Asthma Phenotypes Research Articles

Promoting Prevention and Targeting Remission of Asthma: A European Forum for Research and Education in Allergy and Airway Diseases Consensus Statement on Raising the Bar in Asthma Care.

Asthma is a common multifaceted respiratory disease with a major impact on quality of life. Despite increased insights into mechanisms underlying various asthma phenotypes and endotypes and the availability of targeted biologic treatment options, the disease remains uncontrolled in a substantial proportion of patients with risk of exacerbations, requiring systemic corticosteroids, and with progressive disease. Current international guidelines advocate a personalized management approach to patients with uncontrolled severe asthma. The European Forum for Research and Education in Allergy and Airway Diseases asthma expert panel was convened to discuss strategies to optimize asthma care and to prevent systemic corticosteroid overuse and disease progression. In this meeting report, we summarize current concepts and recommendations and provide a rationale to implement personalized asthma management at earlier stages of the disease. The ultimate goal is to move away from the current one-size-fits-most concept, which focuses on a symptom-driven treatment strategy, and shift toward a phenotype- and endotype-targeted approach aimed at curbing the disease course by improving clinical outcomes and preserving health-related quality of life. Herein, we provide a consensus view on asthma care that advocates a holistic approach and highlight some unmet needs to be addressed in future clinical trials and population studies.

Longitudinal multi-trajectory phenotypes of severe eosinophilic asthma on type 2 biologics treatment

BackgroundLimited understanding exists regarding the progression trajectory of severe eosinophilic asthma (SEA) patients on type 2 biologics therapies. ObjectiveWe aim to explore distinct longitudinal phenotypes of these patients based on crucial asthma biomarkers. MethodsWe enrolled 101 adult patients with SEA. Of these, 51 were treated with anti-IL5/IL5Rα or anti-IL5/IL5RαR antibody, and 50 with anti-IL-4Rα antibody. Multi-trajectory analysis, an extension of univariate group-based trajectory modeling, was used to categorize patients based on their trajectories of forced expiratory volume in 1 s (FEV1), blood eosinophil counts (BEC), and fractional exhaled nitric oxide (FeNO) levels at baseline, and after 1, 6, and 12 months of treatment. Associations between trajectory-based clusters and clinical parameters were examined. ResultsAmong anti-IL5/IL5Rα antibody-treated patients, 2 clusters were identified. The cluster characterized by higher baseline BEC and lower FEV1 showed a better response, with improvements in FEV1 and reductions in BEC over time. Among anti-IL-4Rα antibody-treated, 3 clusters were identified. Clusters with moderate BEC and FeNO at baseline demonstrated better improvements in FEV1 and reductions in FeNO, despite increased BEC during follow-up. Conversely, individuals with extremely low FeNO and high BEC at baseline were more likely to experience poorer progression, demonstrating an increase in FeNO and a reduction in FEV1. ConclusionTo optimally monitor treatment response in SEA patients on type 2 biologics, integrating longitudinal biomarker features is essential.

Phenotyping Asthma Exacerbations: One Step Further in the Management of Severe Asthma.

Asthma, a prevalent chronic respiratory disease, manifests in heterogeneous phenotypes and endotypes, necessitating bespoke therapeutic approaches. Asthma exacerbations are characterized by worsening of symptoms and decline in lung function and present substantial challenges despite advances in understanding and treatment. Viral respiratory infections, notably those caused by rhinovirus, serve as primary triggers, with allergic sensitization and environmental exposures increasing susceptibility. Deficient antiviral responses in asthmatic airway epithelial cells, particularly impaired interferon production, perpetuate inflammation and hyperresponsiveness, contributing to exacerbations. Additionally, genetic polymorphisms influence host responses and susceptibility. Recent studies underscore the association between specific inflammatory profiles, particularly eosinophil-mediated inflammation, and the frequency of exacerbations. Biologic therapies targeting inflammatory pathways show promise in reducing the frequency of exacerbations, thus underscoring the importance of understanding inflammatory phenotypes when selecting treatment. Notably, T2 inhibitors may modulate immune responses, potentially mitigating viral exacerbations. Characterizing exacerbations is crucial for optimizing therapeutic strategies. Evidence suggests a dissociation between baseline inflammatory profiles and exacerbation phenotypes, highlighting the need for individualized management. Phenotyping exacerbations using sputum analysis helps to identify predominant inflammatory patterns and thus inform treatment decisions. The varied responses to biologic therapies further emphasize the importance of phenotyping exacerbations in refining treatment algorithms. In conclusion, phenotyping asthma exacerbations provides valuable insights into underlying inflammatory mechanisms and enables personalized therapy. Understanding the complex interplay between viral triggers, inflammatory pathways, and responses to treatment is essential if we are to effectively manage severe asthma and reduce the burden of exacerbations. Further research into the mechanistic actions of biologic therapies in mitigating viral exacerbations is warranted to optimize asthma management strategies.

