Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

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Pharmacological Rationale for Targeting IL-17 in Asthma

Frontiers in Allergy ◽

10.3389/falgy.2021.694514 ◽

2021 ◽

Vol 2 ◽

Author(s):

Siti Farah Rahmawati ◽

Maurice te Velde ◽

Huib A. M. Kerstjens ◽

Alexander S. S. Dömling ◽

Matthew Robert Groves ◽

...

Keyword(s):

Severe Asthma ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Experimental Models ◽

Airflow Limitation ◽

Interleukin 17 ◽

Asthma Phenotype ◽

T Helper 2 ◽

Bronchial Biopsies

Asthma is a respiratory disease that currently affects around 300 million people worldwide and is defined by coughing, shortness of breath, wheezing, mucus overproduction, chest tightness, and expiratory airflow limitation. Increased levels of interleukin 17 (IL-17) have been observed in sputum, nasal and bronchial biopsies, and serum of patients with asthma compared to healthy controls. Patients with higher levels of IL-17 have a more severe asthma phenotype. Biologics are available for T helper 2 (Th2)-high asthmatics, but the Th17-high subpopulation has a relatively low response to these treatments, rendering it a rather severe asthma phenotype to treat. Several experimental models suggest that targeting the IL-17 pathway may be beneficial in asthma. Moreover, as increased activation of the Th17/IL-17 axis is correlated with reduced inhaled corticosteroids (ICS) sensitivity, targeting the IL-17 pathway might reverse ICS unresponsiveness. In this review, we present and discuss the current knowledge on the role of IL-17 in asthma and its interaction with the Th2 pathway, focusing on the rationale for therapeutic targeting of the IL-17 pathway.

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Identification of asthma phenotypes based on extrapulmonary treatable traits

European Respiratory Journal ◽

10.1183/13993003.00240-2020 ◽

2020 ◽

pp. 2000240 ◽

Cited By ~ 2

Author(s):

Patricia Duarte Freitas ◽

Rafaella França Xavier ◽

Vanessa Marie McDonald ◽

Peter Gerard Gibson ◽

Laura Cordova-Rivera ◽

...

Keyword(s):

Physical Activity ◽

Cluster Analysis ◽

Health Status ◽

Asthma Control ◽

Severe Asthma ◽

Sedentary Time ◽

Depression Symptoms ◽

Uncontrolled Asthma ◽

Asthma Phenotypes ◽

Physically Inactive

BackgroundAsthma is a heterogeneous and complex disease, and the description of asthma phenotypes based on extrapulmonary treatable traits has not been previously reported.Objectiveto identify and characterise clusters based on clinical, functional, anthropometrical, and psychological characteristics in participants with moderate-to-severe asthma.MethodsThis is a cross-sectional multicentre study involving centres from Brazil and Australia. Participants (N=296) with moderate-to-severe asthma were consecutively recruited. Physical activity and sedentary time, clinical asthma control, anthropometric data, pulmonary function, psychological, and health-status were evaluated. Participants were classified by hierarchical cluster analysis and the clusters compared using ANOVA, Kruskal-Wallis, and Chi-square tests. Multiple logistic and linear regression models were performed to evaluate the association between variables.ResultsWe identified four clusters: (1)controlled asthma who were physically active, (2)uncontrolled asthma who were physically inactive and more sedentary, (3)uncontrolled asthma with low physical activity, who were also obese and experienced anxiety and/or depression symptoms (4)very uncontrolled asthma, who were physically inactive, more sedentary, obese and experienced anxiety and/or depression symptoms. Higher levels of sedentary time, female sex, and anxiety symptoms were associated with increased odds of exacerbation risk while being more active showed a protective factor for hospitalisation. Asthma control was associated with sex, the occurrence of exacerbation, physical activity, and health-status.ConclusionTraits such as physical inactivity, obesity, and symptoms of anxiety and/or depression were associated with worse asthma outcomes, and closely and inextricably with asthma control. This cluster analysis supports the importance of assessing extrapulmonary traits to improve personalised management and outcomes for people with moderate and severe asthma.

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