Biomarkers of type 2 and non-type 2 inflammation in asthma exacerbations.

Introduction: In adult-onset asthma, two major endotypes have been proposed: T2 with eosinophilia and non-T2 characterised by neutrophils and interleukin (IL)-17. The objective of the study was to examine the endotype marker profile in patients with severe asthma who were hospitalized for exacerbations, with a focus on differentiating between viral and non-viral triggers. Material and methods: Forty-nine patients with asthma, admitted for exacerbations, and 51 healthy controls (HCs) were recruited. We further categorized the exacerbated asthma patients into two groups: non-viral infected (n = 38) and viral infected (n = 11) groups. Blood was drawn and a nasopharyngeal swab taken at the time of admission and eosinophil numbers, eosinophil cationic protein (ECP), immuno- globulin E (IgE), tryptase and viral infection were determined. Additionally, levels of IL-17, IL-33 and IL-31 were assessed. Results: The majority of patients had adult onset asthma (age of diagnosis, 42.8 ±16.1) with a duration of 7.7 ±10.8 years, 24.5% being atopic. Patients had higher levels of eosinophils, ECP and IgE than healthy controls (eosinophils, p = 0.003; ECP and IgE, p = 0.0001). Immunohistochemistry confirmed eosinophils as a source of ECP. Tryptase (p = 0.0001), IL-17 (p = 0.0005), IL-31 (p = 0.0001) and IL-33 (p = 0.0002) were also higher in patients than controls. ECP correlated with tryptase (r = 0.08, p = 0.62). IL-17 showed the best correlation with other mediators, including ECP (r = 0.35, p = 0.24), tryptase (r = 0.69, p = 0.0001), IgE (r = 0.50, p = 0.0001), IL-33 (r = 0.95, p = 0.0001) and IL-31 (r = 0.89, p = 0.0001). IgE, IL-17, and IL-31 had a high AUC when differentiating those with severe and non-severe asthma. The group with exacerbated viral infection showed elevated levels of serum IL-17 and IL-31 compared to the non-infected group. Conclusions: Patients with asthmatic exacerbations were found to have higher levels of both T2 and non-T2 inflammatory markers than healthy controls. In the study, levels of IgE, IL-17, and IL-31 differentiated between patients with severe and non-severe asthma. The last two cytokines were also able to distinguish between exacerbated asthma caused by viral infection and exacerbated asthma caused by non-viral infection.

A preliminary review of the utility of artificial intelligence to detect eosinophilic chronic rhinosinusitis.

KEY POINTS: While typically diagnosed with biopsy, ECRS may be predicted preoperatively with the use of AI. Various AI models have been used, with pooled sensitivity of 0.857 and specificity of 0.850. We found no statistically significant difference between the accuracy of various AI models.

Update on Inflammatory Biomarkers for Defining Asthma Phenotype.

Asthma is a chronic heterogeneous disease characterized by various symptoms and persistent airway inflammation, resulting in progressive lung function decline. Classifying asthma phenotypes/endotypes is crucial because the underlying mechanisms and long-term outcomes vary from patient to patient. Recent trials have identified several biomarkers for classifying asthma phenotypes/endotypes, and current treatments have been developed on the basis of these biomarkers. Conventional biomarkers, including immunoglobulin E, blood/sputum eosinophil counts, airway obstruction or reversibility, and fractional exhaled nitric oxide, are widely used to diagnose asthma. However, these markers have some limitations, necessitating the discovery of additional biomarkers. Therefore, this review summarizes recently suggested biomarkers for representing type 2-high (eosinophilic) vs. type 2-low (neutrophilic) asthma, non-steroidal anti-inflammatory drug-exacerbated respiratory disease, and severe asthma. Additionally, we discuss the potential benefits of these biomarkers in classifying specific phenotypes/endotypes and managing asthmatic patients.

When the Nose Meets the Lab: Histopathological Analysis in Chronic Rhinosinusitis with Nasal Polyps for Routine Clinical Practice.

