The impact of comorbidities on severe asthma Purpose of review Severe asthma is often associated with numerous comorbidities that complicate disease management and affect patient's outcomes. They contribute to poor disease control and mimic asthma symptoms. Although some comorbidities such as obstructive sleep apnea, bronchiectasis, and chronic obstructive pulmonary disease are generally well recognized, many other may remain undiagnosed but may be detected in an expert specialist setting. The management of comorbidities seems to improve asthma outcomes, and optimizes therapy by avoiding overtreatment. The present review provides recent knowledge regarding the most common comorbidities which are associated with severe asthma. Recent findings Comorbidities are more prevalent in severe asthma than in mild-to-moderate disease or in the general population. They can be grouped into two large domains: the pulmonary domain and the extrapulmonary domain. Pulmonary comorbidities include upper respiratory tract disorders (obstructive sleep apnea, allergic and nonallergic rhinitis, chronic rhinosinusitis, nasal polyposis) and middle/lower respiratory tract disorders (chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis and fungal sensitization, bronchiectasis, dysfunctional breathing). Extrapulmonary comorbidities include anxiety, depression, gastro-esophageal reflux disease, obesity, cardiovascular, and metabolic diseases. Summary The identification of comorbidities via multidimensional approach is needed to initiate appropriate multidisciplinary management of patients with severe asthma. Correspondence to Paola Rogliani, Department of Experimental Medicine, Via Montpellier 1, 00133 Rome, Italy. Tel: +39 06 2090 4656; fax: +39 06 2090 4656; e-mail: paola.rogliani@uniroma2.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Precision medicine and treatable traits in chronic airway diseases - where do we stand? Purpose of review To provide an update on the implementation of precision medicine, based on treatable traits and mechanisms, in the daily clinical management of chronic airways diseases. Recent findings Recent insights into the complex and heterogeneous nature of chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma identified several clinical and inflammatory phenotypes. This shifted the management focus of these diseases away from the prototypic disease labels and paved the way for developing novel targeted therapies. The concept of precision medicine aims to link the right patient to the right treatment, while minimizing the risk of adverse effects. Several treatable features (’treatable traits’) have now been identified for these chronic airway diseases, including pulmonary, extra-pulmonary, and psychological/lifestyle/environmental traits. As the next step, innovative detection techniques should clarify underlying mechanisms and molecular pathways of these treatable traits and novel reliable point-of-care (composite) biomarkers to help predict responders to targeted therapies must be developed. Summary Precision medicine links the right patient to the right treatment. Identification of treatable traits in asthma and COPD will help optimize the treatment approach in these heterogeneous diseases. Furthermore, in-depth identification of underlying molecular pathways and reliable biomarkers in chronic airways diseases to guide targeted treatment in individual patients is in progress. Correspondence to Charlotte Suppli Ulrik, MD, DMSc, FERS, Department of Respiratory Medicine, Hvidovre Hospital, Respiratory Research Unit, DK-2650 Hvidovre. e-mail: csulrik@dadlnet.dk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The burden of corticosteroid overload in severe and difficult to treat asthma: how to reduce this? Purpose of review Severe asthma is a serious condition that requires an individualized approach combining several treatment agents administered simultaneously in order to reach adequate control. Glucocorticosteroid treatment, as the cornerstone of asthma pharmacotherapy, has great disease-controlling capability, although it may induce a vast amount of severe adverse effects. This review describes our current knowledge of the monitoring and managing options of these adverse effects and possibilities to prevent them, including new therapeutic options. Recent findings A large amount of new drugs is emerging, which may offer a better control of glucocorticosteroid-induced adverse effects. At the same time, major achievements in our understanding of the underlying mechanisms in severe asthma and in the field of biologic agents may help to substantially reduce the need of glucocorticosteroids in the first-line treatment. Summary We discuss new insights and approaches to treatment strategy of severe asthma allowing less oral glucocorticosteroid use and hence, substantial less severe adverse effects of the treatment. Correspondence to Tomas Slisz, MD, Department of respiratory Medicine, 1st Faculty of Medicine of Charles University and Thomayer Hospital, Videnska 800, 140 59, Prague 4, Czech Republic. Tel: +42 0261082373; e-mail: tomas.slisz@ftn.cz Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Precision medicine in severe pediatric asthma: opportunities and challenges Purpose of review Severe pediatric asthma exerts a substantial burden on patients, their families and society. This review provides an update on the latest insights and needs regarding the implementation of precision medicine in severe pediatric asthma. Recent findings Biologicals targeting underlying inflammatory pathways are increasingly available to treat children with severe asthma, holding the promise to enable precision medicine in this heterogeneous patient population with high unmet clinical needs. However, the current understanding of which child would benefit from which type or combination of biologicals is still limited, as most evidence comes from adult studies and might not be generalizable to the pediatric population. Studies in pediatric severe asthma are scarce due to the time-consuming effort to diagnose severe asthma and the challenge to recruit sufficient study participants. The application of innovative systems medicine approaches in international consortia might provide novel leads for – preferably noninvasive – new biomarkers to guide precision medicine in severe pediatric asthma. Summary Despite the increased availability of targeted treatments for severe pediatric asthma, clinical decision-making tools to guide these therapies are still lacking for the individual pediatric patient. Correspondence to Dr Susanne J.H. Vijverberg, Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, PO Box 22700, 1105 AZ Amsterdam, the Netherlands. Tel: +31 20 566 27 63; e-mail: s.j.vijverberg@amsterdamumc.nl This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ecological interactions in asthma: from environment to microbiota and immune responses Purpose of review Asthma is a heterogeneous condition shaped not only by genetics but also host conditioning by environmental factors. Recognizing the ecological context of microbe-immune interactions across environments and body sites is a necessary step toward better understanding how human microbiota influence or drive the pathogenesis and pathophysiology of asthma in its various presentations. Recent findings There is increasing evidence of a critical role for microbiota in asthma pathogenesis and outcomes across various body compartments, including the upper and lower airways, and gut. We discuss recent studies from this area including: development of a method to quantify microbial farm-effect in nonfarm environments, relationships between environmental microbial exposures and asthma prevalence across different geographies, microbiome-mediated responses to ozone, and microbiome-immune interactions within and across body compartments. Beyond bacteria, recent reports of asthma-associated differences in archaea and fungal organisms also are highlighted. Summary Collective evidence warrants application of an ecological framework to advance mechanistic insights into microbiota-immune interactions in asthma. This is necessary to achieve goals of developing successful therapeutic interventions targeting modification of microbiomes. Correspondence to Yvonne J. Huang, MD, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109-5642, USA. Tel: +1 734 936 5047; e-mail: yvjhuang@umich.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Anti-alarmin approaches entering clinical trials Purpose of review The alarmins, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, are upstream regulators of T2 (type 2) inflammation and found to be expressed at high levels in airway epithelium of patients with T2 asthma. This review will summarize how alarmins regulate the inflamed asthmatic airways through previously described and newly identified mechanisms. Recent findings Alarmins drive allergic and nonallergic asthma through activation of innate lymphoid cell 2 (ILC2), which are a rich source of cytokines such as IL-5 and IL-13, with resulting effects on eosinophilopoeisis and remodelling, respectively. Findings from bronchial allergen challenges have illustrated widespread expression of alarmins and their receptors across many effector cells in airways, and recent studies have emphasized alarmin regulation of CD4+ T lymphocytes, eosinophils and basophils, and their progenitors. Furthermore, a link between alarmins and lipid mediators is being uncovered. Summary Alarmins can drive well defined inflammatory pathways through activation of dendritic cells and polarizing T cells to produce type 2 cytokines, as well as they can directly activate many other effector cells that play a central role in allergic and nonallergic asthma. Clinical trials support a central role for TSLP in driving airway inflammation and asthma exacerbations, while ongoing trials blocking IL-33 and IL-25 will help to define their respective role in asthma. Correspondence to Gail M. Gauvreau, McMaster University, 1200 Main St W., HSC 3U26, Hamilton, ON L8N 3Z5, Canada. Tel: +1 905 525 9140 x22791; e-mail: gauvreau@mcmaster.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.