Asthma Endotypes Research Articles

Asthma and COVID-19: Unveiling Outcome Disparities and Treatment Impact Based on Distinct Endotypes.

Epidemiologic studies on asthmatics and in vitro data suggest a protective role of T2 inflammation in SARS-CoV-2 infection. Using a large, multisite cohort, we studied clinical outcomes following SARS-CoV-2 infection in multiple asthma endotypes and examined the effects of T2-directed biologics in infected asthmatics.in Methods: The National COVID Cohort Collaborative (N3C) Data Enclave was used to identify and stratify asthmatic patients by endotype to include non-T2 and T2 asthmatics, as well as exposure to T2-directed biologic therapy. We evaluated the risk of hospitalization, invasive mechanical ventilation, and 90-day mortality by endotype and exposure to biologics. For this study, 402,376 patients met inclusion criteria, of which 138,142 (34%) were characterized as non-T2 and 264,234 (66%) as T2 asthmatics, a group further divided into 104,823 (26%) atopic, 84,440 (21%) eosinophilic, and 74,971 (19%) T2-high asthmatic endotypes. Compared to non-T2 asthmatics, atopic and T2-high asthmatics experienced decreased odds of hospitalization, and 90-day mortality. Conversely, eosinophilic asthmatics experienced higher odds of hospitalization, intubation, and 90-day mortality. Exposure to T2-directed biologic therapies did not alter outcomes after propensity score matching. In contrast, maximum eosinophil count and recent systemic corticosteroid use were directly correlated with increased odds of all outcomes. COVID-19 outcomes differ depending on asthma endotype, with atopic asthmatics experiencing lower odds and eosinophilic asthmatics experiencing higher odds of deleterious outcomes. T2-directed biologic treatment did not alter these outcomes but recent systemic corticosteroid use predisposes all asthmatics patients to adverse outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Severe asthma phenotypes and endotypes

Introduction. Severe asthma is a heterogeneous disease with several phenotypes and endotypes. However, little is known about frequency of severe asthma phenotypes and endotypes in Russia.Aim. To assess frequency of severe asthma phenotypes and endotypes compared with mild/moderate asthma.Materials and methods. Cross-sectional single center study included 643 adult outpatients with mild/moderate asthma and 314 patients with severe asthma (SA) aged 18–90 years. Spirometry and bronchodilator reversibility testing were carried out. Fractional exhaled nitric oxide (FeNO) was measured by a chemiluminescent analyzer (logan 4100, UK). Hypersensitivity to common inhalant allergen was assessed by skin prick and blood specific IgE level. Peripheral blood eosinophil counts were measured by automatic analyzer. Asthma control and asthma-related quality of life were assessed by using ACQ-5 and SGRQ.Results. Allergic phenotype was more frequent in patients with mild/moderate asthma than in those with SA, but aspirin-induced asthma, steroid-dependent asthma, asthma with persistent airflow limitation and concomitant COPD, asthma with late onset and obesity were more frequent in SA. The majority of patients with SA had several phenotypes (mean 3 phenotypes) and at least one marker of T2-high endotype.Conclusion. The most frequent phenotypes of SA were allergic, with persistent airflow limitation, with concomitant obesity and COPD. Occurrence of asthma phenotypes differed between patients with SA and mild/moderate asthma. The majority of SA patients have T2-endotype.

Innate players in Th2 and non-Th2 asthma - emerging roles for the epithelial cell, mast cell and monocyte/macrophage network.

Asthma is one of the most common chronic respiratory diseases and is characterized by airway inflammation, increased mucus production and structural changes in the airways. Recently, there is increasing evidence that the disease is much more heterogeneous than expected, with several distinct asthma endotypes. Based on the specificity of T cells as the best-known driving force in airway inflammation, bronchial asthma is categorized into T helper cell (Th)2 and non-Th2 asthma. The most studied effector cells in Th2 asthma include T cells and eosinophils. In contrast to Th2 asthma, much less is known about the pathophysiology of non-Th2 asthma, which is often associated with treatment resistance. Besides T cells, the interaction of myeloid cells such as monocytes/macrophages and mast cells with the airway epithelium significantly contributes to the pathogenesis of asthma. However, the underlying molecular regulation and particularly the specific relevance of this cellular network in certain asthma endotypes remains to be understood. In this review, we summarize recent findings on the regulation of and complex interplay between epithelial cells and the "non-classical" innate effector cells, mast cells and monocytes/macrophages, in Th2 and non-Th2 asthma with the ultimate goal to provide the rationale for future research into targeted therapy regimens.

