Pathogenesis and complications of chronic eye rubbing in ocular allergy, Purpose of review To review the updated literature regarding eye rubbing complications and its association with ocular allergy disorders. Recent findings Atopy and ocular allergy disorders, mainly vernal keratoconjunctivitis (VKC), are strongly associated with rubbing-related complications, most probably via itching and watery eye sensations that trigger the habit of chronic eye rubbing. Vigorous and prolonged rubbing may lead to establishment of corneal remodeling and ectatic disorders, such as keratoconus. Keratoconus development in rubbed eyes can be caused by mechanical mechanisms of corneal thinning and its loss of rigidity, by elevated temperature of the epithelium during rubbing, by increased intraocular pressure (IOP) because of distending forces, and by inflammatory molecules that may serve as a causal mediator between eye rubbing and keratoconus. Other eye rubbing complications include acute hydrops and perforation, IOP spikes, iris prolapse and iridoschisis rupture of lens capsule and IOL dislocation, and even posterior segment disorders, such as glaucomatous optic neuropathy, retinal detachment and extrusion of implanted silicone oil in the eye. Summary Chronic eye rubbing in allergic eye diseases can lead to progression of keratoconus, and to other rare anterior and posterior segment complications. Strategies eliminating eye rubbing and its consequences are vital, mainly among at-risk populations, such as young children and individuals with allergic ocular disorders or corneal transplants. Correspondence to Abraham Solomon, MD, Department of Ophthalmology, Hadassah Medical Center, POB 12000, Jerusalem 91120, Israel. Tel: +972 50 7874664; e-mail: dr.avi.solomon@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of component-resolved diagnosis in Hymenoptera venom allergy Purpose of review Component-resolved diagnostics (CRD) is a new tool aiming at detecting IgE-mediated sensitizations against individual, relevant allergens. Here, we discuss recent literature on molecular diagnosis in the field of Hymenoptera venom allergy (HVA) as well as CRD strengths and weaknesses. Recent findings CRD, using single molecules or panels of allergens, may discriminate between primary sensitization and cross-reactivity in patients with double/multiple positivity in diagnostic tests with whole extracts, allowing the specialist to choose the most suitable venom for specific immunotherapy (VIT), avoiding unnecessary VIT and reducing the risk of side effects. Future availability of the cross-reactive recombinant pairs of allergens of different species may further increase the diagnostic performance. CRD may be useful in patients with negative allergy tests and a proven history of a previous systemic reaction, including those with mast cell disorders, who could benefit from VIT. In honeybee venom allergy, different sensitization profiles have been identified, which could be associated with a greater risk of VIT failure or treatment side effects. Summary CRD is undoubtedly an innovative diagnostic method that leads to a more precise definition of the sensitization profile of the HVA patient. Together with a better knowledge of the molecular composition of different venom extracts, CRD may contribute to optimize patient-tailored therapy. Correspondence to Maria B. Bilò, MD, Allergy Unit, Department of Internal Medicine, University Hospital Ospedali Riuniti di Ancona, - Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60026, Italy. Tel +39 071 5963804;. fax: +39 071 5963253; e-mail: m.b.bilo@univpm.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Insect sting allergy: new guidelines from the European and USA consensus groups: algorithms and recommendations Purpose of review Guidelines on insect sting allergy and venom immunotherapy (VIT) have been updated. This review describes the evolution of these guidelines and their similarities and differences. Recent findings The US and European guidelines show the evolution of guideline development in the grading of recommendations and the transparency of the evaluation of evidence. The US and European guidelines on VIT are similar in most areas and complimentary in others. The European guidelines are limited to VIT and are based on a published systematic review; the US practice parameters cover all areas of the diagnosis and management of insect sting allergy and do not use the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. There is general agreement that both children and adults with cutaneous systemic reactions do not require VIT, and that there is minimal risk associated with β-blockers and angiotensin-converting enzyme inhibitors during VIT. There are minor differences in the details of VIT dose, regimen, and choice of venom, but agreement on the duration and risk factors for relapse after VIT. The US and European guidelines are complementary in their discussion of the relation of mastocystosis and insect sting anaphylaxis and the value of measuring basal serum tryptase. Summary The updated guidelines on insect sting allergy from the US and European groups differ in scope, with a somewhat different focus in specific areas but are complementary overall. Where they overlap, there are relatively few differences in recommendations, and these are subtle. The US practice parameter offers an annotated algorithm for the evaluation and treatment of patients with reactions to insect stings. Correspondence to David B.K. Golden, MD, Johns Hopkins University, 20 Crossroads Drive #16, Owings Mills, Baltimore, MD 21117, USA. Tel: +1 410 363 6144; e-mail: dgolden1@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Anaphylaxis in adolescents Purpose of review The frequency of hospitalization for anaphylaxis has increased over the last 20 years across Europe, Australia, and North America, particularly, for food and medication triggers. Adolescents show the highest risk for morbidity and fatality from food-induced anaphylaxis, yet there is little high-quality evidence addressing the reasons for this disproportionate vulnerability. Recent findings Recent data seem to suggest a possible increasing burden of food-induced anaphylaxis among adolescents. Trends in anaphylaxis mortality are stable in North America and the United Kingdom, but not in Australia where the incidence of fatal anaphylaxis has recently doubled. The age distribution of fatal anaphylaxis varies according to the nature of the culprit trigger, with data suggesting an age-related predisposition to fatal food anaphylaxis in adolescents and young adults. Adolescence represents a critical phase of transition when rapid and substantial physical, emotional, and social changes occur. Therefore, adolescents show challenges in self-management that are different from other age groups, contributing to a higher risk of poor anaphylaxis outcomes. Summary The purpose of this review is to summarize recent data on epidemiology and elicitors of anaphylaxis in adolescents and to address currently known barriers and potential facilitators to self-management of anaphylaxis in this vulnerable age group. Correspondence to Diego G. Peroni, MD, Full Professor of Paediatrics, Section of Paediatrics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy. Tel: +39 50992635; e-mail: diego.peroni@unipi.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Tryptase values in anaphylaxis and insect allergy Purpose of review To recognize the relevance of serum tryptase measurement as a useful tool for the diagnosis of allergic diseases and mast cell disorders. Recent findings Recent data on the role of mast cells and tryptase in allergic and other diseases provide new understanding into the mechanisms and causes of anaphylaxis. Summary Measurement of transiently elevated tryptase levels shortly after a severe reaction can help elucidate mechanism behind the reaction in identifying mast cell activation. Hymenoptera venom allergy represents an important cause of morbidity and mortality worldwide. Venom allergy is a typical IgE-mediated reaction because of sensitization to one or more allergens of the venom, and accounts for 1.5–34% of all cases of anaphylaxis. There is a preferential association between insect venom allergy and mastocytosis. The diagnosis of a clonal mast cell disease leads to therapeutic consequences concerning the treatment of venom allergy. In conclusion, baseline tryptase levels support the clinical diagnosis of anaphylaxis and mast cell disorders, determine venom immunotherapy treatment and is relevant in deciding on lifelong treatment. Correspondence to Patrizia Bonadonna, Allergy Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Piazzale Stefani 1, Verona 37126, Italy. Tel: +39 458126166; fax: +39 458126178; e-mail: patrizia.bonadonna@aovr.veneto.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Gender differences in anaphylaxis Purpose of review Is sexual dimorphism also true in anaphylaxis as described in other allergic diseases? Possible gender differences in the epidemiology, triggers, severity, outcomes of anaphylaxis as well as in the pathogenesis of the disease are discussed. Recent findings Hormonal status and the X-chromosome-coded factors deeply involved in the regulation of T-cell and B-cell responses may influence the gender difference noticed in allergic diseases, such as asthma and rhinitis. Little is known if sex is also relevant for anaphylaxis, although the description of catamenial anaphylaxis is intriguing. However, epidemiologic bias, lack of reliable animal models for the human disease, differences into diagnostic codes and not harmonized clinical grading unfortunately represent hurdles to obtain meaningful information on this topic. Summary The female sex predisposes to a dysregulation of the immune response as suggested by the increased prevalence of autoimmunity and atopy. In anaphylaxis, pathomechanisms are not fully disclosed, triggers are numerous and IgE-dependent mast cell degranulation only represents a part of the story. Improvement into the definition of the disease including a more careful coding system and better investigations about triggers seem the only way to allow a more precise assessment of the possible different risk for women to develop anaphylaxis. Correspondence to Paola Parronchi, MD, Department of Experimental and Clinical Medicine, University of Firenze, Largo Brambilla 3, 50134 Firenze, Italy. Tel: +39 557947421; e-mail: paola.parronchi@unifi.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ocular allergy: update on clinical trials Purpose of review The purpose of this article is to provide an update on the advances made through recent clinical trials regarding the treatment of the signs and symptoms of allergic conjunctivitis and its associated conditions. Recent findings Recent studies have demonstrated significant advancement in the various forms of immunotherapy treatments. Nutritional interventions such as probiotics have surfaced as a viable complementary treatment option. Novel delivery methods such as contact lenses have been further studied along with a new tacrolimus formulation to improve ocular levels of the drug. Summary Currently, the primary advances in treatment for allergic conjunctivitis has shifted from new ophthalmic agents to immunotherapy and improvement of drug delivery. This includes the classic subcutaneous and sublingual and the novel