Stability of Asthma Phenotypes in the Spanish Cohort of the MEGA Project.

Stability of Asthma Phenotypes in the Spanish Cohort of the MEGA Project.

Asthma Phenotyping Via Multiplex Detection of Cytokines on an Electrochemical Sensor

Asthma, a complex and diverse lung condition, is typically associated with chronic airway inflammation. Asthma classification has traditionally relied on clinical symptoms and treatment response. As our understanding of asthma’s heterogeneity grows, phenotyping has become a focus. Cytokines, essential chemical messengers in the immune system, play a pivotal role in the mediation of chronic diseases. They facilitate communication between immune cells and directly impact inflammation. Various cytokines have been implicated in asthma pathogenesis. Leveraging cytokines for asthma phenotyping is valuable, as identifying and quantifying these inflammatory mediators can lead to more precise, targeted treatments. To achieve this, we have developed a customizable electrochemical platform for multiplexed detection of select cytokines for non-invasive cytokine detection in saliva. This platform rapidly detects cytokines within physiological ranges and will aid physicians in asthma phenotyping and treatment planning especially for severe asthmatics.The detection platform leverages subtle changes in impedance at the electrode-electrolyte interface as a function of the chemical interaction between specific antibody-antigen interactions to establish a calibration dose response curve. The platform’s capability to detect and quantify the cytokines in human saliva is demonstrated through spike and recovery experiments.

Maternal asthma during pregnancy and the likelihood of neurodevelopmental disorders in offspring.

Asthma is the most common chronic disease during pregnancy. Maternal asthma has been associated with a multitude of unwanted pregnancy outcomes, in some studies also with neurodevelopmental disorders. Here we investigated associations between maternal asthma and neurodevelopmental disorders. We studied a retrospective population-based cohort of 1 271 439 mother-child pairs from singleton live births in Finland between the years 1996-2018. We used multiple high-cover registers for data collection. Adjusted unconditional Cox regression models were used to investigate associations between maternal asthma, asthma medication used during pregnancy, and offspring's neurodevelopmental disorder diagnoses. We identified 106 163 mother-child pairs affected by maternal asthma. We found that maternal asthma was associated with offspring neurodevelopmental disorders, but the differences in absolute prevalence between the control and exposure groups were small. Attention-deficit hyperactivity disorder (ADHD) was found in 4114 (3.9%) offspring with maternal asthma and in 32 122 (3.0%) controls (adjusted hazard ratio (HR): 1.49; 95% CI 1.44-1.54); autism in 1617 (1.5%) offspring versus 13 701 (1.3%) controls (HR: 1.33; 95% CI 1.26-1.40); motor-developmental disorder in 1569 (1.5%) offspring versus 12 147 (1.1%) controls (HR: 1.37; 95% CI 1.30-1.45); language disorder in 3057 (2.9%) offspring versus 28 421 (2.7%) controls (HR: 1.13; 95% CI 1.08-1.17), learning disabilities in 849 (0.8%) offspring versus 6534 (0.6%) controls (HR: 1.51; 95% CI 1.41-1.62); mixed developmental disorder in 1633 (1.5%) offspring versus 14 434 (1.3%) controls (HR 1.20; 95% CI, 1.14-1.26); and intellectual disability in 908 (0.9%) versus 9155 (0.9%) controls (HR: 1.12; 95% CI 1.04-1.20). No substantial differences were found between allergic and non-allergic asthma phenotypes, and neither allergic tendency nor respiratory infection was associated with a similar likelihood of neurodevelopmental disorders. Maternal asthma and allergic and non-allergic phenotypes showed weak associations with the offspring's neurodevelopmental disorders. The association is concerned especially with learning disabilities, ADHD, motor development, and autism.

