Asthma Subtypes Research Articles

Identifying clinical and demographic characteristic differences between eosinophilic and non-eosinophilic asthma and detecting predictors of eosinophilic asthma among Egyptian asthmatic patients

IntroductionAsthma is a heterogenous disease with various phenotypes that is characterized by airway limitation due to bronchospasm and airway inflammation associated with excessive mucus secretion. Eosinophilic asthma subtype is described as a late onset asthma that presents with more severe respiratory symptoms, and with sputum eosinophilia ≥ 3%. In the current study, we aimed to identify the difference in the clinical and demographic characteristics between eosinophilic and non-eosinophilic asthma subtypes and to determine predictors of eosinophilic asthma.Materials and methodsOne hundred bronchial asthma patients with age ≥ 18 years were divided into two groups according to sputum eosinophilia. All patients were subjected to medical history, Asthma Control Test (ACT), spirometry, serum IgE level, skin prick testing (SPT), and nasal endoscopy to detect nasal polyposis and allergic signs.ResultsNo statistical difference was found between eosinophilic and non-eosinophilic asthma patients regarding age, gender, and body mass index. Patients with sputum eosinophilia had more severe obstruction by spirometry, and positive SPT to food allergens, pollens, and latex with statistical significance (p values 0.001, 0.016, and 0.017 respectively). Additionally, patients with sputum eosinophilia had lower ACT score, higher serum IgE level and higher serum eosinophil count. Total IgE had the highest diagnostic accuracy for discrimination of sputum eosinophilia among asthma patients. Pollen allergy and the severity of airway obstruction by spirometry were independent predictors of eosinophilic asthma.ConclusionPatients with eosinophilic asthma had more severe airway obstruction, lower ACT scores, higher serum IgE level, and serum eosinophil count. Pollen allergy and obstructive pattern by spirometry were independent predictors of eosinophilic asthma.

Childhood blood eosinophils and symptoms of allergic disorders: a cross-sectional study in Southern China

Purpose The relationship between childhood blood eosinophils and subtypes of allergic diseases remains understudied. This study aimed to examine the associations between childhood blood eosinophils and subtypes of asthma, rhinitis and dermatitis, as well as the modifying effect of age. Methods We obtained concurrent blood cell counts and serum Immunoglobulin E (IgE) test results in 5026 children (0–13, years) from First Affiliated Hospital of Guangzhou Medical University from 2014 to 2019. Generalized additive models with multivariable adjustments were utilized to model the exposure-response relationship between eosinophils and allergic symptoms. The robustness of the association was assessed in two age categories (<6, 6–13 years). Results The association of eosinophils with allergic asthma/rhinitis was positively nonlinear, with a plateau at levels of Q4 (≥0.51, 109/L). Conversely, exposure-response curves between eosinophils and the risk of non-allergic asthma and rhinitis were negatively linear, and especially, became statistically significant when levels of eosinophils were larger than Q3 (≥0.30, 109/L). Compared with their counterparts, school-aged children (6–13, years) with a higher level of blood eosinophils (≥0.35, 109/L) were more likely to suffer from allergic asthma [relative excess risk due to interaction (RERI), 2.51; 95% CI, 1.24–3.78], allergic rhinitis (RERI, 2.79; 95% CI, 1.14–4.45) but not allergic dermatitis (RERI not significant). Conclusion Higher eosinophil counts were associated with the increased risk of allergic subtype symptoms and the decreased risk of non-allergic subtypes in children. Moreover, the associations between eosinophils and allergic asthma/rhinitis were accentuated in the school-aged child. These findings may contribute to providing novel insights for clinical administration relevance of allergic-related symptoms. Key messages: There was a positively nonlinear association between childhood eosinophils and allergic asthma/rhinitis. Age modified the associations between eosinophils and allergy-related outcomes. The associations of eosinophil with allergic asthma/rhinitis accentuated in the school-aged child (6–13, years).

