Non-eosinophilic Asthma Research Articles

Association Between Bedroom Particulate Matter Filtration and Changes in Airway Pathophysiology in Children With Asthma

To identify the measurable physiologic changes in the small airways of children with asthma, when employing a 2.5 µm particulate matter (PM2.5) filtration device in their bedrooms.The population enrolled includes children with mild or moderate asthma who live in a suburb of Shanghai, China, during a low-ozone season. A total of 43 children (5–13 years old; 60% boys) are included in the analysis.Patients are randomly assigned into either arm of a double-blind crossover study design with 3 consecutive 14 day periods of true filtration-washout-sham filtration or the reverse order. Impulse oscillometry, spirometry, and fractional exhaled nitric oxide (FeNO) were measured before and after each intervention, and peak flow was measured twice per day at home.PM2.5 concentrations were moderately high (28.6-69.8 μ g/m3) among the enrollees. A decrease in PM2.5 concentration by 63.4% was noted in true filtration bedrooms, when compared with sham filtration. True filtration was associated with improved airway mechanics, as measured by impulse oscillometry (a 22% to 43% decrease in resonant frequency, small airway resistance, and total airway resistance and 73% increase in airway reactance), FeNO, (27.6% decrease) and peak flow measurement (1.6% increase). These airway parameters were significantly associated with bedroom particulate matter reduction. Statistical significance was only noted in children without eosinophilic airway inflammation at the baseline (an absolute eosinophil count of 450 cells per μL and FeNO >35 parts per billion). No large airway parameters (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second to forced vital capacity) differed after 14 days of true filtration.PM2.5 filtration in the bedroom may improve airway mechanics and inflammation in pediatric patients with asthma who do not have eosinophilic inflammation.With this study, the authors expand on previous work by the same group that revealed 1 night of HEPA air filtration improved airway mechanics in healthy adults. The results after 2 weeks indicate a promising intervention for children with noneosinophilic asthma. The authors carefully controlled for a number of confounders, including intercurrent illness, asthma exacerbations, seasonal variation, ozone levels, inhaled corticosteroid use, and secondhand smoke exposure. In future studies, researchers should address patients in different environmental conditions with a larger sample size, for a longer intervention period, before formal recommendations can be made.

Enhanced airway sensory nerve reactivity in non-eosinophilic asthma

BackgroundNeural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics.MethodsThirty-eight asthmatics...

Identifying the Clinical Pattern of Eosinophilic and Non-Eosinophilic Asthma subtype in adult patients with Bronchial Asthma

Abstract Background Context:- Asthma is a heterogenous disease with various phenotypes, it is the most common chronic disease characterized by airway limitation due to bronchospasm and airway inflammation associated with excessive mucus secretion from agitated mucus gland that occur due to air way hyper responiveness. Purpose of the study Comparison between eosinophilic and non-eosinophilic asthma patients. Patients and Methods 100 bronchial asthma patients of age ≥ 18 years old divided into2 groups according to blood eosinophilia. All patients were subjected to: history. Total Asthma Control Test. Spirometry. Sputum eosinophil count. IgE levels 6-Skin prick testing (SPT). Nasal endoscopy. Results the mean age of all patients was (35.4 ± 12.8) years, majority (61%) of patients were males,; the mean ACT score was (18.7 ± 2); 39% of cases have obstructive pattern by spirometry, 39% of cases had abnormal nasal endoscopy, SPT had significant relation with asthma, there is significant correlation between total IGE,sputum eosinophilia with eosinophilic asthma. Conclusion Blood eosinophils had the highest accuracy in the identification of sputum eosinophilia in asthma. Total IgE values and sutum eosinophilia were markedly increased in patients with eosinophilic asthma more than patients with non-eosinophilic asthma.

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

Serum microRNAs Catalog Asthma Patients by Phenotype.

