was negatively associated with LOS (P-trend=0.014). Compared with the non-eosinophilic AECOPD group, the eosinophilic group had a 58% lower risk of treatment failure (OR=0.42, 95% CI: 0.20– 0.89) in patients treated with systemic corticosteroids, but no association was observed in those treated with inhaled corticosteroids (ICS) only (OR=0.95, 95% CI: 0.60– 1.52). The eosinophilic group had an increased risk of 90-day re-admission in patients treated with ICS only (HR=1.51, 95% CI: 1.00– 2.29), but not in patients treated with systemic corticosteroids during hospitalization (HR=0.67, 95% CI: 0.39– 1.15). No statistically significant results were found for 180-day, 1-year, or 3-year readmission risk.Conclusion: Elevated blood eosinophils in AECOPD were associated with shorter length of stay and improved response to treatment with systemic corticosteroids, but not inhaled corticosteroids. Our study suggested that a therapeutic approach of using systemic corticosteroid may benefit patients present with eosinophilic AECOPD.Keywords: chronic obstructive pulmonary disease, eosinophilic inflammation, glucocorticoids, interaction

Introduction: Asthma is a chronic disease that affects populations worldwide. The purpose of this study was to investigate the expression of TCN1 in sputum and its correlation with inflammation and lung function in asthma. Methods: We recruited 141 subjects, detected TCN1 mRNA level by quantitative reverse transcription polymerase chain reaction, detected TCN1 protein expression by Western blot, detected TCN1 protein level by enzyme-linked immunosorbent assay, and analyzed the correlation between TCN1 and fraction of exhaled nitric oxide (FeNO), IgE, EOS%, lung functions, and some Th2 cytokines. The diagnostic value of TCN1 was evaluated by receiver operating characteristics curve. The expression of TCN1 was further confirmed by human bronchial epithelial cell in vitro. Results: Compared with the health group, the expression of TCN1 in induced sputum cells increased in asthma group and was correlated with FeNO, IgE, and EOS%. TCN1 level was also elevated in the induced sputum supernatant of asthma patients. The protein level of TCN1 in induced sputum supernatant was correlated with FeNO, IgE and PC-20, forced expiratory volume in the first second (FEV1)%pred, FEV1/FVC, and some cytokines (IL-4, IL-5, IL-10, IL-13, MUC5AC). TCN1 was also differentially expressed in patients with different severity of asthma. Four weeks after ICS treatment, the expression of TCN1 in induced sputum supernatant increased. In vitro, the protein level of TCN1 in human bronchial epithelial cells' supernatant increased after stimulated with IL-4 and IL-13. Conclusion: The expression of TCN1 was increased in asthma patients' sputum, and was positively correlated with some inflammatory markers, negatively correlated with lung function. TCN1 may be used as a potential biomarker for the diagnosis and treatment of asthma. [ABSTRACT FROM AUTHOR]

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production. [ABSTRACT FROM AUTHOR]

Introduction: Eotaxin-2 and -3 of the C-C chemokine subfamily function as potent chemoattractant factors for eosinophil recruitment and various immune responses in allergic and inflammatory airway diseases. Mucin 5AC (MUC5AC), a major gel-forming secretory mucin, is overexpressed in airway inflammation. However, the association between mucin secretion and eotaxin-2/3 expression in the upper and lower airway epithelial cells has not been fully elucidated. Therefore, in this study, we investigated the effects of eotaxin-2/3 on MUC5AC expression and its potential signaling mediators. Methods: We analyzed the effects of eotaxin-2 and -3 on NCI-H292 human airway epithelial cells and primary human nasal epithelial cells (HNEpCs) via reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. Along with immunoblot analyses with specific inhibitors and small interfering RNA (siRNA), we explored the signaling pathway involved in MUC5AC expression following eotaxin-2/3 treatment. Results: In HCI-H292 cells, eotaxin-2/3 activated the mRNA expression and protein production of MUC5AC. A specific inhibitor of C-C motif chemokine receptor 3 (CCR3), SB328437, suppressed eotaxin-2/3-induced MUC5AC expression at both the mRNA and protein levels. Eotaxin-2/3 induced the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and p38, whereas pretreatment with a CCR3 inhibitor significantly attenuated this effect. Induction of MUC5AC expression with eotaxin-2/3 was decreased by U0126 and SB203580, specific inhibitors of ERK1/2 and p38 mitogen-activated protein kinase (MAPK), respectively. In addition, cell transfection with ERK1/2 and p38 siRNAs inhibited eotaxin-2/3-induced MUC5AC expression. Moreover, specific inhibitors (SB328437, U0126, and SB203580) attenuated eotaxin-2/3-induced MUC5AC expression in HNEpCs. Conclusion: Our results imply that CCR3-mediated ERK1/2 and p38 MAPK are involved in the signal transduction of eotaxin-2/3-induced MUC5AC overexpression. [ABSTRACT FROM AUTHOR]

