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Original Article Highlights From This Issue

A telemedicine-based drug allergy service model can result in time and cost savings, while improving patient access to specialist care Predictive Nomogram for Severe COVID-19 and Identification of Mortality-Related Immune Features Cai et al 177 What is already known about this topic? The identified risk factors for home epinephrine-treated reactions during OIT and for high failure rate following such reactions enable stratification of patients' risk and might assist in patient selection for OIT Prevalence of Physician-Reported Food Allergy in Canadian Children Singer et al 193 What is already known about the topic? The increased prevalence of food allergy in Israeli young children constitutes an important public health concern with tremendous implications for risk management The EXiLE test can be a suitable alternative with respect to cost and sampling constraint Added Diagnostic Value of Peanut Component Testing: A Cross-Sectional Study in Australian Children Kaur et al 245 What is already known about this topic? A number of studies have suggested that IgE to peanut component Ara h 2 may be a better predictor to differentiate sensitization and clinical reactivity to peanut


Patient Characteristics and Risk Factors for Home Epinephrine-Treated Reactions During Oral Immunotherapy for Food Allergy Nachshon et al 185
What is already known about this topic? Studies of risk factors for severe reactions during oral immunotherapy (OIT) described thus far, including age, asthma, degree of sensitization, pre-OIT reaction severity, and initial reaction threshold, are limited and require validation in a large cohort.
What does this article add to our knowledge? Milk OIT is a risk factor for home epinephrine-treated reactions and for poor outcome following such reactions. Epinephrine-treated reactions before OIT or during clinic updosing, asthma, and a lower tolerated dose provide additional risk factors.
How does this study impact current management guidelines? The identified risk factors for home epinephrine-treated reactions during OIT and for high failure rate following such reactions enable stratification of patients' risk and might assist in patient selection for OIT.

Singer et al 193
What is already known about the topic? Self-reported prevalence of food allergy in Canada is approximately 8%, but physician-reported prevalence rates have never been documented.
What does this article add to our knowledge? Physician-reported prevalence of pediatric food asthma in Canada is 2.53%. Children with food allergy were more likely to be atopic, less likely to be obese, and more likely to have a psychiatric comorbidity.
How does this study impact current management guidelines? Physician-reported prevalence rates are lower than self-report rates.
Further studies into the association of food allergy and psychiatric comorbidities are necessary.

Garkaby et al 200
What is known already about the topic? Food allergies are on the rise worldwide. A previous, cross-sectional study published in 2002 estimated the prevalence of food allergy among Israeli young children (<2 years) at 0.85%, with high sesame and low peanut prevalence.
What does this article add to our knowledge? We revealed a substantial increase in the prevalence of food allergy among Israeli young children in 18 years. The distribution and ranking of the main food allergens was similar, with high sesame and low peanut prevalence.
How does this study impact current management guideline? The increased prevalence of food allergy in Israeli young children constitutes an important public health concern with tremendous implications for risk management. Our findings strengthen the call for community-based allergy testing.

Understanding Food-Related Allergic Reactions Through a US National Patient Registry Fierstein et al 206
What is already known about this topic? Evidence from small clinical samples suggests that unintentional reactions are common among children and adults living with food allergy. Cross-contamination is a common cause of reactions.
What does this article add to our knowledge? In a large national patient registry, half of patients had 1 or more reactions per year. Although most reactions were due to unintentional exposure, 1 in 10 reactions were due to intentional exposure.
How does this study impact current management guidelines? Although providing patient education around food allergen avoidance is a recommended part of patient care, exposure avoidance-both intentional and unintentional-remains challenging. Current guidelines should take into account motivations behind both intentional and unintentional exposures.

Improvements in Quality of Life in Children Following Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in the PEPITES and PEOPLE Studies DunnGalvin et al 216
What is already known about this topic? Food allergy quality of life has been consistently shown to be impaired in children with peanut allergy and their caregivers due to the burden of constant vigilance, including the fear of reactions due to accidental exposure.
What does this article add to our knowledge? Epicutaneous immunotherapy with DBV712 250 mg led to significant improvements in food allergy quality of life in peanut-allergic children after 24 months of treatment, largely driven by patients experiencing any improvement in eliciting dose. This was noted in all Food Allergy Quality of Life Questionnaire-Parent Form and 2 of 4 Food Allergy Quality of Life Questionnaire-Child Form domains.
How does this study impact current management guidelines? These findings suggest that improvements in total and domain-specific food allergy quality of life as a result of increased eliciting doses after DBV712 250 mg treatment represent important patient-centered outcomes as part of the overall clinical benefits of therapy.

