The Journal of Allergy and Clinical Immunology: In Practice 2019 Highlights

Special Article

The Journal of Allergy and Clinical Immunology: In Practice 2019 Highlights Michael Schatz, MD, MSa, Scott H. Sicherer, MDb, David A. Khan, MDc, and Robert S. Zeiger, MD, PhDa,d Pasadena, Calif; New York, NY; and Dallas, Texas This article provides highlights of the clinically impactful original studies and reviews published in The Journal of Allergy and Clinical Immunology: In Practice in 2019 on the subjects of anaphylaxis, asthma, dermatitis, drug allergy, food allergy, immunodeficiency, immunotherapy, rhinitis/sinusitis, and urticaria/angioedema/mast cell disorders. Within each topic, practical aspects of diagnosis and management are emphasized. Treatments discussed include lifestyle modifications, allergen avoidance therapy, positive and negative effects of pharmacologic therapy, and various forms of immunologic and desensitization management. We designed this review to help readers consolidate and use this extensive and practical knowledge for the benefit of their patients. Ó 2020 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2020;-:---)

INTRODUCTION 2019 was another year of growth for The Journal of Allergy and Clinical Immunology: In Practice (JACI: In Practice) in the number of submissions, number of issues (8), and printed pages. Most importantly, we believe our 2019 growth provided more clinically impactful information aimed at enhancing the quality of care for asthma and allergic and immunologic diseases and improving the quality of life (QOL) for those who suffer from these conditions. As in our 2018 Highlights review,1 we have chosen in this review to highlight our most impactful 2019 original research articles regarding the conditions most commonly evaluated and managed by clinical allergists and immunologists.

a

Department of Allergy, Kaiser Permanente Southern California, San Diego, Calif Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY c Department of Internal Medicine, Division of Allergy & Immunology, University of Texas Southwestern Medical Center, Dallas, Texas d Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif Conflicts of interest: M. Schatz reports royalty payments from UpToDate; grants to his institution from the National Heart, Lung, and Blood Institute, and from ALK Pharma, Merck, and Teva; and personal fees from the American Academy of Allergy, Asthma & Immunology, as Editor-in-Chief of The Journal of Allergy and Clinical Immunology: In Practice. S. H. Sicherer reports royalty payments from UpToDate and from Johns Hopkins University Press; grants to his institution from the National Institute of Allergy and Infectious Diseases, Food Allergy Research and Education, and HAL Allergy; and personal fees from the American Academy of Allergy, Asthma & Immunology, as Deputy Editor of the Journal of Allergy and Clinical Immunology: In Practice (JACI: In Practice). D. A. Khan reports membership on an Aimmune Data Safety Monitoring Committee and personal b

San Diego and

ANAPHYLAXIS Several studies elucidated the epidemiology and clinical care related to anaphylaxis (Table I). McCall et al23 focused on anaphylaxis in pregnancy, evaluating anaphylaxis codes in the National Inpatient Sample database from 2004 to 2014. They found a rate of anaphylaxis during pregnancy of 3.8 per 100,000 hospitalizations during pregnancy, without a change over the study period. Factors associated with anaphylaxis included cesarean delivery, history of an allergic reaction, and nonwhite race. Ramsey et al24 used the Virtual Pediatric Systems database to describe anaphylaxis admissions to North American pediatric intensive care units (PICUs) from 2010 to 2015. They identified 1989 anaphylaxis admissions out of 604,279 admissions to 131 PICUs. The fatality rate was 1%. Only 13% of the PICU admissions were children younger than 2 years; however, anaphylaxis may be difficult to diagnose in that age group.25 Peanut was the most common identified trigger of anaphylaxis, but lack of an identified cause was common. In another study, Le et al26 specifically focused on the topic of anaphylaxis from an unknown cause. They used an emergency department (ED) registry across Canada to follow patients with anaphylaxis from an unknown trigger. A total of 295 cases were identified, and they noted that children, compared with adults, were more likely to be prescribed an epinephrine autoinjector, be followed up by an allergist, and eventually have a trigger identified. These studies underscore differences in risks, treatment approaches, and outcomes across different age groups that deserve attention to improve care. Several 2019 studies provided insight into anaphylaxis management. Clark et al27 compared ED treatment of acute foodallergic reactions from 1999 to 2001 with those in the period

fees from the American Academy of Allergy, Asthma & Immunology, as Associate Editor of JACI: In Practice. R. S. Zeiger reports being a consultant to AstraZeneca, Genentech, Novartis, Teva, GlaxoSmithKline, and Regeneron Pharmaceuticas; grants to his institution from the National Heart, Lung, and Blood Institute, and from Aerocrine, Genentech, ALK Pharma, Medimmune/AstraZeneca, Merck, GlaxoSmithKline, Teva, and Quest Diagnostics; and personal fees from the American Academy of Allergy, Asthma & Immunology, as Deputy Editor of JACI: In Practice . Received for publication January 3, 2020; accepted for publication January 3, 2020. Available online -Corresponding author: Michael Schatz, MD, MS, Department of Allergy, Kaiser Permanente Medical Center, 7060 Clairemont Mesa Blvd, San Diego, CA 92111. E-mail: [email protected]. 2213-2198 Ó 2020 American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2020.01.002

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Abbreviations used ACCI- Asthma Control and Communication Instrument ACD- Allergic contact dermatitis ACO- Asthma/chronic obstructive pulmonary disease overlap ACQ- Asthma Control Questionnaire AD- Atopic dermatitis AERD- Aspirin-exacerbated respiratory disease BAL- Bronchoalveolar lavage C1-INH- C1-inhibitor COPD- Chronic obstructive pulmonary disease CRS- Chronic rhinosinusitis CRSsNP- Chronic rhinosinusitis without nasal polyps CRSwNP- Chronic rhinosinusitis with nasal polyps CSU- Chronic spontaneous urticaria CVID- Common variable immune deficiency DOCK8- Dedicator of cytokinesis 8 DRESS- Drug reaction with eosinophilia and systemic symptoms ED- Emergency department ESS- Endoscopic sinus surgery FDA- Food and Drug Administration FENO- Fractional exhaled nitric oxide FPIES- Food proteineinduced enterocolitis syndrome HDM- House-dust mite HSCT- Hematopoietic stem cell transplantation ICM- Iodinated contrast media ICS- Inhaled corticosteroid JACI: In Practice- The Journal of Allergy and Clinical Immunology: In Practice JAU- Japanese allergy units JC- Japanese cedar LRBA- LPS-responsive beige-like anchor LTRA- Leukotriene receptor antagonist MAX- Medicaid Analytic eXtract OA- Occupational asthma OFC- Oral food challenge OIT- Oral immunotherapy OR- Odds ratio PARC- Predicting Asthma Risk in Children PICU- Pediatric intensive care unit PM- Particulate matter PUFA- Polyunsaturated fatty acid QOL- Quality of life RAG- Recombination activating gene RCT- Randomized controlled trial RTI- Respiratory tract infection SAR- Systemic adverse reaction SCAR- Severe cutaneous adverse reaction SCIT- Subcutaneous immunotherapy SIE- Self-injectable epinephrine SJS- Stevens-Johnson syndrome SLIT- Sublingual immunotherapy SR- Systemic allergic reaction STAT3- Signal transducer and activator of transcription 3 TEN- Toxic epidermal necrolysis T2- Type 2

2013 to 2015. They found statistically significant improvements in treatment with epinephrine (38% to 56%), prescriptions of epinephrine at discharge (24% to 54%), and allergist referral (14% to 24%). They noted, however, that although a patient receiving 3 or more guideline recommendations quadrupled in

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this time frame, it remained low at 23%, suggesting considerable room for improvement. Several studies evaluated adherence to self-injectable epinephrine (SIE). Robinson et al2 queried students aged 10 to 14 years and their parents regarding carrying SIE. They identified 234 students with likely IgE-mediated food allergy who were prescribed SIE (out of an initial general population survey of 9816). Unfortunately, carrying rates of the SIE were low, especially in circumstances such as being out of parental supervision. For example, 28% never carried it when they were by themselves, 28% never carried it when with friends, and 36% never carried it for sports activities. Portnoy et al3 reported on a survey from 2013 to 2014 of children and adults who were identified through pharmacy prescriptions of SIE to learn about their carrying adherence and confidence regarding using the devices. The authors noted differences in these reported outcomes according to the type of device prescribed, favoring the Auvi-Q over EpiPen. The primary reasons (unadjusted analysis) for not carrying SIE were not thinking that there would be exposure to an allergen triggering a severe reaction, reasoning that it had not been used before, and forgetting. A strong lesson about the value of proper first-aid use of epinephrine for anaphylaxis was demonstrated in a study by Gabrielli et al4 who used a Canadian registry that enrolls patients with anaphylaxis presenting to EDs. Of 3498 cases of anaphylaxis (80% pediatric), only 31% received prehospital epinephrine. However, 46% received antihistamines and 2% corticosteroids. Prehospital use of epinephrine was associated with reduced risk of receiving multiple epinephrine doses (odds ratio [OR], 0.23) as was use of antihistamines (OR, 0.61), whereas prehospital corticosteroid use was associated with intensive care unit admission (OR, 2.84). Prompt access to epinephrine is important, including during travel, although commercial airlines do not stock SIE. Shaker and Greenhawt28 found through modeling that stocking commercial airplanes with SIE was cost-effective. There is controversy about the impact of beta-blockers and angiotensin-converting enzyme inhibitors on increasing the risk and severity of anaphylaxis. Tejedor-Alonso et al5 undertook a systematic review and meta-analysis on this subject. They identified 21 studies including 22,313 patients for analysis of severity and 18,101 for analysis of new cases. They found that these drugs increased severity but not risk of anaphylaxis. However, there were insufficient data to adjust for the cardiovascular disease risk that also is associated with increased severity. They caution that the quality of evidence supporting increased severity due to these medications is low, and observational studies that control for this confounder are needed. Nonetheless, the study demonstrates a profile of patients at high risk of severe anaphylaxis, namely, older patients with cardiovascular disease requiring these medications.

ASTHMA We were fortunate to be able to publish many fine articles on the subject of asthma in 2019 (Table II). The highlights include those focused on epidemiology, comorbidities, adherence, special populations, phenotypes and endotypes, infection, asthma control, and severe or difficult asthma and biologics. Epidemiology One major goal of clinical epidemiology is to identify risk factors for development of illness, potentially identifying targets for prevention. Several such studies regarding asthma were published

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TABLE I. Summary of anaphylaxis and food allergy highlights Anaphylaxis  Studies regarding patient’s reasons for not carrying SIE identified responses that could be reviewed in counseling to improve carrying rates2,3: teenagers being alone without supervision, being with friends, and doing sporting activities; not thinking that there would be exposure to an allergen triggering a severe reaction; reasoning that it had not been used before; and forgetting.  A registry study found that prehospital use of epinephrine was associated with reduced risk of receiving multiple epinephrine doses (OR, 0.23) as was use of antihistamines (OR, 0.61) while prehospital corticosteroid use was associated with intensive care unit admission (OR, 2.84), underscoring the value of first-aid treatment with epinephrine.4  A meta-analysis found that beta-blockers and angiotensin-converting enzyme inhibitors increased the severity but not the risk of anaphylaxis, although there were insufficient data to adjust for cardiovascular disease as a risk factor.5 Food allergy  Labial food challenges ahead of OFC had poor predictive utility.6  Almond food challenges are usually “passed” (92%), suggesting they could be performed with higher patient-staff ratios.7  Most people allergic to salmon or cod (bony fish) should tolerate ray (cartilaginous fish).8  Exercise and aspirin (more so than alcohol) reduce the threshold of reactivity to wheat, and wheat allergy due to these augmentation factors should be considered in cases of unexplained anaphylaxis.9  In a review of 261 adults with alpha-gal syndrome, some notable features that can aid diagnosis and management included that atopic disposition was not a risk factor, that alpha-gal levels did not correlate with severity, and that about 15% experienced symptoms in less than 2 h.10  In differentiating FPIES from infants with infection having overlapping symptoms, children with FPIES were more likely to present with lethargy, floppiness, and pallor, and have a normal C-reactive protein, leukocytosis, thrombocytosis, low mean platelet volume, and elevated albumin/globulin ratio.11  OFC for FPIES may be safe and effective using a protocol with a single in-clinic one-third serving size, 4-h observation, and then, if no symptoms, gradual introduction to a full serving over 9-12 d at home.12  Studies relating diet to food allergy outcomes noted early exposure to cow’s milk (before 3 mo) was associated with less cow’s milk allergy13 and that maternal perinatal diets high in baked/sugary foods (trans fats) were associated with infants developing food allergy.14  Several studies on peanut, sesame, and milk OIT provide insights on safety and utility of the approach.15-20  A small follow-up study of using omalizumab to initiate peanut OIT suggests that about half did not have long-term success.21  A study following children started on omalizumab for asthma who had coincident food allergy found overall an 8-fold increase in threshold, that 70% tolerated a complete challenge dose, and that accidental reaction rates fell dramatically.22

last year. Prediction of childhood asthma was addressed in a study that provided additional validation data for the 10-item Predicting Asthma Risk in Children (PARC) tool.29 PARC’s predictive properties were determined in the Leicestershire Respiratory Cohort and compared with the Avon Longitudinal Study of Parents and Children cohort of 2690 children with preschool respiratory symptoms, of whom 373 (14%) had asthma at school age. Discriminative performance of the PARC tool was similar in the Avon Longitudinal Study of Parents and Children (area under the curve ¼ 0.77) as in the Leicestershire Respiratory Cohort (0.78) for predicting childhood asthma. A PARC score cutoff of 4 showed the highest sum of sensitivity (69%) and specificity (76%) and positive and negative likelihood ratios of 2.87 and 0.41, respectively. The similar performance of the PARC tool in 2 different cohorts supports its external validation. Suaini et al30 compared the prevalence and risk factors for allergic rhinitis, asthma, and aeroallergen sensitization at age 6 years between East Asianeborn and Caucasian-born parents in a longitudinal study of children recruited at age 1 year. Of the patients evaluated at 6 years, 3015 had Caucasian-born parents and 415 had East Asianeborn parents. Compared with children with Caucasian-born parents, children of East Asianeborn parents had significantly more allergic rhinitis and aeroallergen sensitization, but similar asthma prevalence at age 6 years. Irrespective of ancestry, children with IgE-mediated food allergy and eczema in infancy were 3-fold more likely to have asthma and 2fold more likely to have allergic rhinitis at age 6 years. The effect of polyunsaturated fatty acids (PUFAs) on the development of allergic diseases including asthma is unsettled,

given their known modulation of immune function. Lee-Sarwar et al31 investigated the associations of PUFA plasma levels and dietary intake with the development of asthma and allergy. Total, omega-3, and omega-6 plasma PUFA relative abundances were significantly and inversely associated with both the development of asthma and/or recurrent wheeze and allergic sensitization at age 3 years. Similarly, dietary PUFA intake was inversely associated with asthma and/or recurrent wheeze for omega-6 PUFA only. These outcomes were strongest among participants with both high umbilical cord blood 25-hydroxyvitamin D and high PUFA at age 3 years. The beneficial effect of PUFA dietary intake and plasma levels on reducing asthma/wheeze and atopy at age 3 years may be modulated by antenatal vitamin D level. Nwaru et al32 evaluated the relationship between sensitization to cat, dog, and horse antigens (whole allergens and components) and the risk of asthma and rhinitis in a population-representative sample of 1872 Swedish adults. Sensitization was associated with increased risks of asthma, rhinitis, and concomitant asthma and rhinitis, and with increased fractional exhaled nitric oxide (FENO), eosinophil levels, and bronchial hyperreactivity. Relationships were generally stronger with components than with whole allergens. A study by Yang et al33 examined the relationship between serum levels of cadmium and lead and current wheeze, current asthma, and lung function in a cross-sectional study of 13,888 US adults aged 20 to 79 years in 2007-2012 National Health and Nutrition Examination Surveys. The findings suggest that exposure to cadmium is associated with an increased risk of wheeze and asthma in US adults who currently smoke.