Protocolo diagnóstico y terapéutico del asma de difícil control

Severe difficult-to-control or uncontrolled asthma is defined as the impossibility of controlling symptoms and exacerbations despite using high-dose inhaled corticosteroids and a long-acting beta2-agonist in the previous year, or oral glucocorticoids for six months or more of the last year. The first step to take with these patients is to rule out other concomitant diseases, verify their compliance with the indicated treatment, and differentiate which phenotype they have (T2 allergic or eosinophilic asthma or non-T2 asthma) according to their clinical and blood test characteristics. Based on said phenotype, biologic treatment can be administered via anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab, and benralizumab), or anti-IL-4/IL-13 (dupilumab) monoclonal antibodies in T2 asthma subtypes. To treat non-T2 type asthma, bronchial thermoplasty, systemic glucocorticoids, or even azithromycin can be considered.

Subtyping children with asthma by clustering analysis of mRNA expression data.

Background: Asthma is a heterogeneous disease. There are several phenotypic classifications for childhood asthma. Methods: Unsupervised consensus cluster analysis was used to classify 36 children with persistent asthma from the GSE65204 dataset. The differentially expressed genes (DEGs) between different asthma subtypes were identified, and weighted gene co-expression network analysis (WGCNA) was carried out. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed for DEGs and critical gene modules. Protein–protein interactions (PPI) were constructed to obtain the hub genes. Finally, differences in the immune microenvironment were analyzed between different subtypes. Results: Two subtypes (C1, C2) were identified using unsupervised consensus clustering. The DEGs between different asthma subtypes were mainly enriched in immune regulation and the release of inflammatory mediators. The important modular genes screened by WGCNA were mainly enriched in aspects of inflammatory mediator regulation. PPI analysis found 10 hub genes (DRC1, TTC25, DNALI1, DNAI1, DNAI2, PIH1D3, ARMC4, RSPH1, DNAAF3, and DNAH5), and ROC analysis demonstrated that 10 hub genes had a reliably ability to distinguish C1 from C2. And we observed differences between C1 and C2 in their immune microenvironment. Conclusion: Using the gene expression profiles of children’s nasal epithelium, we identified two asthma subtypes that have different gene expression patterns, biological characteristics, and immune microenvironments. This will provide a reference point for future childhood asthma typing and personalized therapy.

Overview of recent advancements in asthma management

Asthma is a common but complex heterogenous inflammatory airway disorder. Despite significant developments in our understanding of the pathophysiology and treatment of asthma, it remains a major cause of mortality and morbidity. Optimal management involves addressing modifiable risk factors, titration of inhaled pharmacotherapy in a stepwise approach and, in severe disease, consideration of biologic agents. Appreciation of the clinical characteristics of asthma and recognition of the immune pathways involved has allowed the development of phenotypic and endotypic subtypes of asthma to be better defined. This has revolutionised asthma management, allowing risk stratification of patients, targeted use of biologic agents to modify cytokine responses that drive asthma and improved patient outcomes. Patient education and engagement are critical to the management of this disease in an era of personalised medicine and a rapidly changing global environment.

Pediatric and adult asthma clinical phenotypes: a real world, big data study based on acute exacerbations

Introduction Asthma is a heterogeneous disease with a range of observable phenotypes. To date, the characterization of asthma phenotypes is mostly limited to allergic versus non-allergic disease. Therefore, the aim of this big data study was to computationally derive asthma subtypes from the OneFlorida Clinical Research Consortium Methods We obtained data from 2012-2020 from the OneFlorida Clinical Research Consortium. Longitudinal data for patients greater than two years of age who met inclusion criteria for an asthma exacerbation based on International Classification of Diseases codes. We used matrix factorization to extract information and K-means clustering to derive subtypes. The distributions of demographics, comorbidities, and medications were compared using Chi-square statistics. Results A total of 39,807 pediatric patients and 23,883 adult patients met inclusion criteria. We identified five distinct pediatric subtypes and four distinct adult subtypes. Pediatric subtype P1 had the highest proportion of black patients, but the lowest use of inhaled corticosteroids and allergy medications. Subtype P2 had a predominance of patients with gastroesophageal reflux disease, whereas P3 had a predominance of patients with allergic disorders. Adult subtype A2 was the most severe and all patients were on biologic agents. Most of subtype A3 patients were not taking controller medications, whereas most patients (>90%) in subtypes A2 and A4 were taking corticosteroids and allergy medications. Conclusion We found five distinct pediatric asthma subtypes and four distinct adult asthma subtypes. Future work should externally validate these subtypes and characterize response to treatment by subtype to better guide clinical treatment of asthma.