Background: Aspirin‐exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin‐tolerant asthma (ATA). Objectives: This study aimed to investigate the long‐term clinical outcomes between AERD and ATA. Methods: AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real‐world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. Results: Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p <.05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p <.01) than those with ATA. In a 10‐year follow‐up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. Conclusion and Clinical Relevance: We demonstrated that AERD patients presented poorer long‐term clinical outcomes than ATA patients in real‐world data analyses. [ABSTRACT FROM AUTHOR]

Non-allergic rhinitis with eosinophilia syndrome (NARES) is a chronic inflammatory rhinopathy characterized by nasal obstruction, rhinorrhea, sneezing and/or an itchy nose. Although eosinophilic nasal cytology is common in NARES patients, identifying the condition is challenging due to a lack of consensus on the diagnostic processes and the role of nasal cytology in clinical practice. Patients may undergo several allergy tests with negative or inconclusive results and are eventually diagnosed with idiopathic/aspecific rhinitis. Treatment options may include intranasal corticosteroids, intranasal antihistamines or a combination of both types of medication. This case report describes a patient with NARES who was unresponsive to conventional therapies and experienced significant improvement after treatment with Mepolizumab, a drug approved for severe asthma with hypereosinophilia, hypereosinophilic syndrome (HES), chronic rhinosinusitis with nasal polyposis (CRSwNP) and eosinophilic granulomatosis with polyangiitis (EGPA). Mepolizumab was administered once a month at a dose of 100 mg subcutaneously. The patient experienced a complete remission of symptoms a year after starting the off-label treatment. Blood counts remained stable and no adverse effects were observed. Mepolizumab appears to be a potential therapeutic alternative in patients with NARES who are unresponsive to conventional therapies. [ABSTRACT FROM AUTHOR]

Case summary: A 9-year-old neutered female domestic shorthair cat was presented for investigation of a cranial mediastinal mass. Moderate peripheral eosinophilia and mild-to-moderate polyclonal gammopathy were identified. A thoracoabdominal CT scan documented a cranial mediastinal mass encircling the trachea. Ultrasound-guided fine-needle aspiration and core-needle biopsy were performed, but cytology and histopathology were inconclusive. Surgical debulking was performed. Further histological samples identified severe pyogranulomatous and eosinophilic fibrosing mediastinitis, consistent with feline eosinophilic sclerosing fibroplasia. Gram staining and fluorescence in situ hybridisation (FISH) identified numerous Gram-positive coccoid bacteria. Eosinophilia and hyperglobulinaemia resolved after surgery and combined antimicrobial and immunosuppressive therapy. The cat died 3 months later after developing acute haemorrhagic diarrhoea and dyspnoea. Relevance and novel information: Eosinophilic sclerosing fibroplasia is reportedly mainly confined to the gastrointestinal tract in cats. Less commonly, extragastrointestinal cases have been described. Lesions in the mediastinal or sternal lymph nodes have been reported, all in association with evident gastrointestinal involvement. The presence of pleural effusion was variable in these cases. To the authors' knowledge, this is the first report of eosinophilic sclerosing fibroplasia presenting due to lower respiratory signs in a cat. Intralesional bacteria were identified using Gram staining and FISH examination. The presence of intralesional bacteria in the normally sterile mediastinal tissue may support the involvement of penetrating injuries in the pathogenesis of the disease. Eosinophilic sclerosing fibroplasia should be suspected in any cat with abdominal and/or thoracic masses, particularly if associated with peripheral eosinophilia and polyclonal gammopathy. [ABSTRACT FROM AUTHOR]