Asthma is a chronic inflammatory condition of the airways with a complex pathophysiology. Stratification of asthma subtypes into phenotypes and endotypes should move the field forward, making treatment more effective and personalized. Eosinophils are the key inflammatory cells involved in severe eosinophilic asthma. Given the health threat posed by eosinophilic asthma, there is a need for reliable biomarkers to identify affected patients and treat them properly with novel biologics. microRNAs (miRNAs) are a promising diagnostic tool. The aim of this study was to identify serum miRNAs that can phenotype asthma patients. Serum miRNAs of patients with eosinophilic asthma (N=40) and patients with noneosinophilic asthma (N=36) were evaluated using next-generation sequencing, specifically miRNAs-seq, and selected miRNAs were validated using RT-qPCR. Pathway enrichment analysis of deregulated miRNAs was performed. Next-generation sequencing revealed 15 miRNAs that were expressed differentially between eosinophilic and noneosinophilic asthma patients, although no differences were observed in the miRNome between atopic and nonatopic asthma patients. Of the 15 miRNAs expressed differentially between eosinophilic and noneosinophilic asthma patients, hsa-miR-26a-1-3p and hsa-miR-376a-3p were validated by RT-qPCR. Expression levels of these 2 miRNAs were higher in eosinophilic than in noneosinophilic asthma patients. Furthermore, expression values of hsa-miR-26a-1-3p correlated inversely with peripheral blood eosinophil count, and hsa-miR-376a-3p expression values correlated with FeNO values and the number of exacerbations. Additionally, in silico pathway enrichment analysis revealed that these 2 miRNAs regulate signaling pathways associated with the pathogenesis of asthma. hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used to differentiate between eosinophilic and noneosinophilic asthma.

Asthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities

We developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry). We sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU). Patients age 13 years and older with active asthmaand blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Databaseand the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinicaland HCRU characteristics were described for each phenotype. Of 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year). The eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.

Airway Hyperresponsiveness to Inhaled Mannitol Identifies a Cluster of Noneosinophilic Asthma Patients with High Symptom Burden

Patients with asthma are heterogeneous in clinical presentation and in response to treatment. Despite this, tools to guide treatment are limited and include mainly measures of eosinophilic inflammation and symptoms. Airway hyperresponsiveness (AHR) to mannitol is present in patients across inflammatory phenotypes and improve with inhaled corticosteroids. To investigate whether measuring AHR to mannitol in addition to eosinophilic inflammation and symptoms adds information to the phenotypic characterization of patients with asthma. A total of 317 patients with asthma from 6 different cohorts were included in the analysis. All patients had measures of AHR to mannitol, blood eosinophils, and Asthma Control Questionnaire 5 available. A cluster analysis using Ward minimum variance method was performed. The distribution of fraction of exhaled nitric oxide, immunoglobulin E, lung function, induced sputum inflammatory cell count, age of onset, and severity of disease was compared between clusters. Four clusters were identified. Three of the clusters had proportionate levels of AHR, eosinophilic inflammation, and symptoms, but 1 cluster presented with low levels of eosinophilic inflammation and a significant symptom burden. Half of the subjects in this cluster presented with AHR to inhaled mannitol. Lung function, fraction of exhaled nitric oxide, body mass index, and immunoglobulin E were normal. Information on AHR to mannitol in addition to blood eosinophils and symptoms identifies a subgroup of asthma patients with symptomatic, noneosinophilic disease. Airway hyperresponsiveness to mannitol may provide a treatable trait in a subgroup of patients with noneosinophilic asthma.

