ORIGINAL ARTICLE HIGHLIGHTS FROM THIS ISSUE

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1 ORIGINAL ARTICLE HIGHLIGHTS FROM THIS ISSUE The Urticaria Activity Score Validity, Reliability, and Responsiveness Hawro et al 1185 What is already known about this topic? The urticaria activity score (UAS) is an established instrument to measure the activity of chronic spontaneous urticaria. Two versions of this tool exist. For one of them, critical clinimetric data are still missing. What does this article add to our knowledge? We show that both UAS tools have good clinimetric properties. We define the minimal important difference and the smallest detectable change for both instruments. How does this study impact current management guidelines? The guideline-recommended version of the UAS with once-daily documentation of symptoms is valid, reliable, and sensitive to change. Validity, reliability and responsiveness of the UAS version that requires twice-daily documentation are confirmed. Predicting Chronic Spontaneous Urticaria Symptom Return After Omalizumab Treatment Discontinuation: Exploratory Analysis Ferrer et al 1191 What is already known about this topic? Omalizumab treatment can control symptoms in a high percentage of patients with chronic spontaneous urticaria (CSU), but symptoms can return, either fast or slow, after stopping treatment. What does this article add to our knowledge? The results of this study suggest that it is possible to selectively identify patients with CSU who are at risk of rapid symptom return after omalizumab treatment discontinuation. How does this study impact current management guidelines? Based on our findings, a simple digital tool could be developed and used to estimate the probability of rapid symptom return after CSU treatment discontinuation, which could improve the management of patients with CSU in the clinic. Omalizumab for the Treatment of Solar Urticaria: Case Series and Systematic Review of the Literature Snast et al 1198 What is already known about this topic? Solar urticaria (SU) is a rare type of inducible urticaria appearing within minutes of sunlight exposure. Although most patients can control the disease with antihistamines and leukotriene antagonists, a minority of patients require third-line therapies. What does this article add to our knowledge? Treatment with omalizumab resulted in clinical improvement for 80% of patients with antihistamine refractory SU, and 50% of patients became symptom free. Patients who fail to improve on standard omalizumab dose may benefit from higher monthly dosages. How does this study impact current management guidelines? This study highlights the efficacy and safety of omalizumab in the treatment of antihistamine refractory SU. Idiopathic Nonhistaminergic Acquired Angioedema Versus Hereditary Angioedema Andrási et al 1205 What is already known about this topic? The current classification of angioedema without wheals distinguishes 4 acquired and 3 hereditary forms of the disease. Idiopathic nonhistaminergic acquired angioedema (InH-AAE) and hereditary angioedema with unknown origin (U-HAE) could be difficult to diagnose. What does this article add to our knowledge? This is the first study comparing the clinical symptoms of InH-AAE and U-HAE seen in 2 separate patient populations with those of C1-INH-HAE. How does this study impact current management guidelines? The clinical pictures of InH-AAE and U-HAE were similar; however, these 2 disease forms were different from C1-INH-HAE, but the disease burden was similar in these 3 types of angioedema. 23A

2 24A JULY/AUGUST 2018 Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families Veronez et al 1209 What is already known about this topic? Hereditary angioedema (HAE) with mutations in the F12 gene (FXII-HAE) is a rare genetic disease with characteristics similar to those of angioedema with C1 inhibitor deficiency, which mainly affects female patients, increasing the expression and severity of symptoms. What does this article add to our knowledge? The higher frequency of symptomatic male patients in the Brazilian population suggests that the gender penetrance previously described for FXII-HAE should be reconsidered. We report the highest number of families with FXII-HAE outside the European continent. How does this study impact current management guidelines? Our results demonstrate the usefulness of genetic testing to diagnose patients presenting with clinical features of HAE with normal C1 inhibitor, including male patients, even in the absence of a family history or estrogen influence. Risk of Immediate-Type Allergy to Local Anesthetics Is Overestimated Results from 5 Years of Provocation Testing in a Danish Allergy Clinic Kvisselgaard et al 1217 What is already known about this topic? Immediate-type allergy to local anesthetics (LAs) is considered rare by allergists. However, many health care professionals and patients still overestimate the risk of immediate-type LA allergy and potential cross-reactivity. What does this article add to our knowledge? Immediate-type allergy to LAs is extremely rare. Reactions most commonly have another nonallergic mechanism such as vasovagal reactions, or are caused by other simultaneous exposures such as chlorhexidine and latex, which should always be coinvestigated. How does this study impact current management guidelines? Skin testing with LAs may be false positive and should always be followed by subcutaneous provocation. Low-risk patients may be managed with placebo-controlled subcutaneous provocation with the culprit LA without prior skin testing. Acetyl Salicylic Acid Challenge in Children with Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs Differentiates Between Cross-Intolerant and Selective Responders Blanca-López et al 1226 What is already known about this topic? In adults several phenotypes of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs are recognized. They can be cross-intolerant or selective. Within the cross-intolerant, 3 subtypes are well differentiated with respiratory or cutaneous manifestations. What does this article add to our knowledge? Different phenotypes of cross-intolerant reactions in children are observed after confirmation by acetyl salicylic acid challenge. Following skin involvement, the most common association was respiratory plus cutaneous; isolated respiratory symptoms were infrequent. How does this study impact current management guidelines? In children with a history of hypersensitivity reactions to nonsteroidal antiinflammatory drugs, the administration of acetyl salicylic acid is the most appropriate initial way to establish the diagnosis. Successful Intravenous Immunoglobulin Treatment in Pediatric Severe DRESS Syndrome Marcus et al 1238 What is already known about this topic? Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous and systemic delayed drug reaction. The treatment consists of withdrawal of the offending drug, and in severe cases, corticosteroids are added. The treatment of steroid-resistant cases is unclear. What does this article add to our knowledge? We describe 7 pediatric patients with severe DRESS syndrome who were treated successfully with intravenous immunoglobulin (IVIG) with minimal side effects. How does this study impact current management guidelines? IVIG treatment may hasten recovery in pediatric patients with severe DRESS syndrome, especially in patients with a severe course not responding to steroid treatment. Skin Testing for Suspected Iodinated Contrast Media Hypersensitivity Schrijvers et al 1246 What is already known about this topic? A subgroup of iodinated contrast medium (ICM) hypersensitivity reactions is immunologically mediated, potentially life threatening, and can be diagnosed using skin testing. Skin testing is preferred early (1-6 months) after the event. However, the negative predictive value of skin testing is insufficiently evaluated. What does this article add to our knowledge? Skin testing for potential ICM hypersensitivity can identify safe alternative(s) for reexposure, especially in patients with a history of an immediate hypersensitivity reaction. Reactions on re-exposure are infrequent and mostly milder.

3 VOLUME 6, NUMBER 4 25A How does this study impact current management guidelines? Our work validates the role of skin testing to identify safe alternatives and offers an allergologist-driven, clinical history-, and skin-test-based approach to guide ICM re-exposure, without the need for provocation testing outside an imaging context. Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers Duvauchelle et al 1257 What is already known about this topic? Adrenaline autoinjectors used in anaphylaxis should have a sufficient needle length to reach the muscle. Their performance was analyzed using a novel combination of ultrasonography, adrenaline plasma level assays, and cardiovascular responses in human volunteers. What does this article add to our knowledge? Subcutaneous as well as intramuscular adrenaline, delivered using an autoinjector with a relatively short needle, may ensure optimal bioavailability and cardiovascular response, even in overweight women. The analysis of early bioavailability parameters and cardiovascular response is necessary to assess the speed of action of the devices. How does this study impact current management guidelines? The prediction of adrenaline autoinjector efficacy in anaphylaxis should be based on the combined assessment of ultrasonographic depot localization, the analysis of biphasic and parallel patterns of plasma adrenaline levels, and the cardiovascular responses in various categories of healthy volunteers. Utility of Risk Stratification for Paclitaxel Hypersensitivity Reactions Otani et al 1266 What is already known about this topic? Paclitaxel hypersensitivity reactions (HSRs) can be managed by reexposure with or without additional premedications and/or a slower infusion rate, or desensitization. Safe, effective risk stratification strategies are needed to identify patients who can tolerate reexposure without desensitization and patients who need desensitization. What does this article add to our knowledge? The severity of the initial HSR can be used to safely risk stratify patients to reexposure with additional premedications and a slower infusion rate, or desensitization. How does this study impact current management guidelines? A management strategy where the initial risk stratification is based on the severity of the initial HSR can be used to safely reintroduce patients to paclitaxel over consecutive dosing. Impact of Rhinitis on Work Productivity: A Systematic Review Vandenplas et al 1274 What is already known about this topic? Information on the economic impact of allergic rhinitis on work productivity remains fragmented and therefore cannot be taken efficiently into account by the medical community and policy makers. What does this article add to our knowledge? This systematic review confirms that rhinitis impacts at-work productivity more than absenteeism and provides a summary estimate that may serve as guidance for physicians and public health interventions. How does this study impact current management guidelines? Physicians should draw more attention to the burden of allergic rhinitis on work productivity, and inform the patient of the possible occupational impacts of the condition and the benefits of treatment. The Combined Utility of Ex Vivo IFN-g Release Enzyme-Linked ImmunoSpot Assay and In Vivo Skin Testing in Patients with Antibiotic-Associated Severe Cutaneous Adverse Reactions Trubiano et al 1287 What is already known about this topic? The individual use of in vivo skin testing and ex vivo IFN-g release enzyme-linked immunospot (ELISpot) assay for assigning drug causality in severe cutaneous adverse reactions (SCARs) shows promise, yet the joint utility in antibiotic-associated SCARs remains ill-defined. What does this article add to our knowledge? The combined use of in vivo and ex vivo diagnostics in antibiotic-associated SCARs assigned causality safely in 79% of cases, and IFN-g release ELISpot assay demonstrated good sensitivity and high specificity. How does this study impact current management guidelines? Skin testing (in vivo) and IFN-g release ELISpot assay (ex vivo) are complementary approaches that may prove safe and effective in ascertaining antibiotic causality and improve, often difficult antibiotic prescribing, after SCARs.