Walnut Allergy Across Europe: Distribution of Allergen Sensitization Patterns and Prediction of Severity Lyons et al 225
What is already known about this topic? Although walnut is one of the tree nuts most often reported to elicit food-allergic reactions in Europe and worldwide, data on sensitization to individual walnut components and their geographical and clinical relevance are scarce.
What does this article add to our knowledge? Patterns of IgE sensitization to 7 walnut components in 12 European countries are presented, along with a highly discriminative model combining serological and clinical information for prediction of walnut allergy severity.
How does this study impact current management guidelines? Molecular diagnostics in walnut allergy reveal varied patterns of sensitization across Europe, and can help accurately distinguish mild to moderate from severe walnut allergy when considered in combination with extract-based testing and clinical background.

Cell-Based Functional IgE Assays Are Superior to Conventional Allergy Tests for Shrimp Allergy Diagnosis
Wai et al 236 What is already known about this topic? Shrimp allergy is prevalent, but conventional diagnostic methods including skin prick test (SPT) and specific IgE (sIgE) measurements have low specificity. Testing for tropomyosin improves diagnostic accuracy for shrimp allergy in Caucasians, but this has not been replicated among Asians.
What does this article add to our knowledge? BAT has superior diagnostic performance for shrimp allergy than SPT and sIgE measurement. Tropomyosin may not be the most appropriate diagnostic marker in the Chinese population. The IgE crosslinkingeinduced luciferase expression (EXiLE) test can be a good alternative to BAT.
How does this study impact current management guidelines? A single step of BAT may replace SPT and sIgE in the diagnosis of patients with clinical history suggestive of shrimp allergy. The EXiLE test can be a suitable alternative with respect to cost and sampling constraint.

Kaur et al 245
What is already known about this topic? A number of studies have suggested that IgE to peanut component Ara h 2 may be a better predictor to differentiate sensitization and clinical reactivity to peanut.
What does this article add to our knowledge? This study suggests that polysensitization to Ara h 1, 2, and 3 may be a better marker to not only predict the outcome of peanut challenge but also the severity of reaction at challenge.
How does this study impact current management guidelines? Combination of Ara h 1, 2, and 3 may be a helpful diagnostic test to identify patients with persistent peanut allergy regardless of whether they were sensitized or had clinical reaction in the past.

Understanding Precautionary Allergen Labeling (PAL) Preferences Among Food Allergy Stakeholders Gupta et al 254
What is already known about this topic? Food allergy (FA) prevalence is 7.6% and 10.8% among US children and adults, respectively. FA families must practice constant vigilance while shopping for foods, as precautionary allergen labeling (PAL) is voluntary.
What does this article add to our knowledge? This study adds to literature on FA consumers' understanding of PAL. Results suggest that FA consumers are largely unaware of PAL policies, purchase products with PAL based on specific wording, and prefer clear and consistent product labeling.
How does this study impact current management guidelines? The United States lacks clear requirements for the use of PAL, which results in confusion and risk-taking among FA consumers. Food manufacturers and government agencies need timely data from stakeholders, researchers, and allergists to make policy.

A Prospective Validation of the NUT CRACKER Diagnostic Algorithm for Walnut and Pecan Allergy with Prediction of Severity Goldberg et al 265
What is already known about this topic? We previously devised an algorithm using skin prick tests, basophil activation tests, and co-allergy status to reduce the need for oral food challenges (OFCs) in patients with suspected walnut/pecan allergies.
What does this article add to our knowledge? In a large-scale prospective trial, this study validates a novel diagnostic algorithm for walnut and pecan allergy. It further demonstrates that basophil reactivity reflects the clinical manifestations of tree nut OFC.
How does this study impact current management guidelines? Given the high prevalence in tree nuteallergic patients of cross-reactivities to several nuts, this algorithm will decrease the number of OFCs needed to be performed, while maintaining accuracy of diagnosis.

Cottel et al 275
What is already known about this topic? Peanut allergy is one of the most frequent causes of anaphylaxis in children with food allergies. Oral food challenge remains the gold standard to evaluate the threshold dose and severity of peanut allergy.
What does this article add to our knowledge? This study reports the relevance of allergen-specific and noneallergen-specific basophil activation test parameters to determine the severity and threshold dose of a peanut-allergic reaction in children.
How does this study impact current management guidelines? Introduction of these multivariable models in routine practice could avoid an oral food challenge in some children with peanut allergy.