BackgroundIdiopathic inflammatory airway disease (IAD) in cats often is described as asthmatic (eosinophilic) or bronchitic (neutrophilic), but this designation requires collection of airway fluid and it fails to consider cats with mixed airway inflammation.ObjectiveTo identify clinical features that would differentiate inflammatory disease types.AnimalsForty-nine cats with nonspecific airway inflammation identified by bronchoscopic bronchoalveolar lavage (BAL) between 2011 and 2018 were evaluated.MethodsThis is a retrospective study. Cats were categorized by BAL differential cytology as having eosinophilic (eosinophils >20% with neutrophils 50%), mixed (eosinophils 20%-50% and neutrophils >14% or discordant inflammation from 2 BAL sites), or neutrophilic (neutrophils >14% and eosinophils

Elevated eosinophil counts in blood and tissue are a feature of many pathological processes. Eosinophils can migrate and accumulate in a wide variety of tissues and, by infiltrating a target organ, can mediate the development of several inflammatory diseases. The normalization of eosinophilia is a common biomarker of a treatable trait and can also be used as a prognostic and predictive biomarker since it implies a reduction in type 2 inflammation that contributes to disease pathogenesis. Biological therapies targeting this cell type and its proinflammatory mediators have been shown to be effective in the management of a number of eosinophilic diseases, and for this reason they constitute a potential common strategy in the treatment of patients with various multimorbidities that present with type 2 inflammation. Various biological options are available that could be used to simultaneously treat multiple target organs with a single drug, bearing in mind the need to offer personalized treatments under the umbrella of precisionmedicine in all patients with eosinophil-associated diseases (EADs). In addition to reviewing these issues, we also discuss a series of perspectives addressing the management of EAD patients from a multidisciplinary approach, with the collaboration of health professionals from different specialties who manage the different multimorbidities that frequently occur in these patients. We examine the basic principles of care that this multidisciplinary approach must cover and present a multidisciplinary expert opinion regarding the ideal management of patients with EADs, from diagnosis to therapeutic approach and follow-up. [ABSTRACT FROM AUTHOR]

Purpose of Review: The present review aims to systematically assess published data to elucidate benralizumab efficacy on nasal outcomes in comorbid patients. Recent Findings: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the nasal cavity often associated with severe asthma (SA), contributing to a global disease burden in asthmatics. The two pathologies share common underlying mechanisms (e.g., type-2 inflammation), which sustain symptoms and poor comorbid patient quality of life. Therefore, it is of primary importance to identify the correct therapeutic option in order to achieve the optimal management of patients affected by both pathologies. Benralizumab is a humanized monoclonal antibody directed at the α subunit of the interleukin-5 receptor (IL-5Rα) approved for the treatment of severe eosinophilic asthma. Increasing body of literature provides data on its efficacy also on CRSwNP in the comorbid SA patient. Summary: Based on the data described in this review, when benralizumab is administered to comorbid patients, it does not only control severe asthma but also improves CRSwNP clinical outcomes, although we need further studies to add stronger evidence and to improve the correct pheno-endotyping of the comorbid patient. [ABSTRACT FROM AUTHOR]

Objectives: To determine the average serum periostin level in children with asthma between 6 and 16 y of age, and to find out if the levels correlated with markers of eosinophilic inflammation, asthma control, and severity. Methods: Children under follow-up at a tertiary care centre were enrolled. Children with conditions causing elevated serum periostin other than asthma, or history of systemic steroid use in the past 6 mo were excluded. Serum total IgE and periostin were estimated by ELISA. Results: The median (IQR) serum periostin level was 52.6 (45.4, 58.3) ng/mL. Levels did not vary with age, gender, duration of symptoms, positive family history, or history of exacerbations in the last 6 mo. There was no significant correlation with anthropometric parameters or their z scores, or markers of eosinophilic inflammation in blood including serum total IgE, eosinophil percentage or absolute eosinophil count. There was no difference in median periostin levels of children with different asthma symptom control or asthma severity. Conclusions: In a group of 26 Indian children with physician-diagnosed asthma, serum periostin showed no significant correlation to markers of eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

Background: Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown. Methods: We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl-knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation. Results: Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl-knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells. Conclusions: Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma.

BackgroundPerturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma.ResultsBacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p

Elevated eosinophil counts in blood and tissue are a feature of many pathological processes. Eosinophils can migrate and accumulate in a wide variety of tissues and, by infiltrating a target organ, can mediate the development of several inflammatory diseases. The normalization of eosinophilia is a common biomarker of a treatable trait and can also be used as a prognostic and predictive biomarker since it implies a reduction in type 2 inflammation that contributes to disease pathogenesis. Biological therapies targeting this cell type and its proinflammatory mediators have been shown to be effective in the management of a number of eosinophilic diseases, and for this reason they constitute a potential common strategy in the treatment of patients with various multimorbidities that present with type 2 inflammation. Various biological options are available that could be used to simultaneously treat multiple target organs with a single drug, bearing in mind the need to offer personalized treatments under the umbrella of precision medicine in all patients with eosinophil-associated diseases (EADs). In addition to reviewing these issues, we also discuss a series of perspectives addressing the management of EAD patients from a multidisciplinary approach, with the collaboration of health professionals from different specialties who manage the different multimorbidities that frequently occur in these patients. We examine the basic principles of care that this multidisciplinary approach must cover and present a multidisciplinary expert opinion regarding the ideal management of patients with EADs, from diagnosis to therapeutic approach and follow-up.

A transcriptional analysis of bronchial biopsies from 51 patients with asthma defined three distinct subgroups based on Th2 and Th17 signatures - Th2-high, Th17-high, and Th2/Th17-low [[21]]. Biology of IL-23/IL-23 receptor (IL-23 R) IL-23 is an IL-12 family cytokine secreted primarily by dendritic cells (DCs), as well as macrophages, B-cells, and endothelial cells [[2]]. In the era of targeted molecular therapies, there is intense interest in modulating IL-23 and its related downstream IL-23/CD4+ T helper 17 (Th17) axis as a novel target for asthma therapy. While the IL-23/Th17 axis has been hypothesized to contribute to the pathogenesis of asthma, it is likely not as simple as Th1 versus Th2 versus Th17. [Extracted from the article]

Abstract Chronic obstructive pulmonary disease (COPD) and asthma are chronic inflammatory diseases of the airways. Galectin-13 has recently been forwarded as a biomarker for airway eosinophilic inflammation in asthma. However, the association between galectin-13 and COPD remains unknown. To examine the changes in galectin-13 expression in acute exacerbations of COPD (AECOPD) and the stable phase of COPD and unveil the association between galectin-13 expression and eosinophilic inflammation in COPD, we measured plasma galectin-13 expression in different phases of COPD patients (n = 60, 44 AECOPD patients, and 16 stable COPD patients) and healthy controls (n = 15). Plasma levels of galectin-13 in 60 COPD patients were further analyzed and compared to systemic inflammation, airway eosinophilic inflammation, and lung function. The plasma galectin-13 level was markedly increased in subjects with AECOPD compared to stable COPD patients and healthy controls. Plasma galectin-13 levels in COPD subjects were positively correlated with serum CRP (rs  = 0.46, p = 0.0003), peripheral blood eosinophilia count (rs  = 0.57, p<0.0001), and FeNO (rs  = 0.46, p = 0.0002). In addition, the level of galectin-13 was negatively correlated with FEV1 (rs  = −0.43, p = 0.0001), FEV1 pred (%) (rs  = −0.544, p<0.0001), as well as FEV1/FVC (rs  = −0.46, p<0.0001). Multiple linear regression analysis suggested that plasma galectin-13 levels were affected by FEV1 pred (%), peripheral blood eosinophilia count, and FeNO. We concluded that galectin-13 levels were increased in COPD patients, and elevated galectin-13 expressions related to airway eosinophilic inflammation. Galectin-13 may facilitate the identification of COPD endotypes and may become a potential therapeutic target. [ABSTRACT FROM AUTHOR]

[Display omitted] The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (r s values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/μL and 42% of participants with blood eosinophil counts between 150 and 299 cells/μL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation. [ABSTRACT FROM AUTHOR]

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production.