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TABLE II. Summary of asthma highlights Epidemiology  The PARC tool, which predicts childhood asthma, was validated in a longitudinal study.29  Irrespective of ancestry, children with IgE-mediated food allergy and eczema in infancy were 3-fold more likely to have asthma and 2-fold more likely to have allergic rhinitis at age 6 y.30  The beneficial effect of PUFA dietary intake and plasma levels on reducing asthma/wheeze and atopy at age 3 y may be modulated by antenatal vitamin D level.31  Sensitization to cat, dog, or horse antigens was associated with increased risks of asthma, rhinitis, and concomitant asthma and rhinitis, and with increased FENO, eosinophil levels, and bronchial hyperreactivity.32  Exposure to cadmium was associated with an increased risk of wheeze and asthma in US adults who currently smoke, and exposure to cadmium or lead had negative effects on lung function in nonsmoking US adults who participated in the National Health and Nutrition Examination Surveys.33 Comorbidities  In 206 patients with asthma from Japan, several obesity indices (body mass index, waist circumference, and abdominal visceral and subcutaneous fat) were associated with reduced QOL in females, but only the visceral fat area was associated with reduced QOL in males as well as with reflux, depression scores, and reduced FEV1.34  In an obese asthma cohort from a claims-based health services, compared with individuals with normal glycated hemoglobin, those in the prediabetes range had a 27% higher rate (95% CI, 5%-52%) of asthma exacerbations, and those in the diabetes range had a 33% higher rate (95% CI, 2%-73%) of asthma exacerbations.35  Obesity was associated with an increase in moderate/severe RTIs and increased rates of all-cause and infection-associated asthma exacerbations requiring systemic steroids in adults from a post hoc analysis of 5 large asthma trials.36  A 3-way interaction effect of indoor PM2.5, vitamin D levels, and obesity on asthma symptoms was reported.37  In a study using national cohort samples in Korea, the hazard ratio of the incidence of newly diagnosed depressive disorder was 35% higher in patients with asthma than in patients without asthma, and the hazard ratio of a new diagnosis of asthma was 25% higher in patients with depression than in patients without depression.38 Adherence  In a survey study from Australia, cost-related medication underuse was reported by 52.9% of adults with asthma and 34.3% of parents of children with asthma.39  Implementation of a speech recognition reminder call or text demonstrated a small but significant improvement in percent of days covered of ICS and a decrease in prescription of oral corticosteroids.40  In a systematic review of patient/family-level interventions to improve ICS adherence in adult black/African Americans, only 4 RCTs and 1 pre-post study met the study criteria, and no RCTs found a significant improvement in adherence.41 Special populations  In a large database study of pregnant women with asthma, 19.0% and 18.8% had severe asthma and 16.5% and 28.0% had poorly controlled asthma in commercial and Medicaid populations, respectively, and many women with poorly controlled asthma during pregnancy were not dispensed a longterm controller.42  In a cohort of 35,520 pregnancies in women with asthma and 197,057 pregnant women without asthma, the risk of postpartum depression was increased by nearly 60% in women with asthma.43  On the basis of National Sample Cohort data of Korea, elderly patients with asthma who were newly prescribed LTRAs (n ¼ 1571) had a similar risk of exacerbations to those newly prescribed low-dose ICS (n ¼ 121), possibly related to the higher adherence demonstrated in the LTRA group.44 Phenotypes and endotypes  In a cluster analysis done separately in 421 adult females and 299 adult males, high exacerbation risk clusters in females were atopy/eosinophilpredominant and obesity/neutrophil-predominant, whereas high-risk clusters in males were current smoker/neutrophilic atopic and ex-smoker/ eosinophil-predominant or mixed inflammatory pattern.45  Regarding the OA “phenotype,” one study showed that epoxy compounds elicited positive specific inhalation challenges in 13% of 113 patients with work-related asthma,46 whereas another study47 found that 16% of 997 patients with OA had severe occupational asthma, associated with factors such as longer duration of disease and persistent (vs reduced) exposure to the causal agent at work.  Concordance between 5 definitions of ACO was poor in a study of 1609 patients with asthma and COPD,48 but elevated levels of both serum periostin and YKL-40 may be useful biomarkers to distinguish ACO from asthma or COPD alone.49  Regarding AERD, the use and safety of an abbreviated protocol for aspirin challenge was described that could usually be completed within a day,50 and ESS was shown to decrease subsequent reactions to aspirin challenge,51 suggesting that patients with suspected AERD should be challenged before ESS but should be desensitized after ESS.  Using latent class analysis in preschool-age children with recurrent wheeze, it was found that sensitization and allergen exposure were helpful to predict future exacerbations and to identify children most responsive to daily ICS treatment.52 Infection  In a meta-analysis of 16 studies, nasal Staphylococcus aureus colonization was associated with increased asthma prevalence (OR, 1.19; 95% CI, 1.061.34), with an even higher risk in patients with CRS (OR, 1.87; 95% CI, 1.18-2.97).53  In 82 patients hospitalized for asthma exacerbations, patients with positive viral nasopharyngeal culture samples (n ¼ 40) presented with lower serum IgG concentrations than those with a negative viral sample.54  In 28,289 patients with asthma from the UK Optimum Care Database55 who were treated for nonpneumonic lower RTIs, prescribing of 7 d of amoxicillin was associated with a reduced need for a second antibiotic within 14 d of the index prescription. (continued)

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TABLE II. (Continued) Asthma control  A study conducted in 1697 patients suggests that physicians overestimate asthma control (as defined by ACQ), especially in patients who have not received lung function assessment.56 In conjunction with the observation in a managed-care population of 1745 patients that there was only a weak and statistically insignificant association between FEV1%predicted and 5-item ACQ/6-item ACQ scores,57 the studies suggest that both a validated control tool and pulmonary function should be used to assess asthma control, rather than relying on either measure alone.  The ACCI, a 12-item self-reported questionnaire, was validated among urban, black, Hispanic, and/or poor adolescents.58  Although parents may overestimate the level of their child’s asthma control, their recognition of poorly controlled asthma in their child is confirmed by future need for acute care.59  Regarding achieving asthma control, improvements with tiotropium in pulmonary function were generally consistent across the range of baseline IgE levels and blood eosinophil counts in children aged 6-17 y.60  On the basis of 2 studies of risk factors for loss of asthma control,61,62 patients with a smoking history, exacerbations in the previous year, lower asthma control scores, and lower pulmonary function may be poor candidates for step-down therapy and need to be followed more closely for loss of asthma control.  Poor-urban residence may be an independent factor associated with poor asthma control and suboptimal treatment, even after adjusting for ethnicity.63  Unexpectedly, there was a significant time-trend increase in asthma attacks among children, possibly due to the significant decrease in the use of ICS and other controllers among the children.64  The utility of T2 biomarkers to help predict future exacerbations differs by age in children and adolescents.65 Severe or difficult asthma and biologics  Interviews with patients with severe asthma revealed issues with their understanding of severe asthma, emotional impact of living with severe asthma, public perceptions of asthma, and concerns about medications.66  In neutrophil-predominant severe asthma in children, their neutrophils exhibited a highly proinflammatory phenotype with surface markers that regulate neutrophil activation, recruitment/migration, granule release, and enhanced survival.67  In multivariable analyses, black children aged 6-11 y with severe- to difficult-to-treat asthma had significantly higher total serum IgE levels, a higher frequency of very poorly controlled asthma and use of systemic corticosteroids, poorer asthma-specific QOL, and ED visits by month 12 of followup.68  Factors that may contribute to or be associated with asthma being severe or difficult to control in adults include (1) dysfunctional breathing, especially in patents with anxiety, depression, and more severe sinonasal disease,69 (2) chronic cough,70 and (3) bronchiectasis.71  Important differences in BAL granulocytic patterns were observed in severe, therapy-resistant pediatric asthma, with 32% of the children having eosinophilic infiltration, which could be amenable to anti-T2 biological therapies, and in 12%, a treatable bacterial pathogen.72  Two indirect comparisons of asthma biologics reported that (1) reslizumab was superior to benralizumab regarding asthma control, QOL, FEV1, and exacerbations in patients with eosinophilic asthma (300 or 400) receiving step 4/5 care and having 2 or more exacerbations in the previous year,73 and (2) mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts,74 but results based on this indirect methodology should be interpreted with caution.75  In 29 patients who had previously failed therapy with omalizumab and who had peripheral eosinophilia 400/mL in the previous year, improvements regarding impairment, exacerbations, and corticosteroid requirement were observed over a 24-wk period with intravenous reslizumab.76  A pooled analysis of 6 RCTs suggested that the antieIL-13 drug tralokinumab was well tolerated and modestly improved FEV1 in patients with moderate to severe asthma, but it did not render clinically important improvements in asthma-related QOL and it only reduced asthma exacerbations in patients with severe asthma with high FENO levels.77 Other  In 200 adults with recently diagnosed asthma, the patient-reported trigger of onset, such as upper respiratory symptoms, new allergic sensitization, and pneumonia, was associated with specific clinical, functional, and inflammatory characteristics.78  In a review of the content and quality of 23 mHealth asthma management apps, focusing on the presence or absence of behavior change techniques (BCTs), Kiss myAsthma and AsthmaMD used at least 8 BCTs and had good quality scores.79

Moreover, the results suggest that exposure to cadmium or lead has negative effects on lung function in nonsmoking US adults. Based on all these studies, reduced allergen sensitization, increased PUFA dietary intake, and less exposure to pollutants could lower the prevalence of allergic rhinitis and asthma.

Comorbidities An important comorbidity of asthma is obesity, and 4 of last year’s studies shed new light on the relationship between obesity and asthma. Goudarzi et al34 evaluated the relationship between visceral adiposity, as assessed by computed tomography scan, and asthma QOL in 206 patients with asthma from Japan. All obesity indices (body mass index, waist circumference, and abdominal visceral and subcutaneous fat) were associated with

reduced QOL in females, but only the visceral fat area was associated with reduced QOL in males. The visceral fat area was also associated with reflux, depression scores, and reduced FEV1. The second obesity study by Wu et al35 sought to determine the association between prediabetes/diabetes and asthma exacerbations in an obese asthma cohort created from a claims-based health services database spanning 2010 to 2015. In the fully adjusted model, compared with individuals with normal glycated hemoglobin, those in the prediabetes range had a 27% higher rate (95% CI, 5%-52%) and those in the diabetes range had a 33% higher rate (95% CI, 2%-73%) of asthma exacerbations. Results support evidence that insulin resistance and metabolic syndrome, metabolic features common in prediabetes/diabetes, can influence asthma morbidity. The mechanistic and clinical

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interventional implications of the observations from both these obesity studies warrant further study. The third obesity study36 investigated the relationship between body mass index classification and the risk of self-reported respiratory tract infections (RTIs) and related asthma morbidity in a post hoc analysis of 5 large asthma trials (n ¼ 747 children and 1287 adults). In children, body mass index did not affect any RTI or related asthma outcomes. However, in adults, obesity was associated with an increase in moderate/severe RTIs and increased rates of all-cause and RTI-associated asthma exacerbations requiring systemic steroids. These observations suggest the possibility that weight reduction could reduce the risks of infection-induced exacerbations in obese adults with asthma. Finally regarding obesity, Bose et al37 provided new information concerning the effect of the 3-way interaction of indoor particulate matter (PM) 2.5, vitamin D levels, and obesity on asthma symptoms.37 PM and symptoms were assessed for 9month follow-up in 210 urban children aged 5 to 12 years with physician-diagnosed asthma. About a 25% significant increase in daytime asthma symptoms was observed only in obese children with low 25-OH vitamin D levels (15.5 ng/mL) in homes with higher PM2.5 levels. In contrast, obese children with higher 25-OH vitamin D levels appeared protected against the adverse effects of increased PM2.5 levels on asthma symptoms. The findings suggest that vitamin D status should be determined to optimize the vitamin D level in obese children, which may help reduce asthma morbidity driven by indoor air pollution. Another important comorbidity of asthma is depression, and valuable information on the interrelationships between asthma and depression came from a study by Choi et al.38 The aim of this study was to determine the bidirectional relationships between development of asthma and development of depression using national cohort samples in Korea. The hazard ratio of the incidence of newly diagnosed depressive disorder was 35% higher in patients with asthma than in patients without asthma, and the hazard ratio of a new diagnosis of asthma was 25% higher in patients with depression than in patients without depression. Further studies will be necessary to determine whether this bidirectional relationship can be altered by treatment of either entity.

Adherence Poor adherence to inhaled asthma medications is a welldocumented challenge in the care of patients with asthma. Articles published in the past year in the journal attempted to understand this problem and identify effective forms of intervention. Laba et al39 attempted to estimate the extent of costrelated underuse of medications for asthma and associated factors by means of an online, cross-sectional survey of adults (n ¼ 792) and parents (n ¼ 609) of children 5 to 17 years old with asthma in Australia. Cost-related underuse was reported by 52.9% of adults and 34.3% of parents, predominantly decreasing or skipping doses to make medications last longer. Higher odds of cost-related underuse were observed with younger adults, having concerns about medications, less comfort talking to prescribers about cost or changing medications, feeling less engaged with prescribers about medication decisions, and with poorer asthma control. The authors concluded that awareness of these issues and effective engagement with patients are needed to reduce this potential cause of poor adherence and suboptimal asthma outcomes.

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With regard to intervention, Cvietusa et al40 reported implementation of a speech recognition intervention (reminder call or text sent 5-11 days before the patient was scheduled to run out of controller medication) in 36,356 patients with asthma in the Kaiser Permanente Colorado population. Patient adherence to inhaled corticosteroids (ICSs) demonstrated a small but significant improvement (percent of days covered 39.5% to 41.7%; P < .0001) and a decrease in prescription of oral corticosteroids (26.4% to 23.8%; P ¼ .02). The small cost of the intervention appeared to be worth the small improvement in these outcomes. In contrast, results from a systematic review of patient/familylevel interventions to improve ICS adherence in adult black/ African Americans were disappointing.41 Only 4 randomized controlled trials (RCTs) and 1 pre-post study met the study criteria, and only 1 study was informed by both behavior theory and stakeholder engagement. No RCTs found a significant improvement in adherence. More intervention studies informed by behavior theory and stakeholder engagement are needed.