Androgen Plays a Potential Novel Hormonal Therapeutic Role in Th17 Cells Predominant Neutrophilic Severe Asthma by Attenuating BECs Regulated Th17 Cells Differentiation via MBD2 Expression.

T helper 17 (Th17) cells subtype of non-T2 asthma is less responsive (resistant) to inhaled corticosteroids (ICS), so also called severe asthma. Methyl-CpG-binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, showing the possibility of a therapeutic target in severe asthma. Androgen tends to show beneficial therapeutic effects and is a "hot research topic," but its role in the differentiation and expression of Th17 cells via MBD2 is still unknown. The aim of this study was to evaluate how sex hormone interacts with MBD2 and affects the differentiation and expression of Th17 cells in severe asthma. Here, first, we measured the concentration of androgen, estrogen, and androgen estrogen ratio from subjects and correlated it with severe asthma status. Then, we established an animal model and bronchial epithelial cells (BECs) model of severe asthma to evaluate the role of MBD2 in the differentiation and expression of Th17 cells (IL-17), the therapeutic potential of sex hormones in severe asthma, and the effect of sex hormones in BECs regulated Th17 cells differentiation via MBD2 at the cellular level. Increased MBD2 expression and Th17 cells differentiation were noted in the animal and the BECs severe asthma models. Th17 cell differentiation and expression were MBD2 dependent. Androgen attenuated the differentiation of BECs regulated Th17 cells via MBD2 showing BECs as a therapeutic target of androgen, and these findings postulate the novel role of androgen in Th17 cells predominant neutrophilic severe asthma therapy through targeting MBD2.

Identification of pyroptosis-related subtypes and establishment of prognostic model and immune characteristics in asthma.

BackgroundAlthough studies have shown that cell pyroptosis is involved in the progression of asthma, a systematic analysis of the clinical significance of pyroptosis-related genes (PRGs) cooperating with immune cells in asthma patients is still lacking.MethodsTranscriptome sequencing datasets from patients with different disease courses were used to screen pyroptosis-related differentially expressed genes and perform biological function analysis. Clustering based on K-means unsupervised clustering method is performed to identify pyroptosis-related subtypes in asthma and explore biological functional characteristics of poorly controlled subtypes. Diagnostic markers between subtypes were screened and validated using an asthma mouse model. The infiltration of immune cells in airway epithelium was evaluated based on CIBERSORT, and the correlation between diagnostic markers and immune cells was analyzed. Finally, a risk prediction model was established and experimentally verified using differentially expressed genes between pyroptosis subtypes in combination with asthma control. The cMAP database and molecular docking were utilized to predict potential therapeutic drugs.ResultsNineteen differentially expressed PRGs and two subtypes were identified between patients with mild-to-moderate and severe asthma conditions. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes. Poor control subtypes were closely related to glucocorticoid resistance and airway remodeling. BNIP3 was identified as a diagnostic marker and associated with immune cell infiltration such as, M2 macrophages. The risk prediction model containing four genes has accurate classification efficiency and prediction value. Small molecules obtained from the cMAP database that may have therapeutic effects on asthma are mainly DPP4 inhibitors.ConclusionPyroptosis and its mediated immune phenotype are crucial in the occurrence, development, and prognosis of asthma. The predictive models and drugs developed on the basis of PRGs may provide new solutions for the management of asthma.

Subtypes of Asthma and Cold Weather-Related Respiratory Symptoms.