Tingting Wei,&ast; Xiaocen Wang,&ast; Ke Lang,&ast; Cuicui Chen, Yansha Song, Jinlong Luo, Zhaolin Gu, Xianglin Hu, Dong Yang Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Yang; Xianglin Hu, Email yang.dong@zs-hospital.sh.cn; xianglinhero@163.comRationale: Eosinophilic inflammation is related to the progression and outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Till now, few studies have focused on low EOS in AECOPD.Objective: To reveal the clinical characteristics, therapeutic responses and prognosis of patients hospitalized of AECOPD with low EOS.Methods: The electronic database of Zhongshan Hospital, Fudan University was used. Cohort 1 included 608 patients with hospitalized AECOPD. Study population 2 consisted of 166 patients with AECOPD admission at least twice. Impact of low EOS on NIMV treatment, length of hospital stays and 12-month AECOPD-related readmission were analyzed with multivariable logistic regression model. Thirty-five hospitalized AECOPD patients were prospectively recruited as cohort 3 to explore the association between EOS and other immune cells using Spearman correlation coefficient for ranked data.Results: EOS level was suppressed on admission in AECOPD patients, and significantly improved after hospitalized treatment (P < 0.05). For inflammatory markers, leucocytes, neutrophils and lactate dehydrogenase levels were higher, while lymphocytes, monocytes and interleukin-6 levels were lower in the low-EOS group than those in the non-low EOS group (P < 0.05). Low EOS (EOS < 50 cells/μL) was an independent risk factor of NIMV use (OR = 1.86, 95% CI = 1.26 ∼ 2.73). The EOS percentage was positively correlated with the T cell percentage (r = 0.46, P < 0.05) and negatively correlated with the natural killer cell percentage (r = − 0.39, P < 0.05). The patients with low EOS had lower level of CD4+ T cell (P < 0.05) than that of patients with non-low EOS.Conclusion: Low EOS might be a stable phenotype in patients with hospitalized AECOPD and could be used to inform NIMV management, hyperinflammatory state and impaired immunity situation.Keywords: chronic obstructive pulmonary disease, acute exacerbation, eosinophilic inflammation, prognostic phenotype, noninvasive mechanical ventilation

Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells. Keywords: detergent; eosinophilic inflammation; epithelial barrier theory; SDS EN detergent eosinophilic inflammation epithelial barrier theory SDS 1422 1424 3 06/02/23 20230601 NES 230601 Since the 1960s, there has been an increasing prevalence of allergic, autoimmune, and metabolic diseases. Tissue eosinophilia, inflammation, abscess formation, CD4+ T cell infiltration, and remodeling are observed. [Extracted from the article]

Introduction: CXCL14 involved in inflammatory processes was upregulated in the asthma expression profile datasets in our pilot study. However, the expression of CXCL14 in induced sputum and its potential clinical role in asthma were poorly reported. Objective: We sought to detect CXCL14 expression in airway epithelium and induced sputum cells of asthma and explore its potential clinical implications. Methods: The expression of CXCL14 in asthma was analyzed using R software based on multiple microarray datasets, including GSE43696, GSE63142, GSE67940, and GSE76262. Subsequent verification of the CXCL14 expression pattern in induced sputum and bronchial epithelium cells was performed by qRT-PCR and ELISA. Besides, the correlations between CXCL14 and eosinophilic inflammation indicators (FeNO, EOS#, and IgE), Th2 signature genes (SERPINB2, POSTN, and CLCA1), inflammatory cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, TSLP, IL-8, IL-17A, IFN-γ, and IL-2), and airway obstruction indicators (pulmonary function and mucin secretion) were further explored. Results: The expression of CXCL14 in epithelium and sputum cells was upregulated in asthma and positively correlated with clinical eosinophilic indicators. The protein levels of CXCL14 were positively associated with Th2 signature genes (SERPINB2, POSTN, and CLCA1) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, and TSLP). Increased expression of CXCL14 was also observed in BEAS-2B cells stimulated by the cytokine IL-4. Furthermore, the expression of CXCL14 was positively correlated with MUC5AC secretion and negatively associated with pulmonary function. Conclusions: Upregulated CXCL14 in asthma was positively correlated with inflammatory indicators and negatively correlated with pulmonary function, which indicated that upregulated CXCL14 might act as a pathogenic gene through involvement in Th2 inflammation in asthma. [ABSTRACT FROM AUTHOR]