Th2 and IL-17 responses inChlamydia pneumoniae-stimulated PBMC in asthmatic and non-asthmatic subjects

Abstract Background Chlamydia pneumoniae (C. pneumoniae) is a gram-negative intracellular bacterium that causes respiratory infections in humans, including asthmatic and non-asthmatic subjects. C. pneumoniae activates cells in vitro and produces cytokines that may contribute to the inflammatory responses observed in asthma. Different asthma endotypes are described, including Th2-high and Th2-low. Th2-low endotypes are characterized by IL-17 production and neutrophilic inflammation. The aim of this study was to investigate the role of C. pneumoniae in regulating Th2 versus Th17 responses in peripheral blood mononuclear (PBMC) from subjects with or without asthma. Methods PBM) (1×106/mL) from asthmatic (N=6) and non-asthmatic subjects (N=14) were infected +/- C. pneumoniae TW-183 at a multiplicity of infection (MOI) = 0.1, using dose responses (1:10, 1:100), and cultured 48 hrs. Cytokine responses (Interferon (IFN)-gamma, Interleukin (IL)-2, IL-4, IL-17 A/F) were measured in supernatants (ELISA). Results Comparison of cytokine responses (the mean differences in non-asthmatic versus asthmatic subjects) were significant for IFN gamma (unstimulated; P<0.0001), IL-2 (unstimulated and 1:100; P<0.0001, P=0.0002, respectively), IL-4 (unstimulated, 1:10, 1:100; P=0.0001, P<0.0001, P<0.0001, respectively) and IL-17 A/F (unstimulated, P<0.0001) (Wilcoxon signed-rank test). Cytokine levels were higher in asthmatic subjects for IFN-gamma (unstimulated,1:10, 1:100), IL-2 (unstimulated), and IL-17 A/F (unstimulated) compared with non-asthmatic subjects. However, IL-4 levels were higher in non-asthmatics (unstimulated, 1:10, 1:100). Conclusion Differences in Th2 and IL-17 cytokines responses in PBMC from subjects with and without asthma may indicate the involvement of cell-mediated immunity, while Th17 responses, which were increased in subjects with asthma at baseline, did not increase further in response to C. pneumoniae stimulation.

Immunologic aspects of asthma: from molecular mechanisms to disease pathophysiology and clinical translation.

In the present review, we focused on recent translational and clinical discoveries in asthma immunology, facilitating phenotyping and stratified or personalized interventions for patients with this condition. The immune processes behind chronic inflammation in asthma exhibit marked heterogeneity, with diverse phenotypes defining discernible features and endotypes illuminating the underlying molecular mechanisms. In particular, two primary endotypes of asthma have been identified: "type 2-high," characterized by increased eosinophil levels in the airways and sputum of patients, and "type 2-low," distinguished by increased neutrophils or a pauci-granulocytic profile. Our review encompasses significant advances in both innate and adaptive immunities, with emphasis on the key cellular and molecular mediators, and delves into innovative biological and targeted therapies for all the asthma endotypes. Recognizing that the immunopathology of asthma is dynamic and continuous, exhibiting spatial and temporal variabilities, is the central theme of this review. This complexity is underscored through the innumerable interactions involved, rather than being driven by a single predominant factor. Integrated efforts to improve our understanding of the pathophysiological characteristics of asthma indicate a trend toward an approach based on disease biology, encompassing the combined examination of the clinical, cellular, and molecular dimensions of the disease to more accurately correlate clinical traits with specific disease mechanisms.

Metabolic and ionic control of T cells in asthma endotypes.

CD4+T cells play a central role in orchestrating the immune response in asthma, with dysregulated ion channel profiles and altered metabolic signatures contributing to disease progression and severity. An important classification of asthma is based on the presence of T-helper cell type 2 (Th2) inflammation, dividing patients into Th2-high and Th2-low endotypes. These distinct endotypes have implications for disease severity, treatment response, and prognosis. By elucidating how ion channels and the energy metabolism control Th cells in asthma, this review contributes to the pathophysiological understanding and the prospective development of personalized therapeutic treatment strategies for patients suffering from distinct asthma endotypes.