(1) Poor asthma control increases the occurrence of cold weather-related symptoms among adult asthmatics. We assessed whether the subtype of asthma, taking into account the severity of the asthma, plays a role in these symptoms. (2) We conducted a population-based cross-sectional study of 1995 adult asthmatics (response rate 40.4%) living in northern Finland using a questionnaire that asked about cold weather-related respiratory symptoms including (1) shortness of breath, (2) prolonged cough, (3) wheezing, (4) phlegm production, and (5) chest pain, as well as questions related to the subtype of asthma. For women, the subtypes identified using latent class analysis were: (1) Controlled, mild asthma, (2) Partly controlled, moderate asthma, (3) Uncontrolled, unknown severity, and (4) Uncontrolled, severe asthma, and for men: (1) Controlled, mild asthma, (2) Uncontrolled, unknown severity, and (3) Partly controlled, severe asthma. (3) According to the subtypes of asthma, more severe and more poorly controlled asthma were related to the increased prevalence of cold weather-related respiratory symptoms when compared with those with mild, controlled asthma. This trend was especially clear for wheezing and chest pain. For example, in men, the adjusted prevalence ratio of wheezing was 1.55 (95% CI 1.09–2.19) in uncontrolled asthma with unknown severity and 1.84 (95% CI 1.26–2.71) in partly controlled severe asthma compared with controlled, mild asthma. (4) Our study provides evidence for the influence of subtypes of asthma on experiencing cold weather-related respiratory symptoms. Both women and men reported more cold weather-related symptoms when their asthma was more severe and uncontrolled compared with those who had mild and well-controlled asthma.

Work-Aggravated Asthma in the Workplace Due to Environmental Exposure: A Case Report

Work-aggravated asthma is an important and common subtype of work-related asthma. Air pollutants in the workplace are important risk factors for triggering asthma symptoms. Air pollutants can be caused by the operating conditions of the work process, as well as by indoor and outdoor air pollution. In this study, a case of work-aggravated asthma is discussed. An office worker, who had been following up with a diagnosis of asthma for 6 years, was diagnosed with work-aggravated asthma. The reason underlying this diagnosis was the smoke and dust from nearby factories as well as the antiseptic substances used in the workplace. Following the diagnosis, the patient’s workplace was changed by the management. After such change, the patient’s symptoms have relieved and she needed less inhaler therapy than before. In summary, work-aggravated asthma can be exacerbated by factors in the workplace environment. Hence, the workplace environment should also be carefully questioned while assessing the risk factors at work.

DNA methylation signatures in airway cells from adult children of asthmatic mothers reflect subtypes of severe asthma

Maternal asthma (MA) is among the most consistent risk factors for asthma in children. Possible mechanisms for this observation are epigenetic modifications in utero that have lasting effects on developmental programs in children of mothers with asthma. To test this hypothesis, we performed differential DNA methylation analyses of 398,186 individual CpG sites in primary bronchial epithelial cells (BECs) from 42 nonasthma controls and 88 asthma cases, including 56 without MA (NMA) and 32 with MA. We used weighted gene coexpression network analysis (WGCNA) of 69 and 554 differentially methylated CpGs (DMCs) that were specific to NMA and MA cases, respectively, compared with controls. WGCNA grouped 66 NMA-DMCs and 203 MA-DMCs into two and five comethylation modules, respectively. The eigenvector of one MA-associated module (turquoise) was uniquely correlated with 85 genes expressed in BECs and enriched for 36 pathways, 16 of which discriminated between NMA and MA using machine learning. Genes in all 16 pathways were decreased in MA compared with NMA cases (P = 7.1 × 10−3), a finding that replicated in nasal epithelial cells from an independent cohort (P = 0.02). Functional interpretation of these pathways suggested impaired T cell signaling and responses to viral and bacterial pathogens. The MA-associated turquoise module eigenvector was additionally correlated with clinical features of severe asthma and reflective of type 2 (T2)-low asthma (i.e., low total serum immunoglobulin E, fractional exhaled nitric oxide, and eosinophilia). Overall, these data suggest that MA alters diverse epigenetically mediated pathways that lead to distinct subtypes of severe asthma in adults, including hard-to-treat T2-low asthma.

