Asthma Endotypes Research Articles

Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management.

Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.

Staphylococcus Aureus in chronic airway diseases: An overview.

This review investigates about the role of Staphylococcus Aureus (S. aureus) and S. aureus enterotoxins (SEs) in the pathogenesis of several chronic airway diseases. S. aureus is part of normal human flora and may colonize the skin and the upper airways. SEs acting as superantigens can induce an intense T cell activation and through the release of interleukin (IL) - 4, 5, and 13, can promote a polyclonal IgE response and eosinophilic inflammation. S. aureus can damage epithelial cells inducing the release of the so-called "alarmins" responsible of the activation of Type 2 innate lymphoid cells (ILC-2) linked to an IL-5 mediated airway eosinophilic inflammation. SEs sensitization has been recently associated with the eosinophilic endotypes of both nasal polyps and late onset severe asthma. Studies investigating the effect of biological therapies in SEs sensitized patients should be performed in order to better define the role played by S. aureus in the different endotypes of severe asthma and/or chronic rhinosinusitis.

Associations between fungal and bacterial microbiota of airways and asthma endotypes

The relationship between asthma, atopy, and underlying type 2 (T2) airway inflammation is complex. Although the bacterial airway microbiota is known to differ in asthmatic patients, the fungal and bacterial markers that discriminate T2-high (eosinophilic) and T2-low (neutrophilic/mixed-inflammation) asthma and atopy are still incompletely identified. The aim of this study was to demonstrate the fungal microbiota structure of airways in asthmatic patients associated with T2 inflammation, atopy, and key clinical parameters. We collected endobronchial brush (EB) and bronchoalveolar lavage (BAL) samples from 39 asthmatic patients and 19 healthy subjects followed by 16S gene and internal transcribed spacer-based microbiota sequencing. The microbial sequences were classified into exact sequence variants. The T2 phenotype was defined by using a blood eosinophil count with a threshold of 300cells/μL. Fungal diversity was significantly lower in EB samples from patients with T2-high compared with T2-low inflammation; key fungal genera enriched in patients with T2-high inflammation included Trichoderma species, whereas Penicillium species was enriched in patients with atopy. In BAL fluid samples the dominant genera were Cladosporium, Fusarium, Aspergillus, and Alternaria. Using generalized linear models, we identified significant associations between specific fungal exact sequence variants and FEV1, fraction of exhaled nitric oxide values, BAL fluid cell counts, and corticosteroid use. Investigation of interkingdom (bacterial-fungal) co-occurrence patterns revealed different topologies between asthmatic patients and healthy control subjects. Random forest models with fungal classifiers predicted asthma status with 75% accuracy for BAL fluid samples and 80% accuracy for EB samples. We demonstrate clear differences in bacterial and fungal microbiota in asthma-associated phenotypes. Our study provides additional support for considering microbial signatures in delineating asthma phenotypes.

Т2-high and T2-low bronchial asthma, endotype characteristics and biomarkers

Bronchial asthma is a heterogeneous disease with variable course. Identification of pathobiological mechanisms of asthma phenotype, also called as asthma endotypes, is an urgent task to optimize treatment of asthma, especially of severe asthma. Although the author recognizes that T2-low asthma is a serious problem, this article is devoted to the T2-high asthma endotype. Currently, biological agents are available for T2-high asthma only, so the focus on T2 high asthma is important. Current characteristics of uncontrolled, difficult-to-treat and severe asthma, mechanisms of eosinophilic inflammation in T2-high asthma, main cells and mediators involved in the disease, and biomarkers of T2-high asthma were discussed in the article.

Leveraging -omics for asthma endotyping

Leveraging -omics for asthma endotyping

The Children\u2019s Respiratory and Environmental Workgroup (CREW) birth cohort consortium: design, methods, and study population

BackgroundSingle birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood.Methods and resultsCREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes.ConclusionsThe overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.