Long-term adherence to inhaled corticosteroids in clinical phenotypes of adult-onset asthma

Long-term adherence to inhaled corticosteroids in clinical phenotypes of adult-onset asthma

Classification of non-acute bronchial asthma according to allergy and eosinophil characteristics: a retrospective study

BackgroundInvestigating the endotypes of the different asthma phenotypes would help disease monitoring, prognosis determination, and improving asthma management standardization. This study aimed to classify asthma into four endotypes according to the allergic and eosinophilic characteristics and explore the phenotypes (clinical characteristics, pulmonary functions, and fractional expired nitric oxide (FeNO)) of each endotype.MethodsThis retrospective study included non-acute asthma patients treated at the First Hospital of Shanxi Medical University (05/2016–01/2018). The patients were classified into the eosinophilic allergic, eosinophilic non-allergic, non-eosinophilic allergic, and non-eosinophilic non-allergic asthma endotypes. Serum sIgE, lung function, FeNO, and induced sputum cytology were tested and compared among groups.ResultsOf the 171 included patients, 22 had eosinophilic allergic asthma, 17 had eosinophilic non-allergic asthma, 66 had non-eosinophilic allergic asthma, and 66 had non-eosinophilic non-allergic asthma. Lung function measurements (FEV1%, FEF25%, FEF50%, FEF75%, and FEF25–75%) showed that airway dysfunction was worse in eosinophilic non-allergic asthma than in the other three endotypes (all P < 0.001). In allergic asthma patients, eosinophilic asthma had worse airway dysfunction than non-eosinophilic asthma (all P < 0.05). Similar results were found in non-allergic asthma (all P < 0.01). The FeNO levels in eosinophilic allergic asthma were higher than in eosinophilic non-allergic and non-eosinophilic non-allergic asthma (both P = 0.001).ConclusionsFeNO can objectively reflect eosinophilic airway inflammation in asthma. Endotypic classification of asthma patients regarding the allergic and eosinophilic characteristics is conducive to the effective management of patients with asthma.

Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort

Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). One thousand seven hundred sixteen patients with prospective data were included; 83.8%were identified as most likely (grade 3), 8.3%were identified as likely (grade 2), and 6.3%identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6%of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs6.7 years; P< .001) and worse lung function (postbronchodilator %predicted FEV1, 76.1%vs89.3%; P= .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5%vs62.9%; P= .047), to have eczema (20.8%vs8.5%; P= .003), and to use anti-IgE (32.1%vs13.4%; P= .004) and leukotriene receptor antagonists (50.0%vs28.0%; P= .011) add-on therapy. According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

Elevated serum calprotectin (S100A8/A9) in patients with severe asthma

Objective Asthma is a heterogeneous disease consisting of several inflammatory phenotypes of which neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids. The development of targeted therapies requires the identification of biomarkers to distinguish these phenotypes. Currently, we lack validated biomarkers for non-eosinophilic asthma. The aim of this study is to examine serum calprotectin (SC) in asthmatics and its potential as biomarker for neutrophilic asthma. Methods Hundred-seventeen severe asthmatics were referred for sputum induction and data were obtained from their medical records. To evaluate the association between SC and asthma phenotypes, patients were divided into subgroups based on sputum cell count (3% eosinophils and 61% neutrophils). Additionally, SC levels of asthmatics were compared with these of patients with chronic obstructive pulmonary disease, non-cystic fibrosis bronchiectasis and healthy controls. Results Asthmatics (n = 45) had significantly higher levels of SC than healthy controls. No significant differences were found between the different asthma phenotypes and in comparison with COPD patients. SC was significantly higher in asthmatics with a lower FEV1/FVC ratio (<70) and non-significantly elevated SC levels were seen in asthmatics with frequent exacerbations (>2 in the last year). Conclusion In conclusion, there was no difference in SC levels between the different inflammatory subtypes in asthmatics. Nevertheless, severe asthmatics seemed to have higher SC levels suggesting that SC may be a marker of disease severity rather than a marker for specific inflammatory subtypes in asthmatics. Further research in larger cohorts is necessary to validate SC as biomarker in severe asthmatics.

