Abstract
Monoclonal antibodies targeting IgE or the type-2 cytokines interleukin (IL)-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma, respectively. However, these therapies are not appropriate for 30–50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, “type-2 low” asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, yet poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity and occupational exposures and may be driven by persistent bacterial infections and by activation of a recently described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits that can be identified and addressed. We focus particularly on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally, we review ongoing research into other pathways including tumour necrosis factor, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems; it is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.
Abstract
One-third of severe asthma is type-2 low, presenting a challenge to clinicians. This review provides an overview of the currently available treatment options, other treatable traits and a range of therapies in development. https://bit.ly/2YeNOQd
Footnotes
Number 2 in the series “Innovations in asthma and its treatment” Edited by P. O'Byrne and I. Pavord
Previous articles in this series: No. 1: Asher MI, García-Marcos L, Pearce NE, et al. Trends in worldwide asthma prevalence. Eur Respir J 2020; 56: 2002094.
Author contributions: T.S.C. Hinks, S.J. Levine and G.G. Brusselle jointly conceived the article, conducted the literature review and drafted the manuscript. All authors approved the final manuscript.
Conflict of interest: T.S.C. Hinks reports grants from The Wellcome Trust (Wellcome Trust Fellowships 088365/z/09/z, 104553/Z/14/Z, 211050/Z/18/Z) and the Guardians of the Beit Fellowship (Wellcome-Beit Fellowship 211050/Z/18/A), during the conduct of the study; personal fees for lectures from AstraZeneca and TEVA, personal fees for education presentations from Peer Voice, outside the submitted work.
Conflict of interest: S.J. Levine has nothing to disclose.
Conflict of interest: G.G. Brusselle reports personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, personal fees for advisory board work from Sanofi, outside the submitted work.
Support statement: This work was supported by grants from the Wellcome Trust (104553/z/14/z, 211050/Z/18/z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) (to T.S.C. Hinks), the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (to S.J. Levine), and the BOF19/GOA/008 Concerted Research Action of Ghent University. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 2, 2020.
- Accepted June 1, 2020.
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