Does understanding endotypes translate to better asthma management options for all?

Despite the development of novel treatments, improvement in the design of delivery devices, and new technologies for monitoring and improving adherence, the burden of asthma is not decreasing. Predicting an individual patient's response to asthma drugs remains challenging, and the provision of personalized treatment remains elusive. Although biomarkers, such as allergic sensitization and blood eosinophilia, might be important predictors of response to inhaled corticosteroids in preschool children, these relatively cheap and available investigations are seldom used in clinical practice to select patients for corticosteroid prescription. However, for the majority of patients, response to different treatments cannot be accurately predicted. One of the key factors preventing further advances is the reductionist view of asthma as a single disease, which is forcing patients with different asthma subtypes into a single group for empiric treatment. This inevitably results in treatment failures and, for some, an unacceptable risk/benefit ratio. The approach to asthma today is an example of the traditional symptom (diagnosis)-based, one-size-fits-all approach rather than a stratified approach, and our guidelines-driven management based on a unitary diagnosis might not be the optimal way to deliver care. The only way to deliver stratified medicine and find a cure is through the understanding of asthma endotypes. We propose that the way to discover endotypes, biomarkers, and personalized treatments is through the iterative process based on interpretation of big data analytics from birth and patient cohorts, responses to treatments in randomized controlled trials, and invitro mechanistic studies using human samples and experimental animal models, with technological and methodological advances at its core.

Korean childhood asthma study (KAS): a prospective, observational cohort of Korean asthmatic children

BackgroundAsthma is a syndrome composed of heterogeneous disease entities. Although it is agreed that proper asthma endo-typing and appropriate type-specific interventions are crucial in the management of asthma, little data are available regarding pediatric asthma.MethodsWe designed a cluster-based, prospective, observational cohort study of asthmatic children in Korea (Korean childhood Asthma Study [KAS]). A total of 1000 Korean asthmatic children, aged from 5 to 15 years, will be enrolled at the allergy clinics of the 19 regional tertiary hospitals from August 2016 to December 2018. Physicians will verify the relevant histories of asthma and comorbid diseases, as well as airway lability from the results of spirometry and bronchial provocation tests. Questionnaires regarding subjects’ baseline characteristics and their environment, self-rating of asthma control, and laboratory tests for allergy and airway inflammation will be collected at the time of enrollment. Follow-up data regarding asthma control, lung function, and environmental questionnaires will be collected at least every 6 months to assess outcome and exacerbation-related aggravating factors. In a subgroup of subjects, peak expiratory flow rate will be monitored by communication through a mobile application during the overall study period. Cluster analysis of the initial data will be used to classify Korean pediatric asthma patients into several clusters; the exacerbation and progression of asthma will be assessed and compared among these clusters. In a subgroup of patients, big data-based deep learning analysis will be applied to predict asthma exacerbation.DiscussionBased on the assumption that asthma is heterogeneous and each subject exhibits a different subset of risk factors for asthma exacerbation, as well as a different disease progression, the KAS aims to identify several asthma clusters and their essential determinants, which are more suitable for Korean asthmatic children. Thereafter we may suggest cluster-specific strategies by focusing on subjects’ personalized aggravating factors during each exacerbation episode and by focusing on disease progression. The KAS will provide a good academic background with respect to each interventional strategy to achieve better asthma control and prognosis.

Childhood asthma in the new omics era: challenges and perspectives.

