Publications by authors named "Jonathan M Spergel"

215 Publications

Multi-ethnic genome-wide and HLA association study of total serum IgE.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Department of Human Genetics, University of Chicago, Chicago, IL.

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.

Objective: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901).

Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article's Online Repository at www.jacionline.org.

Results: We identified six loci at genome-wide significance (P<5x10-9), including four loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, also identified in prior GWAS of atopic dermatitis and asthma. In the HLA allele association study, HLA-A*02:01 was associated with decreased tIgE (discovery P = 2x10, replication P = 5x10, discovery+replication P=4x10) and HLA-DQB1*03:02 was strongly associated with decreased tIgE in Hispanic/Latino ancestry populations (Hispanic/Latino discovery+replication P=8x10-8).

Conclusion: We performed the largest GWAS and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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http://dx.doi.org/10.1016/j.jaci.2021.09.011DOI Listing
September 2021

The atopic march: Where we are going? Can we change it?

Ann Allergy Asthma Immunol 2021 09;127(3):283-284

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2021.06.022DOI Listing
September 2021

Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis and other atopic comorbidities.

Allergy Asthma Proc 2021 Sep;42(5):425-431

Department of Infection, Immunity, and Cardiovascular Disease, Sheffield Dermatology Research, University of Sheffield, Sheffield Children's Hospital, Sheffield, United Kingdom.

Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. This pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed treatment-emergent adverse events (TEAEs). This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), www.clinicaltrials.gov.
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http://dx.doi.org/10.2500/aap.2021.42.210064DOI Listing
September 2021

Anaphylaxis knowledge gaps and future research priorities: A consensus report.

J Allergy Clin Immunol 2021 Aug 12. Epub 2021 Aug 12.

Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.

Background: Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively.

Objective: We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility.

Methods: We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale.

Results: The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices.

Conclusions: We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.035DOI Listing
August 2021

Management of Eosinophilic Esophagitis During Oral Immunotherapy.

J Allergy Clin Immunol Pract 2021 Sep 27;9(9):3282-3287. Epub 2021 Jul 27.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Ga. Electronic address:

Food allergies are antigen-driven diseases that can lead to IgE-mediated reactions of immediate hypersensitivity (eg, anaphylaxis triggered by a single food) or non-IgE reactions of delayed hypersensitivity such as eosinophilic esophagitis (eg, inability to eat multiple foods manifesting as abdominal pain, choking, dysphagia, vomiting, reflux, food impaction). Although both types of disease have their own unique set of challenges in diagnosis and management, it is a particularly vexing problem when a patient is afflicted by both conditions. This situation can happen when individuals with IgE-mediated food allergy undergo desensitization using currently available forms of oral immunotherapy. In this Grand Rounds Review, we review diagnostic approaches to oral immunotherapy-associated eosinophilic esophagitis, potential relationships between primary and secondary eosinophilic esophagitis, potential management approaches, areas of uncertainty, and upcoming research. Optimally supporting patients in their journey with food allergy requires shared decision making regarding alternative management strategies and the stimulation of robust research.
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http://dx.doi.org/10.1016/j.jaip.2021.07.017DOI Listing
September 2021

RNA sequencing identifies global transcriptional changes in peripheral CD4 cells during active oesophagitis and following epicutaneous immunotherapy in eosinophilic oesophagitis.

Clin Transl Immunology 2021 22;10(7):e1314. Epub 2021 Jul 22.

Division of Allergy and Immunology The Children's Hospital of Philadelphia Philadelphia PA USA.

Objective: There are no disease-modifying therapies for the treatment of eosinophilic oesophagitis (EoE), which is driven by non-IgE-mediated allergic inflammation. A recent clinical trial of milk epicutaneous immunotherapy (EPIT) has shown initial promise, with 47% of treated EoE patients tolerating milk without recurrence of disease. Mechanisms of EPIT in EoE have not been studied in humans. Here, we identify transcriptional changes in the peripheral CD4 T-cell compartment during active EoE and following EPIT.