Special populations Two special populations addressed were pregnant women and the elderly. Cohen et al42 described the prevalence, severity, and control of asthma during pregnancy in cohorts within 2 large US health care claims databases: the Truven Health MarketScan Commercial Claims and Encounters Database (private insurance) and the nationwide Medicaid Analytic eXtract (MAX) (public insurance). Among 604,420 pregnant women in MarketScan and 2,071,359 pregnant women in MAX, 20,104 (3.3%) and 120,745 (5.8%) had asthma, respectively. Among pregnant women with asthma, 19.0% and 18.8% had severe asthma and 16.5% and 28.0% had poorly controlled asthma in MarketScan and MAX, respectively. Many women with poorly controlled asthma during pregnancy were not dispensed a longterm controller (38.4% in MarketScan and 43.3% in MAX). This study shows the disturbing results that poorly controlled asthma is more frequent among publicly versus privately insured pregnancies in the United States, and that dispensing of longterm controller medications during pregnancy remains low, even for symptomatic patients. The other study of asthma during pregnancy reported a novel adverse outcome. In a cohort of 35,520 pregnancies in women with asthma and 197,057 pregnant women without asthma extracted from the Quebec Asthma and Pregnancy Database, Blais et al43 noted that the risk of postpartum depression was increased by nearly 60% in women with asthma (adjusted OR, 1.58; 95% CI, 1.50-1.67). Vigilance for postpartum depression must be maintained in pregnant women with asthma so that appropriate management or referral can be instituted when the condition is identified. Regarding the elderly, Hong et al44 compared the effectiveness of leukotriene receptor antagonists (LTRAs) versus ICSs in elderly patients with asthma in real-world settings. Records were extracted from 2003-2010 National Sample Cohort data of Korea for the elderly with asthma who were newly prescribed LTRAs (n ¼ 1571) or low-dose ICSs (n ¼ 121). The risks of asthma exacerbation in the LTRA and low-dose ICS groups after propensity weighting were not significantly different (hazard ratio, 0.98; 95% CI, 0.65-1.54). The proportion with high adherence (medication possession ratio  80%) in the LTRA group was higher than that in the low-dose ICS group. The similar effectiveness of LTRAs and low-dose ICSs regarding the risk of asthma exacerbation in elderly patients with mild asthma

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in these real-world settings may be due to the increased adherence with the LTRA regimen.

Phenotypes and endotypes The heterogeneity of asthma has long been recognized, and a substantial amount of recent work has been focused on the concepts of phenotypes and endotypes to understand this heterogeneity in a way that would have mechanistic and therapeutic implications. Several articles provided novel insight into asthma phenotypes and endotypes. In the Taiwanese Adult Asthma Cohort study,45 asthma phenotypes/endotypes were defined by cluster analysis separately in adult females (n ¼ 421) and males (n ¼ 299). The relationships of the clusters to asthma exacerbations were explored. High-risk clusters in females were atopy/ eosinophil-predominant and obesity/neutrophil-predominant; high-risk clusters in males were current smoker/neutrophilic atopic and ex-smoker/eosinophil-predominant or mixed inflammatory pattern. This study identified sex differences in phenotype/endotype patterns, and the therapeutic implications of these differences warrant further exploration. Another form of asthma that could be considered a phenotype, occupational asthma (OA), was studied in two 2019 reports. Epoxy compounds, such as 2-component epoxy resin systems used in industrial and construction coating and triglycidyl isocynaurate, mostly encountered in polyester powder paints, are well-known skin sensitizers, but their respiratory-sensitizing potential is largely unknown. From data collected from the Finnish Institute of Occupational Health, 113 patients with work-related asthma underwent placebo-controlled specific inhalation challenge with epoxy compounds, with positive challenges in 15 (13%).46 A high index of suspicion for OA should be maintained for patients with epoxy compound exposure who present with respiratory symptoms. Vandenplas et al47 characterized the burden and determinants of severe OA in a large multicenter cohort of subjects with OA. The study included 997 subjects with OA ascertained by a positive specific inhalation challenge completed in 20 tertiary centers in 11 European countries. Overall, 162 (16.2%) subjects were classified as having severe OA. Adjusted analysis revealed that severe OA was associated with persistent (vs reduced) exposure to the causal agent at work, a longer duration of the disease, a low level of education, childhood asthma, and sputum production. This study indicates that a substantial proportion of subjects with OA experience severe asthma and identifies potentially modifiable risk factors for severe OA that should be targeted to reduce the adverse impacts of the disease. Asthma/chronic obstructive pulmonary disease (COPD) overlap (ACO) is another condition now being considered as an asthma phenotype. One issue in studies evaluating this condition has been the variable definitions used to identify the condition. A study by Barczyk et al48 aimed to assess the concordance between 5 different ACO definitions in 1609 patients with asthma and COPD and to estimate the definition-based ACO prevalence and characteristics. Overall, the level of agreement between different ACO definitions was poor. Definition-based ACO prevalence ranged between 3.8% (Spanish criteria) and 18.4% (clinician’s diagnosis). A total of 573 (33.4%) patients met the criteria from at least 1 ACO definition. Significant differences between patients identified by the various definitions were found for sex distribution, age at diagnosis, pulmonary function, smoking status, symptoms, and exacerbations. The results suggest that the

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current ACO definitions identify distinct populations that share only a small number of common features and present with different disease phenotypes. Studies of ACO must be interpreted in the context of the ACO definition used. Another study49 explored serum markers of ACO in patients with asthma (n ¼ 177), ACO (n ¼ 115), or COPD (n ¼ 61). ACO was defined in this study as (1) patients with asthma older than 40 years with postbronchodilator FEV1/forced vital capacity ratio of less than 0.7 and a history of smoking or reduced diffusing capacity of the lungs for carbon monoxide or low attenuation area on chest computed tomography, or (2) patients with COPD with 2 of the following criteria: history of asthma, peripheral eosinophilia greater than or equal to 250 cells/mL, FENO more than 35 ppb, or serum total IgE more than 100 IU/ mL The authors found that serum periostin level was high in asthma and ACO, whereas the level of serum YKL-40, a secreted glycoprotein possibly involved in the pathogenesis of COPD, was high in ACO and COPD. The proportion of patients with high levels of both markers was significantly higher in those with ACO than in those with asthma or COPD. If confirmed in other populations, these findings may facilitate more accurate identification of ACO and more targeted interventions for this phenotype. Two articles provide useful caveats regarding the classic asthma phenotype of aspirin-exacerbated respiratory disease (AERD). DeGregorio et al50 described the use and safety of an abbreviated protocol for aspirin challenge in patients with suspected AERD with a starting dose of 40.5 mg and escalating doses (81, 162.5, 325) at 90-minute intervals. Of 44 patients, 43 patients reacted (most commonly at the 81-mg dose) and 41 (93%) completed the procedure in 1 day. No patient required epinephrine, ED visit, or hospitalization. In a study by Jerschow et al,51 28 patients with documented AERD were challenged with aspirin before and 3 to 4 weeks after endoscopic sinus surgery (ESS). After ESS, reactions were less severe in all patients, and 12 of 28 patients had no detectable reaction. On the basis of these observations, the authors concluded that patients suspected of having AERD should be challenged before ESS for optimal diagnostic accuracy, but should be desensitized after ESS as the severity of their aspirin reaction lessens. Finally, regarding phenotypes, Fitzpatrick et al52 used latent class analysis to identify latent classes of recurrent preschool wheeze and their association with future exacerbations and ICS treatment response from 5 clinical trials of 1708 children aged 12 to 71 months with recurrent wheezing. The 4 latent classes of recurrent wheezing identified differed by allergen sensitization and/or exposures. Annualized exacerbation rates in class 1 with minimal sensitization was 0.65, in class 2 with sensitization and indoor pet exposure was 0.93, in class 3 with sensitization and tobacco smoke exposure was 0.60, and in class 4 with multiple sensitizations and eczema was 0.81. Of importance, daily ICS treatment reduced exacerbation rates only in classes 2 and 4. The take-home message was that sensitization and allergen exposure are useful to determine because they are helpful to predict future exacerbations and may help to identify children most responsive to daily ICS treatment.

Asthma and infection Infections are important in the onset of asthma and as triggers of asthma exacerbations. Several studies dealt with infections and asthma. Kim et al53 examined the relationship between nasal

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Staphylococcus aureus colonization and asthma prevalence in a meta-analysis of 16 studies. Nasal SA colonization was associated with increased asthma prevalence in the general population (OR, 1.19; 95% CI, 1.06-1.34), with an even higher risk in patients with chronic rhinosinusitis (CRS) (OR, 1.87; 95% CI, 1.182.97). It remains to be determined whether eradicating nasal SA could reduce the incidence of asthma in those patients. Viruses are a common cause of asthma exacerbations, and Verduyn et al54 evaluated the relationship between serum IgG and positive viral nasopharyngeal cultures in 82 patients hospitalized for asthma exacerbations. The authors found that patients with positive viral nasopharyngeal culture samples (n ¼ 40) presented with lower serum IgG concentrations than did those with a negative viral sample. The IgG level was also lower in patients hospitalized longer and who received a longer course of oral corticosteroids. The mechanistic and therapeutic implications of these intriguing observations require further study. Although most infection-induced asthma exacerbations are due to viruses, bacterial infections can be involved, and antibiotics are frequently used empirically in the treatment of patients with asthma with lower RTIs. Antibiotic prescriptions for nonpneumonic lower RTIs were studied in 28,289 patients with asthma from the UK Optimum Care Database.55 Prescribing of 7 days of amoxicillin was associated with a reduced need for a second antibiotic within 14 days of the index prescription, whereas older age and current smoking increased the risk of repeat antibiotic prescriptions. Pending additional information, this antibiotic program could be considered an option for patients with asthma with nonpneumonic lower RTIs, and further study of the optimal treatment of older patients and smokers is indicated.

Asthma control Asthma control is the goal of therapy and is evaluated by assessing impairment and risk (exacerbations). Several articles provided useful information regarding assessing, achieving, and maintaining asthma control. One study56 analyzed the differences between patients and their physicians in the perception of asthma control in a multicenter, cross-sectional study conducted in 1697 patients visiting primary or secondary facilities for routine asthma reviews. Asthma Control Questionnaire (ACQ) results showed that asthma was well controlled in 52.2% of the patients, but physicians perceived that 79.6% of patients were well controlled. Increased rates of discordance were noted among patients whose asthma was not well controlled and patients who had not received lung function assessment. This study suggests that objective assessment of asthma impairment using validated questionnaires and pulmonary function would increase the accurate identification of uncontrolled asthma. In this regard, Sullivan et al57 assessed the association between FEV1%predicted and ACQ scores in a managed-care population of 1745 patients with persistent asthma. There was no significant association between FEV1%predicted and 5-item ACQ/6-item ACQ scores in unadjusted models. Results support the use of both symptoms and pulmonary function, rather than relying on one measure alone, to assess asthma control in clinical care and outcomes studies. Okelo et al58 provided additional validation data for the Asthma Control and Communication Instrument (ACCI), a 12item self-reported questionnaire, among 280 urban, black, Hispanic, and/or poor adolescents with a mean age of about 13 years

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and with slightly more than half being males and blacks. Good internal reliability and strong concurrent and discriminative validity were documented between the ACCI and the Asthma Control Test and the Pediatric Asthma Quality of Life Questionnaire. The ACCI was good at correctly classifying adolescents with uncontrolled asthma with an area under the curve of 0.83. This validation of the ACCI in adolescents provides a useful tool to help assist in the evaluation of asthma control in urban, minority, and/or poor adolescents. Caregiver perception by questionnaire of a child’s asthma control independent of guideline-based asthma control assessment was studied for its capacity to predict future acute visits in 2 cohorts of low-income, predominately black 5- to 17-year-old children with persistent asthma.59 About 70% of caregivers in both groups rated their child’s asthma control as well controlled, although nearly half of them had very poorly controlled asthma by guideline definition. However, participants whose caregivers reported that their child’s asthma was uncontrolled exhibited greater odds of experiencing an acute visit in the subsequent 3 months compared with participants whose caregivers reported that their child’s asthma was well controlled. Although parents may overestimate the level of their child’s asthma control, their recognition of poorly controlled asthma in their child needs to be carefully heeded and acted upon because it increases the risk for future acute asthma care. Regarding achieving asthma control, tiotropium, a longacting, antimuscarinic bronchodilator, has been shown to be an efficacious and safe add-on therapy in 6- to 17-year-olds with symptomatic asthma despite treatment with ICSs. In a post hoc analysis of 2 phase III trials in patients with symptomatic moderate asthma and 2 phase III trials in patients with symptomatic severe asthma, Szefler et al60 expanded upon these findings by demonstrating that the effectiveness of tiotropium is not influenced by a child or adolescents’ type 2 (T2) status, assessed by serum IgE levels and blood eosinophil counts. Improvements with tiotropium in pulmonary function were generally consistent across the range of baseline IgE levels and blood eosinophil counts. Similar, but less robust, findings were seen for risk of exacerbations and improvement in asthma control. Once asthma control is achieved, the challenge is to maintain it over time, including with recommended step-down therapy. Two studies published in the journal last year shed light on the issue of maintenance of asthma control. The first study61 used data from 304 patients from a 12-month primary care RCT with assessments every 3 months. The risk of loss of asthma control or an asthma exacerbation could be predicted by a score that included sex, smoking, ACQ score at baseline and 3-month follow-up, and exacerbations in the previous year at baseline and the previous 3 months at follow-up. In the second study, Pérez de Llano et al62 investigated factors associated with loss of asthma control when stepping down asthma treatment and developed a score to predict this risk in a derivation cohort of 228 patients and a validation cohort of 114 patients. Medical recordedocumented airway obstruction (FEV1/forced vital capacity < 70%), current FEV1 less than 80% predicted, 1 or more severe exacerbations in the previous 12 months, and Asthma Control Test score less than 25 were independently associated with step-down failure. On the basis of both these studies, patients with a smoking history, exacerbations in the previous year, lower asthma control scores, and lower pulmonary

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function may be poor candidates for step-down therapy and need to be followed more closely for loss of asthma control. Two of last year’s publications studied asthma control in children. The question of whether individual characteristics such as race and ethnicity or place of residence impact asthma control in children was studied by Sullivan et al63 in a cross-sectional analysis of 15,052 children aged 1 to 17 years in the 20002014 Medical Expenditure Panel Survey. In analyses adjusted for potential confounders, children with asthma residing in poorurban areas evidenced several important features of poor asthma control, including lower odds of using controller medications and higher odds of reporting an asthma attack such as an ED visit or hospitalization for asthma, compared with those living elsewhere. Minority ethnicity, including blacks or Hispanics, was also associated with these signs of poor asthma control. These analyses suggested that poor-urban residence may be an independent factor associated with poor asthma control and suboptimal treatment, even after adjusting for ethnicity. These health disparities based on geography need to be better understood to more successfully address these differences from a public health perspective. Sullivan et al64 also studied the trends in asthma control and treatment in the United States among children, particularly the 11% from poor-urban communities, from 2003 to 2014 using the Medical Expenditure Panel Survey. Unexpectedly, there was a significant time-trend increase in asthma attacks among children, possibly due to the significant decrease in the use of ICSs and other controllers among the children. These disappointing findings demand greater attention to better adherence to asthma guidelines in children. Regarding the risk domain of asthma control, previous severe exacerbations requiring systemic corticosteroids have repeatedly been documented as the strongest predictor for future severe exacerbations in children and adolescents. Shah et al65 questioned whether specific T2 inflammatory markers are helpful to increase the predictive accuracy of future exacerbations over a 12-month period in 589 pediatric patients and adolescents/young adults aged 5 to 21 years. Exacerbations requiring corticosteroids occurred in 106 (35.5%) children and 72 (24.8%) adolescents. Elevated blood eosinophils were associated with increased odds and shorter time to first acute visit, but optimal cutoff points differed by age (150 vs 300 cells/mm3 for children vs adolescents, respectively). In children, addition of a second T2 biomarker such as sensitization, nitric oxide, or total IgE level did not improve prediction of exacerbations in children, but in adolescents, the addition of any or multiple allergen sensitizations increased the prediction of exacerbations by 11% and 16%, respectively. These findings support the utility of T2 biomarkers to help predict future exacerbations, although differences occurred by age.