Purpose of reviewChildhood asthma is a heterogeneous inflammatory disease comprising different phenotypes and endotypes and, particularly in its severe forms, has a large impact on the quality-of-life of patients and caregivers. The application of advanced omics technologies provides useful insights into underlying asthma endotypes and may provide potential clinical biomarkers to guide treatment and move towards a precision medicine approach.Recent findingsThe current article addresses how novel omics approaches have shaped our current understanding of childhood asthma and highlights recent findings from (pharmaco)genomics, epigenomics, transcriptomics, and metabolomics studies on childhood asthma and their potential clinical implications to guide treatment in severe asthmatics.SummaryUntil now, omics studies have largely expanded our view on asthma heterogeneity, helped understand cellular processes underlying asthma, and brought us closer towards identifying (bio)markers that will allow the prediction of treatment responsiveness and disease progression. There is a clinical need for biomarkers that will guide treatment at the individual level, particularly in the field of biologicals. The integration of multiomics data together with clinical data could be the next promising step towards development individual risk prediction models to guide treatment. However, this requires large-scale collaboration in a multidisciplinary setting.

Regulation of IL-17A and implications for TGF-β1 comodulation of airway smooth muscle remodeling in severe asthma.

Severe asthma develops as a result of heightened, persistent symptoms that generally coincide with pronounced neutrophilic airway inflammation. In individuals with severe asthma, symptoms are poorly controlled by high-dose inhaled glucocorticoids and often lead to elevated morbidity and mortality rates that underscore the necessity for novel drug target identification that overcomes limitations in disease management. Many incidences of severe asthma are mechanistically associated with T helper 17 (TH17) cell-derived cytokines and immune factors that mediate neutrophilic influx to the airways. TH17-secreted interleukin-17A (IL-17A) is an independent risk factor for severe asthma that impacts airway smooth muscle (ASM) remodeling. TH17-derived cytokines and diverse immune mediators further interact with structural cells of the airway to induce pathophysiological processes that impact ASM functionality. Transforming growth factor-β1 (TGF-β1) is a pivotal mediator involved in airway remodeling that correlates with enhanced TH17 activity in individuals with severe asthma and is essential to TH17 differentiation and IL-17A production. IL-17A can also reciprocally enhance activation of TGF-β1 signaling pathways, whereas combined TH1/TH17 or TH2/TH17 immune responses may additively impact asthma severity. This review seeks to provide a comprehensive summary of cytokine-driven T cell fate determination and TH17-mediated airway inflammation. It will further review the evidence demonstrating the extent to which IL-17A interacts with various immune factors, specifically TGF-β1, to contribute to ASM remodeling and altered function in TH17-driven endotypes of severe asthma.

A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the "Type 2/Non-Type 2 Dichotomy".

Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma.

Spotlight on fevipiprant and its potential in the treatment of asthma: evidence to date.

Asthma is a heterogeneous disease, which may be classified into phenotypes and endotypes based on clinical characteristics and molecular mechanisms. The best described endotype of severe asthma is type 2 (T2)-high asthma, characterized by release of inflammatory cytokines by T helper 2 (TH2) cells and type 2 innate lymphoid cells cells. Prostaglandin D2 contributes to T2 inflammation through binding of the G-protein-coupled receptor chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2). Fevipiprant is an oral competitive antagonist of CRTH2. Early-phase trials have demonstrated safety and potential efficacy in patients with asthma, specifically, improvement in FEV1 and eosinophilic airway inflammation. However, no clear biomarker identified patients who responded favorably to fevipiprant, although patients with moderate-to-severe asthma and evidence of T2 inflammation may be more likely to respond to treatment. Additional studies are needed to determine the efficacy and target population for use of this drug in patients with asthma.

New insights in neutrophilic asthma.

Recent advances in both murine models and clinical research of neutrophilic asthma are improving our understanding on the etiology and pathophysiology of this enigmatic endotype of asthma. We here aim at providing an overview of our current and latest insights on the pathophysiology and treatment of neutrophilic asthma. Activation of the NLRP3 inflammasome pathway with increased IL-1β has been demonstrated in various studies involving patients with asthma. It has been suggested that type 3 innate lymphoid cells are implicated in the inflammatory cascade leading to neutrophilic inflammation. The role of neutrophil extracellular traps is only at the start of being understood and might be an attractive novel therapeutic target. A diverse panel of nonallergic stimuli, such as cigarette smoke, intensive exercise, cold air or saturated fatty acids, have been linked with neutrophilic airway inflammation. Azithromycin treatment could reduce asthma exacerbations and quality of life in patients with persistent asthma. Research of the last few years has accelerated our insights in mechanisms underlying neutrophilic asthma. This is in stark contrast with the lack of efficacy of different therapies targeting neutrophil chemotaxis and/or signalling cascade, such as IL-17A or CXCR2. Macrolide therapy might be a useful add-on therapy for patients with persistent asthma.

