The Journal of allergy and clinical immunology
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J. Allergy Clin. Immunol. · Jul 2019
Randomized Controlled TrialA sputum 6-gene signature predicts future exacerbations of poorly controlled asthma.
Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). ⋯ We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.
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J. Allergy Clin. Immunol. · Jul 2019
ReviewPhenotypes and endotypes of adult asthma: Moving toward precision medicine.
Asthma is a chronic inflammatory disease of the airways that is challenging to dissect into subgroups because of the heterogeneity present across the spectrum of the disease. Efforts to subclassify asthma using advanced computational methods have identified a number of different phenotypes that suggest that multiple pathobiologically driven clusters of disease exist. The main phenotypes that have been identified include (1) early-onset allergic asthma, (2) early-onset allergic moderate-to-severe remodeled asthma, (3) late-onset nonallergic eosinophilic asthma, and (4) late-onset nonallergic noneosinophilic asthma. Subgroups of these phenotypes also exist but have not been as consistently identified. ⋯ This has improved the clinician's approach to characterizing asthmatic patients in the clinic. Being able to define asthma endotypes using clinical characteristics and biomarkers will move physicians toward even more personalized management of asthma and precision-based care in the future. Here we will review the most prominent phenotypes and immunologic advances that suggest these disease subtypes represent asthma endotypes.
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Asthma is a highly heterogeneous disease, often manifesting with wheeze, dyspnea, chest tightness, and cough as prominent symptoms. The eliciting factors, natural history, underlying molecular biology, and clinical management of asthma vary highly among affected subjects. Because of this variation, many efforts have gone into subtyping asthma. ⋯ We discuss the application of -omics approaches, including transcriptomics, epigenomics, microbiomics, metabolomics, and proteomics, to asthma endotyping. -Omics approaches have provided supporting evidence for many existing endotyping paradigms and also suggested novel ways to conceptualize asthma endotypes. Although endotypes based on single -omics approaches are relatively common, their integrated multi-omics application to asthma endotyping has been more limited thus far. We discuss paths forward to integrate multi-omics with clinical features and laboratory parameters to achieve the goal of precise asthma endotypes.
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J. Allergy Clin. Immunol. · Jul 2019
ReviewDoes 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. ⋯ 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 in vitro mechanistic studies using human samples and experimental animal models, with technological and methodological advances at its core.