Interleukin 5 (IL-5) is a major cytokine responsible for eosinophil proliferation, migration and degranulation. Eosinophils play a considerable role in the manifestation of type 2 asthma, and therefore this makes IL-5 a unique and clinically important target for therapeutic intervention. Due to the critical role that IL-5 plays in all areas of eosinophil activity, it has been identified and targeted by three therapeutics, Mepolizumab, Benralizumab and Reslizumab. This review describes the IL-5 pathway and presents the clinical trial history of the three IL-5 inhibitors, to provide insight into the role of IL-5 in clinical asthma presentation. Additionally, this review aims to foster further investigation into the IL-5 pathway by describing current novel therapeutic discovery strategies with monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL‐1β overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro‐autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy‐enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL‐1β production in ECRS pathogenesis. Methods: We investigated the therapeutic effects of trehalose and saccharin on macrophage IL‐1β production and eosinophilia in the mouse model of ECRS with myeloid cell‐specific autophagy‐related gene 7 (Atg7) deletion. The mechanisms underlying their anti‐inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors. Results: Unexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy‐independent effect was associated with reduced macrophage IL‐1β expression. Various sugars recapitulated the anti‐inflammatory effect of trehalose, and saccharin was particularly effective amongst other sugars. The mechanistic study revealed an involvement of sweet taste receptor (STR), especially T1R3, in alleviating macrophage IL‐1β production and eosinophilia in CRS, which was supported by genetic depletion of T1R3 or overexpression of T1R2/T1R3 in macrophages and treatment with the T1R3 antagonist gurmarin. Conclusion: Our results revealed a previously unappreciated anti‐inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment. [ABSTRACT FROM AUTHOR]

Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown. We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl -knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation. Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl -knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells. Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma. [ABSTRACT FROM AUTHOR]

We investigated the effects of low dose rate radiation (LDR) on M1 and M2 macrophages in an ovalbumin-induced mouse model of allergic airway inflammation and asthma. After exposure to LDR (1 Gy, 1.818 mGy/h) for 24 days, mice were euthanized and the changes in the number of M1 and M2 macrophages in the bronchoalveolar lavage fluid and lung, and M2-associated cytokine levels, were assessed. LDR treatment not only restored the M2-rich microenvironment but also ameliorated asthma-related progression in a macrophage-dependent manner. In an ovalbumin-induced mouse model, LDR treatment significantly inhibited M2, but not M1, macrophage infiltration. M2-specific changes in macrophage polarization during chronic lung disease reversed the positive effects of LDR. Moreover, the levels of cytokines, including chemokine (C-C motif) ligand (CCL) 24, CCL17, transforming growth factor beta 1, and matrix metalloproteinase-9, decreased in ovalbumin-sensitized/challenged mice upon exposure to LDR. Collectively, our results indicate that LDR exposure suppressed asthmatic progression, including mucin accumulation, inflammation, and Type 2 T helper (Th2) cytokine (interleukin (IL)-4 and IL-13) production. In conclusion, LDR exposure decreased Th2 cytokine secretion in M2 macrophages, resulting in a reduction in eosinophilic inflammation in ovalbumin-sensitized/challenged mice. [ABSTRACT FROM AUTHOR]

Samter's triad, also known as aspirin-exacerbated respiratory disease, is characterized by nasal polyposis, bronchial asthma, and aspirin intolerance. Here, we present a case of a 36-year-old woman with a history of Samter's triad and recurrent dacryocystitis. After combined dacryocystorhinostomy and endoscopic sinus surgery, pathological specimens of the lacrimal sac showed respiratory fibrosis with chronic inflammation and eosinophilic infiltration. Our case demonstrates that Samter's triad is a potential etiology for inflammatory nasolacrimal duct obstruction.