Molecular markers of type 2 airway inflammation are similar between eosinophilic severe asthma and eosinophilic chronic obstructive pulmonary disease

Airway and systemic eosinophilia are important treatable traits in both severe asthma and COPD. The molecular basis of eosinophilia in COPD is poorly understood but could involve type 2 cytokines (IL5, IL13) and prostaglandin D2 (PGD2 ). This study included non-obstructive airways disease (OAD) controls (n=19), a COPD cohort (n=96) and a severe asthma cohort (n=84). Demographics, exacerbation history, disease impact (SGRQ) and spirometry were assessed. Participants were categorized as eosinophilic using either sputum eosinophil proportion (≥3%) or blood eosinophil count (≥300/μL). Sputum type 2 inflammatory measures included PGD2 by ELISA and gene expression (qPCR) of IL5, IL13 and the haematopoietic PGD2 synthase (HPGDS). Type 2 markers did not differ across groups except HPGDS mRNA which was highest in non-OAD controls and lowest in COPD. IL5 and IL13 mRNA and PGD2 levels were significantly increased in eosinophilic vs non-eosinophilic severe asthma but did not differ between eosinophilic COPD and eosinophilic severe asthma or non-eosinophilic COPD. HPGDS expression was higher in eosinophilic severe asthma compared with eosinophilic COPD. Results were similar using sputum or blood eosinophil cut-offs. Sputum IL5 and IL13 were highly intercorrelated in severe asthma (r=0.907, p<0.001) and COPD (r=0.824, p<0.001), were moderately correlated with sputum eosinophils in severe asthma (IL5 r=0.440, p<0.001; IL13 r=0.428, p<0.001) and were weakly correlated in COPD (IL5 r=0.245, p<0.05; IL13 r=0.317, p<0.05). Molecular markers of type 2 airway inflammation do not differ between eosinophilic asthma and eosinophilic COPD; however, the relationship between eosinophilia and type 2 airway markers appears weaker in COPD than in severe asthma.

Sputum mast cell/basophil gene expression relates to inflammatory and clinical features of severe asthma

Mast cells (MCs) and basophils are important in asthma pathophysiology, however direct measurement is difficult, and clinical and inflammatory associations in severe asthma are poorly understood. Transcriptomic hallmarks of MCs/basophils may allow their measurement in sputum using gene expression. This study sought to develop and validate a sputum MC/basophil gene signature and investigate its relationship to inflammatory and clinical characteristics of severe asthma. A total of 134 candidate MC/basophil genes (identified by the Immunological Genome Project Consortium) were screened in sputum microarray for differential expression among control subjects (n= 18), patients with eosinophilic (n= 29), and patients with noneosinophilic asthma (n= 30). Candidate genes were validated by confirming correlation of gene expression with flow cytometry-quantified sputum MCs and basophils in a separate asthma cohort (n= 20). The validated gene signature was measured in a severe asthma cohort (n= 81), and inflammatory and clinical associations were tested. Through microarray screening and subsequent validation, we found quantitative PCR gene expression of 8 targets correlated with sputum MCs/basophils: TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2. In severe asthma, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophils (TPSB2, CPA3, GATA2, SOCS2, FCER1A, HDC), fractional exhaled NO (GATA2, SOCS2), decreased lung function (KIT, ENO2), and moderate exacerbation history (GATA2, SOCS2). Quantitative PCR-based measures reflect varying sputum MC/basophil abundance, demonstrating associations of MCs/basophils with eosinophilic inflammation, spirometry and exacerbation history in severe asthma.

Serum sphingolipid profile in asthma.

Sphingolipids metabolism is an important cell process and plays critical roles in asthma. However, the involvement of sphingolipids in the pathogenesis of asthma and its subtypes is unknown. The present study aimed to determine the role of sphingolipids in asthma and its subtypes. Clinical data from 51 asthma patients and 9 healthy individuals were collected and serum samples were performed to analyze the levels of serum sphingolipids by liquid chromatography-mass spectrometry-based targeted metabolomics. Results showed that the levels of sphingomyelin (SM) including SM34:2, SM38:1, and SM40:1 were significantly decreased in asthmatic patients compared to healthy controls. Moreover, serum SM levels were obviously decreased in the blood noneosinophilic asthma (bNEA) group compared with blood eosinophilic asthma group. Similar tendencies of serum SM level changes were observed in the early-onset group compared with late-onset group. Correlation analysis revealed that SM 40:1 was negatively related to sputum IL-17A (r=-0.621, P=0.042). The present study presented that the SM may be a protective factor of asthma and contributes to the mechanism of asthma, especially bNEA. SM may be a potential biomarker and therapeutic target in asthma.