Pyroptosis in asthma: inflammatory phenotypes, immune and non-immune cells, and novel treatment approaches.

Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed.

Unraveling heterogeneity and treatment of asthma through integrating multi-omics data.

Asthma has become one of the most serious chronic respiratory diseases threatening people's lives worldwide. The pathogenesis of asthma is complex and driven by numerous cells and their interactions, which contribute to its genetic and phenotypic heterogeneity. The clinical characteristic is insufficient for the precision of patient classification and therapies; thus, a combination of the functional or pathophysiological mechanism and clinical phenotype proposes a new concept called "asthma endophenotype" representing various patient subtypes defined by distinct pathophysiological mechanisms. High-throughput omics approaches including genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome enable us to investigate the pathogenetic heterogeneity of diverse endophenotypes and the underlying mechanisms from different angles. In this review, we provide a comprehensive overview of the roles of diverse cell types in the pathophysiology and heterogeneity of asthma and present a current perspective on their contribution into the bidirectional interaction between airway inflammation and airway remodeling. We next discussed how integrated analysis of multi-omics data via machine learning can systematically characterize the molecular and biological profiles of genetic heterogeneity of asthma phenotype. The current application of multi-omics approaches on patient stratification and therapies will be described. Integrating multi-omics and clinical data will provide more insights into the key pathogenic mechanism in asthma heterogeneity and reshape the strategies for asthma management and treatment.

Perturbations in the airway microbiome are associated with type 2 asthma phenotype and severity

BackgroundAirway microbiome has been linked to asthma heterogeneity, yet little is known about the associations between airway microbiota and type 2 (T2) asthma phenotype and severity. ObjectiveTo determine the relationship of nasopharyngeal (NP) and induced sputum (IS) microbiota to the phenotypic features of T2 asthma. MethodsNP and IS samples from subjects with T2 mild-to-moderate asthma (n = 23), subjects with severe asthma (n = 21), and healthy controls (n = 16) were analyzed. Bacterial microbiota and functional profiles were compared. The correlation between microbial communities and clinical and inflammatory features was evaluated in individuals with asthma of 2 statuses. ResultsDifferences in NP and IS microbiota were associated with T2 asthma phenotype. Alterations in NP microbiota were more reflective of T2 inflammation and severity, with additional stratification of a subgroup characterized by significant elevations in T2 inflammatory biomarkers and reductions in bacterial richness and diversity (P < .05). Burkholderia-Caballeronia-Paraburkholderia, Ralstonia, and Rhodococcus were identified as hub taxa within NP microbial network in T2 severe asthma, which were prevalent in the entire airway and involved in bacterial functions including inflammatory and steroid responses (P < .05). The composition and diversity of IS microbiota were complex, with Veillonella as the most altered genus, having an increase with increasing asthma severity. ConclusionOur work revealed the significant associations of microbiota perturbations throughout the entire respiratory tract to the extent of T2 inflammation, phenotype and severity in T2 asthma. The specific taxa identified invite further mechanistic investigations to unravel their possibility as biomarkers and therapeutic targets for T2 severe asthma.

Asthma Increases Long-term Risk of Death by Suicide: A Nationwide Population-based Cohort Study