Methods: RNA isolation, sequencing and integrative data analysis were performed on peripheral CD4 T cells isolated from 15 of 20 patients enrolled in a clinical trial of EPIT for EoE. Gene expression changes in peripheral CD4 T cells were examined during diet therapy and following trial of milk antigen EPIT.

Results: We identify 244 differentially expressed genes in peripheral blood CD4 cells of EoE patients consuming versus those eliminating milk, and 129 DEGs in CD4 cells were isolated after EPIT versus after placebo (FDR ≤ 0.05). Gene set enrichment analysis identifies enrichment of hallmark interferon-α and interferon-γ response pathways in peripheral CD4 T cells from EoE patients during active disease on a milk-containing diet. We demonstrate overlap of this gene signature with the altered gene expression signature seen in EoE patient biopsy tissue. EPIT therapy response is associated with significant enrichment in pathways related to T-cell receptor signalling ( = 1.16 × 10), antigen presentation and costimulation, and cytokine signalling ( = 1.11 × 10), as well as upregulation of genes associated with regulatory T-cell function.

Conclusions: EoE is associated with distinct global transcriptional changes in CD4 T cells, one feature of which is an IFN response signature. Clinically favorable response to EPIT is likely multifactorial but is associated with a distinct transcriptional profile in peripheral CD4 cells supporting the hypothesis that EPIT alters peripheral CD4 responses in EoE patients.
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http://dx.doi.org/10.1002/cti2.1314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296633PMC
July 2021

Development of the Child- and Parent-Rated Scales of Food Allergy Anxiety (SOFAA).

J Allergy Clin Immunol Pract 2021 Jul 12. Epub 2021 Jul 12.

Food Allergy Center, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa. Electronic address:

Background: Anxiety can be excessive and impairing in children with food allergy (FA). There is no accepted condition-specific measure of anxiety for this population.

Objective: To evaluate the validity and reliability of new child- and parent-rated measures of FA-related anxiety in youth.

Methods: Items for the Scale of Food Allergy Anxiety (SOFAA) were developed by a cognitive-behavioral therapist specializing in pediatric anxiety, in consultation with FA medical professionals and parents of children with FA. Dyads (n = 77) of children with FA (aged 8-18 years; 42.9% females) and their parents (95.5% females) completed full versions of the SOFAA (21 items; scored 0-4) via online survey.

Results: The child-rated SOFFA-C mean score was 29.1 ± 18.3; the parent-rated SOFAA-P mean score was 33.9 ± 16.1. Higher scores indicate higher reported anxiety. Coefficient alphas were 0.94 and 0.92. Factor analyses and item-response theory analyses supported the creation of the 14-item SOFAA-C-brief and the 7-item SOFAA-P-brief, accounting for 93% and 79% of total variance, respectively. Correlations revealed strong convergence between child- and parent-report for both the full (r = 0.85) and brief (r = 0.79) versions. Correlations with a generic measure of child anxiety (Screen for Child Anxiety Related Disorders) and the Food Allergy Quality of Life Questionnaire ranged from moderate to strong, whereas those with a generic measure of child eating problems (About Your Child's Eating) were weak to moderate, supporting convergent and divergent validity. Scores of 48 dyads who completed SOFAAs at time 2 (mean, 16.0 days) appeared stable over time, supporting test-retest reliability.

Conclusions: The 21-item SOFAA-C and SOFAA-P are reliable and valid scales for measuring condition-specific anxiety in youth with FA. As shorter screening measures, the SOFAA-C-brief and the SOFAA-P-brief are also reliable and valid.
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http://dx.doi.org/10.1016/j.jaip.2021.06.039DOI Listing
July 2021

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

J Allergy Clin Immunol 2021 Jul 6. Epub 2021 Jul 6.

Inform Diagnostics, Irving, Tex; Department of Pathology, Baylor College of Medicine, Houston, Tex.