Abstract Background Eosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL‐1β overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro‐autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy‐enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL‐1β production in ECRS pathogenesis. Methods We investigated the therapeutic effects of trehalose and saccharin on macrophage IL‐1β production and eosinophilia in the mouse model of ECRS with myeloid cell‐specific autophagy‐related gene 7 (Atg7) deletion. The mechanisms underlying their anti‐inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors. Results Unexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy‐independent effect was associated with reduced macrophage IL‐1β expression. Various sugars recapitulated the anti‐inflammatory effect of trehalose, and saccharin was particularly effective amongst other sugars. The mechanistic study revealed an involvement of sweet taste receptor (STR), especially T1R3, in alleviating macrophage IL‐1β production and eosinophilia in CRS, which was supported by genetic depletion of T1R3 or overexpression of T1R2/T1R3 in macrophages and treatment with the T1R3 antagonist gurmarin. Conclusion Our results revealed a previously unappreciated anti‐inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. Severe respiratory viral infection in early life is intimately associated with childhood recurrent wheezing and is a risk factor for asthma later in life. Although eosinophilic airway inflammation is an important trait in asthma of children, the roles of pulmonary eosinophils in the disease have been inadequately understood. Here, we show that RSV infection in neonatal mice causes eosinophilia after allergen stimulation. We showed that RSV infection in neonatal mice exacerbated allergic asthma to allergen stimulation that was accompanied with increased detection of eosinophils in the lungs. In addition, we also detected accumulation of ILC2, CD4+ T cells, and macrophages. Importantly, adoptive transfer of eosinophils from asthmatic mice with early-life RSV infection exacerbated pulmonary pathologies associated with allergic respiratory inflammation in naive mice in response to foreign antigen. The induction of asthmatic symptoms including AHR, tracheal wall thickening, and mucus production became more severe after further stimulation in those mice. The expression of antigen presentation-related molecules like CD80, CD86, and especially MHC II was markedly induced in eosinophils from OVA-stimulated asthmatic mice. The accumulation of CD4+ T cells in the lungs was also significantly increased as a result of adoptive transfer of eosinophils. Importantly, the deterioration of lung pathology caused by adoptive transfer could be effectively attenuated by treatment with indomethacin, a nonsteroidal anti-inflammatory drug. Our findings highlight the significance of eosinophil-mediated proinflammatory response in allergic disease associated with early-life infection of the respiratory tract. [ABSTRACT FROM AUTHOR]

Nowadays, there are a number of respiratory illnesses that directly affect children. Exhaled nitric oxide measurement (FeNO) is one of the modern methods of investigation used for diagnosing and controlling allergic eosinophilic airway inflammation. It is a simple, painless and time-saving method for the patient. Because of its non-invasiveness and simplicity, it is a valuable diagnostic method, especially in younger children. Measurement of FeNO is a recognized biomarker and an accurate quantitative indicator in the detection, assessment and monitoring of airway inflammation, including asthma. However, only a few studies assess the relationship between FeNO and level of air pollution. The aim of our study is to determine the relationship between FeNO in third-grade students of primary schools and the level of air pollution in Ruzomberok. 146 children aged 8-10 years were included in the research. This is the first stage of a wider research project involving FeNO measurements in children at different times of the year. The goal of the research is to determine the concentration of FeNO in the studied group of children in the autumn when air pollution is lower than in second stage which is observed in winter. The study showed elevated values of FeNO>20 ppb in 11% of the tested children and correct values

Abstract Background Idiopathic inflammatory airway disease (IAD) in cats often is described as asthmatic (eosinophilic) or bronchitic (neutrophilic), but this designation requires collection of airway fluid and it fails to consider cats with mixed airway inflammation. Objective To identify clinical features that would differentiate inflammatory disease types. Animals Forty‐nine cats with nonspecific airway inflammation identified by bronchoscopic bronchoalveolar lavage (BAL) between 2011 and 2018 were evaluated. Methods This is a retrospective study. Cats were categorized by BAL differential cytology as having eosinophilic (eosinophils >20% with neutrophils 50%), mixed (eosinophils 20%‐50% and neutrophils >14% or discordant inflammation from 2 BAL sites), or neutrophilic (neutrophils >14% and eosinophils

Background: Childhood obesity has been suggested as a risk factor for bronchial asthma. The aim of this study was to clarify the relationship between clinical factors related to obesity, including adipocytokines and eosinophilic inflammation, as candidate pathogenesis mechanisms of bronchial asthma in Japanese children and adolescents.Methods: Forty-one children and adolescents visiting our outpatient clinic were enrolled. The relationship between participants' clinical and demographic characteristics and fraction of exhaled nitric oxide (FENO) or blood eosinophil (B-Eos) count values were analyzed.Results: No significant correlation was observed between either FENO or B-Eos count values and the body mass index z-score. FENO was high (≥35 ppb) in 8 cases and normal (