BackgroundPrevious studies have identified an increased risk of suicidal behaviors among individuals with asthma. ObjectiveWe evaluated the long-term risk and factors related to suicide in the adult population with asthma. MethodsThis study used the Korean National Health Insurance Service data. We investigated the risk of suicide concerning the presence or absence of asthma and potential risk factors for suicide among 3,914,041 adults ≥ 20 years of age. ResultsDuring a median follow-up of 12.3 years (interquartile range, 12.1–12.6 years), 1,383 (0.48%) individuals with asthma died by suicide. Individuals with asthma had an increased risk of suicide compared to controls (adjusted hazard ratio [aHR] = 1.26, 95% confidence interval [CI] = 1.19–1.33). Suicide risk was especially high in individuals with asthma phenotypes: hospitalization-prone (aHR = 1.61, 95% CI = 1.40–1.84), non-obese (aHR = 1.37, 95% CI = 1.27–1.64), and asthma-chronic obstructive pulmonary disease overlap (ACO) (aHR = 1.47, 95% CI = 1.22–1.76). Coexisting underweight status (aHR = 2.54, 95% CI = 2.05–3.16), mental health disorders (schizophrenia [aHR = 3.38, 95% CI = 2.28–5.02], depression [aHR = 3.24, 95% CI = 2.85–3.68], and anxiety disorder [aHR = 2.47, 95% CI = 2.00–3.05]), and cancers (aHR = 2.22, 95% CI = 1.73–2.84) further increased the suicide risk. ConclusionAsthma was associated with an increased risk of suicide, particularly in hospitalization-prone, non-obese, and ACO phenotypes. The risk was further increased when asthma coexisted with underweight status, mental health disorders, or cancers.

The use of a long-acting muscarinic antagonist in the treatment of asthma: A tertiary asthma center experience.

We aimed to investigate the frequency and sociodemographic and clinical distinguishing features of asthmatic patients in whom long-acting muscarinic antagonists (LAMA) were added to maintenance therapy in our clinic. In this cross-sectional study, data on sociodemographic, phenotypic, and clinical characteristics of patients with asthma using Steps 4 and 5 medications, who were followed up in our center for at least 1 year, were obtained from file records. Whether the patients received add-on LAMA for at least 6 months was also noted. A total of 279 patients with asthma using Steps 4 and 5 medications (female/male: 215/64) with a mean age of 50.84 ± 12.42 years were included in the study. Seventy-nine (28.3%) patients (female/male: 60/19) with a mean age of 52.45 ± 11.61 years used LAMA as an add-on treatment; 28 (37.8%) at Step 4 and 51 (24.8%) at Step 5. In Steps 4 and 5, there was no difference in terms of age, sex, body mass index, smoking status, being allergic or eosinophilic, phenotype, and asthma onset between patients with and without add-on LAMA. Asthma control in the previous year was better, and minimum forced expiratory volume in 1s (FEV1) was lower in patients with LAMA than in those without in Step 4 (P = 0.001 and P = 0.030, respectively). In Step 5, the rate of being well-controlled was higher in those without add-on LAMA (P < 0.001). The number of exacerbations in the previous year was higher, and minimum and maximum FEV1 were lower in patients with add-on LAMA (P < 0.001 and P < 0.001, respectively). Our study showed that add-on LAMA treatment was effective in increasing asthma control in patients using Step 4 medication independent of baseline characteristics and asthma phenotype.

MicroRNA-155-5p Differentially Regulates IL-13Rα1 and IL-13Rα2 Expression and Signaling Driving Abnormal Lung Epithelial Cell Phenotype in Severe Asthma.

MicroRNA (miR)-155-5p increases in innate and adaptive immune cells in response to IL-13 and is associated with the severity of asthma. However, little is known about its role in airway structural cells. Bronchial epithelial cells (BECs) isolated from healthy donors and patients with severe asthma were stimulated with IL-13. miR-155-5p expression and release were measured by real-time (RT)-PCR in BECs and in their derived exosomes. Modulation of miR-155-5p in BECs was performed using transfection of miR-155-5p inhibitor and mimic. IL-13 receptor α1 (IL-13Rα1), IL-13Rα2, MUC5AC, IL-8, and eotaxin-1 expression was measured by RT-PCR and Western blot analysis. The BEC repair process was assessed by a wound-healing assay. IL-13Rα1 and IL-13Rα2 expression and downstream pathways were evaluated by Western blot analysis. A dual luciferase assay was used to identify miR-155-5p target genes associated with IL-13R signaling. BECs from patients with severe asthma showed increased expression and exosomal release of miR-155-5p at baseline with amplification by IL-13 stimulation. BECs from patients with asthma expressed more IL-13Rα1 and less IL-13Rα2 than those from healthy donors, and IL-13Rα1 but not IL-13Rα2 induced miR-155-5p expression under IL-13 stimulation. miR-155-5p overexpression favored MUC5AC, IL-8, and Eotaxin-1 through the IL-13Rα1/SOCS1/STAT6 pathway while delaying the repair process by downregulating IL-13Rα2/MAPK14/c-Jun/c-fos signaling. The dual luciferase assay confirmed that miR-155-5p modulates both IL-13R pathways by directly targeting SOCS1, c-fos, and MAPK14. miR-155-5p is overexpressed in BECs from patients with severe asthma and regulates IL-13Rα1 and IL-13Rα2 expression and signaling, favoring expression of mucin- and eosinophil-related genes to the detriment of airway repair. These results show that miR-155-5p may contribute to airway epithelial cell dysfunction in patients with severe asthma.