Delayed and Severe Reactions to Baked Egg and Baked Milk Challenges Yonkof et al 283
What is already known about this topic? Some children react to baked egg and baked milk challenges.
What does the article add to our knowledge? Compared with other oral food challenge reactions, baked egg and baked milk reactions were characterized by increased frequencies of epinephrine administration and lower respiratory tract reactions, respectively, as well as delayed reactions 60 minutes or later after the challenge ended.
How does this study impact current management guidelines? Consider amended dose-escalation protocols and prolonged observation after baked egg and baked milk challenges.
Adult and Pediatric Food Allergy to Chickpea, Pea, Lentil, and Lupine: A Scoping Review Hildebrand et al 290 What is already known about this topic? Plant-based diets are increasingly popular, and legume protein is appearing in more manufactured prepackaged foods. In Canada, legumes (except soy and peanut) are not always required to be labeled if they are components of an ingredient, which puts legume-allergic consumers at risk for accidental legume consumption.
What does this article add to our knowledge? Nonpriority legume allergy varied by type, and by region. These allergies have been implicated in severe allergic reactions. Yet, studies on public health knowledge and educational needs are near-absent.
How does this study impact current management guidelines? The labeling and educational needs of patients with nonpriority legume allergy are poorly characterized, thus underscoring a need for further research on the burden of nonpriority legume allergy, in partnership with clinicians, scientists, the food industry, and patients.

Infant Allergy Testing and Food Allergy Diagnoses Before and After Guidelines for Early Peanut Introduction Lo et al 302
What is already known about this topic? Current guidelines recommend screening and early peanut introduction in high-risk (severe eczema and/or egg allergy) infants; panel testing is discouraged, as allergy tests have poor positive predictive value when assessing foods never previously ingested.
What does this article add to our knowledge? Within a large national claims database, we show an increase in allergy testing (including in infants not high risk) after Learning Early About Peanut Allergy publication and National Institute of Allergy and Infectious Diseases guideline publication. Multiallergen testing is common and food allergy diagnoses are increasing.
How does this study impact current management guidelines? Peanut allergy screening may have additional unintended effects of increased testing to multiple foods, resulting in identification of clinically irrelevant sensitization. Allergy testing may delay introduction of foods if families are awaiting testing (or oral food challenges) before eating.

Caregiver-Reported Presentation of Severe Food-Induced Allergic Reactions in Infants and Toddlers Pistiner et al 311
What is already known about this topic? There are unique challenges to recognizing anaphylaxis in infants and toddlers, and current diagnostic criteria and anaphylaxis action plans do not specifically address this younger population.
What does this article add to our knowledge? This study identifies infant-and toddler-specific symptoms and signs reported by primary caregivers during their child's most severe allergic reaction when less than 36 months of age.
How does this study impact current management guidelines? Findings may advance the recognition of symptoms and signs of anaphylaxis in infants and toddlers and help guide the development of age-specific diagnostic criteria and anaphylaxis guidelines.

Penumarti et al 321
What is already known about this topic? Food products used in oral immunotherapy (OIT) trials need to conform to Food and Drug Administration (FDA) guidelines for orally delivered drugs. Limited information exists on the suitability of commercially available tree nut flours for use in OIT protocols.
What does this article add to our knowledge? Tree nut flours are often contaminated with high levels of microbes and do not meet the FDA guidelines on OIT drug products. We demonstrated that gamma irradiation of walnut, cashew, hazelnut, and almond flours decreased bioburden without altering the allergenic protein content.
How does this study impact current management guidelines? Irradiation of tree nut flours represents an effective method to generate drug products for use in OIT trials. These drug products remain stable for at least 24 months when refrigerated.

Which Are the Optimal Criteria for the Diagnosis of Allergic Bronchopulmonary Aspergillosis? A Latent Class Analysis Saxena et al 328
What is already known about this topic? Several criteria are available for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). However, in the absence of a reference standard, the diagnostic performance of the various criteria remains unknown.
What does this article add to our knowledge? The International Society for Human and Animal Mycology-ABPA Working Group diagnostic criteria were found to perform slightly better than the Rosenberg-Patterson criteria on latent class analysis. The diagnostic performance improved by modifying the existing International Society for Human and Animal Mycology criteria.
How does this study impact current management guidelines? We evaluated various benchmarks for identifying ABPA among patients with asthma and provide an updated optimal criterion. Our data support modifying the original International Society for Human and Animal Mycology criteria for improved sensitivity. The new criteria will help standardize the diagnosis of ABPA for future research and practice.