Severe or difficult asthma and biologics One of the most challenging medical conditions for patients and clinicians is severe or difficult asthma. Fortunately, with the advent of biological therapies for severe asthma, the lives of many patients with severe asthma have improved substantially. Several articles provided additional information regarding severe or difficult asthma and the use of asthma biologics. Apps et al66 explored patient perceptions of living with severe asthma and the experience of managing severe asthma in interviews with 29 participants. The analysis resulted in 4 major themes: understanding of severe asthma, emotional impact of living with severe

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asthma (subtheme: fear of hospitalization), public perceptions of asthma, and concerns about medications. The authors concluded that health care professionals need to consider and discuss with patients their perceptions of severe asthma and the relevant treatments. Severe asthma in children is poorly understood, leading Grunwell et al67 to characterize the inflammatory airway environment in 67 children with neutrophil-predominant severe asthma refractory to high-dose ICS treatment requiring bronchoscopy with bronchoalveolar lavage (BAL) determination. Increased markers of neutrophil activation/degranulation and a greater magnitude of airway proinflammatory cytokine and chemokine release were noted in these children. Given the poor response to ICSs, children with predominately neutrophilic severe asthma need new therapies that target neutrophils to reduce inflammation due to neutrophil activation. Racial disparities in asthma-related health outcomes in 86 black and 262 white children aged 6 to 11 years with severe to difficult-to-treat asthma enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens 3-year observational study were explored by Guilbert et al.68 Compared with white children, black children were significantly more male, obese, from lower income families, had higher total serum IgE levels, a higher frequency of very poorly controlled asthma and use of systemic corticosteroids, poorer asthma-specific QOL, and ED visits by month 12 of follow-up. These differences remained significant in multivariable analyses after adjustment for potential confounders. The increase in asthma morbidity in black compared with white children could not be explained by differences in demographic characteristics and other baseline features. Findings such as these and the known poorer asthma outcomes in blacks demand more intensive management and study of this racial group. Four reports explored other factors that may contribute to asthma being severe or difficult to control. Three of the studies were in adults. A study by Denton et al69 evaluated dysfunctional breathing, a disruption to the normal biomedical pattern of breathing, the most well-described example of which is hyperventilation, in 157 patients with difficult asthma. The authors found that dysfunctional breathing was present in almost 50% of patients and was associated with poorer asthma status. Risk factors included anxiety, depression, and more severe sinonasal disease. This article shows that dysfunctional breathing is very common in patients with difficult asthma and highlights an important interaction between several treatable contributing factors in these patients. Chronic cough was explored as a marker of asthma severity in 855 individuals with asthma from the Copenhagen General Population Study, of whom 70 (8%) had chronic cough.70 Chronic cough in individuals with asthma was associated with a more severe disease phenotype in terms of worse respiratory symptoms, greater health care utilizations, lower lung function, and higher levels of systemic inflammatory biomarkers in blood. The mechanistic and therapeutic implications of these findings merit further study. The third article71 described 437 patients in the Severe Asthma Network in Italy. Bronchiectasis was found in 16% of patients and was associated with more frequent severe exacerbations, higher blood eosinophils, and higher total IgE level. A high index of suspicion should exist for coexisting bronchiectasis in patients with severe asthma, although the therapeutic implications of this association remain to be defined.

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The relationship of refractory lung inflammation and infectious species as factors contributing to poorly controlled asthma in children was studied by Teague et al72 in 126 children with severe asthma. During indicated bronchoscopy, investigators reported on BAL cell count and differential and bacterial and viral studies. Differences in clinical characteristics were noted by 4 granulocytic patterns: (1) children with pauci-granulocytic BAL (52.0%) had less postbronchodilator airflow limitation, less blood eosinophilia, and less detection of BAL enterovirus compared with children with mixed granulocytic BAL; (2) children with mixed granulocytic BAL (22.0%) required more maintenance prednisone, and had greater blood eosinophilia and allergen sensitization compared with those with paucigranulocytic BAL; (3) children with isolated neutrophilia BAL (15.9%) had less blood eosinophilia than those with mixed granulocytic BAL, but greater prevalence of potential bacterial pathogens compared with those with pauci-granulocytic BAL; and (4) children with isolated eosinophilia BAL (9.5%) had features similar to those with mixed granulocytic BAL. Important phenotypic differences in BAL granulocytic patterns were observed in severe, therapy-resistant pediatric asthma. Importantly, BAL revealed that 32% of the children had eosinophilic infiltration, which could be amenable to anti-T2 biological therapies, and in 12%, a treatable bacterial pathogen. Several 2019 articles provided valuable information regarding the use of asthma biologics in practice. One question is whether there are subgroups of patients who are more responsive, based on biomarkers or clinical characteristics. Casale et al80 described 622 patients completing a 48-week, prospective, single-arm multicenter study of omalizumab in patients 12 years and older with allergic asthma. Omalizumab initiation resulted in improved exacerbation rates and improved Asthma Control Test scores compared with pretreatment values, regardless of baseline biomarker (blood eosinophils and FENO) status. Weinstein et al81 presented a post hoc analysis of 2 phase 3 clinical trials studying reslizumab in patients with uncontrolled asthma and peripheral eosinophilia (400/mL) who reported having CRS with nasal polyps (CRSwNP). Compared with placebo, add-on reslizumab reduced the frequency of clinical asthma exacerbations in patients with CRSwNP by 79% in patients with aspirin sensitivity and by 84% in patients without aspirin sensitivity. Patients with CRSwNP (with or without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, asthma control, and asthma QOL compared with placebo. The availability of 5 asthma biologics has given clinicians choices for individual patients, but the absence of head-to-head comparisons of the various asthma biologics has often made these choices difficult. One approach to this problem has been the use of indirect comparisons of drug efficacy in similar patients across different clinical trials with different drugs. Casale et al73 reported this type of comparison of reslizumab versus benalizumab, identifying 11 studies, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. The authors found that reslizumab was superior to benralizumab regarding asthma control, QOL, FEV1, and exacerbations in patients with eosinophilic asthma (300 or 400) receiving step 4/5 care and having 2 or more exacerbations in the previous year. Busse et al74 described a similar indirect comparison of mepolizumab, benralizumab, and reslizumab in patients with severe eosinophilic asthma, according to baseline blood eosinophil

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counts. Based on 11 studies, the results suggested that mepolizumab was associated with significantly greater improvements in clinically significant exacerbations and asthma control compared with reslizumab or benralizumab in patients with similar blood eosinophil counts. Although these indirect comparisons are the best that can be done at this time, Mauger and Apter,75 in an accompanying editorial, recommend caution in their interpretation due to many factors, especially regarding the true comparability of the included trials. Another form of an indirect comparison is to assess medication effectiveness in patients who have failed another medication. A study by Pérez de Llano et al76 sought to evaluate the efficacy and safety of weight-based intravenous reslizumab dosing in 29 patients who had previously failed therapy with omalizumab and who had persistent uncontrolled asthma and peripheral eosinophilia (400/mL) in the previous year. Improvements regarding impairment, exacerbations, and corticosteroid requirement were observed over a 24-week period. The authors concluded that reslizumab is an effective and safe option for patients with severe eosinophilic asthma and a history of omalizumab failure. In addition to the available biologics, many new biologics are being studied. Zhang et al77 presented a meta-analysis that assessed the efficacy and safety of subcutaneous injection of the antieIL-13 drug tralokinumab in patients with moderate to severe asthma. The pooled analysis of 6 RCTS suggested that tralokinumab was well tolerated and modestly improved FEV1 and forced vital capacity in patients with moderate to severe asthma. It did not render clinically important improvements in asthma-related QOL, nor did it reduce asthma exacerbations, except in a post hoc subgroup analysis of patients with severe asthma with high FENO levels.

Other asthma articles Two other 2019 asthma articles are worth highlighting. In 200 adults with recently diagnosed asthma followed for 5 years, Coumou et al78 found that the patient-reported trigger of onset was associated with specific clinical, functional, and inflammatory characteristics: “New allergic sensitization” (11%) was associated with mild atopic asthma and relatively young age at onset; “pneumonia” (8%) with previous smoking, low IgE, and the highest remission rate; “upper respiratory symptoms” (22%) with high exhaled nitric oxide and eosinophilia; and “stressful life event” (7%) with high medication use, low T2 markers, and no disease remission. “No trigger identified” (38%) showed no specific associations. Ramsey et al79 reviewed the content and quality of mHealth asthma management apps that are available to patients. Twentythree apps were coded for the presence or absence of behavior change techniques, and the quality of the apps was scored as well. Behavior change techniques that were most commonly used were instruction, behavior-health link, self-monitoring, feedback, teach to use prompts/cues, consequences, and others’ approval. Kiss myAsthma and AsthmaMD used at least 8 behavior change techniques and had good quality scores. DERMATITIS Skin problems discussed in 2019 JACI: In Practice articles (Table III) include dermatitis and urticaria/angioedema (see below). The scope of practice of the allergist-immunologist includes the care of patients with allergic contact dermatitis. Watts et al82 argue that this disease is increasingly presenting to

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TABLE III. Summary of dermatitis and urticaria highlights Dermatitis  Allergic contact dermatitis was diagnosed in almost half the patients presenting to an allergy practice with suspicion of this diagnosis, emphasizing the value of incorporating patch testing in allergy practices.82  About 60% of adults with AD report pain, emphasizing the value of asking about and monitoring this complaint during treatment.83 Urticaria  Patients with chronic spontaneous urticaria have higher expression of FcεRI, but expression does not correlate with disease activity.84,85  Systemic reactions occur commonly in patients with cold urticaria, and epinephrine autoinjectors should be considered for all patients86  Tacrolimus may be another alternative agent for patients with refractory CU.87  Routine laboratory testing is not helpful and adds unnecessary cost in patients with CU.88

allergists and that testing should be undertaken to avoid delayed or missed diagnosis and treatment. They reported on 156 patients presenting to their allergy practice over an 18-month period with suspected allergic contact dermatitis who underwent testing. Allergic contact dermatitis was diagnosed in 49%, with the most common allergens being nickel (28%), p-phenylendiamine (8%), and cobalt (8%). They assigned a designation of relevance on the basis of correlation with history of exposure and assigned this to 31% for having current relevance and 18% for past relevance. Follow-up of those prescribed avoidance for currently relevant positives revealed improvement or resolution in all. They did not find a relationship of positive test results to atopy status. On the basis of these observations, they encourage all allergy practices to consider incorporating patch testing. Atopic dermatitis (AD) is a common chronic disease in adults, but health utilization has not been extensively studied. Silverberg et al89,90 used a US representative Web-based panel of adults who were queried for determination of AD and its severity, health care utilization, and other factors. Overall, 10.4% reported a diagnosis of AD/eczema, and 32% of them were severe according to at least 1 of 3 criteria. Severe AD was associated with being uninsured, not having full prescription coverage, and prescription denials. Ten percent had 1 or more urgent care visits, which was more common among blacks, Hispanics, those with lower education levels, and those having prescription denials. AD was associated with higher total quality-adjusted lifeyears loss than autoimmune disorders, diabetes, food allergy, and heart disease. The authors emphasize that these findings should be used to better prioritize resource allocation and improve access to care for adults with AD. Another possibly underappreciated aspect of AD is pain. Silverberg et al83 queried 602 adults with AD, of whom 61% reported pain, with 33% reporting pain at least once per week and 5% reporting pain daily. The pain was mostly due to scratching and skin inflammation (fissures, inflammation), and only 10% was due to burning from using creams or ointments. The authors suggest that pain should be monitored and that pain reduction should be part of treatment goals of AD.

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DRUG ALLERGY Many articles published in 2019 issues of JACI: In Practice covered topics related to drug hypersensitivity (Table IV). Key highlights covered the topics of epidemiology and morbidity of drug allergy labels, allergy to penicillin, beta-lactam, and chemotherapeutics, and severe cutaneous adverse reactions (SCARs). In addition, electronic consultations or e-consults in allergy were described, which were particularly useful for drug allergy. Phadke et al104 studied the outcomes of e-consults from 2016 to 2018 and in-person consult data from 2014 to 2018 in an allergy/ immunology academic center. E-consults increased from 1% to 10% of all new consults and were used more frequently than inperson consults for adverse drug reactions (66% vs 9%) and immunodeficiency (15% vs 2%). Diagnostic, therapeutic, or alternative referral recommendations were made in 13% of the 306 completed e-consults, and 60% subsequently required inperson allergy/immunology consultation. E-consults were completed in a median of 11 minutes and were associated with a significant decrease in median in-person consult wait time by 1.5 fewer calendar days. E-consult implementation was successful in screening patients to appropriate alternative specialty care, decreased time to in-person appointment, and provided expedited, problem-focused care. Epidemiology and morbidity There are limited data on the epidemiology of drug allergy in the United States. Wong et al105 used an informatics approach to search the allergy field in a database of 2.7 million patients over a 13-year period in the Boston area. Overall 13.8% reported reactions consistent with a drug allergy. Females had almost twice the prevalence of males (17.6% vs 9.2%). Immediate reactions were recorded most commonly, with hives, itching, and angioedema accounting for nearly 50% of reports. Penicillins accounted for the largest proportion of immediate reactions, whereas sulfonamides accounted for most cases of SCAR and fixed drug eruptions. A penicillin allergy label has been shown in several large studies of adults to be associated with significant morbidity and even mortality. Lucas et al106 evaluated 1672 pediatric inpatients and identified 88 with antibiotic allergies, mostly beta-lactam allergies (predominantly penicillin). Children with antibiotic allergy labels were more likely to receive macrolides and quinolones and had longer hospital stays. Although the size of this study is smaller than those of previous adult studies, the data are consistent in showing morbidity associated with a beta-lactam allergy label. Few studies have evaluated the QOL of patients labeled as drug allergic. Gastaminza et al91 used a validated drug allergy QOL tool to assess 360 Spanish patients scheduled for a drug allergy evaluation. Patients with more than 1 reported drug allergy had a lower QOL before evaluation. Psychological wellbeing correlated with the drug allergy QOL results. There was an improvement in drug allergy QOL scores after a drug allergy evaluation, with no difference in improvement between patients confirmed to have drug allergy (43% of patients) and those who were shown not to be drug-allergic and delabeled. Longer followup and studies in patients with a lower prevalence of true drug allergy are needed to generalize these findings.