Obesity and adult asthma: diagnostic and management challenges.

Despite advances in our understanding of the obese asthma phenotype, heterogeneity and large gaps in knowledge have hindered significant advances in directed interventions. Obesity is associated with poorer asthma-related outcomes and increased risk of progression to severe asthma. Obese asthma is associated with variability in the expression of inflammatory markers, lung function impairments, and response to conventional and biologic therapies. In addition, traditional asthma biomarkers are not as reliable in obese patients. Several mechanistic pathways that uniquely impact asthma in obesity have been identified. Pathways involving innate lymphoid cells (ILC) type 2 (ILC-2) cells, surfactant protein-A, cell division control protein (CDC)42, interleukin (IL)-6, IL-17, and IL-33 are likely causal inflammatory pathways. Obesity also confounds lung function parameters making accurate diagnosis more challenging. As such, personalized asthma therapies directed towards obese asthma endotypes remain elusive. Obesity confounds traditional asthma biomarkers and lung function measurements, thus defining obese asthma endotypes remains challenging. Novel pathways are being identified and hold promise for future targeted therapies. However, we are in dire need of updated guidelines regarding asthma diagnosis in obese patients and the development of biomarkers that more accurately identify specific endotypes.

Clinical Issues in Severe Asthma: Debates and Discussions About Personalizing Patient Management

An outsized proportion of asthma-related morbidity and mortality is borne by the 5%to 15%of affected patients who have severe forms of the disease. These patients experience poorly controlled symptoms and frequent exacerbations despite daily treatment with high-dose inhaled corticosteroids and other long-acting controller medications. Ongoing research has elucidated key pathophysiologic processes and other clinical parameters related to asthma severity and persistence. In many cases, the patient's medical history, clinical presentation, and results from biomarker testing can help classify severe asthma phenotypically. Increasingly, this approach can allow health-care providers to personalize maintenance regimens using targeted therapies for the identified endotypes; that is, asthma phenotypes linked to specific underlying disease mechanisms and proinflammatory signaling cascades. Several biologic medications are now available to treat certain cohorts with severe asthma, and a number of other targeted agents are in late-stage development. Pulmonologists and asthma specialists who manage patients with severe asthma need to stay current on the latest published trial data for newer targeted therapies, approvals from the US Food and Drug Administration, and actionable best-practice recommendations on evaluating and treating patients with severe asthma. During this web-based Clinical Issues program (available online at https://courses.elseviercme.com/asthma18/761e), a panel of expert faculty discuss a series of topics related to the pathophysiology and heterogeneity of severe asthma, including the following: characterizing severe asthma phenotypes and endotypes; identification of patients with severe asthma; and the role of biomarkers in asthma phenotyping. The faculty also highlight the identification and management of comorbid conditions commonly associated with asthma. An overview of new and emerging biologic therapies for severe asthma is provided, followed by a detailed discussion on personalizing treatment for patients with severe asthma.