4 26A JULY/AUGUST 2018 Clinical Phenotypes of Nasal Polyps and Comorbid Asthma Based on Cluster Analysis of Disease History Wu et al 1297 What is already known about this topic? Nasal polyps and comorbid asthma is a common unified airway disease. What does this article add to our knowledge? Nasal polyps and comorbid asthma exhibits 3 clinical phenotypes with distinct natural courses. How does this study impact current management guidelines? Identification of phenotypes of nasal polyps and comorbid asthma might be diagnostically and therapeutically useful. Phenotypical Differences of Childhood- and Adult-Onset Atopic Dermatitis Silverberg et al 1306 What is already known about this topic? The risk factors and clinical characteristics of adult-onset atopic dermatitis are poorly understood. What does this article add to our knowledge? Adults with atopic dermatitis have high rates of self-reported adult-onset atopic dermatitis, lower prevalence of personal or family history of atopic disease, and distinct phenotypes with less flexural lesions and more involvement of the hands and/or head/neck. How does this study impact current management guidelines? Clinicians caring for patients with atopic dermatitis should recognize the phenotypes associated with adult-onset atopic dermatitis. Further studies are needed to determine whether these phenotypes are associated with different treatment outcomes. The Value of Fractional Exhaled Nitric Oxide and Forced Mid-Expiratory Flow as Predictive Markers of Bronchial Hyperresponsiveness in Adults with Chronic Cough Bao et al 1313 What is already known about this topic? Small-airway dysfunction contributes to the pathophysiology of even the mildest forms of classical asthma. It may exist in cough-variant asthma, and its presence could be helpful in predicting bronchial hyperresponsiveness (BHR). What does this article add to our knowledge? Small-airway dysfunction is present in patients with chronic cough and BHR. Forced expiratory flow between 25% and 75% (FEF 25%-75% ) can be used to predict BHR when combined with fractional exhaled nitric oxide (FENO). How does this study impact current management guidelines? FENO > 43 ppb and FEF 25%-75% < 78.5% strongly predicted positive BHR in Chinese patients. This method is more accessible and convenient than bronchial provocation tests, especially for doctors in primary hospitals. Natural History of Benign Nonimmediate Allergy to Beta-Lactams in Children: A Prospective Study in Retreated Patients After a Positive and a Negative Provocation Test Tonson la Tour et al 1321 What is already known about this topic? Although it has been shown that the sensitivity to beta-lactams (BL) decreases over time in patients with an immediate hypersensitivity, data are lacking regarding the natural history of nonimmediate hypersensitivity to BL. What does this article add to our knowledge? Our results showed that the vast majority of children (89%) with benign nonimmediate BL allergy become tolerant after 3 years. From another point of view, the negative predictive value of the drug provocation test (DPT) using a 2-day protocol was 96.7%. How does this study impact current management guidelines? Our data strongly suggest that a follow-up DPT is safe and useful to assess tolerance acquisition in children with nonimmediate BL allergy. In addition, our data support the use of a 2-day protocol DPT. Longitudinal Evaluation of Chronic Rhinosinusitis Symptoms in a Population-Based Sample Sundaresan et al 1327 What is already known about this topic? Chronic rhinosinusitis (CRS) is a prevalent and disabling condition of the nose and sinuses. It is a heterogeneous disease, with various symptom combinations. Its natural history in the general population has not been previously studied. What does this article add to our knowledge? Less than half with symptoms meeting CRS European Position Paper on Rhinosinusitis epidemiologic criteria were stable over a 6-month time period in the general population. Multiple and severe symptoms and earlier age of onset predict disease persistence, and not treatment.