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TABLE IV. Summary of drug allergy highlights  QOL is improved in patients after a drug allergy evaluation.91  The negative predictive value of a complete penicillin skin test kit is 98% in those with convincing histories of immediate penicillin-allergic reactions.92  Direct penicillin challenge in patients with low-risk allergy histories is less costly and achieve a high rate of delabeling.93,94  Prolonged penicillin challenges are not required for accurate delabeling.95,96  Risk of cross-reactivity in penicillin-allergic patients to cephalosporins is related to similarity in R1 groups and is very low to carbapenems.97  Drug challenges can eliminate the need for empiric desensitizations in patients with histories of hypersensitivity reactions to chemotherapeutics and biologics.98  The predictive value of skin tests to ICM appears dependent on a positive skin test result to the culprit agent.99,100  The vast majority of children with immediate reactions to vaccines are found not to be allergic.101  Pharmacogenetic screening in patients with allopurinol and chronic kidney disease can reduce the risk of SCARs.102,103

Penicillin and beta-lactams Solensky et al92 reported on a prospective US multicenter study of a penicillin skin test kit containing the major determinant, a minor determinant mixture, and amoxicillin. They enrolled 455 patients with convincing histories of IgE-mediated reactions, of whom 13.8% had positive test results. Of those with positive test results, minor determinant mixture was positive in 90.5%, amoxicillin in 50.8%, and the major determinant in 34.9%. Only 4 subjects were positive to amoxicillin alone. The negative predictive value of negative skin test results for a positive amoxicillin challenge was 97.9%. Food and Drug Administration (FDA) approval of this penicillin skin test kit is pending. Taremi et al107 evaluated the safety and efficacy of penicillin skin testing in 100 immunocompromised patients with leukemia or genitourinary malignancies. Ninety-five percent had negative skin test results and challenge. Neutropenia, severe thrombocytopenia, systemic steroids, and other immunosuppressive medications did not appear to alter the results. This study provides reassurance that immunocompromised patients can safely undergo penicillin skin testing. Kleris et al108 developed a dedicated penicillin allergy skin testing clinic and were able to evaluate 104 patients in the first year, compared with an average of 21 patients per year over the previous 7 years. Up to 6 patients could be scheduled starting at 9 AM and finishing by noon, showing marked efficiency. Siew et al109 performed a multivariate logistic regression analysis on 1092 patients who underwent penicillin skin testing at a UK referral center in an attempt to identify low-risk characteristics. Three factors related to the previous reaction were associated with a high risk of a true IgE-mediated reaction: anaphylaxis, reaction within a year, and the ability to name the type of penicillin. The absence of these factors combined to have a negative predictive value of 98.4% for an immediate reaction to penicillin. Some caveats of this study include a higher prevalence of penicillin allergy in their population and a relatively high number (43%) who could recall the actual name of the penicillin; this may limit the generalizability of these findings. Mohamed et al110 reported on a similar retrospective study from

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the United Kingdom evaluating risk stratification of penicillin allergy in 231 patients. They also found anaphylaxis and recent history (5 years) as well as hospitalization for the reaction as predictors for true allergy. Low-risk patients with benign rashes, gastrointestinal symptoms, and vague symptoms (without severe asthma or COPD) comprised 62% of patients and had a negative predictive value of 94%. These 2 studies suggest that risk stratification may be helpful in determining how to best delabel patients with penicillin allergy. Iammatteo et al93 took the above concept further by using a risk stratification process to perform direct placebo-controlled amoxicillin challenges in 155 adults and children with nonelifethreatening histories of penicillin allergy. Only 4 patients (2.6%) had objective reactions, all mild, resulting in a higher rate of delabeling than reported by the same authors when using penicillin skin tests. Twenty percent of subjects reported subjective nonallergic reactions to either amoxicillin or placebo, with the most common being pruritus or oropharyngeal symptoms. Four patients had objective nocebo effects including urticaria, vomiting, decreased peak flow, and coughing. Mustafa et al94 performed the first RCT evaluating penicillin skin testing versus direct amoxicillin challenge in low-risk patients. Low-risk patients had histories of cutaneous- only penicillin reactions, with reactions more than 1 year ago for ages 5 to 17 years, and more than 10 years ago for adults. Eighty patients were randomized to penicillin skin test followed by amoxicillin challenge, and 70 were randomized to direct amoxicillin challenge. Direct amoxicillin challenges were performed by one-tenth dose followed 30 minutes later by a full dose with 30 minutes of additional monitoring. In the direct challenge group, 96.2% were delabeled, which was not significantly different, compared with 87.5% in the skin test group. Of the 3 positive direct challenges, all were mild rashes that responded to antihistamine therapy. Total cost differences were markedly different at $29,093 for the skin test group versus $4239 for the direct challenge group. These studies add to the growing body of evidence that direct challenges may be appropriate for patients with low-risk histories of penicillin allergy. There has been some controversy regarding the duration of a challenge after negative penicillin testing, with some authors suggesting a need for prolonged challenges of 3 to 7 days. Two studies in the journal refute this concept. García Rodríguez et al95 performed a hospital challenge followed by prolonged beta-lactam challenges, but starting only after the patient was observed the length of time they initially reported from the first dose to the appearance of their symptoms. Ninety-seven children underwent a hospital challenge after negative penicillin skin test results, resulting in 3 immediate and 8 delayed reactions. These delayed reactions occurred 6 hours to 7 days after the challenge. Only 3 children reacted with the prolonged challenge, 1 who had a concomitant viral illness. Similarly Van Gasse et al96 performed amoxicillin clavulanic (or amoxicillin) challenges in 132 patients (mean age, 41 years), with a 7-day prolonged challenge in 19 patients immediately after the initial negative challenge and in 119 patients after a 1-week washout period. Similar to the aforementioned study of García Rodríguez et al,95 5 patients had reactions during the washout period and only 1 of 116 patients had a delayed reaction after the washout. The ability to detect only 1 mild delayed reaction per 116 prolonged challenges is convincing evidence against performing prolonged challenges. Despite penicillin delabeling efforts, many patients do not have their medical record changed to indicate penicillin

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tolerance. Lachover-Roth et al111 surveyed 654 patients approximately 3 years after they were delabeled of penicillin allergy. Fifty-one percent still retained a penicillin allergy label. More than one-third of delabeled patients who did not use penicillin refused to use penicillin because they did not think they could be taken safely (despite a negative 5-day challenge). This study and others highlight the need for educational efforts for effective and persistent delabeling. Risk of cross-reactivity in penicillin-allergic patients who receive other beta-lactams remains an area of confusion. Picard et al97 performed a meta-analysis of studies that were predominantly done in Europe, with most patients being allergic to aminopenicillins. Cross-reactivity was based on skin test positivity to other beta-lactams. The risk of cross-reactivity was highest (16.45%) with cephalosporins sharing an identical R1 side chain as an aminopenicillin. In contrast, cephalosporins with disparate side chains had a risk of cross-reactivity of only 2.11%, regardless of the cephalosporin generation. The risk of crossreactivity with carbapenems was very low at 0.87%. This meta-analysis confirms the importance of R1 side chains in assessing the risk of cross-reactivity among penicillins and cephalosporins.

Other drugs Two articles dealt with hypersensitivity to chemotherapeutics. Platinin allergy is well known; however, the rate of crossreactivity among the platins carboplatin, oxaliplatin, and cisplatin is not clear. Pasteur et al112 performed a retrospective study of 97 patients found to be allergic to platins with confirmation by skin testing. Cross-reactivity between carboplatin and oxaliplatin was high at 37% to 45%. In contrast, cross-reactivity was found in 0% (0 of 51) of oxaliplatin-allergic patients and in 7% (3 of 43) of carboplatin-allergic patients. In 24 patients with either carboplatin or oxaliplatin allergy, none reacted to cisplatin. This study adds to other studies showing a generally high degree of tolerance of cisplatin in patients with sensitivity to other platins. In patients with histories of reactions to chemotherapeutics or biologics, rapid drug desensitizations are often performed, even in cases of negative skin testing results. Madrigal-Burgaleta et al98 reported on their experience using drug provocation tests (performed in the intensive care unit) in patients with negative skin test results to chemotherapeutics or biologics. Patients were eligible for drug challenges if they were deemed not to be at high risk on the basis of several risk factors, including low lung function, beta-blocker use, severe reactions, and institutional factors. Of 499 presumed hypersensitive patients, 103 had positive skin test results, and, of the remainder, 341 were eligible for drug provocation tests. Negative challenges occurred in 67% of these patients, which led to exclusion of a hypersensitivity diagnosis in 44% of all referred patients. However, among those with positive challenges, 27% were classified as severe, with 4 patients having anaphylactic shock. This study shows that drug provocation tests in select patients can markedly reduce the need for desensitizations but needs to be approached with caution. An et al113 reported on data from a Korean database of more than 11.7 million uses of iodinated contrast media (ICM) resulting in approximately 50,000 hypersensitivity cases. Immediate hypersensitivity reactions accounted for 88.6% of cases compared with 11.4% with delayed reactions. Urticaria and itching accounted for more than 90% of immediate reactions,

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with anaphylaxis occurring in 0.6% of immediate reactions. Interestingly, different contrast media had different rates of hypersensitivity reactions independent of volume of usage, with iomeprol having the highest rate of adverse reactions even though it was the fifth most commonly used agent. The role of skin testing to ICM in patients with histories of reactions is evolving. Kwon et al99 evaluated 69 patients with reactions to ICM via skin testing to a panel of 7 ICM. Thirtyeight patients had positive skin test results to the culprit ICM (culpritþ group), and 16 received ICM again. Eleven patients received skin testenegative ICM and had no reactions. Interestingly, 5 patients received alternative ICM that were skin test positive and 4 of 5 had reactions despite premedication. There were 31 patients who had negative skin test results to the culprit ICM (culprite group), and 22 received ICM again. All 5 patients with positive skin test results to alternative ICM in the culprite group tolerated the ICM. However, despite premedication, there were 2 of 17 reactions in those with negative skin test results, including 1 patient who reacted to one ICM yet tolerated another. The authors suggest that if one finds a positive skin test result to the culprit ICM, using a skin testenegative alternative ICM is recommended, but there appears little predictive value for alternative ICMs when the culprit ICM skin test result is negative. Further larger prospective studies are needed to follow up on these interesting observations. Trautmann et al100 found similar results by performing intravenous provocation tests to ICM skin testenegative alternatives in patients with culprit ICMþ skin test results. No patient had reactions, including 10 with histories of immediate reactivity and 8 with delayed reactions. They also identified 2 patients with delayed reactions to ICM, negative ICM skin test results but positive repeated open application testing to iodine tincture, suggestive of true iodine allergy. Allergic reactions to vaccines are rare, and few studies have reported on evaluations of a large group of patients. Cheung et al101 reported their retrospective experience with evaluating 73 Australian children suspected of having vaccine allergy. Most had immediate reactions, with 69% reporting reactions within 15 minutes. Evaluation with vaccine challenge (n ¼ 59) or skin testing (n ¼ 18) revealed only 8% with confirmed allergy. All patients with a confirmed allergy had a history of anaphylaxis or a reaction within 15 minutes. Of those deemed most likely to have true anaphylaxis, 3 of 4 had confirmed allergy. The authors propose an algorithm to evaluate children using a risk stratification process for skin testing versus vaccine challenge. Allergic reactions to excipients are well known but may often go unrecognized, and the mechanism of these reactions is often unclear. Stone et al114 performed investigations into 2 patients who had allergic reactions to both methylprednisolone and colonoscopy bowel preparations. Skin testing and specific IgE test results were positive to polyethylene glycol and/or structurally relayed polysorbates. A review of the literature identified 53 patients with anaphylaxis to polyethylene glycol bowel preparations or laxatives. Use of skin testing to evaluate these patients appears useful.

SEVERE CUTANEOUS ADVERSE REACTIONS Several articles dealt with SCAR. Wolfson et al115 used a novel method of searching the “Allergy” field in the electronic health record to identify potential cases of drug reaction with

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eosinophilia and systemic symptoms (DRESS). Sixty-nine cases of DRESS were identified over a 36-year period in a Boston area health care database. Vancomycin was the most common culprit causing DRESS (39% of cases) and was typically associated with renal disease. Patients hospitalized for DRESS had a mean length of stay of 15 days. The cost of hospitalization for patients with DRESS was more than $17,000 per patient. Limited data are available on outcomes of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Antoon et al116 analyzed a US pediatric hospital administrative database and identified 898 children diagnosed with SJS (86%) or TEN (14%). Twenty-three percent were admitted to the intensive care unit, with a median length of stay of 8 days, longer for those with TEN (15.5 days). Corticosteroids and/or intravenous immunoglobulin were used in almost half the patients, with heterogeneity of use based on region. Despite the frequent use, benefit was not seen for length of stay or need for mechanical ventilation. Mortality was much lower than in adult populations at 0.56% overall and 3.2% for TEN. Although this study was limited by available patient-specific information in the database, the large, multicenter nature of the study provides useful information. Some drugs may have different clinical presentations of SCAR. Park et al117 compared 106 patients with SCAR from allopurinol with 639 patients with SCAR from other drugs. Patients with allopurinol-induced SJS/TEN had longer latency periods and were older and had more comorbid disease, which may have contributed to a higher death rate in these patients compared with that in patients with other drugeinduced SCAR. Some unique predictors of mortality in patients with allopurinol-induced SJS/TEN included eosinophilia (uncommon for most patients with SJS/TEN), low baseline alanine aminotransferase levels, and low platelet counts. Pharmacogenomics have been used successfully for certain drugs and in certain populations to reduce the risk of SCAR. Park et al102 performed prospective screening for HLA-B*58:01 in 542 Korean patients before allopurinol therapy in a high-risk group with chronic kidney disease (a risk factor for allopurinolinduced SCAR). Febuxostat, an alternative drug, was administered in 7.2% of patients who tested positive for HLA-B*58:0, whereas allopurinol was administered to those with negative screening. No cases of SCAR were noted in these patients, compared with a rate of 0.95% in historical controls, demonstrating the effectiveness of this screening method. Shim et al103 performed a retrospective study of Korean patients who underwent pharmacogenetic screening and were treated with allopurinol. They identified other HLA risk alleles that increased the likelihood of allopurinol SCAR in those positive to HLA-B*58, including B75, DR13 homozygosity, and DR14. In patients with severe kidney disease, the risk was additive, up to 40% in those with HLA-B58 homozygosity and B75. Prospective studies are needed to determine the utility of these additional risk alleles. Klaewsongkram et al118 evaluated 160 Thai patients with various SCARs to determine the utility of pharmacogenomic testing and enzyme-linked immunospot assays. In 32 cases, pharmacogenomic screening may have prevented the development of SCAR. Unfortunately, 79% of patients would not have benefited, including none of the patients with acute generalized exanthematous pustulosis. Interestingly, enzyme-linked immunospot assays were positive in 45.7% of 116 tested patients, more often in patients with DRESS and SJS/TEN. Better pharmacogenomic tests for other drugs and availability of validated commercial assays for enzyme-linked immunospot assays are needed.