Airway reversibility in asthma and phenotypes of Th2-biomarkers, lung function and disease control

BackgroundHigh bronchodilator reversibility in adult asthma is associated with distinct clinical characteristics. In this study, we aim to make a comparison with T-helper 2 (Th2)-related biomarkers, lung function and asthma control between asthmatic patients with high airway reversibility (HR) and low airway reversibility (LR).MethodsPatients with asthma diagnosed by pulmonologist according to Global Initiative for Asthma guidelines were recruited from the outpatient department of our hospital from August 2014 to July 2017. Patients were divided into HR and LR subgroups based on their response to bronchodilators of lung function (HR = Δforced expiratory volume in one second (FEV1) postbronchodilator ≥ 20%). Blood eosinophil count and serum IgE level, which are biomarkers of T-helper (Th)-2 phenotypes, were detected for patients. Asthma Control Test (ACT) was used to assess asthma control after the first-month initial treatment.ResultsA total of 265 patients with asthma were followed 1 month after initial treatment. HR group shows a higher level of Th2-high biomarkers (blood eosinophil count (10^9/L): 0.49 ± 0.28 vs 0.36 ± 0.19, P < 0.01; IgE (ng/ml): 1306 ± 842 vs 413 ± 261, P < 0.01), lower baseline lung function (FEV1%pred: 51.91 ± 19.34% vs 60.42 ± 19.22%, P < 0.01; forced expiratory flow (FEF)25–75: 0.76 ± 0.37 vs 1.00 ± 0.67, P < 0.01; FEF25–75%pred: 21.15 ± 10.09% vs 29.06 ± 16.50%, P < 0.01), and better asthma control (ACT score: 22 ± 4 vs 20 ± 4, P = 0.01) than LR group. HR was associated with a decreased risk of uncontrolled asthma after the first-month initial treatment (adjusted OR: 0.12 [95% confidence intervals: 0.03–0.50]).ConclusionsHR is a physiologic indicator of lower lung function and severe small airway obstruction, and is more related with an increased level of Th2-biomarkers than LR. Moreover, HR may indicate controlled asthma after the first-month initial treatment. This finding may contribute to identification of asthma endotype.

33 - S-glutathionylation of pyruvate kinase M2 is associated with metabolic reprogramming and cytokine production in the development of allergic obese airway disease

Early on-set allergic obese asthma is an important global clinical problem due to the mounting number of patients and their disease severity that is poorly controlled with available therapeutics. Alterations in metabolism and accompanying changes in redox homeostasis are known to contribute to obesity-associated diseases. Protein S-glutathionylation (PSSG) is a redox-based modification of protein cysteines involving the conjugation of glutathione to the reactive thiol group. We have discovered a direct correlation between PSSG chemistry, glycolysis and inflammation in the lungs from mice fed a high fat diet for 15 weeks. Analysis of lung tissue from obese mice identified that the glycolytic enzyme pyruvate kinase M2 (PKM2), known to catalyze the final step in glycolysis, is a target of s-glutathionylation in the lung tissue from obese mice. Furthermore, we have identified that oxidative stress and s-glutathionylation of PKM2 are increased in primary tracheal epithelial cells cultured in high glucose (25 mM) and treated with palmitate compared to MTECs cultured in normal glucose (5.6 mM). The objective of this study was to identify the s-glutathionylated proteome and investigate if s-glutathionylation of PKM2 alters its protein function to enhance inflammation in the lung tissue from mice treated with house dust mite and subjected to diet induced obesity, a model of early on-set allergic obese asthma. Here we show that s-glutathionylation of PKM2 decreases its glycolytic enzyme activity. This correlates with the upregulation of the inflammatory cytokines thymic stromal lymphopoietin (TSLP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), known to contribute to steroid resistance and neutrophil infiltration in the lung during obesity. Treatment of primary mouse tracheal epithelial cells with the PKM2 small molecule activator TEPP46 attenuates mRNA expression and secretion of TSLP and GM-CSF. Overall, these findings suggest that unique redox perturbations and glycolysis may contribute to the enigmatic endotype of allergic obese asthma.