PURPOSE OF REVIEW: We aimed to review the latest evidence regarding the value of tissue histopathological analysis in chronic rhinosinusitis with nasal polyps (CRSwNP) and to facilitate tissue analysis by proposing a pragmatic checklist for clinical settings. RECENT FINDINGS: CRSwNP is a chronic inflammatory disease that severely impairs the patient's quality of life. The severity of the disease can be correlated with nasal polyps enriched in eosinophils/IL-5 and, although ≥ 10 eosinophils per high power field are considered enough to determine an eosinophilic CRS, this cut-off value, the biopsy method, and the sampling location are still a matter of debate. Besides, tissue eosinophil values might also have some added value when combined with other cellular counts (e.g., eosinophil-to-lymphocyte ratio, Charcot-Leyden crystals). Structured histopathology analysis of sinonasal tissue-including, for instance, tissue remodelling biomarkers, fibrosis, and eosinophilic aggregates-has proven to be a valuable tool for healthcare professionals to identify different pheno-endotypes of CRSwNP and to improve the prioritisation of candidates to targeted therapies. Patients with CRSwNP are treated according to their severity with corticosteroids (intranasal and systemic), endoscopic sinus surgery, and/or biological therapy. A panel of expert ear, nose, and throat specialists and pathologists proposed a pragmatic checklist to improve the clinical practice around tissue analysis in CRSwNP, to facilitate communication between hospital-based healthcare professionals, and to standardize the evaluation of inflammatory biomarkers.

First episode depression during the perinatal period is associated with atopic diseases and persistently increased eosinophil and basophil levels.

PURPOSE: A previous diagnosis of depression is a strong predictor for perinatal depression, apart from other mental disorders, stress, and atopies. It is less clear which factors interfere if perinatal depression occurs as a first depression episode (fePND). METHODS: We examined the associations with atopies and related blood parameters using data of CoLaus|PsyCoLaus. RESULTS: Newly occurring depression during the perinatal period but not recurrent depression was associated with a lifetime diagnosis of allergies and asthma together with persistently increased levels of basophils and eosinophils. CONCLUSION: The results imply that immune function may play a relevant role in the risk of a fePND. If confirmed and detailed, these findings could serve as the basis for designing preliminary prevention strategies by observing eosinophil and basophil levels as well as symptoms of atopic diseases before/during pregnancy.

Blood eosinophil count is associated with early atherosclerotic artery changes in asthma.

OBJECTIVE: Asthma is linked to atherosclerosis, yet the underlying mediators remain elusive. Eosinophils may contribute to both asthmatic and atherosclerotic inflammation. Hence, this study aimed to explore the potential associations of eosinophils with artery changes among patients with asthma. METHODS: We assessed strain values of the common carotid arteries (CCAs) via vascular speckle tracking and compared asthma patients with low (< 300/µl) and high (≥ 300/µl) blood eosinophil counts (BEC). RESULTS: We enrolled 100 patients, 42 with a BEC of < 300 and 58 with a BEC of ≥ 300 n/µl. Patients with high BEC exhibited more severe disease, characterized, e.g., by a higher frequency of acute exacerbations (1.3 ± 2.1 vs. 2.6 ± 2.4 n/year, p = 0.005). Both groups presented similar profiles in terms of conventional cardiovascular risk. The high BEC group demonstrated elevated arterial stiffness, reflected by reduced radial strain (mean radial strain of the right CCA: 2.7 ± 1.4% for BEC ≥ 300 n/µl vs. 3.5 ± 1.7% for BEC < 300 n/µl, p = 0.008; left CCA: 2.6 ± 1.4% vs. 4.1 ± 2.2%, p < 0.001). A weak yet statistically significant negative correlation was observed between BEC and radial strain for the right CCA (R2 = 0.131, b=-0.001, p = 0.001) and left CCA (R2 = 0.086, b=-0.001, p = 0.015). However, the prevalence of cerebrovascular disease was similar in both groups (31,0% vs. 50,0%, p = 0.057). CONCLUSION: We identified a correlation between BEC and vascular stiffness, which supports the hypothesis that eosinophils may promote atherosclerosis. CLINICAL TRIAL NUMBER: Due to the exploratory and predominantly retrospective nature of the study, trial registration was not conducted. The only prospective procedure conducted was the angiological sonography to evaluate the current state. No ensuing health-related interventions were performed specifically for this study.

PD-1 deficiency impairs eosinophil recruitment to tissue during Trichinella spiralis infection.

