Asthma/obstructive pulmonary disease overlap: update on definition, biomarkers, and therapeutics Purpose of review Asthma/chronic obstructive pulmonary disease overlap (ACO) continues to be a poorly understood condition. This review discusses newly proposed criteria and potential biomarkers in ACO, to aid in diagnosis and research studies, and prudent therapeutic approaches. Recent findings A global expert panel proposed an operational definition consisting of major and minor criteria as a step toward defining ACO. Serum periostin and YKL-40 may serve as biomarkers for ACO. Clinically, a reasonable therapeutic approach to ACO is the early addition of a long-acting β-agonist (LABA) and/or a long-acting muscarinic antagonist (LAMA) to an inhaled corticosteroid (ICS). Summary Both the proposed criteria and the described biomarkers for ACO can help guide clinicians in identifying this condition as well as aid researchers in designing much needed future studies. In the meantime, clinicians can treat potential ACO patients using the above approach, until therapeutic studies in clearly defined ACO patients are performed. Correspondence to John Oppenheimer, MD, Rutgers New Jersey Medical School, The State University of New Jersey, Mailing Address: 8 Saddle Road, Cedar Knolls, NJ 07927, USA. Tel: +1 973-972-2500; fax: +1 973-540-0472; e-mail: nallopp22@gmail.com. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Biologicals for severe asthma: what we can learn from real-life experiences? Purpose of review Severe asthma is a serious disease affecting about 5–10% of asthmatic patients. Often patients with this kind of asthma requires periodical courses or daily intake of oral corticosteroids, to control symptoms. In the last few years several biological drugs have been developed with the aim to decrease exacerbations and reduce or suspend intake of systemic steroids in severe asthmatic patients. Clinical trials demonstrated the efficacy and the safety of biological antibodies in asthma, but it is already known that randomized controlled trials alone are not sufficient to provide complete information on a drug. Recent findings After marketing of monoclonal antibodies has been developed several real-life studies with the aim to observe how drugs, tested only on trial patients, are able to provide adequate effectiveness even on ‘real’ patients; indeed, it is well known that the latter differ in some characteristics from the patients of the trials. Summary The results of this analysis confirm the good efficacy of the biologics similarly in real-life patients, also ensuring a promising safety even in periods of observation longer than those of the randomized controlled trials. Correspondence to Diego Bagnasco, MD, Allergy & Respiratory Diseases, IRCCS Policlinico S. Martino –University of Genoa, Genoa, Italy. E-mail: dott.diegobagnasco@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Systemic biomarkers of eosinophilic chronic rhinosinusitis Purpose of review The current understanding of eosinophilic chronic rhinosinusitis (CRS) has developed rapidly over the past decades. Classification of CRS based on the inflammatory endotype more accurately reflects the underlying pathophysiology and better directs treatment. Corticosteroids and more recently biologic agents, target the eosinophil inflammatory that drives this subtype of CRS. Tissue sampling is not always accessible or available and surrogate markers are sought to define this endotype of CRS. The purpose of this review is to assess current systemic predictors of eosinophilic CRS (eCRS) diagnosis. Recent findings Blood eosinophils are a moderate surrogate predictor of eCRS. A blood eosinophil count of more than 0.24 × 109/l predicts eCRS with tissue eosinophilia of more than 10 eosinophils per high-power field. It has been further shown that a blood eosinophil count more than 0.45 × 109/l is associated with need for long-term systemic therapy following endoscopic sinus surgery. Other biomarkers reviewed include IgE, eosinophilic cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, IL-5, periostin, eotaxin-3 and IL-16. Summary There remains limited data surrounding the prognostic use of biomarkers in eCRS. However, peripheral eosinophilia best predicts the eosinophilic density that best predicts the eCRS phenotype. In addition, it is also prognostic of need for more intensive therapy. Simple haematoxylin and eosin stained sinus mucosa still remains the most reliable tissue for assessment and is more accessible than bronchial biopsies Correspondence to Jacqueline Ho, 67 Burton Street, Darlinghurst 2010, NSW, Australia. Tel: +61 293604811; fax: +61 293609919; e-mail: drjacquelineho@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Mechanisms of allergy and adult asthma Purpose of review Allergic asthma reflects the interplay between inflammatory mediators and immune, airway epithelial, and other cells. This review summarizes key insights in these areas over the past year. Recent findings Key findings over the past year demonstrate that epithelial cells mediate tight junction breakdown to facilitate the development of asthma-like disease in mice. Innate lymph lymphoid cells (ILC), while previously shown to promote allergic airway disease, have now been shown to inhibit the development of severe allergic disease in mice. Fibrinogen cleavage products (previously shown to mediate allergic airway disease and macrophage fungistatic immunity by signaling through Toll-like receptor 4) have now been shown to first bind to the integrin Mac-1 (CD11c/CD18). Therapeutically, recent discoveries include the development of the antiasthma drug PM-43I that inhibits the allergy-related transcription factors STAT5 and STAT6 in mice, and confirmatory