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment.

BackgroundAutophagy has been proven to play an important role in the pathogenesis of asthma and the regulation of the airway epithelial immune microenvironment. However, a systematic analysis of the clinical importance of autophagy-related genes (ARGs) regulating the immune microenvironment in patients with asthma remains lacking.MethodsClustering based on the k-means unsupervised clustering method was performed to identify autophagy-related subtypes in asthma. ARG-related diagnostic markers in low-autophagy subtypes were screened, the infiltration of immune cells in the airway epithelium was evaluated by the CIBERSORT, and the correlation between diagnostic markers and infiltrating immune cells was analyzed. On the basis of the expression of ARGs and combined with asthma control, a risk prediction model was established and verified by experiments.ResultsA total of 66 differentially expressed ARGs and 2 subtypes were identified between mild to moderate and severe asthma. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes, and the low-autophagy subtype was closely associated with severe asthma, energy metabolism, and hormone metabolism. The autophagy gene SERPINB10 was identified as a diagnostic marker and was related to the infiltration of immune cells, such as activated mast cells and neutrophils. Combined with asthma control, a risk prediction model was constructed, the expression of five risk genes was supported by animal experiments, was established for ARGs related to the prediction model.ConclusionAutophagy plays a crucial role in the diversity and complexity of the asthma immune microenvironment and has clinical value in treatment response and prognosis.

A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

BackgroundAsthma is a heterogeneous disease; therefore, biomarkers that can assist in the identification of subtypes and direct therapy are highly desirable. Asthma is a chronic inflammatory disease that leads to changes in the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) degradation causing fragments of type I collagen that is released into circulation.ObjectiveHere, we asked if MMP-generated type I collagen (C1M) was associated with subtypes of asthma.MethodsC1M was serologically assessed at baseline in the adult participants of the All Age Asthma study (ALLIANCE) (n = 233), and in The Prospective Epidemiological Risk Factor study (PERF) (n = 283). In addition, C1M was assessed in mice sensitized to ovalbumin (OVA) and challenged with OVA aerosol. C1M was evaluated in mice with and without acute neutrophilic inflammation provoked by poly(cytidylic-inosinic) acid and mice treated with CP17, a peptide inhibiting neutrophil accumulation.ResultsSerum C1M was significantly increased in asthmatics compared to healthy controls (p = 0.0005). We found the increased C1M levels in asthmatics were related to blood neutrophil and body mass index (BMI) in the ALLIANCE cohort, which was validated in the PERF cohort. When patients were stratified into obese (BMI > 30) asthmatics with high neutrophil levels and uncontrolled asthma, this group had a significant increase in C1M compared to normal-weight (BMI < 25) asthmatics with low neutrophil levels and controlled asthma (p = 0.0277). C1M was significantly elevated in OVA mice with acute neutrophilic inflammation compared to controls (P = 0.0002) and decreased in mice treated with an inhibitor of neutrophil infiltration (p = 0.047).Conclusion & clinical relevanceC1M holds the potential to identify a subtype of asthma that relates to severity, obesity, and high neutrophils. These data suggest that C1M is linked to a subtype of overall inflammation, not only derived from the lung. The link between C1M and neutrophils were further validated in in vivo model.Trial registration(ALLIANCE, NCT02419274).