Bioinformatics analysis of G protein subunit gamma transduction protein 2-autophagy axis in CD11b+ dendritic cells as a potential regulator to skew airway neutrophilic inflammation in asthma endotypes.

Asthma is a heterogeneous inflammatory disease with two main clinical endotypes: type 2 (T2) high and low asthma. The plasticity and autophagy in dendritic cells (DCs) influence T helper (Th)2 or Th17 differentiation to regulate asthma endotypes. Enhanced autophagy in DCs fosters Th2 differentiation in allergic environments, while reduced autophagy favors Th17 cell differentiation in sensitized and infected environments. Autophagy regulation in DCs involves interaction with various pathways like G protein-coupled receptor (GPCR), mammalian target of rapamycin (mTOR), or phosphoinositide 3-kinase (PI3K) pathway. However, specific molecules within DCs influencing asthma endotypes remain unclear. Gene expression data series (GSE) 64896, 6858, 2276, and 55247 were obtained from gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between CD103+ and CD11b+ DCs after induction by ovalbumin (OVA) and lipopolysaccharide (LPS) were analyzed using GEO2R. DEGs were examined through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses. The hub gene network was construct with STRING database and Cytoscape. Autophagy differences in DCs and the selected hub gene in GSE6858, GSE2276, and GSE55247 were evaluated using student t tests. Our analysis identified 635 upregulated and 360 downregulated genes in CD11b+ DCs, compared to CD103+ DCs. These DEGs were associated with "PI3K-AKT signaling pathway," "Ras signaling pathway," and so forth. Thirty-five hub genes were identified, in which G protein subunit gamma transduction protein 2 (Gngt2) in CD11b+ DCs exhibited a relatively specific increase in expression associated with autophagy defects under the induction environment similar to T2 low asthma model. No significant difference was found in lung Gngt2 expression between T2 high asthma model and control group. Our analysis suggested Gngt2 acted as an adapter molecule that inhibited autophagy, promoting Th17-mediated airway inflammation via the GPCR pathway in a T2 low asthma mice model. Targeting this pathway provides new asthma treatment strategies in preclinical research.

Clinical remission and control in severe asthma: agreements and disagreements.

Over the last two decades, we have witnessed great advancements in our understanding of the immunological pathways of asthma, leading to the development of targeted therapies, such as biologic drugs, that have radically and definitively changed the clinical outcomes of severe asthma. Despite the numerous therapeutic options available, ~4-10% of all people with asthma have severe or uncontrolled asthma, associated with an increased risk of developing chronic oral corticosteroid use, fixed airflow limitation, exacerbations, hospitalization and, finally, increased healthcare costs. The new concept of disease modification in asthma comes from the evolution of asthma management, which encompasses phenotyping patients with different inflammatory endotypes characterizing the disease, followed by the advent of more effective therapies capable of targeting the proximal factors of airway inflammation. This treat-to-target approach aims to achieve remission of the disease. Because the novel treatment paradigm for severe asthma with the advent of biologic therapies is no longer clinical control but rather clinical remission - a step closer to the concept of cure - a deeper and more accurate understanding of the critical causal mechanisms and endotypes of asthma is necessary to achieve the goal of clinical remission, which has the potential to generate real life-changing benefits for patients. This review aims to frame the evolution of the debated concept of clinical remission and provide clinicians with insights that may be helpful in achieving remission in the greatest number of patients.

Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study

IntroductionAsthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive...

Aspergillus-sensitized asthma in children.