Blockade of programmed cell death 1 (PD-1) is considered a promising strategy for controlling pathogen infection by enhancing host immune cell function. Eosinophils, which play a crucial role in type 2 immune responses, are essential components of the host defense against helminth infection. Here, we investigate the role of PD-1 in eosinophilia during Trichinella spiralis infection in mice. PD-1-deficient (PD-1-/-) mice exhibit delayed expulsion of adult worms and increased muscle larva burdens compared to wild-type mice following infection. Additionally, PD-1-/- mice display impaired recruitment of eosinophils to parasite-invaded tissues, attributed to decreased upregulation of adhesion molecules on both eosinophils and vascular endothelium after infection. The compromised Th2 cytokine response further contributes to impaired adhesion interactions, affecting eosinophil migration and cytotoxicity against larvae in vitro within T. spiralis-infected PD-1-/- mice. Our findings demonstrate a positive role for PD-1 in the recruitment of eosinophils, suggesting its involvement in host defense against helminth infection.

Association between Acute Tobacco Exposure and Fractional Exhaled Nitric Oxide in Patients with Chronic Obstructive Pulmonary Disease: National Health and Nutrition Examination Survey (NHANES) 2007-2012.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a marker of type 2 airway inflammation. Tobacco exposure can lower FeNO levels. However, the effect of acute tobacco exposure on FeNO in patients with chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to investigate the relationship of acute tobacco exposure with FeNO and eosinophils in COPD patients. METHODS: This retrospective cohort study included 445 patients with COPD based on the 2007-2012 National Health and Nutrition Examination Survey. Serum cotinine levels were examined to assess environmental tobacco smoke exposure. The patients were divided into five groups based on cotinine levels: Q1 (first quintile), Q2 (second quintile), Q3 (third quintile), Q4 (fourth quintile) and Q5 (fifth quintile). Logistic regression models and linear logistic regression models were used to evaluate the relationship between serum cotinine and FeNO and EOS levels. RESULTS: Approximately 16.5% (75/445) of the participants had elevated FeNO (>25 bbp). In the unadjusted model, COPD patients with the lowest quintile of serum cotinine levels (0.011-0.0185 ng/mL) had higher FeNO levels compared to those with the highest quintile (≥309 ng/mL) (odds ratios (OR), 5.86 [2.11-16.20]). These findings remained consistent even after adjusting for covariates of demographics, lifestyle, diabetes, coronary heart disease, tumours, hypertension, using oral or inhaled steroids within 2 days, asthma and respiratory symptoms within 7 days. Furthermore, a standard deviation increase of ln-transformed cotinine levels was associated with decreased FeNO levels (OR, 0.45 [0.33, 0.60]). No significant correlation was observed betweenserum cotinine and blood eosinophils. After high extents of tobacco exposure, no correlation was found between FeNO and eosinophils. Our findings indicate that high cotinine levels are associated with decreased FeNO in COPD patients but not with blood eosinophils. This reveals that smoking may affect FeNO levels in patients with COPD, whereas it does not appear to influence blood eosinophil levels.

The Enhanced Role of Eosinophils in Radiomics-Based Diagnosis of Microvascular Invasion and Its Association with the Immune Microenvironment in Hepatocellular Carcinoma.

Objective: To investigate the role of eosinophil counts (EC) in microvascular invasion (MVI) for enhancing the radiomics based diagnostic model. Additionally, its correlation with early recurrence and tumor immune microenvironment was explored. Methods: Propensity score matching was employed to evaluate on 462 cases whether EC was an independent risk factor for MVI. Subgroup analyses examined EC's effect on MVI across varying hypersplenism degrees. Univariate-multivariate logistic regression identified MVI's independent factors to develop a diagnostic model. Univariate-multivariate COX regression determined early recurrence factors. Co-detection by indexing (CODEX) constructed the immune score (IS), and Spearman correlation analyzed its association with peripheral immunity. Results: EC was an independent risk factor for MVI (p=0.038, OR=1.304 (95% CI: 1.014-1.677)), and its effect on MVI disappeared with the severity of hypersplenism. The diagnostic model with EC was significantly improved (AUC=0.787 (95% CI: 0.737-0.836) vs AUC=0.748(95% CI: 0.694-0.802, p=0.005)). MVI was an independent risk factor for early recurrence (p<0.001, HR = 2.254 (95% CI: 1.557-3.263)). IS was negatively correlated with lymphocyte counts (R=-0.311, p=0.022), and positively correlated with EC (R=0.301, p=0.027) and RS (R = 0.315, p = 0.018). Conclusion: EC was an independent risk factor for MVI and was related to the tumor immune microenvironment. EC should be included in the diagnosis of MVI to improve diagnostic efficiency.

Does Eosinophil Heterogeneity Translate into Functional Diversity? A Review of the Evolving Paradigm of Eosinophil Heterogeneity in Asthma.

