Defining Asthma Phenotypes Research Articles

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According to general estimates, from 3�5 % and up to 10 % of patients with asthma have a severe course of the disease, which often continues to remain uncontrolled, despite the maximum use of inhaled corticosteroids and additional controller drugs. Severe asthma creates a large physical, mental, emotional, social and economic burden for patients and is often associated with multimorbidity. The heterogeneity of asthma drives research aimed at defining asthma phenotypes that ultimately reflect different underlying disease mechanisms, including pathogenetic processes and response to environmental factors. The clinical phenotypes of asthma are closely related to the underlying inflammatory processes in this disease and therefore can be divided into 2 main inflammatory phenotypes determined by the dominant immunological pathways that determine the pathology of bronchial asthma: eosinophilic and non-eosinophilic. Phenotyping patients is important for the differential diagnosis of asthma, risk assessment, treatment selection, and monitoring response to treatment. Accurate identification of the phenotype is particularly important for the selection of a biological drug for the treatment of severe asthma and for predicting the response to treatment with it. But these phenotypes are not fixed and can change over time in response to new environmental triggers (viral infections, inhaled allergens, smoking, air pollution). The main cytokines in the T2 type of inflammation in the airways, which is characteristic of severe asthma, are IL-4, IL-5 and IL- 13, IL-17, but an equally significant role in this process is also played by alarmins (inflammation mediators produced, in particular, cells of the bronchial epithelium), which include IL-33, IL-25 and thymic stromal lymphopoietin (TSLP). Clinical features of asthma associated with TSLP include: 1) degree of severity; 2) risk and frequency of exacerbations; 3) the degree of lung function decline; 4) decrease in the patient's response to glucocorticosteroids; 5) decrease in immune response and susceptibility to acute respiratory viral infections; 6) potential remodulation of the respiratory tract; 7) bronchial hyperreactivity and mucus blockage. Therefore, the role of TSLP in the pathogenesis of severe asthma is very significant, so its therapeutic effect (anti-TSLP therapy using tezepelumab) can be considered a new promising direction of biological therapy for patients with bronchial asthma, especially in its severe form. Key words: bronchial asthma, severe form, type 2 inflammation, biomarkers of inflammation, thymic stromal lymphopoietin, biological therapy, tezepelumab.

Approaches to studying the pathogenesis of asthma

A phenotype describes a group of patients who present with similar clinically observable characteristics. An endotype is a subgroup of patients who share the same pathophysiologic processes that lead to disease presentation. Asthma is a complex chronic disorder that consists of many identifiable phenotypes and two generally accepted endotypes. Understanding the characteristics of the underlying inflammation requires lung biopsies or bronchoalveolar lavage studies, which are invasive and potentially dangerous. There are ongoing investigations that study biomarkers to define asthma phenotypes and endotypes. This article reviews the potential utility of pharmacogenomics, exhaled breath condensates, and serum biomarkers in defining asthma phenotypes and endotypes.
 
 Key words: asthma, pathogenesis, pharmacogenetics, exhaled condensates, biomarkers

A Comprehensive Survey on Role of Learning Approaches in Respiratory Disease Management with Special Focus on Asthma

Asthma is a heterogeneous disorder with many phenotypes. We discuss the phenotypic characterization of asthma by which disease causality and ultimately management approaches can be developed to improve asthma control while avoiding adverse effects and decreasing the risk of serious outcomes. Thus the discussions would aim at phenotyping asthma based on clinical as well as physiological characteristics as Asthma is defined and diagnosed by a combination of clinical symptoms and physiologic abnormalities by deploying different learning techniques for devising novel approaches, while performing evaluation of the same, which would better define asthma phenotypes that may improve the understanding of the underlying pathobiology of the phenotypes and lead to targeted therapies for individual phenotypes. The approaches developed would serve to cluster, classify and further perform analysis and predict the severity of the disease in future effectively.

Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.

Phenotypes of asthma in low-income children and adolescents: cluster analysis.

ABSTRACTObjective: Studies characterizing asthma phenotypes have predominantly included adults or have involved children and adolescents in developed countries. Therefore, their applicability in other populations, such as those of developing countries, remains indeterminate. Our objective was to determine how low-income children and adolescents with asthma in Brazil are distributed across a cluster analysis. Methods: We included 306 children and adolescents (6-18 years of age) with a clinical diagnosis of asthma and under medical treatment for at least one year of follow-up. At enrollment, all the patients were clinically stable. For the cluster analysis, we selected 20 variables commonly measured in clinical practice and considered important in defining asthma phenotypes. Variables with high multicollinearity were excluded. A cluster analysis was applied using a twostep agglomerative test and log-likelihood distance measure. Results: Three clusters were defined for our population. Cluster 1 (n = 94) included subjects with normal pulmonary function, mild eosinophil inflammation, few exacerbations, later age at asthma onset, and mild atopy. Cluster 2 (n = 87) included those with normal pulmonary function, a moderate number of exacerbations, early age at asthma onset, more severe eosinophil inflammation, and moderate atopy. Cluster 3 (n = 108) included those with poor pulmonary function, frequent exacerbations, severe eosinophil inflammation, and severe atopy. Conclusions: Asthma was characterized by the presence of atopy, number of exacerbations, and lung function in low-income children and adolescents in Brazil. The many similarities with previous cluster analyses of phenotypes indicate that this approach shows good generalizability.