Background: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments.

Objective: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE.

Methods: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists.

Results: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life.

Conclusions: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.001DOI Listing
July 2021

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

J Allergy Clin Immunol Pract 2021 Jun 18. Epub 2021 Jun 18.

Department of Paediatrics, Royal College of Surgeons, Dublin, Ireland.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.
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http://dx.doi.org/10.1016/j.jaip.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248554PMC
June 2021

Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo. Electronic address:

Background: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.

Objectives: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.

Methods: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.

Results: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRS: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).

Conclusions: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.
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http://dx.doi.org/10.1016/j.jaci.2021.05.034DOI Listing
June 2021

Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms Following Dilation in Adults With Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol 2021 May 29. Epub 2021 May 29.

Digestive Health Institute, Children's Hospital Colorado, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Aurora, Colorado.

Background & Aims: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and eosinophils per high-power field (eos/hpf).

Methods: Adults enrolled in a multisite prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers OMEGA observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsy specimens. Patients were stratified based on dilation status as absent, performed 1 year or less before endoscopy, and performed more than 1 year before endoscopy. Assessments included Spearman correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf.

Results: Among 100 patients (n = 61 males; median age, 37 y), 15 and 40 patients underwent dilation 1 year or less and more than 1 year before index endoscopy, respectively. In nondilated patients, the association between eos/hpf and symptoms was moderate (rho = 0.49; P < .001); for a 10-eos/hpf increase, the predicted EEsAI increased by 2.69 (P = .002). In patients dilated 1 or less and more than 1 year before index endoscopy, this association was abolished (rho = -0.38; P = .157 for ≤1 y and rho = 0.02; P = .883 >1 y); for a 10-eos/hpf increase, the predicted EEsAI changed by -1.64 (P = .183) and 0.78 (P = .494), respectively. Dilation modified the association between symptoms and eos/hpf (P = .005 and P = .187 for interaction terms of eos/hpf and dilation 1 or less years before and more than 1 year before index endoscopy, respectively).

Conclusions: In nondilated EoE adults, eos/hpf correlates modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than 1 year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up evaluation.
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http://dx.doi.org/10.1016/j.cgh.2021.05.049DOI Listing
May 2021

Differences in oral food challenge reaction severity based on increasing age in a pediatric population.

Ann Allergy Asthma Immunol 2021 May 16. Epub 2021 May 16.

Division of Allergy and Clinical Immunology, Rochester Regional Health, Rochester, New York.

Background: Food allergy reactions range from mild to severe with differences in age appearing to be an important factor associated with reaction severity.

Objective: To define differences in oral food challenge (OFC) reaction severity in pediatric patients from infancy to adolescence using objective clinical outcomes and standardized reaction grading tools.

Methods: Retrospective review of all positive OFC results at 2 large institutions between September 2016 and February 2019. Reaction severity was defined by presence of cardiovascular, neurologic, lower respiratory, or laryngeal symptoms, epinephrine requirement, and grading using 2 established food allergy reaction scales.

Results: Infants and toddlers had fewer reactions involving cardiovascular, neurologic, lower respiratory, or laryngeal symptoms compared with older age groups. Epinephrine was also required less frequently during reactions in infants and toddlers, compared with older age groups. There was no difference in reaction severity in infants and toddlers based on clinical history of eczema. Increasing age was significantly correlated with increased epinephrine requirement (R = 0.12, P = .002), elevated Consortium of Food Allergy Research score (R = .012, P = .003), and approached significance for increased Practical Allergy score (R = .005, P = .05). History of asthma and sesame allergy were identified to be positively correlated with more severe reactions.

Conclusion: Infants and young toddlers have less severe reactions during OFCs compared with older age groups supporting early food introduction practices. In children under 12 months of age, severe reactions are most rare calling into question screening practices using specific allergy testing before food introduction. Standardized reaction grading tools may be valuable instruments to categorize reaction severity during OFCs.
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http://dx.doi.org/10.1016/j.anai.2021.05.013DOI Listing
May 2021

CON: Peripheral intravenous access should always be secured before initiating food protein-induced enterocolitis syndrome oral food challenge.