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FOOD ALLERGY The scope of food allergy articles published in the 2019 pages of the journal included those on diagnosis, prevention, and treatment (Table I). DIAGNOSIS The criterion standard for diagnosing food allergy is the oral food challenge (OFC). Some practices, particularly in Europe, perform an initial labial/lip dose challenge to decide whether to proceed to ingestion of the food. The approach is not standardized and not well studied. Vazquez-Ortiz et al6 surveyed practices in the United Kingdom and found that 81% of the 67% of clinics responding performed this step, but there was wide variation in the approach, interpretation, and response regarding proceeding after the test. One-third of respondents did not proceed to the OFC if there were subjective symptoms. The investigators undertook a study using the “lip dose challenge” in 198 children and determined a sensitivity of 32%, specificity of 98%, and false-negative rate of 68%. They concluded that the test was unlikely to confer any advantage and cautioned against its use. Several insights on specific types of food allergies were elucidated in studies using OFCs. Virkud et al7 reported their experience with 603 almond OFCs in 590 patients aged 1 to 66 years. Overall, 92% tolerated the OFC, and those who reacted had mild symptoms, with only 0.5% having anaphylaxis. Some predictors of reactions included high almond-specific IgE and large skin tests, as well as prior almond reactions. The success rate was much higher for almond compared with other foods, and the authors suggested that almond OFCs could be conducted with higher patient-staff ratios or performed at home depending on test results, recognizing anaphylaxis is still a risk. Unlike almond, walnut allergy is more often severe, and Ballmer-Weber et al119 reported on IgE response to specific component walnut allergens in 91 patients with walnut allergy and 24 tolerant controls. They noted that patients younger than 14 years had severe reactions, whereas 38% of those older than 14 years had mild reactions. Severe reactions were associated with stronger responses to walnut extract, Jug r 1, and Jug r 4, but not Jug r 3 or Jug r 5. Another food that creates diagnostic dilemmas is fish because clinical cross-reactivity is not well studied. Kalic et al8 evaluated patients with allergy to bony fish (cod, salmon) and challenged 11 of them to a cartilaginous fish (ray), with only 1 reacting. Results correlated with high responses to betaparvalbumins in the bony fish compared with alphaparvalbumins in the cartilaginous types. Another tricky diagnosis regards wheat allergy because responses are often affected by augmentation factors. Christensen et al9 tested 25 adults with wheat-dependent, exercise-induced anaphylaxis and noted that only 48% reacted to wheat at rest, but 92% reacted with exercise and 84% with aspirin ingestion. Alcohol did not increase reactivity as much (56% reacted). They noted that thresholds of reactivity also decreased when wheat ingestion was associated with exercise or aspirin and even more with their combination. These findings should increase suspicions to query about wheat consumption and augmentation factors when evaluating patients with unexplained anaphylaxis. Unexplained anaphylaxis should also raise suspicions about the alpha-gal syndrome. Wilson et al10 described characteristics of 261 adults and children with this syndrome of delayed

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anaphylaxis, typically starting 3 to 6 hours after consumption of mammalian meat. Some of the notable findings that can aid diagnosis and management included regionality (where bites of the Lone star tick or chiggers occur), that atopic disposition was not a risk factor, that alpha-gal levels did not correlate with severity, and about 15% experienced symptoms in less than 2 hours. Food proteineinduced enterocolitis syndrome (FPIES) also presents a diagnostic challenge, and, without simple tests, an OFC is required to determine resolution or in some cases confirmation of an initial diagnosis. Initial misdiagnosis is often related to attributing the repetitive vomiting and diarrhea to an infection. Lee et al11 performed a retrospective case-control study comparing FPIES cases to those with similar symptoms diagnosed with viral/bacterial causes. They confirmed that children with FPIES were more likely to present with lethargy, floppiness, and pallor than those with infection, who were more likely to present initially with fever, tachypnea, tachycardia, and diarrhea. Regarding the laboratory evaluation, a normal C-reactive protein, leukocytosis, thrombocytosis, low mean platelet volume, and elevated albumin/globulin ratio were more likely seen in FPIES. Although these findings may help differentiate the presentations and reduce initial misdiagnosis, OFCs are often still needed, at least to detect resolution. Wang et al12 reported on their experience doing briefer than typical FPIES OFCs using a one-third serving size, 4-hour observation, and then gradual introduction to a full serving over 9 to 12 days at home. They reviewed 169 OFCs following this approach in which 30 were positive. Of the positive challenges, 17 had symptoms while under observation and 13 at home. Of the home reactions, all occurred later in the day of the initial feeding or in the first few days of home feeding, and only 1 presented to an emergency room and did not need treatment. The authors suggested that their protocol appears safe and can add efficiency.

Prevention Insights on prevention and risk factors are vital to inform approaches to reduce the apparent increase in the prevalence of food allergies. Peters et al13 performed a population-based food allergy study of 2715 Australian infants to assess timing of exposure to cow’s milk before or after age 3 months in relation to allergy to this food as defined by a positive milk skin prick test result and reported reaction at age 12 months. They found that 42% of the infants had early exposure and that this was associated with a reduced risk of allergy (adjusted OR, 0.31; 95% CI, 0.10-0.91). The primary limitation was that the study was observational, and a randomized trial would be needed to confirm the finding. In a dietary study from Korea, Kim et al14 evaluated the maternal perinatal diet in 1628 infants in relation to the outcome of physician-confirmed food allergy. They used a cluster analysis to identify 5 dietary patterns, and maternal diets high in baked and sugary foods—a diet high in trans fats—were associated with food allergy (adjusted OR, 1.52; P ¼ .02). They also found polymorphisms in specific proinflammatory and detoxification pathways that increased susceptibility to food allergy with this diet. Aside from diet composition, the hygiene hypothesis is a major theory to explain the increase in food allergy, and early exposure to antibiotics as a risk factor would support this theory. Li et al120 used a 2006-2010, 28-state Medicaid registry and

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analyzed pediatric antibiotic users versus nonusers in relationship to time to having recorded a food allergy diagnostic code. They found that antibiotic use was associated with a faster development of food allergy (hazard ratio, 1.40; 95% CI, 1.34-1.45). Although suggestive, the authors also point out limitations in their approach, including confounding and limitations of using codes, although significance remained after adjusting for confounders, including AD.

Treatment Late-phase trials of commercial approaches to peanut oral immunotherapy (OIT)121 and epicutaneous immunotherapy122 are leading to having the first approved food allergy therapies. A number of studies on food allergy treatment have given additional insights into therapies. Wasserman et al15 reviewed their more than 8 years’ experience with peanut OIT in a practice setting having treated 270 children. They used a variable approach to desensitization dosing, and 79% were able to reach a target goal. Over the long-term, 16 patients had sustained unresponsiveness or infrequent dosing, and 140 were known to still be on treatment (166 of 270 who began). The authors emphasized that the results from their office setting were similar to those from research settings. Soller et al16 reported a “real-world” experience with peanut OIT in 270 preschool-age children, noting generally good success reaching 300 mg (90%) and relatively mild side effects. A caveat may have been that this group had less severe allergy than groups in other research studies, because most had no entry OFC and almost half who underwent OFC reacted at doses close to the maintenance dose. The aforementioned studies used various dosing approaches. Blumchen et al17 randomized 62 children aged 3 to 17 years to peanut OIT with 125 to 250 mg maintenance (considered low dose) over a slow protocol over up to 14 months versus placebo, aiming for a “bite-safe” threshold of 300 mg, which was achieved by 74% versus 16% of placebo. They also found that 41.9% tolerated 4500 mg peanut in the treatment group versus 3.2% of controls. This study and others published this year on OIT emphasized improved QOL in those treated.123 Nachshon et al18 shared their experience with sesame OIT in 60 children (with comparisons to historical controls). They reported that 88.4% were desensitized to sesame compared with none of the controls, and 95% were desensitized to more than 1000 mg. Milk is another important allergen because avoidance can also affect growth and nutrition.124 De Schryver et al19 reported their experience with milk OIT and focused on side effects. The 6- to 18-year-old children had to react to less than 200 mL of milk for randomization to treatment or placebo, 52 were randomized 1:1 (later, 15 of 26 placebo crossed over to OIT), and the maintenance dose was 200 mL. Over the course of the study, 27% of those treated discontinued treatment, and the mean number of anaphylactic reactions was 6 and the mean number of nonanaphylactic allergic reactions was 17. The authors noted that children with higher alpha-lactalbumin and casein IgE at baseline were at a higher risk for the adverse reactions. In a randomized approach, Howe et al20 took a novel approach to instructing peanut OIT subjects that nonanaphylactic symptoms were a sign that desensitization was occurring, versus the usual instruction that symptoms are side effects. Those instructed on a positive mind-set about symptoms demonstrated less anxiety, fewer calls to the treatment center,

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TABLE V. Summary of immunodeficiency highlights  Outcomes in DOCK8 deficiency, which causes a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy due to biallelic variations, were described in 81 patients who underwent successful treatment with HSCT.125  The diagnostic and therapeutic management was described for the largest WHIM syndrome cohort of 18 patients with CXCR4 mutations and characterized with WHIM.126  A retrospective study determined the clinical, mycological, and imaging data of all the 74 pulmonary aspergillosis cases with autosomal-dominant STAT3 deficiency. Because almost half the patients experienced recurrences despite prolonged antifungal treatment and/or surgery, more optimal treatments are needed.127  MHC class II deficiency leads to defective CD4(þ) T-cell function, impaired antigen presentation, results in combined immunodeficiency due to a genetic disorder in 1 of 4 gene mutations, and is more common than thought in Egypt due to a high rate of consanguinity.128  Early-onset multiorgan autoimmune and lymphoproliferative disease due to STAT3 gain-of-function germline mutations was reported in a systematic review. Biologic therapy with antieIL-6 receptor mAb therapy and Jak inhibitors, but not HSCT, was successful in controlling the disease in some of the patients.129  Outcomes and treatment strategies were described in 85 patients with recombination activating gene deficiency, of which 63 had secondary autoimmunity and hyperinflammation.130  LRBA deficiency, which presents with susceptibility to infections, autoimmunity, and lymphoproliferation, was shown to be responsive to long-term treatment with the cytotoxic T-lymphocyteeassociated antigen 4-immunoglobulin (abatacept) as targeted therapy.131  CVID and IgG deficiency do not share the same disease spectrum, with CVID being associated with more immune dysregulatory manifestations and markers of a more severe immune defect.132  Significantly higher peak absolute eosinophil counts were observed in patients with neoplasms and immune deficiencies than in patients with overlap hypereosinophilic syndrome and atopic diseases.133 WHIM, Warts, hypogammaglobulinemia, infections, and myelokathexis.

had fewer symptoms, skipped less doses, and had greater increases in peanut-specific IgG4 than controls. These various OIT studies add important information on nuances on dosing, age effects, and patient approaches to inform practice as these therapies become more commonplace and FDA-approved approaches reach the clinic. Another approach to OIT has included omalizumab to reduce side effects. Yee et al21 published 72-month follow-up of their cohort of 13 patients who underwent peanut OIT under treatment with omalizumab. Their earlier study used omalizumab in the first 3 months of treatment as adjunctive therapy and showed faster successful desensitization, but in this follow-up report, 6 (46%) eventually discontinued therapy because of side effects. Those who stopped therapy had higher 12-month peanut and Ara h 2 IgE, and the authors speculate that longer treatment with omalizumab may be needed. Because omalizumab alters the threshold of reactivity, Fiocchi et al22 reported their observational experience in 15 children allergic to 37 foods who were on omalizumab for severe asthma. OFCs were used to compare the thresholds before treatment to those during treatment. The authors noted a mean increase in threshold for milk, egg, wheat, and hazelnut from 1012 mg to 8727 mg (P < .001), and 70% tolerated a complete challenge dose after 4 months of therapy. Those able to ingest the foods had them added to their diet. They also noted accidental reaction rates fall from 42 to 2. The approach of using omalizumab as monotherapy for food allergy is now in clinical trials (NCT03881696), as are additional studies of adjunctive approaches.

IMMUNODEFICIENCY Submissions on immunodeficiency are increasing to JACI: In Practice, including many rare disorders only recently identified (Table V). Their reporting in the journal will further educate our readers and add to their ability to diagnose and treat these new conditions.