Oral Corticosteroid Treatment Patterns of Patients in the United States with Persistent Asthma Tran et al 338
What is already known about this topic? Oral corticosteroids (OCS) are used to manage asthma exacerbations and severe, uncontrolled asthma, but OCS are associated with adverse effects. Limited data are available on the extent and pattern of OCS prescription in asthma treatment.
What does this article add to our knowledge? Patients with persistent asthma in the United States, including those who have mild to moderate asthma, have substantial exposure to OCS, particularly when considering a definition that considers cumulative dosage.
How does this study impact current management guidelines? Physicians should be aware that frequent exposure to OCS may put their patients at risk for experiencing adverse effects and that other options to control patients' asthma should be considered.

Multidimensional Assessment of Asthma Identifies Clinically Relevant Phenotype Overlap: A Cross-Sectional Study Han et al 349
What is already known about this topic? Asthma is a heterogeneous disease with multiple phenotypes; however, the relevance of phenotype overlap remains largely unexplored.
What does this article add to our knowledge? Phenotype overlap is extremely common in asthma and is associated with clinical and inflammatory profiles. Patients with phenotypes associated with mixed T2 and non-T2 inflammation have elevated T2 inflammation biomarkers but worse asthma control.
How does this study impact current management guidelines? Multidimensional asthma assessment identifies clinically relevant phenotype overlap. Despite increased T2 inflammation, patients with phenotypes associated with mixed T2 and non-T2 inflammation might be unresponsive to medications owing to increased non-T2 inflammation.

McDowell et al 365
What is already known about this topic? Morbidity from glucocorticoid (GC) exposure in severe asthma (SA) is described at population level, but because of the absence of a suitable tool, GC toxicity at the individual patient level has not been systematically captured and reported previously.
What does this article add to our knowledge? The Glucocorticoid Toxicity Index 2.0 identifies GC toxicity systematically in routine SA clinic, revealing unidentified toxicities and wide variation in cumulative toxicity in individual patients. Toxicity correlated poorly with prednisolone exposure compared with age and quality-of-life measures.
How does this study impact current management guidelines? This study proposes that measuring GC toxicity systematically in individual patients is an important part of routine care. Reliance on recent GC exposure as guidance for which patients would derive most benefit from biologic therapies may be imprecise.

Oral Corticosteroids and Risk of Preterm Birth in the California Medicaid Program Palmsten et al 375
What is already known about this topic? Oral corticosteroids are associated with an increased risk of preterm birth (PTB) among women with asthma.
What does this article add to our knowledge? For asthma, only higher oral corticosteroid doses early in pregnancy, but not later, were associated with increased PTB risk. There was no association between asthma controller therapies and PTB.
How does this study impact current management guidelines? Our findings support the treatment goal of controlling asthma symptoms during pregnancy and are reassuring for women who can manage asthma during pregnancy with lower oral corticosteroid doses and controller therapies.

Sansing-Foster et al 385
What is already known about this topic? Psychiatric safety concerns following montelukast use have primarily been generated from postmarketing case reports. Observational studies have reported conflicting findings.
What does this article add to our knowledge? In this large observational study, in patients with asthma treated with montelukast or inhaled corticosteroids, risks of hospitalizations for depression or self-harm were similar. Psychiatric comorbidity was common, and most psychiatric adverse events occurred in patients with a past psychiatric history.
How does this study impact current management guidelines? Risk of hospitalizations for depression or self-harm appear to occur more frequently in patients with a past psychiatric history.

Lee et al 394
What is already known about this topic? Cross-sectional data have suggested that blood eosinophil count is related to a decline in lung function in a healthy population. However, the consistency of blood eosinophil count over time has not been properly assessed.
What does this article add to our knowledge? In a long-term longitudinal follow-up, we found that blood eosinophil count is associated with a decline in forced expiratory volume in 1 second (FEV 1 ), and a consistently high count is an independent risk factor for an accelerated decline in FEV 1 .
How does this study impact current management guidelines? These results suggest the use of the blood eosinophil count to identify healthy individuals at high risk for developing chronic lung disease, which in turn may enable a tailored preventive strategy.