evidence of the efficacy of the antifungal agent voriconazole in human asthma. Summary Studies over the past year provide critical new insight into the mechanisms by which epithelial cells, ILC, and coagulation factors contribute to the expression of asthma-like disease and further support the development antiasthma drugs that block STAT factors and inhibit fungal growth in the airways. Correspondence to Evan Li, MD, Department of Medicine, Biology of Inflammation Center, Baylor College of Medicine, One Baylor Plaza Suite M915, Houston, TX 77030, USA. Tel: +1 713 798 3090; e-mail: evanli44@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Systemic and breath biomarkers for asthma: an update Purpose of review Finding suitable biomarkers to phenotype asthma, identify individuals at risk of worsening and guide treatment is highly prioritized in asthma research. We aimed to provide an analysis of currently used and upcoming biomarkers, focusing on developments published in the past 2 years. Recent findings Type 2 inflammation is the most studied asthma mechanism with the most biomarkers in the pipeline. Blood eosinophils and fractional exhaled nitric oxide (FeNO) are those most used clinically. Recent developments include their ability to identify individuals at higher risk of exacerbations, faster decline in lung function and more likely to benefit from anti-IL-5 and anti-IL-4/-13 treatment. Certain patterns of urinary eicosanoid excretion also relate to type 2 inflammation. Results of recent trials investigating the use of serum periostin or dipeptidyl peptidase-4 to guide anti-IL-13 therapy were somewhat disappointing. Less is known about non-type 2 inflammation but blood neutrophils and YKL-40 may be higher in patients with evidence of non-type 2 asthma. Volatile organic compounds show promise in their ability to distinguish both eosinophilic and neutrophilic asthma. Summary The ultimate panel of biomarkers for identification of activated inflammatory pathways and treatment strategies in asthma patients still lies in the future, particularly for non-type 2 asthma, but potential candidates are available. Correspondence to Andrei Malinovschi, MD, PhD, Department of Medical Sciences, Clinical Physiology, Uppsala University, 751 85 Uppsala, Sweden. E-mail: Andrei.Malinovschi@medsci.uu.se Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Differential expression and role of S100 proteins in chronic rhinosinusitis Purpose of review Immune system modulators have been under investigation to help elucidate the underlying pathophysiologies of chronic rhinosinusitis (CRS). Psoriasin (S100A7) and calgranulins (S100A8, S100A9, and S100A12) are S100 proteins that have been studied for their immune-mediating responses to pathogens within the context of CRS. This review highlights the expression patterns and proposed roles of S100 proteins in CRS with (CRSwNP) and without (CRSsNP) nasal polyps. Recent findings Elevated levels of S100A7 and S100A12 were measured in the sinonasal tissues of patients with CRSsNP compared with CRSwNP and controls. S100A12 expression in CRSsNP was significantly correlated to disease severity. Contrastingly, increased S100A8, S100A9, and S100A8/A9 levels were demonstrated in the nasal polyp tissues of patients with CRSwNP compared with those in inferior turbinate and uncinate tissues of patients with CRSsNP and controls. Summary The reported differential expression patterns and activities of psoriasin and calgranulins suggest that S100 proteins exert unique and concerted roles in mediating immunity in different subtypes of CRS. These studies will enable further investigations focused on understanding the immune-modulating mechanisms of S100 proteins in different inflammatory signaling pathways and disease phenotypes of CRS toward the pursuit of identifying new biomarkers and targets for improved outcomes. Correspondence to Jeremiah A. Alt, MD, Ph.D., FACS, University of Utah School of Medicine, Division of Otolaryngology – Head and Neck Surgery, 50 North Medical Drive, Room 3C120, Salt Lake City, UT 84132, USA. Tel.: +1 801 585 7143;. fax: +1 801 585 5744; e-mail: jeremiah.alt@hsc.utah.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Pulmonary rehabilitation: promising nonpharmacological approach for treating asthma? Purpose of review Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation with a history of respiratory symptoms that vary over time and in intensity, together with variable expiratory airflow limitation. The goal of asthma treatment is to reach symptoms control, reduction in future risk and improvement in quality of life (QoL). Guideline-based pharmacologic therapies and the effect of inhaled steroids and bronchodilators have been widely studied over the past decades. We provide an overview of the available evidence on pulmonary rehabilitation as a nonpharmacologic therapy in asthmatic patients. Recent findings Recently, some studies have highlighted the promising role of nonpharmacologic therapies in asthma, such as pulmonary rehabilitation demonstrating that a pulmonary rehabilitation programme consisting of exercise training, breathing retraining, educational and psychological support, improve exercise capacity, asthma control and QoL and reduce dyspnea, anxiety, depression and bronchial inflammation at any step of the disease. Summary Pulmonary rehabilitation shows positive results on exercise tolerance, respiratory symptoms and QoL in asthmatic patients at any steps of the diseases. However, additional information is required to better characterize rehabilitation programmes in order to improve clinical care in asthma. Correspondence to Dina Visca, Istituti Clinici Scientifici Maugeri IRCCS, Respiratory Rehabilitation of the Institute of Tradate, via Roncaccio 16, 21049 Tradate, Varese, Italy. Tel: +39 0331829598; e-mail: dina.visca@icsmaugeri.