Immune inflammation regulated by CD4+ cells (T cells type 2) is integral to the pathogenesis of most cases of bronchial asthma (BA). However, not all mechanisms of chronic inflammation in BA are studied well enough. More recently the role of periostin (extracellular matrix protein) in development of eosinophilic inflammation and airway remodeling at BA has been revealed. The effect of periostin on BA course and development can be confirmed by its high expression in bronchial epithelium of patients with BA. This review shows current data on periostin structure and synthesis, correlation between periostin and BA course and development and pulmonary function test. Special attention is given to the periostin role in BA in children.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. Severe respiratory viral infection in early life is intimately associated with childhood recurrent wheezing and is a risk factor for asthma later in life. Although eosinophilic airway inflammation is an important trait in asthma of children, the roles of pulmonary eosinophils in the disease have been inadequately understood. Here, we show that RSV infection in neonatal mice causes eosinophilia after allergen stimulation. We showed that RSV infection in neonatal mice exacerbated allergic asthma to allergen stimulation that was accompanied with increased detection of eosinophils in the lungs. In addition, we also detected accumulation of ILC2, CD4+ T cells, and macrophages. Importantly, adoptive transfer of eosinophils from asthmatic mice with early-life RSV infection exacerbated pulmonary pathologies associated with allergic respiratory inflammation in naive mice in response to foreign antigen. The induction of asthmatic symptoms including AHR, tracheal wall thickening, and mucus production became more severe after further stimulation in those mice. The expression of antigen presentation-related molecules like CD80, CD86, and especially MHC II was markedly induced in eosinophils from OVA-stimulated asthmatic mice. The accumulation of CD4+ T cells in the lungs was also significantly increased as a result of adoptive transfer of eosinophils. Importantly, the deterioration of lung pathology caused by adoptive transfer could be effectively attenuated by treatment with indomethacin, a nonsteroidal anti-inflammatory drug. Our findings highlight the significance of eosinophil-mediated proinflammatory response in allergic disease associated with early-life infection of the respiratory tract.

Antisynthetase syndrome (AS) is a rare autoimmune disease characterized by autoantibodies against aminoacyl-transfer RNA synthetase and clinical features which can include interstitial lung disease (ILD). Current available evidence of treatment is based on expert opinions and case reports. Here, we present a patient with an initial diagnosis of eosinophilic pneumonia, who was later diagnosed with anti-PL7 antisynthetase syndrome with ILD and eosinophilic inflammation. The patient was non-responsive to classic immunosuppressants but responded remarkably well to intravenous immunoglobulin.

J Mark FitzGerald,1 Eugene R Bleecker,2 Arnaud Bourdin,3 William W Busse,4 Gary T Ferguson,5 Laura Brooks,6 Peter Barker,6 Ubaldo J Martin6 1Centre for Heart and Lung Health, The Lung Centre Vancouver General Hospital, UBC Institute for Heart and Lung Health, Vancouver, BC, Canada; 2Divisions of Pharmacogenomics and Genetics, Genomics and Precision Medicine, University of Arizona College of Medicine, Tucson, AZ, United States; 3Department of Respiratory Diseases, Hôpital Arnaud De Villeneuve, Montpellier, France; 4Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, United States; 6AstraZeneca, Gaithersburg, MD, United StatesCorrespondence: J Mark FitzGeraldThe Lung Centre, Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre, 2775 Laurel Street, Vancouver BC V5Z 1M9, CanadaTel +1604-875-4122Email mark.fitzgerald@vch.caBackground: Benralizumab is an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody. Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma.Objective: We explored whether benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile.Methods: Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and Results: Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events.Conclusion: This benralizumab 2-year integrated analysis further supports long-term use of benralizumab for patients with severe, uncontrolled eosinophilic asthma.Keywords: asthma, benralizumab, clinical features, eosinophilic inflammation, interleukin-5 receptor, safety

Abstract Severe asthma can be associated with eosinophilic or allergic phenotypes or both. Eosinophilic inflammation is associated with exacerbations and disease severity due to biological activity of interleukin‐5 (IL‐5). Patients with severe asthma have reported reduced lung function and poor health‐related quality of life (HRQoL) and may require systemic corticosteroids for its management. Thus, treatment targeting IL‐5 can help improve quality of life and reduce the use of systemic corticosteroids in severe asthma. Mepolizumab is approved for treating severe eosinophilic asthma as it helps reduce exacerbations, improve lung function and asthma control, and reduce the use of systemic glucocorticoids. This further helps in enhancing HRQoL of these patients. This case series includes four adult patients suffering from severe eosinophilic asthma who were treated with mepolizumab.