5 VOLUME 6, NUMBER 4 27A How does this study impact current management guidelines? CRS symptoms have high lifetime prevalence. Symptom profiles at baseline were associated with change in symptoms over 6 months. Understanding this variation could lead to better understanding of CRS phenotypes and management. Food Allergy Is an Important Risk Factor for Childhood Asthma, Irrespective of Whether It Resolves Vermeulen et al 1336 What is already known about this topic? Allergic sensitization, including food sensitization, is positively associated with asthma or respiratory symptoms; however, the role of clinical food allergy in this relationship has not been explored at the population level. What does this article add to our knowledge? This article provides evidence that oral food challengeeconfirmed food allergy in infancy is associated with an increased risk of asthma at the age of 4 years irrespective of whether the early food allergy resolves. The risk is higher for those with multiple food allergies and those with coexistent eczema. How does this study impact current management guidelines? This data can be used by clinicians to inform families of children with food allergies about their child s risk of developing asthma in early childhood, and to identify children who may need closer follow-up and monitoring of their respiratory health. Understanding whether the prevention of early life food allergy prevents the development of later asthma will be an important challenge for the future. Health Care Resource Utilization and Costs Among Adults with Atopic Dermatitis in the United States: A Claims-Based Analysis Drucker et al 1342 What is already known about this topic? Atopic dermatitis (AD) is associated with significant direct medical costs but updated estimates are needed. What does this article add to our knowledge? Adjusted incremental annual direct costs for patients with AD in this US study were $3,302. Costs are higher in patients with more severe disease. How does this study impact current management guidelines? Patients, clinicians, and payers should be aware of the costs associated with AD and factor these into clinical decision making. Use of a Penicillin Allergy Screening Algorithm and Penicillin Skin Testing for Transitioning Hospitalized Patients to First-Line Antibiotic Therapy Ramsey et al 1349 What is already known about this topic? The penicillin allergy label has significant public health implications. Different inpatient approaches at academic centers addressing this problem include skin testing by pharmacists or infectious disease providers, and an algorithm to direct cephalosporin challenges. What does this article add to our knowledge? This article describes an allergy/pharmacist antimicrobial stewardship initiative in which patients were identified for inpatient penicillin skin testing based on high-risk, second-line antibiotic use in a community hospital setting. How does this study impact current management guidelines? This study provides another approach for penicillin allergy de-labeling, which is in line with multiple national guidelines. Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures Lopez-Gonzalez et al 1356 What is already known about this topic? Rapid drug desensitization is a helpful therapeutic tool that enables paclitaxel to be safely administered to paclitaxel-hypersensitive patients. What does this article add to our knowledge? It is unclear whether systematic premedication with antihistamines and corticosteroids makes rapid drug desensitization to paclitaxel safer. How does this study impact current management guidelines? Premedication regimens for rapid drug desensitization may be increasingly tailored to prevent adverse effects from unnecessary systematic administration of drugs. Asthma, Family History of Drug Allergy, and Age Predict Amoxicillin Allergy in Children Faitelson et al 1363 What is already known about this topic? To date, physicians are unable to predict who will fail or pass oral graded challenge with amoxicillin, which is commonly used to rule out alleged amoxicillin allergy in children. What does this article add to our knowledge? The presence of asthma, family history of drug allergy, and older age at reaction are associated with a higher risk of failing the oral challenge. Skin prick test was not helpful in diagnosing amoxicillin allergy.

6 28A JULY/AUGUST 2018 How does this study impact current management guidelines? Recognizing risk factors for amoxicillin allergy in the pediatric population can assist the allergist in deciding what will be the optimal setting of an oral challenge for individual patients. Anaphylactic Reactions After Discontinuation of Hymenoptera Venom Immunotherapy: A Clonal Mast Cell Disorder Should Be Suspected Bonadonna et al 1368 What is already known about this topic? There are no data on the presence and prevalence of mastocytosis in patients who experience severe reactions from Hymenoptera stings after the termination of an effective venom immunotherapy (VIT) course. What does this article add to our knowledge? Mastocytosis should be suspected in those patients with Hymenoptera allergy who experience severe reactions and anaphylaxis after stopping VIT that had been previously protective. How does this study impact current management guidelines? A proper diagnostic procedure for mastocytosis should be considered in patients developing severe reactions at re-sting after VIT discontinuation. VIT should therefore be continued lifelong in subjects with mastocytosis and venom allergy. Antituberculosis Drug-Associated DRESS: A Case Series Allouchery et al 1373 What is already known about this topic? Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially lifethreatening adverse drug reaction. Antituberculosis drugs are not commonly associated with DRESS. What does this article add to our knowledge? We described 67 cases of antituberculosis drug-associated DRESS. Liver, kidneys, and bone marrow were the most frequently involved organs. The use of systemic corticosteroids was not associated with a flare of underlying tuberculosis infection. How does this study impact current management guidelines? The diagnosis of antituberculosis drug-associated DRESS should not be dismissed. A drug allergy evaluation must be performed to optimize the second-line treatment of tuberculosis infection.