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of epigenetics in allergy and asthma development Purpose of review Epigenetic mechanisms are known to play a crucial role in the pathogenesis of asthma, allergic rhinitis, atopic dermatitis, food allergy, and other allergic disorders, especially through mediating the effects of the environmental factors, well recognized allergy-risk modifiers. The aim of this work was to provide a concise but comprehensive review of the recent progress in the epigenetics of allergic diseases. Recent findings Recent few years have substantially expanded our knowledge on the role of epigenetics in the pathogenesis and clinical picture of allergies. Specifically, it has been shown that epigenetic marks, especially DNA methylation, possess a diagnostic potential for atopic sensitization, asthma, allergic rhinitis, and food allergy. DNA methylation can be a predictor of clinical responses in controlled allergen challenges, including oral food challenges. Furthermore, direct or indirect targeting epigenetic mechanisms, this time especially histone modifications, was able to favorably affect expression of the genes underlying allergies and generally improve airway biology in allergic diseases or their animal models. Summary Further studies are needed to explore the diagnostic and therapeutic potential of epigenetic modifications in allergies and to develop respective clinical tools. Correspondence to Harald Renz, MD, Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany. Tel: +49 6421 58 66235; fax: +49 6421 58 65594; e-mail: renzh@med.uni-marburg.de Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.co-allergy.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Th2 inflammatory responses in the development of nasal polyps and chronic rhinosinusitis Purpose of review Pathogenesis of nasal polyp has been largely studied based on innate and adaptive immunity of sinonasal mucosa. So far, various factors have been identified that trigger an inflammatory response in the pathogenesis of nasal polyps. In this review, we summarized recently updated information in the understanding of mechanisms in the development of chronic rhinosinusitis with nasal polyp (CRSwNP) focusing on Th2 inflammation. Recent findings Endotype of CRSwNP presented mainly Th2-skewed inflammation, and it has been associated with refractoriness and comorbidities. Staphylococcus aureus can drive Th2 inflammation by producing enterotoxins and serine protease-like protein. Moreover, S. aureus directly affected mucosal barrier function and enhanced Th2 cytokine production by fast induction of epithelial-derived innate cytokines. Epithelial-derived innate cytokines, including TSLP, IL-25, and IL-33, promote Th2 responses via the development of innate lymphoid cells. Mast cell expresses IL-5, IL-13, and periostin, and it plays a role in the pathogenesis of nasal polyps through orchestrating eosinophil infiltration. Formation of eosinophil extracellular traps and Charcot–Leyden crystals is strongly associated with disease severity and viscous mucus plug production. Therefore, it needs to be investigated mechanistically. The role of neutrophils in Th2 inflammation has been poorly understood but appears to enhance Th2 inflammation and make it more resistant to steroid therapy. Summary There is growing evidence of the role of S. aureus in innate and acquired immunity, which contribute to Th2 inflammation in CRSwNP. Innate immunity, including epithelial-derived cytokines, plays a crucial role in the development of CRSwNP by inducing various pathways and need to be investigated more as Th2-targeted biomarkers. Recently, the role of neutrophilic inflammation in Th2 inflammation has started to be studied but still remains unclear. Correspondence to Dae Woo Kim, MD, PhD, Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, 425 Shindaebang 2-dong, Dongjak-gu, Seoul 07061, Korea. Tel: +82 2 870 2446; e-mail: kicubi@daum.net Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Eosinophilic otitis media and comorbid asthma Purpose of review Eosinophilic otitis media (EOM) is an intractable otitis media characterized by numerous eosinophils infiltrating the middle ear cavity, which is part of the upper airway. EOM shows a high rate of comorbidity with asthma. They are considered to have a ‘one airway, one disease’ relationship. Here, we summarize our current knowledge regarding the characteristics of EOM, EOM's relationship with asthma and the efficacy of optimal treatments for EOM. Recent findings The greater the severity of asthma, the more pronounced the development of EOM. Asthma control is usually inadequate in asthmatics who develop EOM, and appropriate strengthening of asthma inhalation therapy leads to improvement in the EOM. EOM severity can be divided into mild, moderate, and severe. Intratympanic infusion therapy using a topical steroid such as triamcinolone acetone is effective for mild EOM, whereas moderate EOM requires a systemic steroid in addition to triamcinolone acetone, and severe EOM forms granulation tissue that requires surgical removal. Recently, the effectiveness of molecularly targeted drugs is being reported, but more data need to be accumulated. Summary EOM and asthma are closely related. Optimal asthma treatment is important for treating EOM. Treatments commensurate with the severity of EOM are being developed. Correspondence to Manabu Nonaka, MD, PhD, Department of Otolaryngology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel: +81 3 3353 8111; fax: +81 3 5269 7617; e-mail: nonaka-m@twmu.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.