Allergy and Clinical Immunology

Role of T cells in non-immediate drug allergy reactions Purpose of review Nonimmediate drug hypersensitivity reactions (NI-DHR) constitute the most complex group of drug allergy, with many drugs involved. Both parent drugs and their reactive metabolites can be implicated. Although with some drugs the number of metabolites is limited, with others it is quite extensive and many still remain to be identified. The diagnostic approaches are insufficient for the diagnosis and realistic approaches that reproduce the pathological response are lacking. Recent findings A wider view has now been considered, with the inclusion of several mechanisms that may contribute to drug hypersensitivity reactions (DHR): the classical hapten hypothesis, the danger signal and the pharmacological interaction. Monitoring the acute response provides relevant information about the mechanisms involved, with the identification of a large number of genes that can be over-expressed or under-expressed in the acute phase of the response. Assessment of risk of developing reactions can be verified by HLA associations. Summary Further knowledge of these NI-DHR, including molecular genetics and transcriptomic analysis, has enabled a better understanding and management of these reactions. Correspondence to E. Gómez, Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Brunngasse, 40. 4153. Reinach. BL., Switzerland. Tel: +41 76 321 40 37; e-mail: enriquegomezalcaide@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Treatable traits in chronic rhinosinusitis with nasal polyps Purpose of review Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory sinonasal disease that deserves a multidisciplinary precision medicine approach. In a precision medicine model, a more pragmatic approach taking in consideration disease features that are potentially treatable should be considered. Recent findings Several treatable traits in CRSwNP can be identified: from disease-related ones, to extra-ENT features, to behavioral and environmental factors. This review article summarizes primarily the recent findings of CRSwNP-related treatable traits and how they can be modified by given treatments. Summary The advent of biological agents acting directly to the endotype underlying CRSwNP pushes the scientific community to integrate clinical, surgical and immunological evaluations for each single patient; this naturally leads to the identification of specific treatable traits that can serve as possible outcomes for any single biological. Correspondence to Enrico Heffler, Personalized Medicine, Asthma and Allergy, Humanitas University, Via Rita Levi Montalcini 4; 20089 - Pieve Emanuele, Milan, Italy. Tel: +39 0282247013; e-mail: heffler.enrico@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cutaneous drug hypersensitivity: developments and controversies Purpose of review Cutaneous drug hypersensitivity reactions (CDHRs) are a complicated area with multiple clinical manifestations and differential diagnoses, requiring differentiated diagnostic measurements and optimized therapeutic management. Recent findings Disseminated CDHRs to classical drugs can be classified by a simple algorithm, whereas chemotherapeuticals or biopharmaceuticals may show drug-specific and atypical clinical presentations. Controversies in drug hypersensitivity diagnosis exist about the benefit and accuracy of in-vitro tests. Although skin tests are the best means of detecting sensitization to drugs, methods have not been sufficiently standardized. The necessity for skin tests before performing drug provocation test (DPT) and of prolonged DPTs is discussed in selected patients. If a suspicion has been documented, β-lactam allergy should be excluded. The standard allergy diagnosis is done by an allergist. In case of urgent need because of an infection and low risk according to history, faster delabeling pathways have been developed. There is weak evidence that patients with mastocytosis may have a slightly increased risk of developing immediate-type drug hypersensitivity; however, if considerations are taken, drugs do not have to be withheld for this patient group. There is particular need for improved diagnostic measurements in patients with drug-induced severe cutaneous adverse reactions (SCARs), both identifying the offending drug and detecting individuals at risk. Further challenges encompass appropriate treatments during the acute as well as chronic phase of SCARs. Summary Recent literature has contributed to our understanding of clinical manifestations and existing controversies and future needs in this area. Correspondence to Knut Brockow, Department of Dermatology and Allergology Biederstein, School of Medicine, Technical University Munich, Biedersteiner Str. 29, 80802 München, Germany. Tel:+ 0049 89 4140 3182; fax+: 0049 89 4140 3127; e-mail: knut.brockow@tum.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