Dedicator of cytokinesis 8 (DOCK8) deficiency causes a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy due to biallelic variations in the dedicator of DOCK8 gene. Allogeneic hematopoietic stem cell transplantation (HSCT) can cure this immunodeficiency, overcoming the usually poor prognosis without treatment. Aydin et al125 in a retrospective study of 81 DOCK8-deficient patients with HSCT at about age 10 years noted the following after a median follow-up of 26 months post-HSCT: (1) survival in 84%, (2) severe acute III-IV or chronic graft versus host disease in about 10% each, and (3) among the 13 deaths, the causes were 38% each for infections and graft versus host disease, 15% for multiorgan failure, and 8% for preexistent lymphoma. Superior survival occurred with reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan (97%) compared with fully myeloablative busulfan-based regimens (78%). Eczema and infections resolved quicker than food allergies or failure to thrive post-HSCT. The present study confirmed that HSCT is curative in most DOCK8-deficient patients, is the treatment of choice, and reduced-toxicity regimens are best for survival. The diagnostic and therapeutic management of the largest warts, hypogammaglobulinemia, infections, and myelokathexis syndrome cohort of 18 patients with CXCR4 mutations was reported by Dotta et al.126 Disease manifested at a mean of about 2 years, but diagnosis was delayed to age 12.5 years. Initial presentation was a severe bacterial infection (78%), often complicated with bronchiectasis (27%). The following prevalences in patients were found: (1) skin warts in about 6% of patients, (2) human papilloma viruserelated malignancies in 16% of patients, (3) severe neutropenia in 100%, (4) lymphopenia in 88%, and (5) hypogammaglobulinemia in 58%. Treatment included (1) antibiotic prophylaxis in 50%, (2) GCSF in 72%, and (3) immunoglobulin in 55% of patients. These findings highlight that the warts, hypogammaglobulinemia, infections, and myelokathexis syndrome begins in early life, should be suspected when chronic neutropenia is identified, and requires

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TABLE VI. Summary of immunotherapy and rhinitis/sinusitis highlights Immunotherapy  An annual survey completed by AAAAI and ACAAI members from 2008 to 2016 on SCIT-related SRs of varying severity and from 2014 to 2016 on injection-related local cutaneous and systemic infections reported an unexpected slight increase in fatalities. There were no reports of infections due to SCIT.134  Disparities exist among different international classification systems to rate SARs to allergen immunotherapy, which could adversely affect treatment of these SARs and support the need for better harmonization of these classifications.135  SLIT treatment for JC pollinosis was shown effective and safe in a randomized, placebo-controlled, long-term trial.136  HDM SLIT for asthma in Japan was only found effective in a post hoc analysis of a randomized, double-blind study of patients with greater need for albuterol at baseline.137  In contrast, SLIT HDM added to standard asthma pharmacotherapy improved clinical symptoms and pulmonary function, with clinical improvement associated with decrease in T2 airway inflammation.138 Rhinitis/Sinusitis  Step-down therapy guided by the Allergic Rhinitis Control Test (vs no change in therapy) was associated with similar control rates but reduced medication use and calculated medication costs.139  In 4754 patients hospitalized for asthma and 2176 patients hospitalized for COPD, allergic and nonallergic rhinitis were each associated with 3.7- to 4.4-fold increased risks of 30-d hospital readmissions for asthma and 2.4- to 2.6-fold increases in hospital readmissions due to COPD.140  In a systematic review of 8 studies involving 797 adults with bronchiectasis, the 62% of patients with comorbid CRS exhibited poorer QOL and greater disease severity.141  In a cross-sectional analysis of 4320 participants, the odds of depression were 42% higher in subjects with rhinitis compared with those without rhinitis and 2 times higher in subjects with nonallergic rhinitis compared with those without rhinitis.142  Compared with patients with CRSwNP (n ¼ 874), patients with CRSsNP (n ¼ 507) included more female patients (63% vs 45%) and had a lower prevalence of atopy (52% vs 76%) and asthma (36% vs 56%), but atopy was associated with more severe radiographic sinonasal disease in patients with CRSsNP.143  In 121 patients with CRSsNP and 134 patients with CRSwNP, the presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of type 2 endotype; the type 1 endotype was significantly more common in females; and the presence of pus was significantly associated with the type 3 endotype.144 AAAAI, American Academy of Allergy, Asthma & Immunology; ACAAI, American College of Allergy, Asthma, and Immunology.

careful monitoring, timely intervention for lung and human papilloma viruserelated malignancy complications, and early institution of immunoglobulin therapy. Patients with autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency are predisposed to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations frequently due to Aspergillosis species. Dureault et al,127 in a retrospective study, determined the clinical, mycological, and imaging characteristics of all the 74 pulmonary aspergillosis cases in STAT3-deficient patients. Of the17.5% with pulmonary aspergillosis, onset began at a median age of 13 years, with bronchiectasis/ cavitations present in 90% before onset with no invasive aspergillosis cases identified. Classification of the infections included chronic cavity pulmonary aspergillosis (n ¼ 9), single aspergilloma, and allergic bronchopulmonary aspergillosis-like disease (n ¼ 5 for each), and mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis (n ¼ 2). Anti-Aspergillus antibodies were identified in 93%, with Aspergillus species isolated in 71% of episodes. Death occurred in 1 patient. Because almost half the patients experienced recurrences despite prolonged antifungal treatment and/or surgery, more optimal treatments are needed. MHC class II deficiency, which leads to defective CD4(þ) T-cell function, impaired antigen presentation, and resulting combined immunodeficiency, is due to a genetic disorder in 1 of 4 gene mutations (RFXANK, RFX5, CIITA, RFXAP). El Hawary et al128 described the clinical, immunologic, and molecular characteristics of 10 Egyptian patients from 9 different families with MHC class II deficiency. Distinguishing features included failure to thrive in 90%, pneumonia in 80%, and persistent diarrhea in 50%. Before diagnosis, 3 of the 9 patients who received live attenuated polio

vaccine developed acute flaccid paralysis. Mutation analysis revealed many unreported mutations. The high rate of consanguinity may be related to MHC class II deficiency not being rare in Egypt. T-cell receptor excision circles neonatal screening may miss this defect; as such, suspicious clinical signs must be appreciated, and laboratory tests are needed to make an early diagnosis. Fabre et al129 presented a systematic review of the clinical features of patients with early-onset multiorgan autoimmune and lymphoproliferative disease due to STAT3 gain-of-function germline mutations. In the 18 publications meeting study criteria, 42 unique patients were identified with 28 different mutations. Average age of onset was 3 years with the following manifestations (in decreasing order): autoimmune cytopenias and immunodeficiency (67% each), lymphoproliferative disorders (64%), interstitial lung disease (36%), enteropathy (33%), thyroiditis (31%), and diabetes (24%). Immunosuppressive therapy was required in most patients. Of the 5 patients who received HSCT, 4 died from complications. In contrast, targeted biotherapy was helpful in 8 of 9 patients who showed improvement in their autoimmune conditions with antieIL-6 receptor mAb therapy (tocilizumab), and 5 of 9 showed improvement in enteropathy and oxygen support with Jak inhibitors (ruxolitinib or tofacitinib). Given that STAT3 gain-of-function syndrome is a new clinical entity, it needs to be considered when confronted with a patient with early-onset polyautoimmunity, lymphoproliferation, and growth failure and recognized that it may be responsive to targeted biotherapies. Farmer et al130 determined the outcomes and treatment strategies in 85 patients with recombination activating gene deficiency, of whom 63 had secondary autoimmunity and hyperinflammation. From the first clinical sign of immune

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dysfunction, diagnosis of recombination activating gene deficiency was delayed a median of 5 years, even though most patients presented with 2 or more autoimmune or hyperinflammatory complications, including almost 85% with cytopenias and about 20% with either granulomas or inflammatory skin disorders. Autoimmunity was preceded by infection, including from live viral vaccinations, in almost 30% of patients. Autoimmune cytopenias developed around age 2 years, which were refractory in 65% to 73% of patients to intravenous immunoglobulin, steroids, and rituximab. Vigilance is needed to diagnose recombination activating gene deficiency in early life to increase the opportunity for definitive management. Another rare entity to add to the spectrum of primary immunodeficiencies is LPS-responsive beige-like anchor (LRBA) deficiency, which presents with susceptibility to infections, autoimmunity, and lymphoproliferation. Kiykim et al131 evaluated the clinical and immunologic features and long-term efficacy of cytotoxic T-lymphocyteeassociated antigen 4immunoglobulin (abatacept) as targeted therapy in LRBA deficiency. Twenty-two LRBA-deficient patients with a mean age of 13 years were studied and followed for about 3.5 years. More than 85% had recurrent infections, about 80% exhibited immune dysregulation, and almost 75% had lymphoproliferation. Sixteen of the 18 patients who received abatacept demonstrated complete control of lymphoproliferation and chronic diarrhea with improvement in immune dysregulation, particularly autoimmune cytopenias. Control was optimal with weekly or everyother-week administration without serious adverse effects. The biomarker circulating T follicular helper cell frequencies was reliable at detecting disease activity. Earlier diagnosis of LRBA will allow earlier treatment with abatacept to control the disease. The immunologic findings and clinical manifestations of 2 large cohorts of patients with common variable immune deficiency (CVID) or IgG deficiency were compared to better delineate differences between those syndromes. Filion et al132 extracted clinical and laboratory data from electronic medical records of patients at their institution who had received International Classification of Disease codes for either CVID or IgG deficiency. They compared immunologic and clinical data related to infectious manifestations, bronchiectasis, autoimmune diseases, infiltrative inflammatory processes, and lymphoid malignancies. Lower IgG levels, greater unresponsiveness to most vaccines, lower percentages of memory and isotype switchedmemory B cells, and lower CD4 T-cell counts were found more often in patients with CVID than in IgG-deficient patients. In addition, a significantly higher prevalence of bronchiectasis and especially noninfectious complications was noted in patients with CVID. The extensive analyses clearly revealed that CVID and IgG deficiency do not share the same disease spectrum, with CVID being associated with more immune dysregulatory manifestations and markers of a more severe immune defect. Immune deficiencies may be associated with eosinophilia, and Burris et al133 determined the incidence, causes, clinical characteristics, and disease associations of hypereosinophilia (defined as absolute eosinophil count 1500 cells/mm3 on 2 occasions 4 weeks apart) in 176 pediatric patients in a tertiary pediatric medical center. Secondary hypereosinophilia was the most common cause of hypereosinophilia resulting from AD, graft versus host disease, sickle cell disease, and parasitic infections. The incidence of hypereosinophilia was 54.4 per 100,000 persons per year. Median age at diagnosis was 4.6 years, with

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children younger than 1 year and 6 to 11 years accounting for most of the patients. Median peak absolute eosinophil count was 3100 cells/mm3. Significantly higher peak absolute eosinophil counts were observed in patients with neoplasms and immune deficiencies than in patients with overlap hypereosinophilic syndrome and atopic diseases. The authors concluded that hypereosinophilia is more common than previously thought in children and requires a thorough evaluation of causes.

IMMUNOTHERAPY Immunotherapy, both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), was the subject of a number of important 2019 articles in the journal (Table VI). SCIT, the hallmark of allergist treatment in the United States, is effective for many atopic conditions but safety concerns exist. Epstein et al134 sought to identify clinical practice behaviors that could influence fatal and nonfatal systemic allergic reactions (SRs) to SCIT and also to identify SCIT-associated infections. American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology members completed annual surveys from 2008 to 2016 regarding SCIT-related SRs of varying severity and from 2014 to 2016 injection-related local cutaneous and systemic infections. Two confirmed fatalities occurred between 2008 and 2014, with 5 more fatalities occurring from 2015 through 2016 out of 54.5 million injection visits. No infections occurred in 17.3 million injection visits from 2014 to 2016. Fifteen percent of SRs occurred after 30 minutes, with no lower rate of delayed grade 3/4 SR in those practices prescribing epinephrine autoinjectors more than 90% of the time. The unexplained slight increase in SCIT-related fatalities remains a concern. In addition, improved outcomes of delayed SRs were not observed with the prescription of epinephrine autoinjectors, possibly the result of low rates of self-administration. Disparities among different international classification systems to rate systemic adverse reactions (SARs) to allergen immunotherapy could interfere with future care. Vidal et al,135 in a post hoc analysis, compared the ratings of 109 SARs that occurred in the longitudinal European Survey on Adverse Systemic Reactions in Allergen Immunotherapy study using the classifications systems of the European Academy of Allergology and Clinical Immunology, American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma, and Immunology, and the World Allergy Organization. Indeed, disparities in the classification of mild and moderate SARs were observed between the classification systems, with correlations ranging from 0.31 to 0.66. Importantly, correlations of severe reactions were good, with the World Allergy Organization grading system exhibiting the best correlation with the onset of the reaction and the number of System Organ Classes involved in the SARs. It would be productive for the allergy community to agree on a uniform grading system for SARs to avoid the disparities that now exist among the different classification systems. Given the importance of Japanese cedar (JC) pollinosis in Japan, Gotoh et al136 conducted a dose-ranging, long-term (3year treatment, 2-year follow-up), randomized, double-blind, placebo-controlled phase II/III safety and efficacy trial of the JC pollen SLIT tablet in 1042 afflicted patients aged 5 to 64 years. Groups were randomized 1:1:1:1 to receive daily treatment with 2000, 5000, or 10,000 Japanese allergy units (JAU) or placebo. Compared with placebo treatment, relative mean

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reductions in total nasal symptom and medication score were 21.4%, 32.1%, and 31.2% for 2000, 5000, and 10,000 JAU, respectively (P < .001 in all groups). Efficacy was also confirmed for all doses (P < .001) in all active treatment groups for secondary outcomes, including total nasal and ocular symptom and medication scores for the peak symptom period and JC pollen dispersion season. The 5000 JAU dose demonstrated long-term efficacy over the 3-year treatment period. Treatment safety was confirmed, with no occurrences of anaphylaxis and infrequent systemic reactions, the rate of which was similar between SLIT and placebo groups. These encouraging findings add JC to grass, ragweed, and dust mite as effective and safe SLIT treatments for seasonal and perennial allergic rhinitis. House-dust mite (HDM) SLIT has been shown to be effective for allergic asthma in a European clinical trial,145 leading Tanaka et al137 to study its efficacy and safety for allergic asthma in Japan. A total of 826 adults aged 18 to 64 years with allergic asthma were randomized equally to HDM SLIT tablets of 10,000 or 20,000 JAU or placebo. Exacerbations, the primary outcome, and secondary outcomes did not differ between groups. However, a significant difference between the 20,000 JAU and placebo groups was observed in a post hoc analysis among subjects using short-acting beta2-agonists during the baseline period. No deaths or anaphylaxis occurred. Although the trial did not demonstrate any safety concerns, overall efficacy was not found except for patients on short-acting beta-agonists at baseline. Reasons for the discordance between these overall negative findings and the efficacy in other studies of HDM in allergic asthma need to be resolved, but may be due to less HDM monosensitization, reversibility, daytime asthma symptoms, and short-acting b-agonist use at baseline in the Japanese study137 compared with the efficacy noted in the European study.145 As noted above, standardized HDM SLIT has been found effective in the treatment of respiratory allergies. Hoshino et al138 provided pathophysiologic reasons for this benefit in their study of inflammation and structural changes of the airways with HDM SLIT. One hundred and two asthma patients with rhinitis sensitized to HDM were randomized to SLIT plus pharmacotherapy or standard pharmacotherapy alone for 48 weeks. Significant reductions in FENO, airway wall surface area, and wall thickness were accompanied by improvement in airflow limitation and clinical symptom scores in the SLIT plus pharmacotherapy group compared with the pharmacotherapy-alone group. Multivariable analyses showed that reduced FENO was independently associated with an increase in FEV1 in the SLIT-treated group. SLIT HDM added to standard asthma pharmacotherapy improved clinical symptoms and pulmonary function, with the clinical improvement associated with decrease in T2 airway inflammation.