Asthma is the most common chronic respiratory disease in childhood. Aspergillus fumigatus sensitivity may be involved in the pathogenesis of asthma by leading to different clinical presentations. To investigate the demographic, clinical, laboratory, and radiological characteristics of A. fumigatus sensitivity in childhood asthma and identify associated risk factors and diagnostic parameters. A total of 259 children with asthma were included in the study, 7 (2.7%) with allergic bronchopulmonary aspergillosis (ABPA), 84 (32.4%) with A. fumigatus-sensitized asthma (Af-SA), and 168 (64.9%) with A. fumigatus-unsensitized asthma (Af-UA). Aspergillus sensitivity was associated with early asthma onset and longer asthma duration. Total IgE level and asthma severity are highest in ABPA and higher in Af-SA. Absolute eosinophil count was higher, and FEV1 was lower in Af-SA and ABPA. Aspergillus fumigatus was associated with greater odds of being male (odds ratio [OR], 2.45), having atopic dermatitis (OR, 3.159), Alternaria sensitivity (OR, 10.37), and longer asthma duration (OR, 1.266). The best cut-off values for detecting A. fumigatus positivity were 363.5 IU/mL for total IgE and 455 cells/μL for absolute eosinophil count. In Af-SA compared to Af-UA, centrilobular nodules and peribronchial thickening were more common, and the bronchoarterial ratio was higher. Aspergillus sensitivity is a strong allergic stimulus in asthma, leading to laboratory, structural, clinical, and functional consequences. Af-SA is a distinct asthma endotype independent of ABPA that is characterized by increased risk of severe clinical presentations and impaired lung function.

Endotypes of severe neutrophilic and eosinophilic asthma from multi-omics integration of U-BIOPRED sputum samples.

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. To determine whether multi-omics integration of sputum leads to improved granularity of the molecular classification of severe asthma. 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. 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. 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. 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.

Differences in the DNA Methylome of T cells in Adults With Asthma of Varying Severity.

DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes are less well-defined. To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. Peripheral blood T cells from 35 adults with asthma in Beijing, China were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included RUNX3, several members of the HLA family, AGT, PTPRC, PTPRJ, and several genes downstream of the JAK2 and TNF signaling pathway. These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to the phenotype and severity of their overall disease.

Household Use of Irritant and Sprayed Cleaning Products and Asthma Endotypes. A Brief Report.

Household Use of Irritant and Sprayed Cleaning Products and Asthma Endotypes. A Brief Report.

Positioning of Tezepelumab in Severe Asthma.

Asthma is one of the most common chronic diseases and is estimated to be severe in 3%-10% of affected patients. There is a need for additional biologic treatments that are highly efficacious across the spectrum of severe uncontrolled asthma. Currently available drugs inhibit 1 or 2 specific cytokines or IgE antibodies and thus only partially suppress the complex type 2 (T2) inflammatory cascade. Biologics targeting more upstream molecules in the pathophysiological pathway of asthma could treat asthma more effectively. Tezepelumab is a human monoclonal immunoglobulin G2λ antibody that targets the cytokine thymic stromal lymphopoietin (TSLP). It is the first marketed biologic against an epithelial cell-derived cytokine, preventing binding of TSLP to its receptor and reducing the immune stimuli that TSLP can trigger in different asthma endotypes. Tezepelumab reduces downstream biomarkers of inflammation, such as blood and airway eosinophils, FeNO, IgE, IL-5, and IL-13. Tezepelumab provides a clinical benefit in severe asthma, reducing the annualized asthma exacerbation rate in patients with either high or low levels of biomarkers of T2 inflammation, although the effect is greater among those with high levels. The drug has been shown to improve asthma control, quality of life, and lung function and reduce airway hyperresponsiveness. Therefore, tezepelumab can be used across the spectrum of patients with severe uncontrolled asthma, especially in T2-high patients. This review includes a positioning statement by the authors, all of whom are members of the SEAIC Asthma Committee.

Transcriptomic evaluation of skin tape-strips in children with allergic asthma uncovers epidermal barrier dysfunction and asthma-associated biomarkers abnormalities.

