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.

Nonsevere combined immunodeficiency T-cell lymphopenia identified through newborn screening Purpose of review Although severe combined immunodeficiency (SCID) is the primary target condition for newborn screening (NBS), over 25 secondary targets, conditions other than SCID, have been identified. There is no standard method for evaluating neonates with non-SCID T-cell lymphopenia (TCL) and no standard approaches to treatment. We will describe these conditions and discuss recommendations for evaluating and follow-up of non-SCID TCL detected by NBS. Recent findings The birth prevalence of non-SCID TCL detected through SCID NBS is higher than SCID and can be a burden on NBS programs. We will present some publications discussing outcomes and comorbidities in these patients. Summary NBS for SCID has been very successful in identifying infants with SCID at birth to institute early life saving therapies. TCL due to other conditions can cause significant immune deficiency and treatment is dependent on the cause of the defect, as well as the magnitude of the immunodeficiency. Data collection from NBS programs should include assessment of various therapies and clinical outcomes. Better systems for recording long-term outcomes of SCID NBS including both SCID and non-SCID conditions should become a priority for NBS programs. This will help to advance the goal of NBS programs: improve outcomes in the most cost-effective manner. Correspondence to Lisa Kobrynski, MD, MPH, Children's Healthcare of Atlanta, Emory University School of Medicine, 2015 Uppergate Dr, Atlanta, GA 30322, USA. Tel: +1 404 727 3575; e-mail: lkobryn@emory.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Duration of allergen immunotherapy for inhalant allergy Purpose of review We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies. Recent findings Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2–4 months’ immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1–2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment. Summary Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance. Correspondence to Prof Stephen R. Durham, Allergy and Clinical Immunology, Division of Respiratory Science, Imperial College London and National Heart and Lung Institute, Royal Brompton Hospital. Dovehouse Street, London, SW3 6LY, United Kingdom. Tel: +44 (0) 207 351 8024; e-mail: s.durham@imperial.ac.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

An update on X-Linked agammaglobulinaemia: clinical manifestations and management Purpose of review X-linked agammaglobulinaemia (XLA) is a congenital defect of development of B lymphocytes leading to agammaglobulinaemia. It was one of the first primary immunodeficiencies described, but treatment has remained relatively unchanged over the last 60 years. This summary aims to outline the current outcomes, treatments and future research areas for XLA. Recent findings Immunoglobulin therapy lacks IgA and IgM, placing patients at theoretical risk of experiencing recurrent respiratory tract infections and developing bronchiectasis despite best current therapy. Recent cohort studies from Italy and the USA conform that bronchiectasis remains a major burden for this group despite best current efforts. However, gene therapy offers a potential cure for these patients with proven proof of concept murine models. Summary The potential limitations of current immunoglobulin therapy appear to be confirmed by recent cohort studies, and therefore further work in the development of gene therapy is warranted. Until this is available, clinicians should strive to reduce the diagnostic delay, regularly monitor for lung disease and individualize target immunoglobulin doses to reduce infection rates for their patients. Correspondence to Benjamin Martin James Shillitoe, MBBS, MRCPCH, Paediatric Immunology, Floor 4, Block 2, Clinical Resource Building, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. E-mail: Benjamin.shillitoe@nhs.net Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Manufacturing and quality assessment of allergenic extracts for immunotherapy: state of the art Purpose of review The recent developments in the manufacturing and quality assessment of allergenic extracts in Europe are summarized. Recent findings Quality assessment has always been a fundamental part of allergen product evaluation. New analytical methods have been reported that fill currently existing gaps in the characterization of commonly used allergen products. New types of products require innovative considerations and concepts for their assessment. Advanced standardization efforts aim at increasing reliability and comparability of analytical tools applied for allergen product characterization. In consequence, regulatory requirements are updated in line with such developments. Summary Current demands on the quality of allergen products ensure production of well characterized products of consistent quality. While experience with manufacturing processes and successful product characterization approaches increase, accompanying and continuous re-evaluation of underlying quality control and assessment concepts is being performed. Correspondence to Stefan Vieths, PhD, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. Tel: +49 6103 77 2000; e-mail: stefan.vieths@pei.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.