The different faces of the macrophage in asthma Purpose of review Asthma is a chronic inflammatory disease in which changes in macrophage polarization have been shown to contribute to the pathogenesis. The present review discusses the contribution of changes in macrophage function to asthma related to polarization changes and elaborates on possible therapeutic strategies targeting macrophage function and polarization. Recent findings Macrophage function alterations were shown to contribute to asthma pathology in several ways. One is by impaired phagocytosis and efferocytosis. Another is by changing inflammation, by altered (anti)inflammatory cytokine production and induction of the inflammasome. Finally, macrophages can contribute to remodeling in asthma, although little evidence is present in humans yet. Novel therapeutic strategies targeting macrophages include dampening inflammation by changing polarization or by inhibiting the NLRP3 inflammasome, and by targeting efferocytosis. However, many of these studies were performed in animal models leaving their translation to the clinic for future research. Summary The present review emphasizes the contribution of altered macrophage function to asthma, gives insight in possible new therapeutic strategies targeting macrophages, and indicates which knowledge gaps remain open. Correspondence to Barbro N. Melgert, Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Tel: +31-50-3632947; e-mail: b.n.melgert@rug.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.

Long and winding road: from infant wheeze to adult asthma Purpose of review This review aims to recognize the multifactorial cause of asthma, from the influence of mother until adulthood, highlight the main characteristics of the disease at different ages and summarize the evidence of potential prevention strategies. Recent findings To date, regarding the prenatal period, the presence of specific genes, maternal asthma, drugs, and tobacco exposure are the most relevant predisposing features for an asthmatic offspring. For newborns, preterm, bronchopulmonary dysplasia, and low birth weight has been associated with low lung function. Among young children, atopic dermatitis, lower respiratory tract infections, and increased levels of total Immunoglobulin E (IgE) and allergen-specific IgE are important determinants. Breastfeeding has been demonstrated being protective for the onset of asthma. Allergen immunotherapy has also been shown to have significant preventive effect decreasing asthma development. Inhaled corticosteroids use in early childhood prevents exacerbations but does not alter the natural history of asthma. Other interventions, such as the use of palivizumab, probiotics, vitamin D supplementation, and fish consumption presented controversial results. Summary A good knowledge of risk factors for asthma development, from prenatal period to adulthood, may lead to efficacious preventive strategies. Further data of long-term follow-up in population-based studies according to different phenotypes are needed. Correspondence to Silvia Sánchez-García, MD, PhD, Allergy Department, Hospital Infantil Universitario Niño Jesús, Avda Menendez Pelayo 65, 28009 Madrid, Spain. Tel: +34 91 503 59 35; e-mail: ssanchez@salud.madrid.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Epithelial dysfunction in chronic respiratory diseases, a shared endotype? Purpose of review Epithelial barrier defects are being appreciated in various inflammatory disorders; however, causal underlying mechanisms are lacking. In this review, we describe the disruption of the airway epithelium with regard to upper and lower airway diseases, the role of epigenetic alterations underlying this process, and potential novel ways of interfering with dysfunctional epithelial barriers as a novel therapeutic approach. Recent findings A defective epithelial barrier, impaired innate defence mechanisms or hampered epithelial cell renewal are found in upper and lower airway diseases. Barrier dysfunction might facilitate the entrance of foreign substances, initiating and facilitating the onset of disease. Latest data provided novel insights for possible involvement of epigenetic alterations induced by inflammation or other unknown mechanisms as a potential mechanism responsible for epithelial defects. Additionally, these mechanisms might precede disease development, and represent a novel therapeutic approach for restoring epithelial defects. Summary A better understanding of the role of epigenetics in driving and maintaining epithelial defects in various inflammatory diseases, using state-of-the-art biology tools will be crucial in designing novel therapies to protect or reconstitute a defective airway epithelial barrier. Correspondence to Brecht Steelant, PhD, KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Herestraat 49, box 811, 3000 Leuven, Belgium. Tel: +32 16 34 61 65; fax: +32 16 34 60 35; e-mail: brecht.steelant@kuleuven.be Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Small airway disease in chronic obstructive pulmonary disease: insights and implications for the clinician Purpose of review Small airway disease (SAD) is a common feature in chronic obstructive pulmonary disease (COPD) patients. Chronic exposure to cigarette smoking causes inflammation, damage, tissue remodelling and eventually airway loss. These features lead to airflow limitation and defective alveolar ventilation. The aim of this review is to provide clinicians with an up-to-date perspective of SAD in COPD. Recent findings In this review, we will discuss the key pathological features of SAD. We also review state-of-the-art techniques for measuring SAD, including impulse oscillometry and lung imaging methods. We discuss emerging concepts such as SAD in the earlier stages of COPD and the relationship between SAD and emphysema. Summary The current review highlights the importance of targeting small airways early in the course of COPD to tackle disease progression. Correspondence to Dave Singh, The University of Manchester, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. Tel: +44 161 946 4050; e-mail: DSingh@meu.org.