epicutaneous and intralymphatic immunotherapy delivery systems as well as an edible rice vaccine. New targets for treatment have spurred research into new antagonist drugs such as (OC000459), a prostaglandin D2 antagonist. The Marinosolv formulation using tacrolimus shows promise and may be considered for other ophthalmic agents in the future. Other nonpharmacological treatments such as stenting and mechanical barrier gel have demonstrated their usefulness in treating ocular symptoms. Correspondence to Leonard Bielory, MD, University Ophthalmology and Allergy Associates, 400 Mountain Avenue, Springfield, NJ 07081, USA. Tel: +1 973 912 9817; e-mail: drbielory@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Asthma and anaphylaxis Purpose of review Both asthma and anaphylaxis are recognized noncommunicable hypersensitivity conditions, which should be correctly diagnosed and treated/controlled in order to decrease avoidable deaths. Nevertheless, their association is not completely clear. We here propose to review the current and new evidence-based data of asthma and anaphylaxis in the view of the new knowledge in the field that can support the quality practice and empower allergists and health professionals in treating symptoms and preventing death. Recent findings Hypersensitivity life-threatening conditions, such as anaphylaxis and asthma can coexist, mimic or worse each other. Asthma itself is not a strong predictor of more severe anaphylaxis. However, poor asthma control associated with more severe anaphylaxis reactions in all ages. In children, asthma is associated with the severity and recurrences of anaphylactic reactions. Summary Although recent data point for the association between asthma and anaphylaxis, we still do not have harmonized evidence to confirm if we are dealing with two independent comorbidities one worsening each other. However, as far as this review is covering two relevant public health problems in the field of allergy, it is mandatory put in place decisions supporting recommendations to better manage the affected patients and reduce the risk. General strategies should include regular notification of this association, optimization of the classification and coding for anaphylaxis and asthma (new ICD 11 anaphylaxis codes) in order to harmonize epidemiological stratified data, early diagnosis of asthma in childhood, regular investigation of asthma in cases of anaphylaxis and optimization of the asthma control and lung function for all patients with indication to provocation tests, desensitization or allergen immunotherapy regardless to the trigger. Implementation of these strategies will involve national and international support for ongoing efforts in relationship with networks of centres of excellence to provide personalized management for the most at-risk patients and prevent death. Correspondence to Luciana Kase Tanno, MD, PhD, Division of Allergy, Department of Pulmonology, 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.

Impact of climate change on insect–human interactions Purpose of review To update the influence of the global climate change on Hymenoptera venom allergy. Recent findings Climate change facilitates biological invasions of hymenopteran species and plays a role in the impact of introduced species relevant for human health. It contributes to a rise in the incidence of sting injuries and allergy reactions across the world. Summary Global climate change has contributed to the expansion and the redistribution of allergenic insect species, increasing the number of allergy cases caused by stinging insects worldwide. Imported insects are trending species in systemic reactions for multiple stings or hymenopteran venom allergy. They represent a threat for humans and a challenge for the allergists. Correspondence to Arantza Vega, MD, PhD, Allergy Service, Hospital Universitario de Guadalajara, CL Donante de sangre s/n, 19002 Guadalajara, Spain. Tel: +34 949209200 (Ext 927) e-mail: avega@sescam.jccm.es Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Mastocytosis presenting as insect anaphylaxis: gender differences and natural history Purpose of the review Currently, there is strong evidence about an association between hymenoptera venom anaphylaxis (HVA) and mastocytosis. This review is focused on the most relevant clinical and biological features of systemic mastocytosis associated with HVA. Recent findings HVA is a relatively common complication that modifies the natural course of patients with mastocytosis, particularly men with indolent systemic mastocytosis without skin lesions (ISMs−) in whom HVA can be the presenting symptom in up to around one-half of the cases. Patients with ISMs− associated with HVA are typically males with cardiovascular symptoms in the absence of itching, urticaria, and angioedema during anaphylaxis. Noteworthy, ISMs− is characterized by a low bone marrow mast cell load and a low risk for disease progression. Early and more recent studies support that specific venom immunotherapy (VIT) is a well-tolerated and effective treatment in patients with mastocytosis. Summary VIT should be given life-long to all patients with mastocytosis and proven immunoglobulin E (IgE)-mediated HVA. In patients with negative venom skin test and undetectable IgE antibodies, additional studies such as component-based allergy testing might contribute to confirm an IgE-mediated mechanism of anaphylaxis in some cases, thus providing the indication of VIT. Correspondence to Iván Alvarez-Twose, MD, PhD, Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Ctra. Cobisa S/N, Toledo 45071, Spain. Tel.: +34925269336;. e-mail: ivana@sescam.jccm.es Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.