Refractory phenotype of Aspergillus-sensitized asthma with bronchiectasis and allergic bronchopulmonary aspergillosis

BackgroundSensitization to Aspergillus, mucus plugs, and bacterial colonization may coexist and relate to a refractory phenotype during follow-up in asthma with bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA). ObjectiveThis study aimed to clarify the features of Aspergillus-sensitized refractory asthma with bronchiectasis and determine the refractory phenotype in this population and ABPA. MethodsThis study included cases with the oldest available A. fumigatus-specific IgE data and chest computed tomography images from a nationwide survey of refractory asthma with bronchiectasis. The characteristics of the A. fumigatus-IgE positive (Af sIgE+) group were investigated and compared with its nonsensitized counterpart (Af sIgE−) and ABPA group. Cluster analysis was conducted to determine the refractory phenotype. ResultsThe Af sIgE+ group (n = 35) demonstrated type-2 inflammation levels intermediate between the ABPA (n = 42) and Af sIgE− (n = 38) groups while exhibiting higher blood monocyte counts than Af sIgE− group. Cluster analysis conducted in patients with ABPA and Af sIgE+ newly determined two clusters: one was characterized by a younger age of asthma onset with fungal detection in sputum and the other was characterized by mucus plugs, inflammation with eosinophil and monocyte, which was significantly related to mucus plugs, airflow limitation, and trend to show exacerbation. In the latter cluster, mucus plugs persisted and 30% yielded Pseudomonas aeruginosa in the sputum <5 years later. ConclusionThe refractory phenotype with persistent mucus plugs was identified in Aspergillus-sensitized refractory asthma with bronchiectasis and ABPA. Mucus plug prevention is warranted.

Neutrophilic inflammation in sputum or blood does not define a clinically distinct asthma phenotype in ATLANTIS

IntroductionNeutrophilic asthma has been suggested to be a clinically distinct phenotype characterized by more severe airflow obstruction and higher exacerbation risk. However, this has only been assessed in few and smaller studies, using different cut-offs to define neutrophilia, and with conflicting results.We used data from ATLANTIS, an observational longitudinal study including a large number of patients with asthma and healthy controls.AimTo examine if neutrophilic inflammation, either in sputum or blood, is more prevalent in asthma and whether it correlates with disease severity.MethodsATLANTIS included 773 asthma patients, with blood collected from 767 (99%) and sputum from 228 patients (30%). Data were available from 244 healthy controls, all providing blood and 126 (52%) providing sputum. Asthma patients were characterized including parameters of large and small airways disease at baseline and after 6- and 12-months follow-up. Sputum and blood neutrophilia were defined as values exceeding the upper quartile in asthma patients.ResultsThe prevalence of sputum neutrophilia did not differ between asthma patients and healthy controls. Asthma patients with sputum neutrophilia did not display more severe symptoms, large or small airways disease, or more frequent exacerbations. Blood neutrophilia was more common in asthma and associated with higher BMI, female sex, current smoking and systemic corticosteroid use. Patients with blood neutrophilia had a statistically significant, but small, increase in RV/TLC. Blood neutrophilia was not associated with large or small airways disease, or exacerbation risk.ConclusionSputum and blood neutrophilia do not define a distinct clinical phenotype in asthma.

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.