This review provides an overview of evidence supporting the existence of distinct homeostatic and inflammatory eosinophil subpopulations in health and disease. Particular emphasis is placed on describing the phenotypic and functional roles of these eosinophil subtypes in asthma, as well as the phenotypic changes induced by clinical therapy with the anti-IL-5 biologic agent, mepolizumab. Improved understanding of distinct eosinophil phenotypes may enable targeting of select subpopulations in the treatment of patients with type 2 inflammatory diseases such as asthma.

The role of eosinophils in liver disease.

Previously, eosinophils were primarily regarded as effector toxic cells involved in allergic diseases and parasitic infections. Nevertheless, new research has shown that eosinophils are diverse and essential for immune regulation and tissue homeostasis. Their functional plasticity has been observed in patients with inflammatory diseases, cancer, infections, and other disorders. While eosinophils are infrequently observed within the liver during periods of homeostasis, they are recruited to the liver in various liver diseases, including liver parasitosis, acute liver injury, autoimmune liver disease, and hepatocellular carcinoma. Furthermore, eosinophils have demonstrated the capacity to promote liver regeneration. This article explores the multifaceted roles of eosinophils in liver diseases, aiming to provide insights that could lead to more effective clinical therapies for these conditions.

Serum Galectin-10: A biomarker for persistent airflow limitation in adult asthmatics.

Background: Inhaled corticosteroids (ICS) are primary anti-inflammatory medications to control eosinophilic airway inflammation, and prevent asthma exacerbation. However, persistent airflow limitation (PAL) presents in some asthmatics even on ICS treatment, leading to lung function decline. Thus, we evaluated clinical associations of serum galectin-10 (Gal10) and galectin-3 (Gal3) levels in adult asthmatics who had maintained anti-asthma medication. Methods: Sixty-seven asthmatics and 78 healthy controls (HCs) were recruited. Serum Gal10 and Gal3 levels were measured by enzyme-linked immunosorbent assay, and their clinical relevance with inflammatory and lung function parameters was evaluated. Spirometry was performed to assess PAL and small airway dysfunction (SAD). Airway epithelial cells were cocultured with eosinophils/neutrophils, and were exposed to house dust mites to assess the production of Gal10 and Gal3. Results: Serum Gal10 (not Gal3) levels were significantly higher in asthmatics than in HCs (P < 0.001), in asthmatics with PAL than in those without PAL (P = 0.005), and in those with SAD than in those without SAD (P = 0.004). The Gal10-high group had significantly higher levels of peripheral CD66+ neutrophil counts, serum periostin and Gal3, and lower values of FEV1% and MMEF% than the Gal10-low group (P < 0.050 for all). The production of Gal10 and Gal3 was increased in eosinophilic airway model, while Gal10 (not Gal3) levels were increased in neutrophilic airway model as well as house dust mite stimulation. Conclusion: Our findings suggest that serum Gal10 level may be a potential biomarker for PAL in adult asthmatics.

Peripheral Inflammation Featuring Eosinophilia or Neutrophilia Is Associated with the Survival and Infiltration of Eosinophils within the Tumor among Various Histological Subgroups of Patients with NSCLC.

Immune activation status determines non-small cell lung cancer (NSCLC) prognosis, with reported positive/negative associations for T helper type 2 (TH2) responses, including allergen-specific IgE and eosinophils. Our study seeks to explore the potential impact of these comorbid immune responses on the survival rates of patients with NSCLC. Our retrospective study used data from the Data Warehouse of the German Center for Lung Research (DZL) and Lung Biobank at Thoraxklinik Heidelberg. We estimated the association of blood eosinophilia and neutrophilia on survival rates in an inflammatory cohort of 3143 patients with NSCLC. We also tested sensitization to food and inhalants and high-sensitivity C-reactive protein (hs-CRP) in a comorbidity cohort of 212 patients with NSCLC. Finally, we estimated the infiltration of immune-relevant cells including eosinophils, T-cells, and mast cells in a tissue inflammatory sub-cohort of 60 patients with NSCLC. Sensitization to at least one food or inhalant (sIgE) was higher in patients with adenocarcinoma (adeno-LC) than the non-adenocarcinoma (non-adeno-LC). Furthermore, hs-CRP was higher in non-adeno-LC compared with adeno-LC. Peripheral inflammation, particularly eosinophilia and neutrophilia, was associated with poor survival outcomes in NSCLC with a clear difference between histological subgroups. Finally, blood eosinophilia was paralleled by significant eosinophil infiltration into the peritumoral tissue in the lung. This study provides novel perspectives on the crucial role of peripheral inflammation, featuring eosinophilia and neutrophilia, with overall survival, underscoring distinctions between NSCLC subgroups (adeno-LC vs. non-adeno-LC). Peripheral eosinophilia enhances eosinophil infiltration into tumors. This sheds light on the complex interplay between inflammation, eosinophil infiltration, and NSCLC prognosis among various histological subtypes. Further studies are required to underscore the role of eosinophils in NSCLC among different histological subgroups and their role in shaping the tumor microenvironment.