Revealing the role of glycerophospholipid metabolism in asthma through plasma lipidomics

Lipid mediators play an essential role in the pathogenesis of asthma. Many studies on the differential expression of sphingolipids and fatty acid exist, but relatively few concerned about glycerophospholipid (GP) metabolites in asthma. Here, plasma samples from 20 healthy controls and 24 asthmatic patients were collected and analyzed. High-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) revealed that 29 GPs were identified and relatively quantified as differential metabolites for discriminating asthma patients and healthy subjects, consisting of six major subclasses of GPs. Moreover, a significant relevance was found between the selected metabolites and diagnostic and prognostic indicators of asthma. Remarkably, in subgroup analyses, plasma phosphatidic acid (PA), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) levels were higher in patients with eosinophilic asthma than non-eosinophilic asthma. Receiver-operating characteristic curve analysis revealed that the power of plasma PA and PG levels to distinguish between asthmatic patients and healthy subjects was strong (all areas under the curves > 0.9; P < 0.05). Our study characterized circulating GP metabolites in patients with asthma and explored their clinical relevance which may help to develop reliable biomarkers for early and accurate diagnosis based on lipid metabolites and provide novel insight into the role of GPs in asthma.

Biothérapies dans l’asthme sévère de l’adulte: Biotherapies for severe asthma in adults

Biologics available in severe asthma target IgE (omalizumab), IL-5 (mépolizumab, reslizumab), IL-5 receptor (benralizumab) and IL-4/IL-13 receptor (dupilumab). The pharmacokinetic profile of these drugs is related to their IgG structure and characterized by slow elimination. Biotherapies are indicated in severe asthma caused by allergic and/or eosinophilic inflammation. The main therapeutic effect is a reduction in the frequency of severe exacerbations, responsible for emergency room visits and hospitalizations. Several molecules significantly reduce the continuous oral glucocorticoid dose, while asthma control is maintained. Given the current state of knowledge, biologics have a favorable safety profile, with common side effects including injection site reaction and a low risk of anaphylaxis. New biologics are tested in clinical trials, which may provide exciting new directions in the treatment of severe asthma, especially in non-allergic and non-eosinophilic asthma.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Efficacy of Reslizumab Treatment in Exacerbation-Prone Patients with Severe Eosinophilic Asthma

Patients with severe eosinophilic asthma have increased risk of clinical asthma exacerbations (CAEs), impaired lung function, and lower quality of life (QoL) compared with patients with noneosinophilic asthma. The efficacy and safety of intravenous reslizumab have been demonstrated in 2 duplicate, randomized, double-blind, placebo-controlled, phase 3 studies. We present findings from post hoc analyses of the subgroup of patients from the phase 3 studies with severe (Global Initiative for Asthma [GINA] Step 4 or 5) eosinophilic asthma who had ≥2 or ≥3 CAEs in the 12 months before screening. Patients aged ≥12 years with severe eosinophilic asthma were randomized (1:1) to reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Outcomes assessed included CAEs, forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire 6 (ACQ-6) and Asthma QoL Questionnaire (AQLQ) scores. Of 953 patients randomized, 318 (reslizumab: n= 156; placebo: n= 162) and 164 (reslizumab: n= 72; placebo: n= 92) were GINA 4/5 with ≥2 CAEs in the prior year and ≥3 CAEs in the prior year, respectively. Reslizumab significantly improved CAE rate, time to first CAE, and the proportion of patients who experienced ≥1 CAE versus placebo in both CAE subgroups. Improvements in FEV1, ACQ-6 and AQLQ scores, and systemic corticosteroid burden were also observed with reslizumab versus placebo after 52 weeks of treatment in both CAE subgroups. Reslizumab reduced CAE frequency and improved lung function, asthma control, and QoL versus placebo in patients with severe eosinophilic asthma with a high CAE rate before treatment.