Childhood asthma phenotypes in the twenty-first century

Summary A substantial proportion of asthma has its origins in childhood but attempts to identify modifiable exposures that trigger asthma inception have yielded disappointing results. It is increasingly recognised that asthma may not be a single disease entity but instead consists of a number of phenotypes that share common features perhaps with different aetiologies and pathophysiological pathways leading to disease. The aim of this review is to describe approaches to defining asthma phenotypes on the basis of clinical and epidemiological data and to consider the clinical implications of the phenotypes described. Differences in clinical features (atopy, lung function, prognosis) have been associated with phenotypes derived from unsupervised statistical approaches to phenotype definitions. Greater understanding of the genetic pathways underpinning asthma has also led to some insights into asthma endotypes that manifest as different clinical phenotypes. However, the challenge to translate these findings into interventions to change the natural history of asthma has yet to be overcome. Technological advances are driving the creation of massive data resources that can be brought to bear on this problem. Whether they will finally solve the problem of phenotypic complexity in asthma remains to be discovered. If they do, the possibility of personalised interventions for asthma may eventually be realised.

Year in review 2012: Asthma and chronic obstructive pulmonary disease

Year in review 2012: Asthma and chronic obstructive pulmonary disease

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes

Exclusive viral wheeze and allergic wheeze: evidence for discrete phenotypes

To the Editors: There is a broad consensus that childhood wheezing illness consists of several distinct disease entities, but there is no agreement on their number or underlying mechanisms [1]. Commonly used phenotypic classifications are based on clinical or epidemiological criteria [2–6], and there has been little work focusing on causal mechanisms [1, 6, 7]. Trigger factors for wheezing episodes might be indicators of such mechanisms. In young children, wheeze is commonly triggered by respiratory viral infections (colds), physical factors associated with increased breathing (exercise, laughing, crying and excitement) or allergens (aeroallergens and food allergens). These triggers are increasingly used to define asthma phenotypes in young children [3, 5]. Despite this, there are few data on the way in which these triggers change in importance with age or whether different classes of triggers are independent. A close association between different classes of triggers in the same children would suggest a common underlying mechanism while a lack of association might reflect independent causal mechanisms. In this analysis, we describe changes in the prevalence of different parent-reported triggers of wheeze by age in 1–9 yr olds and report statistical associations between different classes of triggers (exercise, allergens and infection). We used data from the …

Assessment of Bronchodilator Responsiveness after Methacholine-Induced Bronchoconstriction