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Exercise and lifestyle changes in pediatric asthma Purpose of review The purpose of this review is to discuss the most recent studies on lifestyle interventions in pediatric asthma. We include studies on physical activity and exercise, sedentary time, nutrition, behavioral therapy and the role of schools. Recent findings Several small studies in children with asthma suggest that exercise interventions can improve aerobic fitness, asthma symptoms or control and quality of life. Existing evidence supports recommending higher intake of fruits and vegetables for asthma risk and control. In contrast, the ‘Western diet’ – high in refined grains, highly processed foods, red meats and fried foods with low intake of fruits and vegetables – has a proinflammatory effect and may alter microbiota composition leading to worse asthma outcomes. Finally, there are opportunities to utilize schools to promote physical activity, though standardization of asthma management in the schools is needed. Summary Assessing physical activity/fitness levels, sedentary time and nutritional status is important in the management of children with asthma, as they are modifiable factors. Larger rigorous studies evaluating lifestyle interventions are needed to better inform current asthma guidelines as well as to understand the underlying mechanism(s) related to physical activity and diet in asthma. Correspondence to Kim D. Lu, MD, Pediatric Exercise and Genomics Research Center (PERC), Department of Pediatrics, University of California, Irvine School of Medicine, 101 Academy Way, Suite 150, Irvine, CA 92617, USA. E-mail: kdlu@uci.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Lost in transition: biomarkers of remodeling in patients with asthma Purpose of review ‘Biomarkers of remodeling’ represent a loose collection of features referring to several biological adaptations of the lung to cope with stressing factors. In addition, remodel-’ing’ infers a dynamic process that would require a spatiotemporal resolution. This review focuses on different aspects of remodeling in pediatric and adult care. Recent findings This review will cover aspects of pediatric remodeling, adult remodeling and techniques and procedures to adequately assess remodeling across different age spectra. In pediatrics, the onset and first features of remodeling are discussed and the continuation into adolescence is addressed. For adults, this review addresses predominant features of remodeling throughout the adult life span and whether there are currently interventions available to treat or reverse remodeling. Summary The term ‘remodeling’ is often referred to via biomarkers that reflect the endstage of a process, although it rather reflects a continuous process starting in childhood and progressing to all age-levels in patients with asthma. Hence, only few biomarkers or surrogates are able to ‘capture’ its spatiotemporal component, and hardly any are ready for routine use in clinical practice. Given the clinical impact of the remodeling processes, new biomarkers are needed to adequately treat patients with asthma and objectively monitor treatment response beyond symptom control and lung function. Correspondence to Markus Weckmann, Department of Pediatric Pulmonology and Allergology, University Children's Hospital, Ratzeburger Allee 160, 23562 Lübeck, Germany. Tel: +49 451 50042991; e-mail: markus.weckmann@uksh.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

How harmless are E-cigarettes? Effects in the pulmonary system Purpose of review Electronic cigarettes have quickly risen to be the leading alternative nicotine source to tobacco. E-cigarette use is hard to research and regulate because of the novelty and rapid evolution of the devices and E-liquids. Epidemiological data on long-term usage is currently lacking, but in smaller cohort studies we are starting to understand the usage patterns and demographics of users, which differ depending on where the study takes place and the regulatory environment. The present review describes the current knowledge of the effects of E-cigarettes on the pulmonary system and knowledge of their usage patterns worldwide. Recent findings E-cigarette use is continuing to rise in young adults in United States and Canada, but not in United Kingdom. These suggest that regulation is influencing uptake in young adults. If E-cigarettes are to be considered as a harm minimisation smoking cessation product, use in young never smokers must be factored into the risk assessment. A recent surge in cases of lung injury associated with vaping in America has resulted in the definition of vaping associated pulmonary injury, although the exact cause remains unknown. Summary It is our opinion that E-cigarettes can no longer be defined as harmless. Further studies are needed to determine the risks for all populations as it is evident that a large proportion of E-cigarette users are never-smokers, meaning they cannot only be considered from a harm reduction perspective. Correspondence to Jack Bozier, Level 3, 431 Glebe Point Road, Glebe 2037, Australia. Tel: +61 02 9114 0363; fax: +619114 0010; e-mail: Jack.Bozier@sydney.edu.au Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.