Real-world phenotyping and risk assessment of childhood asthma burden using national registries.

BACKGROUND: Phenotype classification contributes to risk assessment of asthma. Previous studies have applied this concept primarily to adult populations and in the setting of research protocol assessments which may not be applicable to clinical settings. OBJECTIVE: Exploring the value of routinely collected clinical data for phenotype classification and risk assessment of childhood asthma. METHODS: Using hospital and laboratory data, 29,851 children in a Danish nationwide database aged 2-17 years with ICS-treated asthma in 2015 followed for two years (730 days) were classified to have T2 (elevated blood eosinophils (>300 cells/µL) and/or elevated total- or specific-IgE), and/or non-T2 risk factors (in utero tobacco exposure and/or severe viral infections). Logistic regression was applied to quantify associations of risk factors with asthma severity, control, and exacerbation risk. RESULTS: In a complete case analysis, 85.8 % children had at least one T2 risk factor and 29.3 % had mixed T2/non-T2 risk factors. Elevated blood eosinophils and total/specific IgE were associated with exacerbations (ORs 1.55 (1.38-1.73) and 1.41 (1.20-1.66) and higher asthma severity (1.42 (1.24-1.63) and 1.31 (1.08-1.60)), respectively. Dose-dependency was observed between blood eosinophil counts, total IgE levels, and risk of adverse outcomes. Furthermore, accumulation of risk factors demonstrated an increasing risk, with children with all four risk factors having a high risk of any adverse asthma-related outcome (OR 3.13 (2.03-4.82) CONCLUSION: Asthma phenotypic markers defined in research protocols can be reliably applied in real-world settings by utilizing data collected during routine clinical care and enable better classification of risk of adverse asthma outcomes.

Eosinophilic dialogues: a molecular exploration of sickle cell anemia severity.

Sickle cell anemia (SCA) is a genetically inherited hemoglobinopathy characterized by the abnormal morphology of red blood cells, resulting in vaso-occlusive events and diverse clinical complications. Recent investigations have unveiled a novel dimension in understanding SCA severity through the lens of eosinophilic dialogues. This review article synthesizes current knowledge on the molecular intricacies of eosinophils in the context of SCA, exploring their biology, molecular markers, and interactions with other cellular components. Eosinophil-mediated inflammation and oxidative stress are dissected to elucidate their impact on the disease course. Furthermore, the review evaluates potential therapeutic interventions and outlines future directions in this burgeoning field. The term "Eosinophilic Dialogues" encapsulates the multifaceted molecular exchanges that influence SCA severity, presenting a promising avenue for targeted interventions and improved clinical outcomes. This review serves as a comprehensive resource for researchers, clinicians, and healthcare practitioners engaged in unraveling the complex pathophysiology of SCA and exploring novel therapeutic avenues.

Allergic Bronchopulmonary Aspergillosis/Mycosis: An Allergic Disease or an Eosinophilic Disease?

Allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) is characterized by increased serum levels of total and fungi-specific immunoglobulin E (IgE) and eosinophilic mucus plugs in the airways. Its classification as either an allergic or eosinophilic disease remains controversial. In the present review, we explored this topic based on three clinical studies that analyzed the clinical characteristics of ABPA/ABPM using a cluster analysis, factor analysis, and comparison between ABPM caused by Schizophyllum commune and ABPA. We also compared therapeutic responses to biologics targeting either IgE (omalizumab) or eosinophils (mepolizumab/benralizumab) to elucidate the role of these components in the pathogenesis of ABPA/ABPM. Based on these analyses, eosinophilic mucus plug formation in the airways is considered a cardinal feature of the development of ABPA/ABPM, whereas IgE responses to fungi are important factors that modulate disease manifestation.