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      Asthma Endotyping and Biomarkers in Childhood Asthma

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          Abstract

          Childhood asthma represents a heterogeneous challenging disease, in particular in its severe forms. The identification of different asthma phenotypes has stimulated research in underlying molecular mechanisms, such as the endotypes, and paved the way to the search for related specific biomarkers, which may guide diagnosis, management, and predict response to treatment. A limited number of biomarkers are currently available in clinical practice in the pediatric population, mostly reflecting type 2-high airway inflammation. The identification of biomarkers of childhood asthma is an active area of research that holds a potential great clinical utility and may represent a step forward toward tailored management and therapy: the so-called Precision Medicine. The aim of the present review is to provide an updated overview of asthma endotyping, mostly focusing on novel noninvasive biomarkers in childhood asthma.

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          Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

          Ian D Pavord, Stephanie Korn, Peter Howarth … (2012)
          Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            T-helper type 2-driven inflammation defines major subphenotypes of asthma.

            Prescott G Woodruff, Barmak Modrek, David F Choy … (2009)
            T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination. Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.
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              Type 2 inflammation in asthma--present in most, absent in many.

              John Fahy (2015)
              Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)--has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.
              Article 0 comments Cited 490 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pediatr Allergy Immunol Pulmonol
                Journal ID (iso-abbrev): Pediatr Allergy Immunol Pulmonol
                Journal ID (publisher-id): ped
                Title: Pediatric Allergy, Immunology, and Pulmonology
                Publisher: Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                ISSN (Print): 2151-321X
                ISSN (Electronic): 2151-3228
                Publication date (Print): 01 June 2018
                Publication date (Electronic): 01 June 2018
                Publication date PMC-release: 01 June 2018
                Volume: 31
                Issue: 2
                Pages: 44-55
                Affiliations
                [ 1 ]Pediatric Clinic , Fondazione IRCCS San Matteo, Pavia, Italy.
                [ 2 ]Pediatric Allergy, IRCCS Istituto Giannina Gaslini , Genoa, Italy.
                [ 3 ]IRCCS Ospedale Policlinico San Martino , Genoa, Italy.
                Author notes
                [*]Address correspondence to: Giorgio Ciprandi, MD, IRCCS Ospedale Policlinico San Martino Largo Rosanna Benzi, 10, Genoa 16132, Italy

                gio.cip@ 123456libero.it
                Article
                Publisher ID: 10.1089/ped.2018.0886
                DOI: 10.1089/ped.2018.0886
                PMC ID: 6069590
                PubMed ID: 30069422
                SO-VID: d3203013-117d-41dd-a057-9c945159bb73
                Copyright © © Amelia Licari et al., 2018; Published by Mary Ann Liebert, Inc.
                License:

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

                History
                Date received : 05 February 2018
                Date accepted : 23 March 2018
                Page count
                Figures: 1, Tables: 1, References: 162, Pages: 12
                Categories
                Subject: Review

                Keywords: asthma,children,biomarkers,airway inflammation,eosinophils,exhaled nitric oxide,ige
                Data availability:
                Keywords: asthma, children, biomarkers, airway inflammation, eosinophils, exhaled nitric oxide, ige

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