Clinical Characteristics of Irritant-Induced Occupational Asthma

Work is a substantial contributing factor of adult-onset asthma. A subtype of occupational asthma (OA) is caused by irritant agents, but knowledge of the clinical outcomes of irritant-induced asthma (IIA) is incomplete. To evaluate whether the clinical picture of IIA differs from that of sensitizer-induced OA. This retrospective study analyzed acute and subacute IIA patients diagnosed in an occupational medicine clinic during 2004 to 2018. Sixty-nine patients fulfilled the inclusion criteria, and their characteristics were analyzed at the time of the diagnosis and 6 months later. The results were compared with those of 2 subgroups of sensitizer-induced OA: 69 high-molecular-weight (HMW) and 89 low-molecular-weight (LMW) agent-induced OA patients. Six months after the diagnosis, 30% of the patients with IIA needed daily short-acting β-agonists (SABA), 68% were treated with Global Initiative for Asthma, 2020 report (GINA) step 4-5 medication, and 24% of the patients had asthma exacerbation after the first appointment. IIA depicted inferiority to LMW-induced OA in daily need for SABA (odds ratio [OR]: 3.80, 95% confidence interval [CI]: 1.38-10.46), treatment with GINA step 4-5 medication (OR: 2.22, 95% CI: 1.08-4.57), and exacerbation (OR: 3.85, 95% CI: 1.35-11.04). IIA showed poorer results than HMW-induced OA in the latter 2 of these features (OR: 2.49, 95% CI: 1.07-5.79 and OR: 6.29, 95% CI: 1.53-25.83, respectively). Six months after the OA diagnosis, a significant proportion of the patients with IIA remain symptomatic and the majority of these patients use asthma medications extensively suggesting uncontrolled asthma. The short-term outcomes of IIA appear poorer than that of sensitizer-induced OA.

Lack of Reliability of a Single Peripheral Blood Eosinophil Count as Biomarker for High Th2 Asthma

A peripheral blood eosinophil count (PBEC) of 300 cells/μl is regarded as a major marker of the high Th2 (HTh2) asthma subtype. We hypothesized that analyzing the stability of PBECs over multiple years would demonstrate limitations of a single PBEC ≤ or ≥ 300 cells/μl as a predictable marker of Th2 status.

Utilizing Predictive Inflammatory Markers for Guiding the Use of Biologicals in Severe Asthma.

Asthma is a chronic respiratory disease characterized by chronic airway inflammation and airflow obstruction. Up to ten percent of asthmatics have severe asthma, and many remain uncontrolled despite optimal medical management. With our increased understanding of the heterogeneity of asthma and its complex pathophysiology, several biomarkers have been developed and in the recent past, several biologic therapies for severe asthma have been developed and are now in widespread use. Although these biological agents have shown great benefit in treating severe asthma, not all patients respond equally well, and some do not derive any benefit. As much of the current literature of these medications have not assessed biomarkers or have used different cutoffs, it is often challenging to decide the best medication for an individual patient. Here, we review common asthma subtypes, current available biologic therapies for asthma, the clinical application of currently available type 2 biomarkers, as well as summarizing the evidence on how patient characteristics and biomarkers can help with choosing the optimal biologic for a patient that has the highest likelihood of success.

The role of fungus in the pathogenesis of chronic rhinosinusitis

The etiologic role of fungi in chronic rhinosinusitis remains controversial. The purpose of this review is to further our understanding of molecular immunologic pathways activated by fungi and clinical trials of antifungals in severe subtypes of asthma and allergic fungal rhinosinusitis. Various fungal components such as protease and chitin are capable of eliciting a type 2 innate and adaptive immune response. However, definitive studies on the etiologic role of fungi in chronic rhinosinusitis (CRS) is dependent on the development of a fungi-induced murine model of CRS. Short of this model, extrapolations of observations and results from clinical trials in fungi-induced asthma subtypes support a key role of fungi in the pathophysiology of allergic fungal rhinosinusitis and possibly other CRS endotypes. Fungi plays a key role in the pathophysiology of several subtypes of chronic inflammatory respiratory diseases. However, a fungi-induced murine model of CRS is needed to explicitly investigate the molecular pathways and potential therapeutic targets.

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Characterizing Inflammatory Cell Asthma Associated Phenotypes in Dental Health Workers Using Cytokine Profiling.