Tape-strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma-specific biomarkers in the skin of children with allergic asthma. Skin tape-strips were obtained and analyzed with RNA-Seq from children with moderate allergic asthma (MAA) (n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) (n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) (n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate <0.05. Transcriptomic biomarkers were analyzed for their accuracy in distinguishing asthma from HCs, their relationships with asthma-related outcomes (exacerbation rate, lung function-FEV1, IOS-R5-20, and lung inflammation-FeNO), and their links to skin (barrier and immune response) and lung (remodeling, metabolism, aging) pathogenetic pathways. RNA-Seq captured 1113 in MAA and 2117 DEGs in SAA. Epidermal transcriptomic biomarkers for terminal differentiation (FLG/filaggrin), cell adhesion (CDH19, JAM2), lipid biosynthesis/metabolism (ACOT2, LOXL2) were significantly downregulated. Gene set variation analysis revealed enrichment of Th1/IFNγ pathways (p < .01). MAA and SAA shared downregulation of G-protein-coupled receptor (OR4A16, TAS1R3), upregulation of TGF-β/ErbB signaling-related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial-related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two-gene classifier (TSSC4-FAM212B) was able to differentiate asthma from HCs with 100% accuracy. Tape-strips detected epithelial barrier and asthma-associated signatures in normal-appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes.

Epigenetic Approaches to Identifying Asthma Endotypes.

The prevalence of asthma escalated rapidly in the late 20th century. In 2019, the World Health Organization estimated the global number of people affected by the condition to be approximately 260 million, causing 450,000 deaths during that year. While there have been advances in therapeutics with the emergence of biologics targeting T2-high asthma, there is still little clarity on the mechanisms underlying the origins of both the condition and all of its endotypes. Several biomarkers for particular asthma phenotypes have been documented. These are generally identified from transcriptomics and proteomics protocols and tend to be biased to T2-high phenotypes. In this review, we summarize some suggestions that analysis of epigenomes may provide alternative datasets that inform of broader asthma endotypes and might highlight pathways amenable for therapeutic intervention.

Иммунные механизмы нейтрофильного воспаления при бронхиальной астме

This review presents an analysis of scientific publications in recent years devoted to the study of cellular and molecular mechanisms of neutrophilic airway inflammation as potential therapeutic targets in the treatment of severe, poorly controlled asthma of the neutrophil phenotype, the presence of which is still debated and there is no generally accepted definition. The conditional term "neutrophilic asthma" implies the existence of a certain asthma endotype, in which neutrophils are the main type of cells mediating the pathophysiology and disease symptoms. The involvement of the inverted protein response associated with endoplasmic reticulum (ER) stress and the sensory signal transduction protein in the endoplasmic reticulum membrane in the deregulation of the T helper 17 (Th17) cells function and neutrophilic airway inflammation is considered. Polarization and activation of M1 macrophages play an important role in the neutrophilic inflammation immunopathogenesis, in particular, in asthma associated with obesity. Soluble suppression of tumorigenicity 2 protein is considered as a receptor that promotes neutrophil activation and neutrophilic inflammation. The involvement of neutrophil extracellular traps and the respiratory tract microbiome in the neutrophilic inflammation progression, in particular, the role of bacterial outer membrane vesicles, is discussed. KEYWORDS: neutrophils, neutrophilic inflammation, asthma, Th17 cells, M1 macrophages, suppression of tumorigenicity 2 protein, neutrophil extracellular traps, respiratory tract microbiome. FOR CITATION: Kuzubova N.A., Lebedeva E.S. Immune mechanisms of neutrophilic inflammation in asthma. Russian Medical Inquiry. 2024;8(8):453–458 (in Russ.). DOI: 10.32364/2587-6821-2024-8-8-2.