DYSPNEA, DYSPHAGIA, AND URTICARIA WITH ANGIOEDEMA AFTER CHILDBIRTH

Introduction Our case highlights the challenge in differentiating between hypereosinophilic syndrome (HES) and eosinophilia exacerbating atopic disease. Case Description A 29-year-old woman presents with dyspnea, dysphagia, urticaria and angioedema after childbirth. Evaluation revealed an eosinophil count of 3800/mcL. Infectious, cardiac, and chest imaging studies were normal. Lung function demonstrated FEV1/FVC at 0.85. Bronchial challenge with methacholine was positive. Bone marrow was normocellular with eosinophilia without evidence of PDGFRA, CHIC2, and FIP1L1 rearrangement. Upper endoscopy demonstrated esophageal eosinophilia. She improved on prednisone 40 mg daily, mometasone-formoterol, and montelukast. Dysphagia improved after esophageal dilation. Eosinophil counts remained elevated at 1500/mcL, with difficulty tapering prednisone due to dyspnea. She started interferon-alpha and continued prednisone 20 mg daily for 6 years with significant weight gain. She presented to our center and started mycophenolate-mofetil, discontinued interferon-alpha, and tapered prednisone to 5 mg daily. She then started mepolizumab and stopped prednisone. Six months later she developed dyspnea and urticaria. She switched to omalizumab with improvement and is stable on omalizumab, mycophenolate-mofetil, mometasone-formoterol, and montelukast. Discussion Asthma endotyping prompts checking eosinophil counts to assess for potential benefit with anti-IL5 therapy. Recent data demonstrates mepolizumab improves glucocorticoid sensitive HES, yet our patient responded better to omalizumab. The different biologics can help delineate the differential pathophysiology behind a patient's clinical presentation. Given the emerging overlap in therapeutic management, our case emphasizes the importance to shift the paradigm of understanding eosinophilic inflammation as a spectrum of disease rather than isolated entities, in consideration of both biologic and immune modulating medications.

Gene Coexpression Networks in Whole Blood Implicate Multiple Interrelated Molecular Pathways in Obesity in People with Asthma.

Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity. Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult). A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05). The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity.

Looking for Airways Periostin in Severe Asthma: Could It Be Useful for Clustering Type 2 Endotype?

Severe asthma is heterogeneous clinically and biologically and is often difficult to control. In particular, the type 2 (T2) immunity endotype of severe asthma is gaining increasing interest because it is susceptible to newly developed biologic treatments that can transform the quality of life of these patients. The aim of this study was to analyze periostin concentrations in the airways of patients with severe asthma, evaluating its role in clustering the T2 endotype. We enrolled 40 consecutive patients with severe asthma (T2 endotype: n= 25; non-T2 endotype: n= 15), 21 patients with mild to moderate asthma, and 15 healthy control subjects. All subjects enrolled underwent exhaled breath condensate (EBC) and sputum collection, eosinophil count in blood, fractional exhaled nitric oxide, and IgE measurement. Periostin was assessed by an enzyme-linked immunosorbent assay kit on EBC and induced sputum (IS) supernatant. We were able to detect higher periostin levels in the EBC (0.75 ± 0.46 vs0.70 ± 0.19 vs0.11 ± 0.05ng/mL, P< .05 and P< .01) and in IS (0.55 ± 0.23 vs0.31 ± 0.13 vs0.16 ± 0.120ng/mL, P< .05 and P< .01) of patients with severe asthma compared with patients with mild to moderate asthma and healthy control subjects, respectively. We further found an increase of periostin levels in both samples in T2 endotype compared with non-T2 endotype (EBC: 0.88 ± 0.46 vs0.52 ± 0.46ng/mL; IS: 0.69 ± 0.19 vs0.39 ± 0.16ng/mL; P<.05) and a correlation between periostin levels in EBC and sputum. We found that periostin is measurable in the airways and increased in patients with severe asthma, especially in those from the T2 endotype. Unlike serum periostin, which may be derived from several sources outside the lung, airways periostin is a useful marker of severe eosinophilic asthma and may help to phenotype patients that will respond to the biologic agents.