Cytokines elicit a pro-inflammatory response by modifying the airway microenvironment in patients with acute or chronic asthma. The expression pattern of several distinct cytokines could be a useful discriminator in asthma. This study aimed to identify asthma subject groupings based on common inflammatory patterns and to determine the relationship between these identified patterns and asthma-associated clinical indices. A sub-group of 76 dental healthcare workers (HCWs) identified from a larger cross-sectional study of 454 dental HCWs in five dental institutions were evaluated further. A self-administered questionnaire elicited the health and employment history of subjects. Sera were analyzed for atopic status, latex sensitization, and 12 cytokines (IL-1β, 3, 4, 5, 6, 7, 8, 10, 12p70, eotaxin, GM-CSF, TNF-α). Pre and post-bronchodilator spirometry was performed on all HCWs. Data clustering and factor analysis were used to identify inflammatory cluster patterns of cytokines. Associations between the cytokine cluster groupings and relevant asthma-associated clinical indices were determined using multivariate logistic regression. The classification of asthma subtype based on cytokine patterns demonstrated both eosinophilic and neutrophilic inflammatory responses. Four phenotypically distinct subgroups relating to the severity of inflammation (acute or chronic) of the cell types were identified. Cytokine determinants for the neutrophilic subtype included IL-1β, 6, 8, 10, 12p70, and TNF-α whereas for the eosinophilic subtype these included IL-3, 4, 5, 7, eotaxin, and GM-CSF. The multivariate models showed a significant association between work-related chest symptoms and all four inflammatory patterns. However, stronger associations were observed for the acute neutrophilic (OR = 6.00, p < 0.05) compared to acute and chronic eosinophilic responses (OR = 4.30, p < 0.05; OR = 4.93, p < 0.05), respectively. Subjects with airway obstruction were more likely to have a mixed cellular infiltrate. The odds of work-exacerbated asthma were increased in acute or chronic eosinophilia (OR = 7.75 and 8.12; p < 0.05), respectively as well as with acute neutrophilia (OR = 6) sub-type. This study demonstrated that neutrophilic inflammatory cell asthma phenotypes coexist with eosinophilic inflammatory phenotypes suggesting a possible dual pathway for asthma in dental health workers, probably due to mixed exposures to high molecular weight (e.g., latex) and low molecular weight (e.g., acrylates) agents.

The Transcriptome Characteristics of Severe Asthma From the Prospect of Co-Expressed Gene Modules.

Rationale: Severe asthma is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of asthmatic bronchial epithelial cells have provided biological insights and underscored possible pathological mechanisms; however, the molecular basis in severe asthma is still poorly understood. Objective: The objective of this study was to identify the features of asthma and uncover the molecular basis of severe asthma in distinct molecular phenotype. Methods: The k-means clustering and differentially expressed genes (DEGs) were performed in 129 asthma individuals in the Severe Asthma Research Program. The DEG profiles were analyzed by weighted gene co-expression network analysis (WGCNA), and the expression value of each gene module in each individual was annotated by gene set variation analysis (GSVA). Results: Expression analysis defined five stable asthma subtype (AS): 1) Phagocytosis-Th2, 2) Normal-like, 3) Neutrophils, 4) Mucin-Th2, and 5) Interferon-Th1 and 15 co-expressed gene modules. “Phagocytosis-Th2” enriched for receptor-mediated endocytosis, upregulation of Toll-like receptor signal, and myeloid leukocyte activation. “Normal-like” is most similar to normal samples. “Mucin-Th2” preferentially expressed genes involved in O-glycan biosynthesis and unfolded protein response. “Interferon-Th1” displayed upregulation of genes that regulate networks involved in cell cycle, IFN gamma response, and CD8 TCR. The dysregulation of neural signal, REDOX, apoptosis, and O-glycan process were related to the severity of asthma. In non-TH2 subtype (Neutrophils and Interferon-Th1) with severe asthma individuals, the neural signals and IL26-related co-expression module were dysregulated more significantly compared to that in non-severe asthma. These data infer differences in the molecular evolution of asthma subtypes and identify opportunities for therapeutic development. Conclusions: Asthma is a heterogeneous disease. The co-expression analysis provides new insights into the biological mechanisms related to its phenotypes and the severity.