Роль та важливість FeNO тесту при різних ендотипах бронхіальної астми

Abstract. Bronchial asthma (BA) is one of the most frequent cause of inflammations of the airway and frequently characterized by eosinophilia, IgE production, and Th2 cytokine expression. Despite the wide prevalence of spirometry in BA diagnostic, the significance of FeNO test is the one of sensitive marker of eosinophilic inflammation in early asthma diagnosis. The pathogenesis of allergic inflammation has different endotypes which is poorly understood. The aim of our study is to evaluate the relation between different allergic inflammation indicators (eosinophils and IgE levels) and rates of FeNO results in patients with BA. Materials and methods. In this work we analyzed the basal levels of FeNO NIOX® test, serum IgE levels and eosinophils in patients with first diagnosed asthma before the treatment. In our study we included 125 patients with BA and 20 healthy control. Group 1 (n = 67) were the patients with BA and high IgE (Th-2 endotype), Group 2 (n = 58) — BA and normal IgE levels, but increased eosinophils (eosinophilic asthma). The levels of serum IgE was determined using ELISA. The FeNO results determined by NIOX VERO® analyzer. Results. The serum concentrations of IgE was higher in Group 1 (267.3 ± 57.6) IU/ml, Group 2 (37.2 ± 14.7) IU/ml and had no significant difference than healthy control (24.9 ± 7.7) IU/ml, p &lt; 0.05. Eosinophils were higher in Group 2 (684 ± 228) cells/mcl than in Group 1 (456 ± 177) cells/mcl and control (104 ± 53) cells/mcl, p &lt; 0.01. Also we determined positive strong correlation between serum IgE and blood eosinophils in Group 1 patients (r = 0.823) and no correlation in Group 2 (r = 0.324). The results of FeNO were significantly higher (47.2 ± 6.4) ppb in patients with higher IgE and high eosinophils (Group 1) than in Group 2 (34.6 ± 5.9) ppb and healthy control (12.4 ± 4.3) ppb, p &lt; 0.05. Conclusion. The higher FeNO results were in patient with Th2 asthma endotype than in eosinophilic asthma. We could conclude that patients, which eosinophils induced by allergy, have association between serum IgE, blood eosinophils and FeNO results. Instead, patients with eosinophilic asthma and low serum IgE have other not Th2-induced mechanism of eosinophils activation (recurrent infections, haptens influence, non-steroidal anti-inflammatory drugs intolerance and ect.). We can assume that eosinophils can crystallize in the bronchi of the patients with eosinophilic asthma caused by other cytokines rather than Th2. In this case, FeNO activity depends on the Th2 eosinophils maintenance and more sensitive in patients with allergic exogenous asthma.

Unraveling the Interrelationship of Microbiota, Inflammation and Obesity: Implications for the Pathophysiology of Asthma Endotypes

Unraveling the Interrelationship of Microbiota, Inflammation and Obesity: Implications for the Pathophysiology of Asthma Endotypes

Pharmacologic Treatment of Type 2-High Severe Asthma

Asthma is a common and heterogeneous disease whose treatment has considerably changed over the last decades. While inhaled therapies based on inhaled corticosteroids and long acting β2 agonists are effective in controlling asthma in the majority of patients, about 5% of asthmatics poorly respond to inhaled steroids or inhaled steroids/long acting β2 agonists combinations. These patients are affected by “severe asthma”, which is associated with need of oral corticosteroids, progression of the disease, increased use of healthcare services, deterioration of quality of life, and a significant economic burden on society. Asthma is no longer considered a single disease, but a respiratory syndrome with complex biological network of distinct and interrelating inflammatory and remodeling pathways (endotypes) that are associated with different clinical manifestations (phenotypes) both in the lungs (asthma) and other organs (e.g. nose and skin). Severe asthma endotypes may be broadly regarded as Type 2-high and Type 2-low, a model that has become central to asthma management with the development of novel treatments for the Type 2-high endotypes. The hallmark feature of Type 2-high asthma is eosinophilic inflammation, often associated with increased serum IgE, increased exhaled nitric oxide (FeNO) and blood eosinophilia. The discovery of the main key drivers of Type 2-high inflammation (IgE, cytokines such as interleukin IL-5, -4 and -13) enabled the development of new biological agents directed towards specific molecular targets. These advances have shifted the existing paradigm “one drug fits all” to “patient-tailored” novel therapies. The monoclonal antibodies direct to IgE (omalizumab), IL-5 and IL-5 receptor (mepolizumab, benralizumab, reslizumab), and to the α chain of the IL-4 and IL-13 combined receptor (dupilumab), and more recently, to the thymic stromal lymphopoietin (tezepelumab) have been shown in both clinical trials and real-life studies to control symptoms, reduce asthma exacerbations and improve lung function in severe asthmatics not controlled by full inhalation therapies. More recently, the Single Inhaler Triple Therapy (SITT) containing inhaled steroids, long acting β2 agonists and muscarinic antagonists has been developed, slightly improving the effectiveness/safety of the inhalation therapy. This report aims to review available therapeutic opportunities for patients with severe asthma focusing on patients with Type 2-high severe asthma and how to position these new therapeutic alternatives in clinical practice.