Psychometric Properties of the Asthma Symptom Index in Patients with Severe Asthma Shen et al 400
What is already known about this topic? The Asthma Symptom Utility Index (ASUI) is a well-established and validated measure for evaluation of asthma symptoms and treatment.
What does this article add to our knowledge? The Asthma Symptom Index (ASI) is a modified, shorter version of the ASUI that includes 8 items measuring 4 asthma symptoms and which also demonstrates a good reliability, validity, and responsiveness to capture asthma symptoms.
How does this study impact current management guidelines? The ASI has potential value for use in real-world symptom assessment of patients with severe asthma, helping to monitor patients in a real-world setting and simplify measurement of asthma symptoms.

Riley et al 410
What is already known about this topic? Internationally, adult patients with asthma have poor asthma medication adherence.
What does this article add to our knowledge? This article describes the diverse reasons for asthma medication adherence reported by patients around the world and how they may change based on the sociopolitical context in which patients live.
How does this study impact current management guidelines? On the basis of the findings of this study, providers should inquire about a broad set of reasons for asthma medication nonadherence with focus on the most common barriers reported in a particular country.

Impact of the Asthma Quality Assessment Program on Burden of Asthma Park et al 419
What is already known about this topic? The Korean Health Insurance Review and Assessment Service launched the National Asthma Quality Assessment Program from 2013 to assess whether patients with asthma in Korea were well managed.
What does this article add to our knowledge? The Asthma Quality Assessment Program conducted by the Korean government led to improvements in both the asthma management protocol and prognosis in Korea; however, the effect was restricted to the assessment term.
How does this study impact current management guidelines? Steady application of national management programs, such as Asthma Quality Assessment Program, will encourage patients and clinicians to follow recommended guidelines. Improved compliance of asthma management will be helpful to steadily reduce the social and economic burden of asthma.

The Predicative Clinical Features Associated with Chronic Cough That Has a Single Underlying Cause Lai et al 426
What is already known about this topic? It is important for successful therapy to identify causes of chronic cough. Few studies have investigated the usefulness of the clinical characteristics of cough, concomitant symptoms, and medical history in the diagnosis of chronic cough.
What does this article add to our knowledge? Some clinical features, including nocturnal cough alone, cough after meals, reflux symptoms, and history of sinusitis, presented high specificities, and mild to moderate sensitivities to indicate causes of chronic cough, suggesting their great "rule in" value for diagnosis of chronic cough.
How does this study impact current management guidelines? The timing of cough, concomitant symptoms associated with gastroesophageal reflux or rhinitis/sinusitis, and history of rhinitis are useful in indicating common causes of chronic cough and guiding empiric therapy.

Testing Strategies and Predictors for Evaluating Immediate and Delayed Reactions to Cephalosporins Stone et al 435
What is already known about this topic? Testing strategies for cephalosporin allergy have been poorly defined. Previous studies have suggested that cephalosporin cross-reactivity was primarily based on common shared R1 groupings.
What does this article add to our knowledge? In 2 separate cohorts, allergy to ceftriaxone with R1 cross-reactivity and selective cefazolin allergy were the most common. Selective ampicillin intradermal test positivity in cephalexin-allergic patients was limited to the Australian cohort, and this was associated with aminopenicillin-aminocephalosporin R1 cross-reactivity.
How does this study impact current management guidelines? Cephalosporin skin testing and ingestion challenge using approaches that account for structural similarities in R side chains is a safe and efficacious mechanism to evaluate cephalosporin allergy.

Antineutrophil Cytoplasmic Antibodies and Organ-Specific Manifestations in Eosinophilic Granulomatosis with Polyangiitis: A Systematic Review and Meta-Analysis Chang et al 445
What is already known about this topic? Antineutrophil cytoplasmic antibodies (ANCAs) are one of the pathogenic factors in the development of eosinophilic granulomatosis with polyangiitis (EGPA), but less than half the patients with EGPA have positive ANCA status.
What does this article add to our knowledge? ANCA-positive patients with EGPA have higher risks of peripheral neuropathy, renal involvement, and cutaneous purpura, but they have lower risks of pulmonary and cardiac manifestations than do those with negative ANCA status.
How does this study impact current management guidelines? The findings of our study may provide a principle for survey or follow-up of the organ-specific involvements in patients with EGPA based on their ANCA status.