Allergy and Clinical Immunology

Drug hypersensitivity in HIV infection Purpose of review Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS. Recent findings Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight. Summary IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches. Correspondence to Professor Jonny Peter, Division of Allergy and Clinical Immunology, H52 Old Main Building, Groote Schuur Hospital, Observatory, 7925 Cape Town, South Africa. E-mail: Jonny.Peter@uct.ac.za Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Highlights in allergic contact dermatitis 2018/2019 Purpose of review The purpose was to highlight recent findings especially concerning new and old allergens, trends, diagnosis and causes of contact allergy. Recent findings Nickel is still the most frequent cause of contact allergy in women and piercings remain an important risk factor. Countries with a long history of regulation of contact allergens have the lowest level of contact allergy to nickel and chromium in Europe. Among the most frequent causes of fragrance contact allergy is terpenes, which are oxidized such as limonene, linalool and in some countries: geraniol. Methylisothiazolinone is still causing considerable problems due to hidden exposures. Acrylates are emerging allergens and 2-hydroxyethyl methacrylate has been included in the 2019 update of the baseline series, as many new cases are seen due to long-lasting nail polish based on acrylates and glue (isobornyl acrylate) in insulin pumps. More than 10 new allergens have been described, which need to be considered in diagnosing contact allergy. Summary Allergic contact dermatitis is a frequent problem, it also constitutes a challenge to diagnose due to many potential contact allergens. The main culprit allergens remain the same, new significant causes are found especially within acrylates. Correspondence to Jeanne D. Johansen, DMSc, Professor, Consultant, Department of Dermatology and Allergy, National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark. Tel: +45 38677301; e-mail: Jeanne.duus.johansen@regionh.dk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Dupilumab after the 2017 approval for the treatment of atopic dermatitis: what's new and what's next? Purpose of review The IL-4/13 antagonist dupilumab was approved in 2017 as the first biologic for atopic dermatitis. Here, we comprehensively review compelling new data regarding dupilumab published following the approval. Recent findings Daily clinical practice reports of dupilumab in atopic dermatitis are favorable and in line with the registration trials. Dupilumab does not appear to negatively affect pharmacokinetics of CYP450-metabolized drugs nor vaccination responses. Type 2 inflammation biomarkers in skin and serum are reduced following dupilumab treatment. Dupilumab increases the risk for conjunctivitis, especially with higher baseline atopic dermatitis severity and a history of conjunctivitis, but the underlying mechanisms are unknown. Favorable effects of dupilumab have been reported in treatment-recalcitrant hand eczema and prurigo nodularis cases; for allergic contact dermatitis and alopecia areata, there are conflicting responses to dupilumab, possible stemming from pathophysiological heterogeneity. Summary Daily practice data support the continued use of dupilumab for atopic dermatitis. The only safety signal is an increased risk for conjunctivitis; mechanistic studies into dupilumab-associated conjunctivitis should lead to risk mitigation strategies. Prospective, controlled evaluations are needed for dupilumab in hand eczema and prurigo nodularis. A precision medicine-driven drug-development approach is essential to assess dupilumab for diseases with heterogeneous pathophysiologies, such as alopecia areata and allergic contact dermatitis. Correspondence to Deepak M.W. Balak, MD, PhD, MSc, National Expertise Center for Atopic Dermatitis, Department of Dermatology and Allergology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel: +31 88 75 739 37; e-mail: d.m.w.balak@umcutrecht.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Neurotrophic factors and nerve growth factor in ocular allergy Purpose of review During allergic reaction, nervous and immune systems mutually interact through release of mediators, including neurotrophic factors and nerve growth factor (NGF). These mediators modulate allergic reaction through binding their receptors expressed by immune and structural cells and by stimulating neuropeptide release by nerves. The role of neuropeptides and NGF has been demonstrated in allergic asthma and rhinitis, and, to a lesser extent, in allergic conjunctivitis. The aim of this review are to elucidate the evidence of the role of NGF and neuropeptides in the pathogenesis of allergic conjunctivitis. Recent findings NGF modulates allergic reaction by stimulating release of cytokines, inflammatory mediators and neuropeptides by immune and structural cells and nerve endings at the site of inflammation. Evidence showed that local and systemic NGF levels increase in patients with allergic conjunctivitis, including allergic rhinoconjuncivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis. We recently described an increase of conjunctival p75NTR expression in patients with allergic rhinoconjuncivitis, and an increase of tear levels of NGF after conjunctival provocation test with allergen. Summary NGF modulates ocular allergic reaction. Increasing understanding of the role of neuropeptides in allergic conjunctivitis may pave the way to the development of novel therapeutic approaches and improvement of patients' management. Correspondence to Professor Alessandro Lambiase, Department of Sense Organs, University Sapienza of Rome, Vilae del Policlinico, 155, 00161 Rome, Italy. Tel: +39 064 997 5357; e-mail: alessandro.lambiase@uniroma1.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 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.

Alexandros Sfakianakis
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