Stability of severe asthma phenotypes

Introduction. Severe asthma (SA) is a heterogeneous disease with several phenotypes. There are lack of data about its stability.Aim. To assess stability of SA phenotypes in adult patients during 5 years follow-up.Materials and methods. Prospective study included 117 adult outpatients with allergic SA, 51 severe asthmatics with aspirin-induced disease, 59 patient with persistent airflow limitation (PAL) and 35 patients with SA and concomitant COPD, 65 steroid-dependent severe asthmatics and 89 patients with SA and frequent (≥2 per year) exacerbations. Spirometry and bronchodilator reversibility testing were carried out; fractional exhaled nitric oxide (FeNO) was measured; hypersensitivity to common inhalant allergens (skin prick and blood specific IgE testing) and peripheral blood eosinophil counts were estimated. Asthma control and asthma-related quality of life were assessed by using ACQ-5 and SGRQ questionnaire.Results. During 5-year prospective study stability of aspirin-induced SA and SA with COPD was 100%. Allergic phenotype was stable in 81% of SA cases and in patients with changed atopic status we revealed worsening of symptoms and accelerated lung function decline. Stability of SA phenotype with PAL without COPD was 86% and steroid-dependent SA was stable in 55% of cases. After 5 years of treatment frequent exacerbations remained in 28% of severe asthmatics.Conclusion. The most stable phenotypes of SA were aspirin-induced and asthma with concomitant COPD. Less stable were allergic SA, steroid-dependent SA and phenotype with persistent airflow limitation. The least stable was SA phenotype with frequent exacerbations.

Eosinophil count testing in patients with asthma varies by healthcare provider type in the US: a retrospective study

BackgroundPatients with asthma with an eosinophilic phenotype may be eligible for additional treatment options to improve disease control; however, the prevalence and frequency of eosinophil testing is unknown. This study assessed blood eosinophil count testing prevalence in patients with asthma by exacerbation frequency and healthcare provider (HCP) type.MethodsThis was a retrospective, longitudinal, real-world study (GSK ID: 214470) utilizing the Merative Explorys® Universe electronic health records database. Eligible patients had ≥ 2 asthma diagnostic codes (January 2016–December 2018) (Index date: first asthma diagnosis). Outcomes included patient demographics and clinical characteristics (12 months pre-index [baseline]), and prevalence of blood eosinophil count testing, stratified by exacerbation frequency (infrequent exacerbations [< 2]) or frequent exacerbations [≥ 2] or primary HCP (Allergist/Pulmonologist, a primary care physician [PCP] or other HCP) during the 12 months post-index (follow-up).ResultsOf 400,254 patients included (mean age: 51.2 years; 70.8% female), the most common provider type at baseline was a PCP (76.8%). A higher proportion of patients with frequent exacerbations had blood eosinophil count tests at baseline (55.4–69.5%) and follow-up (67.9–75.1%), compared with patients with infrequent exacerbations (55.5–63.7%, 62.4–67.3%). Significantly more patients in the Allergist/Pulmonologist subgroup had ≥ 1 blood eosinophil count test result compared with patients in the PCP subgroup at both baseline (59.9% vs. 50.7%; p < 0.001) and follow-up (59.0% vs. 56.2%; p < 0.001). In the total population, the mean (SD) number of tests ordered was 3.4 (5.3) and 4.1 (6.4) during the baseline and follow-up periods, respectively. A greater mean number of tests were ordered for patients with frequent exacerbations, most apparently in the Allergist/Pulmonologist subgroup during baseline and follow-up (7.4 vs. 4.9). For patients with frequent exacerbations and blood eosinophil count test results, the mean (SD) number of tests ranged from 3.1 (4.6) to 5.8 (8.3) at baseline and 5.1 (8.5) to 7.4 (10.6) during follow-up.ConclusionsThe prevalence of blood eosinophil count testing in patients with asthma remains suboptimal. Routine blood eosinophil count testing should be considered by HCPs for patients with asthma to increase identification of the eosinophilic asthma phenotype, which may inform the decision to advance to targeted biologic therapy.