RHINITIS/SINUSITIS Rhinitis and sinusitis are common problems encountered by allergists/immunologists and were addressed in several important articles in the pages of the 2019 JACI: In Practice (Table VI). Like asthma, optimal pharmacologic management strategies for rhinitis include stepping up medication to achieve control and stepping down to identify the lowest effective dose to maintain control. Also, similarly to asthma, more attention has been focused on stepping up than on stepping down medication in patients with rhinitis. Stepping down therapy was addressed in a study by Zhu et al139 in which

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228 patients with allergic rhinitis controlled by intranasal steroids plus antihistamine were randomized to step-down therapy when patients were controlled on the basis of the Allergic Rhinitis Control Test versus no change in therapy. At the end of 45 days, control rates were similar between groups, but medication use and calculated medication costs were lower in the Allergic Rhinitis Control Test step-down group. The Allergic Rhinitis Control Test questionnaire would appear to be a useful tool for evaluating the step-down eligibility of patients with controlled allergic rhinitis. Several studies published last year in this journal described important relationships of rhinitis or sinusitis to other conditions. Singh et al140 studied 4754 patients hospitalized for asthma and 2176 patients hospitalized for COPD. Allergic and nonallergic rhinitis were each associated with 3.7- to 4.4-fold increased risks of 30-day hospital readmissions for asthma and 2.4- to 2.6-fold increases in hospital readmissions due to COPD. A systematic review of 8 studies involving 797 adults with bronchiectasis found that 62% of patients had comorbid CRS.141 Moreover, the presence of CRS was associated with poorer QOL and greater disease severity both clinically and radiologically. A third study evaluated the association between depression and rhinitis in a representative sample of US adults by means of a cross-sectional analysis of 4320 participants in the 2005-2006 National Health and Nutrition Examination Survey.142 The odds of depression were 42% higher in subjects with rhinitis compared with those without rhinitis and 2 times higher in subjects with nonallergic rhinitis compared with those without rhinitis. Although none of these associations prove causation, they all suggest the hypotheses that optimal treatment of coexisting rhinitis and sinusitis may decrease the occurrence of asthma or COPD exacerbations and depression and reduce the severity of bronchiectasis, hypotheses that warrant testing. Two 2019 studies provided novel insights into CRS phenotypes and endotypes. One study143 explored the clinical differences between the 2 common phenotypes of CRS, with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), via a database at an academic hospital that identified 5525 patients with confirmed CRS, 82% of whom had CRSsNP and 18% of whom had CRSwNP. Compared with patients with CRSwNP (n ¼ 874), a random subset of patients with CRSsNP (n ¼ 507) included more female patients (63% vs 45%) and had a lower prevalence of atopy (52% vs 76%) and asthma (36% vs 56%). Atopy was associated with more severe radiographic sinonasal disease in patients with CRSsNP. Moving from phenotypes to endotypes, Stevens et al144 identified associations between inflammatory endotypes and clinical presentations in 121 patients with CRSsNP and 134 patients with CRSwNP. The authors identified inflammatory endotypes using markers including IFNg (type 1), eosinophil cationic protein and Charcot-Leyden crystal galectin (type 2), and IL-17A (type 3). The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of type 2 endotype in all patients with CRS. The type 1 endotype was significantly more common in females, and the presence of pus was significantly associated with type 3 endotype in all patients with CRS. When patients with CRSsNP and CRSwNP were analyzed separately, the study found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Although identifying CRS phenotypes may be clinicaly useful, identificaton of inflammatory endotypes

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may allow for more precise and personalized medical treatments in CRS. In addition to information about nasal and sinus disease, the usefulness of telemedicine in allergy practice was described last year in the journal and was particularly applicable to allergic rhinitis. Waibel et al146 evaluated synchronous tele-allergy appointments in a hospital-based allergy clinic in which 360 unique patients participated in 423 synchronous tele-allergy visits, of which 65.0% were new consultations and 28% were conducted for children. The 3 most frequent diagnoses of the consults were allergic rhinitis (35%), asthma (24%), and food allergy (10%). Only 65 (23.4%) of the new patients and 14 (9.5%) of the follow-up patients required an in-person appointment. New visits were significantly more likely to have medication prescribed (64.4% vs 49.0%) and laboratory tests ordered (46.2% vs 7.4%) than return consults, respectively. In an anonymous satisfaction survey, 98.8% of patients recommended telehealth and reported high satisfaction, and patients saved an average of $485 in travel expenses, 438 driving miles, and 2.3 days of work or school per visit. Given patient satisfaction and cost savings, synchronous telemedicine should be considered a useful innovative approach to allergy management.

URTICARIA, ANGIOEDEMA, AND MAST CELL DISORDERS Urticaria Several articles published in 2019 issues of JACI: In Practice dealt with chronic urticaria (CU), including pathophysiology, assessment, and management (Table III). Deza et al84 evaluated the expression of FcεRI, the high-affinity IgE receptor, on basophils in 192 patients with chronic spontaneous urticaria (CSU) and 95 patients with chronic inducible urticaria. Both patients with CSU and patients with chronic inducible urticaria had higher FcεRI expression on basophils than healthy controls. However, this expression was not associated with disease activity, duration, or response to antihistamine therapy. Fourteen patients with chronic inducible urticaria were treated with omalizumab, and 3 did not respond. The 3 omalizumab nonresponders had lower basophil FcεRI expression than responders. Whether this assay would help identify omalizumab nonresponders will require larger studies. Oda et al85 expanded on the findings of the previous study by evaluating the function of basophils activated via the FcεRI receptor in 38 patients with CSU. They also found higher FcεRI expression in patients with CSU than in healthy controls and in patients with AD, and, similarly, did not find a close association with urticaria severity. However, when evaluating CD203c, a marker of basophil activation, expression after stimulation was lower in patients with CSU and lowest in those with severe CSU. When patients with CSU were subdivided into those with low CD203c expression after activation (nonresponders) and those with a normal response (responders), nonresponders had more severe disease activity but interestingly appeared to have a shorter disease duration. These 2 studies add to the literature implicating basophils in the pathogenesis of CU. Yee et al86 reported on the largest experience to date of 415 pediatric patients with acquired cold-induced urticaria (ACU). Similar to other studies, 25.8% had other forms of CU, and only 8.9% had resolution of ACU. Systemic reactions occurred in more than 30%, and anaphylaxis was reported in 18.6%, with some episodes in response to cold air or temperature alone. An ice cube

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test result was positive in approximately 70% of patients, yet 11.7% with a negative test result had a history of cold-induced anaphylaxis. Laboratory tests were not found to be helpful, including cryoglobulins present in only 1 of 71 patients. Most patients responded to antihistamines. The authors suggest that epinephrine autoinjectors should be prescribed for all patients with ACU, and, at the very least, patients and families should be aware of the approximate 1 in 5 risk of anaphylaxis with ACU. Gastaminza et al147 reported the results of the first doubleblind RCT of omalizumab in 22 patients with cholinergic urticaria. The study was blinded for the first 4 months of therapy, and then all subjects were treated with omalizumab for 8 months in an open-label fashion. The primary end point was a negative exercise challenge. At the end of the blinded phase of the study, there was no statistical difference in negative exercise challenges, symptoms, or other medication use. However, at the end of the study, 31% had a negative exercise challenge, and daily symptoms and QOL scores improved from baseline. Although this study suggests that a longer treatment may be required for omalizumab in cholinergic urticaria, confirmation of this finding is needed because of the lack of a longer-term blinded period and the small number of subjects. Dorman et al87 reported their experience with oral tacrolimus in 36 patients with refractory CU, 47% of whom were on chronic oral corticosteroids. Approximately 75% had improvement on tacrolimus, including 11 who went into remission, with control of urticaria after tacrolimus was discontinued. Adverse effects were common but were generally mild. US and international guidelines recommend against extensive laboratory testing in the evaluation of patients with CU.148 Carrillo-Martin et al88 assessed the cost of testing in 725 patients with CU. Seventy-five percent of patients had at least 1 test performed, the mean cost was $569 per patient. In only 3 cases (all skin biopsies showing vasculitis) did test results influence management (0.5%). Interestingly, the cost of tests did not change before or after the US practice parameters were published, although there were some differences in tests ordered, but not consistent with guideline recommendations. This article adds to the overwhelming evidence that laboratory testing for patients with CU without other symptoms is costly and does not lead to improved outcomes.

Angioedema Two articles appeared in last year’s JACI: In Practice on the subject of angioedema, both of which were related to subcutaneous C1-inhibitor (C1-INH) replacement therapy. Craig et al149 described the results of a long-term, open-label safety and effectiveness trial of subcutaneous C1-INH in 126 patients with hereditary angioedema. Patients were randomized to 2 groups treated with either 40 U/kg or 60 U/kg (FDA-approved dose) of subcutaneous C1-INH (HAEGARDA) at a fixed dose for 24 weeks. The second treatment period was a 28-week dose-adjustment period where the dose could be increased if patients had 3 or more attacks in an 8-week period. Subjects (n ¼ 46) in US sites were followed up to an additional 88 weeks. Effectiveness was fairly similar between the 2 groups, with 86% of patients on the FDA-approved dose having less than 1 attack per month, with a median annualized attack rate over the whole study of 1 attack per year. Only 2 patients in the 60-U/kg dose group had the dose increased to 80 U/ kg. Of the smaller group followed for more than 2 years, 82.6% of those treated with 60 U/kg were attack-free in months 25 to 30.

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There were no significant safety concerns and no dropouts related to adverse effects of the treatment. This study confirms the longterm safety and effectiveness of the commercially available subcutaneous C1-INH product. Lumry et al150 reported on a new investigational subcutaneous C1-INH therapy that is a fixed-dose liquid preparation that does not require reconstitution before administration. Sixty patients with hereditary angioedema were randomized in a double-blind crossover design to receive two 14-week periods of subcutaneous liquid C1-INH (2000 units twice weekly) for 14 weeks or placebo. To minimize a carryover effect, data were analyzed at day 1 and day 15. At day 15, liquid C1-INH therapy had an 84.6% reduction in the normalized number of attacks versus placebo; 76.6% had a greater than or equal to 50% reduction in attacks and 38% had a 100% reduction in attacks. Injection-site reactions were higher with liquid C1-INH (59.2%) versus placebo (26.3%) but were mostly mild. Patients reported confidence in self-administration after 1 to 2 study visits, and all respondents were able to self-administer without supervision.

Mast cell disorders Two original articles appeared in 2019 issues of the journal regarding mast cell disorders. Russell et al151 reported on results from a 2010 survey conducted by The Mastocytosis Society that had 420 responders. The focus of this report was on testing, comorbidities, diet and nutrition, and family history. Most responders (n ¼ 201) indicated they had systemic mastocytosis, 93 indicated a diagnosis of cutaneous mastocytosis, 45 mast cell activation syndrome, 18 idiopathic anaphylaxis, and others did not indicate a diagnosis. Of 221 respondents who recalled having a bone marrow biopsy, 98% were adults. Serum tryptase was more than 20 in most respondents. Less than one-third of respondents recalled having testing for a KIT mutation. Thirty-one percent of respondents indicated either osteoporosis or osteopenia; however, when comparing to national references, only males with systemic mastocytosis appeared to have higher rates. There did not appear to be any higher reported rates of comorbidities such as cancer, hyperlipidemia, or coronary artery disease. About 25% reported trying low-histamine diets and half perceived improvement, but about one-third indicated they were not getting adequate nutrition. Interestingly, 22.9% reported possible mast cell disorders in family members. Although respondents’ perceptions of disease may differ from actual disease, this report helps to clarify these patient perceptions. Lemal et al152 reported on the retrospective experience of French mastocytosis centers with omalizumab. Fifty-five patients were treated open label with omalizumab starting at 150 mg every 2 weeks, with options for higher dosing or even more frequent (weekly) dosing. Twenty-nine patients had indolent systemic mastocytosis, 15 had mast cell activation syndrome, and 11 had cutaneous mastocytosis. Overall, 78% of patients had symptom improvement. Anaphylaxis symptoms had the most improvement with omalizumab along with other vasomotor symptoms of malaise, sweating, and palpitations. Cutaneous symptoms of pruritus, flushing, and urticaria also improved, though perhaps not as much as would be expected. A smaller number of patients had a major improvement in gastrointestinal symptoms and dysuria. Neuropsychiatric symptoms and pain overall had modest improvements for most

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patients. Fifteen patients had dose escalation, and 14 had an improved response. One patient had a sustained complete response and was free of all symptoms at follow-up on therapy more than a year later. Tryptase levels remained unchanged and, as expected, IgE levels increased on omalizumab. This study adds to the literature suggesting a benefit in anaphylaxis prevention in patients with primary mast cell disorders, but also suggests that some other symptoms may also improve. A controlled trial is needed to determine how much of these responses may be a placebo effect, although most patients had a persistent response at last follow-up.

CONCLUSIONS The editors hope that the review of these Highlights will help our readers consolidate and use the extensive and practical knowledge published this past year in the journal for the benefit of their patients. We also hope that this review, along with all of our content, will help fulfill what we see as our vision for the journal: to be an indispensable resource for clinicians who manage patients with asthma and patients with allergic, immunologic, and related conditions to optimize the care and health of these patients. Acknowledgment We thank our Managing Editor, Dawn Angel, for her invaluable assistance with the references. REFERENCES 1. Schatz M, Sicherer SH, Khan D, Zeiger RS. The Journal of Allergy and Clinical Immunology: In Practice 2018 Highlights. J Allergy Clin Immunol Pract 2019;7:393-411. 2. Robinson M, Koplin JJ, Field MJ, Sasaki M, Peters RL, McWilliam V, et al. Patterns of carriage of prescribed adrenaline autoinjectors in 10- to 14-year-old food-allergic students: a population-based study. J Allergy Clin Immunol Pract 2019;7:437-43. 3. Portnoy J, Wade RL, Kessler C. Patient carrying time, confidence, and training with epinephrine autoinjectors: the RACE survey. J Allergy Clin Immunol Pract 2019;7:2252-61. 4. Gabrielli S, Clarke A, Morris J, Eisman H, Gravel J, Enarson P, et al. Evaluation of prehospital management in a Canadian emergency department anaphylaxis cohort. J Allergy Clin Immunol Pract 2019;7:2232-2238.e3. 5. Tejedor-Alonso MA, Farias-Aquino E, Pérez-Fernández E, Grifol-Clar E, Moro-Moro M, Rosado-Ingelmo A. Relationship between anaphylaxis and use of beta-blockers and angiotensin-converting enzyme inhibitors: a systematic review and meta-analysis of observational studies. J Allergy Clin Immunol Pract 2019;7:879-897.e5. 6. Vazquez-Ortiz M, Ludman S, Aston A, Noimark L, Turner PJ. Lip dose challenges in food allergy: current practice and diagnostic utility in the United Kingdom. J Allergy Clin Immunol Pract 2019;7:2770-2774.e3. 7. Virkud YV, Chen Y-C, Stieb ES, Alejos AR, Renton N, Shreffler WG, et al. Analysis of oral food challenge outcomes in IgE-mediated food allergies to almond in a large cohort. J Allergy Clin Immunol Pract 2019;7:2359-2368.e3. 8. Kalic T, Morel-Codreanu F, Radauer C, Ruethers T, Taki AC, Swoboda I, et al. Patients allergic to fish tolerate ray based on the low allergenicity of its parvalbumin. J Allergy Clin Immunol Pract 2019;7:500-508.e11. 9. Christensen MJ, Eller E, Mortz CG, Brockow K, Bindslev-Jensen C. Wheatdependent cofactor-augmented anaphylaxis: a prospective study of exercise, aspirin, and alcohol efficacy as cofactors. J Allergy Clin Immunol Pract 2019;7:114-21. 10. Wilson JM, Schuyler AJ, Workman L, Gupta M, James HR, Posthumus J, et al. Investigation into the a-gal syndrome: characteristics of 261 children and adults reporting red meat allergy. J Allergy Clin Immunol Pract 2019;7: 2348-2358.e4. 11. Lee E, Barnes EH, Mehr S, Campbell DE. Differentiating acute food proteininduced enterocolitis syndrome from its mimics: a comparison of clinical features and routine laboratory biomarkers. J Allergy Clin Immunol Pract 2019;7:471-478.e3.

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