New phenotypes in hypersensitivity reactions to nonsteroidal anti-inflammatory drugs Purpose of review Nonsteroidal anti-inflammatory drug (NSAID) is one of the most frequently prescribed medications in the medical field, and hypersensitivity to NSAID is a common adverse drug reaction encountered. However, NSAID hypersensitivity presents a variety of symptoms caused by diverse pharmacological and immunological mechanisms. Recent findings Owing to the heterogeneity of the disease, a new concept for the classification of NSAID hypersensitivity has recently been proposed to diagnose and manage NSAID hypersensitivity for personalized treatment. Acute and delayed reactions were distinguished in this classification, and identification of symptoms and speculation of putative mechanisms help physicians make the right diagnosis. NSAID-exacerbated respiratory disease is a noticeable phenotype of NSAID hypersensitivity that involves upper airway comorbidities (chronic rhinosinusitis with nasal polyps) as well as asthmatic features. The cutaneous phenotypes of NSAID hypersensitivity occur, and cross-reactivity with other types of NSAID should be considered in establishing a proper diagnosis. Hypersensitivity to a single NSAID can present urticaria/angioedema and anaphylaxis, in which an IgE-mediated immune response is suggested to be a prime mechanism. Management of NSAID hypersensitivity reactions includes avoidance, pharmacological treatment following standard guidelines, and aspirin desensitization. Summary The classification, diagnosis, and management of NSAID hypersensitivity should be individually reached by identifying its phenotype. Correspondence to Hae-Sim Park, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea. Tel: +82 31 219 5150; fax: +82 31 219 5154; e-mail: hspark@ajou.ac.kr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Microbiome and skin biology Purpose of review The skin is home to a diverse milieu of bacteria, fungi, viruses, bacteriophages, and archaeal communities. The application of culture-independent approaches has revolutionized the characterization of the skin microbiome and have revealed a previously underappreciated phylogenetic and functional granularity of skin-associated microbes in both health and disease states. Recent findings The physiology of a given skin-niche drives the site-specific differences in bacterial phyla composition of healthy skin. Changes in the skin microbiome have consistently been associated with atopic dermatitis. In particular, Staphylococcus aureus overgrowth with concomitant decline in Staphylococcus epidermidis is a general feature associated with atopic dermatitis and is not restricted to eczematous lesions. Changes in fungal species are now also being described. Changes in the composition and metabolic activity of the gut microbiota are associated with skin health. Summary We are now beginning to appreciate the intimate and intricate interactions between microbes and skin health. Multiple studies are currently focused on the manipulation of the skin or gut microbiome to explore their therapeutic potential in the prevention and treatment of skin inflammation. Correspondence to Liam O'Mahony, Office 450, 4th Floor Food Science and Technology Building, University College Cork, Cork, Ireland. Tel.: +353 21 4901316;. e-mail: liam.omahony@ucc.ie Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Recombinant allergens for immunotherapy: state of the art Purpose of review More than 30 years ago, the first molecular structures of allergens were elucidated and defined recombinant allergens became available. We review the state of the art regarding molecular AIT with the goal to understand why progress in this field has been slow, although there is huge potential for treatment and allergen-specific prevention. Recent findings On the basis of allergen structures, several AIT strategies have been developed and were advanced into clinical evaluation. In clinical AIT trials, promising results were obtained with recombinant and synthetic allergen derivatives inducing allergen-specific IgG antibodies, which interfered with allergen recognition by IgE whereas clinical efficacy could not yet be demonstrated for approaches targeting only allergen-specific T-cell responses. Available data suggest that molecular AIT strategies have many advantages over allergen extract-based AIT. Summary Clinical studies indicate that recombinant allergen-based AIT vaccines, which are superior to existing allergen extract-based AIT can be developed for respiratory, food and venom allergy. Allergen-specific preventive strategies based on recombinant allergen-based vaccine approaches and induction of T-cell tolerance are on the horizon and hold promise that allergy can be prevented. However, progress is limited by lack of resources needed for clinical studies, which are necessary for the development of these innovative strategies. Correspondence to Rudolf Valenta, MD, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel: +43 140400 51080; e-mail: Rudolf.valenta@meduniwien.ac.at Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Use of biologics in chronic sinusitis with nasal polyps Purpose of review Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory condition with different endotypes between patients from eastern or western countries. Targeted biologics are currently used to treat CRSwNP, but the outcomes widely vary. This review focuses on the present use of biologics for treating CRSwNP. Recent findings Monoclonal biologics have been used as an innovative therapy for multiple allergic diseases and comorbid allergic conditions. Over the past several decades, numerous biomarkers have been investigated and were found to be closely correlated with CRSwNP, improving the understanding of inflammatory patterns and endotype classifications for CRSwNP and prompting discussion regarding the use of biologics in CRSwNP. Efficacies vary in reports of different research groups, but it has been found that patients with TH-2-driven inflammatory patterns respond better to the use of biologics than those with non-TH-2-driven CRSwNP. These findings suggest the importance and urgency of developing criteria for biologics in CRSwNP. Summary Precisely determining patient criteria, identifying treatment biomarkers based on endotyping for CRSwNP and determinations of contraindications for long-term utilization may be useful for optimizing treatment strategies and improving the therapeutic efficacy of biologics to achieve long-term control starting at early stages. Correspondence to Luo Zhang, MD, PhD, Beijing TongRen Hospital, Capital Medical University, No. 1, DongJiaoMinXiang, DongCheng District, Beijing, China. Tel: +86 13910830399; e-mail: dr.luozhang@139.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Therapeutic approach of anaphylaxis Purpose of review Anaphylaxis is a recognized cause of death in all ages, which requires prompt recognition and treatment. We here propose to review the current and new pharmacological treatment of anaphylaxis in the view of the new knowledge in the field that can support the quality practice and empower allergists and health professionals with new tools that can be used to treat symptoms and prevent anaphylaxis. Recent findings The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and application of precision medicine. Several biologic therapies and new devices are emerging as potential preventive treatment for anaphylaxis. Summary Adrenaline (epinephrine) is still the first-line treatment for any type of anaphylaxis and is recognized as the only medication documented to prevent hospitalizations, hypoxic sequelae and fatalities. β2-adrenergic agonists and glucagon remains as the second-line treatment of anaphylaxis, meanwhile glucocorticoids and antihistamines should be used only as third-line treatment. Their administration should never delay adrenaline injection in anaphylaxis. More intuitive adrenaline autoinjectors design and features are required as well as a worldwide availability of adrenaline autoinjectors. Biological drugs, such as omalizumab, have been used as therapeutic adjuvants as a preventive treatment of anaphylaxis, but cost-effectiveness should be considered individually. Understanding the specifications of underlying mechanisms can potentially support improvements in the patients' allergological work-up and open the opportunity of developments of potential new drugs, such as biological agents. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among healthcare providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality. Correspondence to Luciana Kase Tanno, MD, PhD, Department of Pulmonology, Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, 371, av. du Doyen Gaston Giraud 34295, Montpellier Cedex 5, France. Tel: +33 467336107; fax: +33 467633645; e-mail: luciana.tanno@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Eosinophilic esophagitis during sublingual and oral allergen immunotherapy Purpose of review The aim of this review is to discuss the current evidence regarding the development of eosinophilic esophagitis (EoE) in individuals undergoing oral and sublingual immunotherapy (SLIT) for both food and environmental allergens. Cumulative incidence of EoE in patients on allergen immunotherapy for peanut, milk, and egg is estimated. Recent findings De novo development of EoE in patients undergoing oral and SLIT has been demonstrated on the scale of case reports and prospective randomized trials. However, few individuals with EoE-like symptoms during immunotherapy undergo endoscopy, and the long-term outcomes of immunotherapy-associated EoE are unknown. Summary Evidence exists to suggest that allergen immunotherapy could place individuals at risk for the development of EoE, the true incidence of which may vary depending on antigen exposure and methods used to define the condition. Correspondence to Jonathan M. Spergel, MD, PhD, Division of Allergy and Immunology, Children's Hospital of Philadelphia, The Wood Building, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA. Tel: +1 215 590 2549; fax: +1 215 590 6849; e-mail: spergel@email.chop.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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