Spirometry is the only objective clinical tool available to physicians in the outpatient setting. Patient history is often unreliable and physical examinations are normal when the child doesn't show symptoms. For that reason, spirometry is currently considered essential for asthma diagnosis, severity stratification, and monitoring asthma control in children ≥5 years.1 Bronchodilator responsiveness (BDR), which is an improvement of forced expiratory volume in 1 second after inhalation of β2-agonists, has traditionally been the definition of asthma2 and has recently been reported to reflect biomarkers of eosinophilic inflammation,3,4 bronchial hyperreactivity,5,6 and airway remodeling.7 BDR has also been regarded as a good predictor of response to therapy,8 a marker for long-term prognosis,5,9 and an important component in defining asthma phenotypes.10,11 Since BDR is usually measured by changes in airflow before and after administration of β2-agonists, it is influenced by the baseline airway tone. If the airways at baseline were fully dilated by asthma treatment, airflow would barely increase. Moreover, asthmatic children usually show prebronchodilator spirometry within the normal range, regardless of their symptom-based severity of asthma control.12 Consequently, impaired β-adrenergic responsiveness, which plays a role in the pathogenesis of asthma, is rarely evident, especially when the children are taking controller medications. In 1999, Hancox et al.13 first introduced the 'challenge-rescue' technique to assess BDR. They measured BDR after bronchoconstriction induced by methacholine, because β2-receptor responsiveness was easier to demonstrate under conditions of increased bronchomotor tone. The challenge-rescue model has been widely used14,15 because it has consistently provided evidence of bronchodilator tolerance, whereas previous studies of stable asthma have not. Moreover, it has obvious clinical relevance; asthmatics usually take β-agonists to relieve symptoms caused by bronchoconstriction.16 Despite the usefulness of this approach, some problems exist in terms of data interpretation. BDR to salbutamol is confounded by spontaneous recovery from the bronchoconstricting effects of methacholine. Although spontaneous recovery for 15 minutes after bronchoconstriction is rare,13 other factors that facilitate recovery from bronchoconstriction may be displayed as an enhanced responsiveness to bronchodilators. On the other hand, geometric factors, such as airway mucus plugging and mucosal edema, might not be discerned from bronchodilator tolerance. Therefore, care must be taken when analyzing BDR data obtained from the challenge-rescue technique. In the present issue of Allergy, Asthma, & Immunology Research, Bauer et al.17 assessed BDR using the challenge-rescue technique and evaluated the clinical factors that may affect BDR in children with mild to moderate asthma. Though the interpretation of the data is complicated, the results provide interesting information. Asthmatic patients with atopy and/or eosinophilia displayed higher BDR as compared with that of non-atopic and/or non-eosinophilic patients, which provides indirect evidence that BDR may be a marker for inflammation. While admitting that bronchoconstriction induced by methacholine may not exactly reflect clinical exacerbation of asthma, the results raise the possibility that more frequent or severe asthma attacks would occur in non-atopic and/or non-eosinophilic children with asthma. Another interesting finding is that no apparent differences were observed among the medication subgroups. Since inhaled long-acting β2 adrenergic agonists or corticosteroids were discontinued seven days prior to testing in this study, it is likely that tolerance to β-agonists would no longer be a concern when medications are withheld for more than seven days. Assessment of BDR following induced bronchoconstriction may be a useful tool for evaluating impaired β-adrenergic responsiveness, which plays a key role in the pathogenesis of asthma. Further studies are needed to extend the application of BDR assessment to determine management options in asthmatic patients.

Severe Asthma Research Program – Phenotyping and Quantification of Severe Asthma

SummaryA unique multi‐center consortium of research centers, the severe asthma research program (SARP), is working to define asthma phenotypes, with a particular focus on severe asthma due to the higher prevalence of exacerbations and hospital visits in these patients. The consortium includes comprehensive studies of physiology, genotype, and inflammatory biomakers in addition to a lung imaging substudy in nearly 400 subjects. The imaging substudy is comparing quantitative computed tomography (CT) measures of airway morphology and parenchymal density to asthma severity and other makers of asthma. Results show increased wall thickness and increased regional air trapping in severe versus non‐severe asthma. Image‐guided bronchoscopic assessment using either CT or hyperpolarized gas magnetic resonance imaging (MRI) shows that highly diseased airways have increased wall thickness on histology and greater inflammatory cell numbers. Large scale imaging studies such as SARP may provide a means to better understand and guide effective treatment of severe asthma.

The search for new asthma phenotypes

There is a longstanding recognition that asthma is a variable disease and attempts to elucidate the causes of asthma have been hampered by its genetic and phenotypic heterogeneity. The recognition...

Hematocytometry analysis as discriminative marker for asthma phenotypes

There is an increasing demand for easy to measure biomarkers in clinical practice. We created the relational database Utrecht Patient Oriented Database (UPOD) to develop tools for identifying new biomarkers for disease. In this study, we used UPOD to identify better biomarkers for discriminating different asthma phenotypes. We performed a prospective study at the University Medical Center (UMC) Utrecht using blood from patients with asthma and a healthy reference group. Since asthma is an inflammatory disease, absolute leukocyte counts and leukocyte differential parameters were analyzed using raw data files and a logistic regression model. We compared 17 difficult-to-treat asthma (DTA) cases, 13 non-difficult-to-treat asthma cases, and 19 healthy volunteers. Absolute leukocyte counts and differential parameters for leukocytes were able to discriminate asthma patients from healthy volunteers. However, among patients with asthma, difficult-to-treat cases could be more accurately defined with a neutrophil morphology change (OR 8.0; 95% CI 1.5-42.0), compared to the absolute neutrophil count (OR 4.0; 95% CI 0.8-21.0). In this asthma patient population, we were able to define asthma phenotypes more precisely using neutrophil morphology parameters, compared to absolute counts. Using UPOD with differential parameters, it is possible to conduct larger scale biomarker studies, combining clinical, laboratory medicine, and epidemiological techniques.

Defining asthma phenotypes based on seasonal distribution of exacerbation in children with bronchial asthma

Defining asthma phenotypes based on seasonal distribution of exacerbation in children with bronchial asthma