Experimental and proteomics evidence revealed the protective mechanisms of Shemazhichuan Liquid in attenuating neutrophilic asthma

BackgroundNeutrophilic asthma (NA) is one of the most important phenotypes of non-Th2 asthma and is often insensitive to glucocorticoid therapy, making current treatment difficult. Shemazhichuan Liquid (SMZCL), a Chinese medicine compound preparation, has unique advantages in the treatment of asthma. However, the underlying mechanisms of SMZCL in treating NA are not fully understood. PurposeThe efficacy and underlying mechanisms of SMZCL on NA were investigated by TMT-labeled quantitative proteomics analysis and in vivo and in vitro experiments. MethodsNA mouse model was constructed by OVA/CFA sensitization followed by a 10-day challenge with 5 % OVA. Lung histopathology, leukocyte counts and cell sorting counts, inflammatory cytokines levels, as well as expression of autophagy markers were then assessed. The specific pathways and proteins of SMZCL for treating NA were further illustrated through TMT-based quantitative proteomics. In addition, RAW264.7 cells were induced by LPS to further explore the mechanism of the main active ingredient of SMZCL on autophagy pathway. ResultsIn vivo, SMZCL contributed to attenuating airway inflammation and collagen disposition, markedly reduced the number of leukocytes, especially neutrophils in bronchoalveolar lavage fluid (BALF), as well as decreased IgE and inflammatory cytokine levels (TNF-α, IL-1β, IL-6 and IL-8) in BALF and serum. Besides, SMZCL elevated the levels of LC3 and ATG5 while inhibiting the expression of p62 and mTOR. Mzb1 and Rab3ip were identified as the critical overlapping DEPs whose expression was inhibited by SMZCL and rapamycin. KEGG enrichment analysis showed that necroptosis process was a key pathway for SMZCL to treat NA airway inflammation. IHC and WB results confirmed that SMZCL and rapamycin inhibited the phosphorylation of RIPK1, PIPK3 and MLKL. In vitro, ATG5 and LC3 proteins were obviously increased while p-mTOR expression was inhibited after amygdalin treatment. ConclusionSMZCL attenuated airway inflammation in NA mainly through inhibition of the mTOR pathway, along with inhibition of the necroptosis pathway regulated by the RIPK1/RIPK3/MLKL axis and inhibition of Mzb1 and Rab3ip expression.

Betamethasone improved near-term neonatal lamb lung maturation in experimental maternal asthma.

Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term=150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45min before tissue collection. Lung function and structure were similar in control lambs (n=16, 11 ewes) and lambs from asthma ewes (n=14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n=12, 8 ewes) compared to those from controls (P=0.003) or asthma ewes (P=0.008). Lung expression of surfactant protein genes SFTPA (P=0.048) and SFTPB (P<0.001), but not SFTPC (P=0.177) or SFTPD (P=0.285), was higher in lambs from asthma+beta than those from asthma ewes. Female lambs had higher tidal volume (P=0.007), dynamic lung compliance (P<0.001), and SFTPA (P=0.037) and SFTPB gene expression (P=0.030) than males. These data suggest that betamethasone stimulates lung maturation and function of near-term neonates, even in the absence of impairment by maternal asthma.

Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism.

Asthma is an inflammatory disease where the balance between Th1/Th2 and Th17/Treg plays a crucial role in its pathogenesis. Shikonin is used to treat a variety of autoimmune diseases due to its good anti-inflammatory activity. However, the effect and mechanism of shikonin on asthma remain unknown. Mice were sensitized with ovalbumin (OVA)/house dust mite (HDM) and treated with shikonin. Lung inflammation was assessed histologically and via flow cytometry. Bronchoalveolar lavage fluid (BALF) was analyzed for cell counts and cytokines. Shikonin's impact on p-STAT3 was studied in vivo and in vitro. Shikonin inhibited OVA or HDM-induced inflammation and airway hyperresponsiveness. Upon treatment, a restoration of the Th1/Th2 and Th17/Treg balance was observed, evidenced by a reduction in IL-4 and IL-17A levels in BALF, alongside an elevation in interferon-gamma and IL-10. Furthermore, shikonin impeded the infiltration of eosinophils, neutrophils, macrophages, and lymphocytes into lung tissue. The observed decrease in STAT3 phosphorylation and diminished nuclear translocation of p-STAT3 confirmed that shikonin promotes the balance of Th1/Th2 and Th17/Treg by regulating airway epithelial STAT3. Shikonin mitigates asthma symptoms through a STAT3-dependent mechanism, indicating its potential as an anti-asthmatic therapeutic agent.