Dataset Information

Stratified approaches to the treatment of asthma.

ABSTRACT: While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here, a novel stratified approach to its treatment is reviewed, based upon identification of causal pathways, with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics in moderate to severe asthma as a group have been disappointing. However, subgroup analyses based upon pathway-specific biomarkers suggest specific endotypes that are responsive. Application of hypothesis-free analytical approaches (the 'omics') to well-defined phenotypes is leading to the stratification of asthma along causal pathways. Refinement of this approach is likely to be the future for diagnosing and treating this group of diseases, as well as helping to define new causal pathways. The identification of responders and nonresponders to targeted asthma treatments provides a new way of looking at asthma diagnosis and management, especially with biologics that are costly. The identification of novel biomarkers linked to well-phenotyped patients provides a stratified approach to disease management beyond simple disease severity and involving causal pathways. In order to achieve this effectively, a closer interaction will be required between industry (therapeutic and diagnostic), academia and health workers.

SUBMITTER: Holgate ST

PROVIDER: S-EPMC3731602 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stratified approaches to the treatment of asthma.

Holgate Stephen T ST

British journal of clinical pharmacology 20130801 2

While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here, a novel stratified approach to its treatment is reviewed, based upon identification of causal pathways, with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Despite strong preclinical data for many ...[more]

PMID: 23163316

Similar Datasets

Project description:Noneosinophilic airway inflammation occurs in approximately 50% of patients with asthma. It is subdivided into neutrophilic or paucigranulocytic inflammation, although the proportion of each subtype is uncertain because of variable cut-off points used to define neutrophilia. This article reviews the evidence for noneosinophilic inflammation being a target for therapy in asthma and assesses clinical trials of licensed drugs, novel small molecules and biologics agents in noneosinophilic inflammation. Current symptoms, rate of exacerbations and decline in lung function are generally less in noneosinophilic asthma than eosinophilic asthma. Noneosinophilic inflammation is associated with corticosteroid insensitivity. Neutrophil activation in the airways and systemic inflammation is reported in neutrophilic asthma. Neutrophilia in asthma may be due to corticosteroids, associated chronic pulmonary infection, altered airway microbiome or delayed neutrophil apoptosis. The cause of poorly controlled noneosinophilic asthma may differ between patients and involve several mechanism including neutrophilic inflammation, T helper 2 (Th2)-low or other subtypes of airway inflammation or corticosteroid insensitivity as well as noninflammatory pathways such as airway hyperreactivity and remodelling. Smoking cessation in asthmatic smokers and removal from exposure to some occupational agents reduces neutrophilic inflammation. Preliminary studies of 'off-label' use of licensed drugs suggest that macrolides show efficacy in nonsmokers with noneosinophilic severe asthma and statins, low-dose theophylline and peroxisome proliferator-activated receptor gamma (PPARγ) agonists may benefit asthmatic smokers with noneosinophilic inflammation. Novel small molecules targeting neutrophilic inflammation, such as chemokine (CXC) receptor 2 (CXCR2) antagonists reduce neutrophils, but do not improve clinical outcomes in studies to date. Inhaled phosphodiesterase (PDE)4 inhibitors, dual PDE3 and PDE4 inhibitors, p38MAPK (mitogen-activated protein kinase) inhibitors, tyrosine kinase inhibitors and PI (phosphoinositide) 3kinase inhibitors are under development and these compounds may be of benefit in noneosinophilic inflammation. The results of clinical trials of biological agents targeting mediators associated with noneosinophilic inflammation, such as interleukin (IL)-17 and tumor necrosis factor (TNF)-α are disappointing. Greater understanding of the mechanisms of noneosinophilic inflammation in asthma should lead to improved therapies.

Project description:BackgroundThe diagnosis of asthma in children is challenging and relies on a combination of clinical factors and biomarkers including methacholine challenge, lung function, bronchodilator responsiveness, and presence of airway inflammation. No single test is diagnostic. We sought to identify a pattern of inflammatory biomarkers that was unique to asthma using a targeted metabolomics approach combined with data science methods.MethodsWe conducted a nested case-control study of 100 children living in a peri-urban community in Lima, Peru. We defined cases as children with current asthma, and controls as children with no prior history of asthma and normal lung function. We further categorized enrollment following a factorial design to enroll equal numbers of children as either overweight or not. We obtained a fasting venous blood sample to characterize a comprehensive panel of targeted markers using a metabolomics approach based on high performance liquid chromatography-mass spectrometry.ResultsA statistical comparison of targeted metabolites between children with asthma (n = 50) and healthy controls (n = 49) revealed distinct patterns in relative concentrations of several metabolites: children with asthma had approximately 40-50% lower relative concentrations of ascorbic acid, 2-isopropylmalic acid, shikimate-3-phosphate, and 6-phospho-d-gluconate when compared to children without asthma, and 70% lower relative concentrations of reduced glutathione (all p < 0.001 after Bonferroni correction). Moreover, a combination of 2-isopropylmalic acid and betaine strongly discriminated between children with asthma (2-isopropylmalic acid ≤ 13 077 normalized counts/second) and controls (2-isopropylmalic acid > 13 077 normalized counts/second and betaine ≤ 16 47 121 normalized counts/second).ConclusionsBy using a metabolomics approach applied to serum, we were able to discriminate between children with and without asthma by revealing different metabolic patterns. These results suggest that serum metabolomics may represent a diagnostic tool for asthma and may be helpful for distinguishing asthma phenotypes.

Dataset Information

Stratified approaches to the treatment of asthma.

Publications

Stratified approaches to the treatment of asthma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets