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.

Precision medicine in atopic diseases Purpose of review To analyze the status of precision medicine in atopic diseases. Recent findings Atopic diseases are increasingly recognized as heterogeneous in nature and they can be quite different in severity, response to therapy, triggers, genetic back ground, ancestral risk and type of inflammation. This significant variability in the landscape of atopic diseases is not reflected in the common treatment guidelines that follow ‘one fits all’ approach for their management. Such an approach is largely based on minimal ‘phenotype’ elements, such as severity of disease and response to therapy and does not reflect the information accumulate in the last 20 years about particular pathogenic pathways (endotypes) leading to disease (phenotypes) based on biomolecular analysis of the single individuals. Accumulating data have defined asthma allergic rhinitis, food allergy based on their endotypes and clinically relevant phenotypes. In general, atopic diseases can be largely classified as high or low Th2 inflammatory status, which may explain the severity and response to therapy. Summary Precision medicine is aiming to use known endotype phenotype to guide specific individualized treatment. The work aimed in deep characterization of diseases to guide the disease management is crucial in light of the availability of ever more precise treatment able to target specific pathways. Correspondence to Antonella Cianferoni, Allergy and Immunology Division, Department of Pediatric, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: CIANFERONIA@E-Mail.chop.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Disorders of CTLA-4 expression, how they lead to CVID and dysregulated immune responses Purpose of review The landscape of common variable immunodeficiency disorder (CVID) is rapidly evolving as the availability of next-generation sequencing leads to the discovery of new monogenic causes with the clinical phenotype of CVID. Herein, the biology of cytotoxic T lymphocyte-associated protein four (CTLA-4), differentially expressed in FDCP6 homolog (DEF6), and lipopolysaccharide responsive beige-like anchor protein (LRBA), and their impact on the development of a dysregulated, rather than an isolated, infectious phenotype of CVID are explored. Recent findings The broad clinical phenotype associated with these monogenic forms of CVID is described, and common approaches to treatment are reviewed. Summary Knowledge of the biology, clinical manifestations, and treatment options trialed thus far in patients with CTLA-4 insufficiency, DEF6 deficiency, and LRBA deficiency are essential in the consideration and effective management of patients with CVID stemming from these monogenic causes. Correspondence to Jennifer Heimall, MD, Children's Hospital of Philadelphia, Division of Allergy and Immunology, Wood 3301, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA. Tel: +1 215 590 2549; e-mail: heimallj@email.chop.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clozapine-associated secondary antibody deficiency Purpose of review Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms. Recent findings Individuals with schizophrenia are at two to five times more likely to develop pneumonia than the general population, in particular, when receiving clozapine. Delayed-onset distinguishes clozapine-associated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper–B cell interactions may inform future clinical studies. Summary The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. On the basis of available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as other potentially autoantibody-mediated diseases. Correspondence to Mark J. Ponsford, Immunodeficiency Centre for Wales; Tenovus Institute, Cardiff University, Cardiff, UK. E-mail: ponsfordm@cardiff.ac.uk 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.

Oral and sublingual immunotherapy for food allergy Purpose of review To critically appraise the recent most relevant studies in the rapidly advancing field of food oral and sublingual immunotherapy. Recent findings Food allergen-specific immunotherapy via oral (OIT) and sublingual route (SLIT) increases the threshold of reactivity to peanut, cow's milk, egg, wheat, and many other foods in the majority of the treated individuals. This desensitized state is contingent upon the continued ingestion of the maintenance doses of the food. Permanent oral tolerance is achievable in a smaller subset of the treated individuals. The optimal duration of therapy has not been firmly established but is likely dependent on the phenotype (severity and persistence). Efficacy of food-OIT is superior compared with SLIT, whereas the safety of OIT is less favorable. Standardization of treatment protocols, maintenance dosing, duration of therapy, target populations and harmonization of the outcomes are top priorities at this stage. Summary OIT and SLIT represent two different routes of food allergen-specific immunotherapy. Although significant progress has been made in the last decade, both treatment modalities are still in the very early stages of development and further investigations are necessary to optimize the protocols and improve safety while maximizing efficacy. Correspondence to Anna Nowak-Wegrzyn, MD, PhD, Allergy and Immunology, Department of Pediatrics, NYU Langone Health, New York, New York, USA. E-mail: anna.nowak-wegrzyn@nyulangone.org 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.