High serum free IL-18 is associated with decreased omalizumab efficacy: findings from a 2-year omalizumab treatment study

Objective Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment. Methods Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined. Results Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios. Conclusions High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

Mammalian Target of Rapamycin Signaling Enhances Ovalbumin-Induced Neutrophilic Airway Inflammation by Promoting Th17 Cell Polarization in Murine Noneosinophilic Asthma Model.

Background: T helper 17 (Th17) is regarded as key immune cell in the pathogenesis of noneosinophilic asthma (NEA) due to the recruitment of neutrophils into the airways. The mammalian target of rapamycin (mTOR) is an important signaling molecule that plays a critical role in immune regulation. This study focused on mTOR signaling pathway in the regulation of Th17-mediated neutrophilic airway inflammation. Methods: Ovalbumin (OVA) T cell receptor transgenic DO11.10 mice (DO11.10 mice) were used to establish NEA model, and few mice received specific mTORC1 inhibitor rapamycin (RAPA) before intranasal administration of OVA. The severity of airway inflammation was determined by differential cell counts in bronchoalveolar lavage (BAL) fluids and histopathologic lung analysis. The levels of various cytokines in BAL fluids and lung tissues were measured. To determine the role of mTORC1 signaling in Th17 differentiation, naive T cells from wild-type (WT) and TSC1 knockout (KO) mice were cultured in Th17 skewing condition with or without RAPA in vitro and the production of IL-17A was compared. Results: Treatment with RAPA markedly attenuated OVA-induced neutrophilic airway inflammation in DO11.10 mice. Also the production of IL-17A was inhibited without affecting the production of interferon-γ (IFN-γ) and IL-4 in lungs. Furthermore, RAPA suppressed differentiation of Th17 cells in vitro, whereas enhanced activity of mTORC1 promoted Th17 cell differentiation and increased the expression of Th17-related transcription factors RORγt and RORα. Conclusion: These results suggested that mTOR promoted Th17 cell polarization and enhanced OVA-induced neutrophilic airway inflammation in experimental NEA.

Biomarker-guided management reduces exacerbations in non-eosinophilic asthma in pregnancy: A secondary analysis of a randomized controlled trial.

The aim of this secondary analysis of a randomized controlled trial (RCT) of asthma management in pregnancy was to determine the treatment decision differences between a symptom control algorithm and a fractional exhaled nitric oxide (FENO)-guided algorithm, and whether the approach was effective in non-eosinophilic asthma (NEA). In this double-blind parallel group RCT, women with asthma were randomized prior to 22 weeks gestation to treatment adjustment according to a symptom control algorithm (control group), or a FENO-guided algorithm (inhaled corticosteroid (ICS) dose adjusted according to FENO with long-acting beta-agonist (LABA) added for uncontrolled symptoms). NEA was classified as baseline blood eosinophils <0.26 × 109 /L and FENO ≤29 ppb. Exacerbations requiring medical intervention were recorded. Among 220 non-smokers (n = 109 control, n = 111 FENO), 1006 treatment decisions were made, with significant group differences after the first and second algorithm applications. 53% of women had NEA. Treatment was better targeted to phenotype in the FENO group: ICS use increased in eosinophilic asthma (EA, 48-86%), while ICS/LABA increased in NEA (11-30%). Fewer women in the FENO group had exacerbations during pregnancy in NEA only (18.9% FENO vs 44% control, P = 0.006). The FENO algorithm was more effective in treating NEA, resulting in reduced exacerbations, compared to a symptom control algorithm. This was not the result of ICS overtreatment, since the benefits occurred at a lower median daily ICS dose. Two applications of the FENO-guided algorithm, one month apart, were sufficient to achieve beneficial effects in terms of asthma exacerbations, among pregnant women with asthma.