Ann Allergy Asthma Immunol 2021 05;126(5):462-463

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.12.018DOI Listing
May 2021

Peripheral markers of allergen-specific immune activation predict clinical allergy in eosinophilic esophagitis.

Allergy 2021 Apr 11. Epub 2021 Apr 11.

Division of Allergy and Immunology, Center for Pediatric Eosinophilic Disorders, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Eosinophilic esophagitis (EoE) is a T-cell-mediated disease that is caused by specific foods and results in esophageal dysfunction. Existing allergy testing modalities are not helpful when attempting to identify EoE-causal foods necessitating empiric food elimination and recurrent endoscopy. The goal of this study was to identify and compare allergen-specific immune features that can be assayed in a minimally invasive manner to predict clinical food allergy in EoE.

Methods: We obtained blood samples from control subjects (n = 17), subjects with clinical EoE milk allergy (n = 17), and subjects with immunoglobulin E-mediated milk allergy (n = 9). We measured total and milk-specific plasma immunoglobulin G (IgG)4 levels and peripheral memory CD4 T helper (T ) cell proliferation and cytokine production after stimulation with endotoxin-depleted milk proteins. Sensitivity and specificity for predicting clinical EoE milk allergy were calculated and compared between approaches.

Results: Total and milk-specific IgG4 levels were not significantly different between control subjects and subjects with clinical EoE milk allergy. Stimulation with milk proteins caused T lymphocytes from subjects with clinical EoE milk allergy to proliferate more (%P1 of 38.3 ± 4.6 vs. 12.7 ± 2.8, p < 0.0001), and produce more type 2 cytokines (%IL-4 of 33.7 ± 2.8 vs. 6.9 ± 1.6, p < 0.0001) than cells from control subjects. Milk-dependent memory T -cell proliferation (sensitivity and specificity of 88% and 82%, respectively) and interleukin 4 (IL-4) production (sensitivity and specificity of 100%) most strongly predicted clinical EoE milk allergy.

Conclusions: Peripheral markers of allergen-specific immune activation may be useful in identifying EoE-causal foods. Assaying milk-dependent IL-4 production by circulating memory T lymphocytes most accurately predicts clinical EoE milk allergy.
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http://dx.doi.org/10.1111/all.14854DOI Listing
April 2021

Intrapartum Group B Streptococcal Prophylaxis and Childhood Allergic Disorders.

Pediatrics 2021 05 8;147(5). Epub 2021 Apr 8.

Divisions of Neonatology,

Objectives: To determine if maternal intrapartum group B (GBS) antibiotic prophylaxis is associated with increased risk of childhood asthma, eczema, food allergy, or allergic rhinitis.

Methods: Retrospective cohort study of 14 046 children. GBS prophylaxis was defined as administration of intravenous penicillin, ampicillin, cefazolin, clindamycin, or vancomycin to the mother, ≥4 hours before delivery. Composite primary outcome was asthma, eczema, or food allergy diagnosis within 5 years of age, identified by diagnosis codes and appropriate medication prescription. Allergic rhinitis was defined by using diagnostic codes only and analyzed as a separate outcome. Analysis was a priori stratified by delivery mode and conducted by using Cox proportional hazards model adjusted for multiple confounders and covariates. Secondary analyses, restricted to children retained in cohort at 5 years' age, were conducted by using multivariate logistic regression.

Results: GBS prophylaxis was not associated with increased incidence of composite outcome among infants delivered vaginally (hazard ratio: 1.13, 95% confidence interval [CI]: 0.95-1.33) or by cesarean delivery (hazard ratio: 1.08, 95% CI: 0.88-1.32). At 5 years of age, among 10 404 children retained in the study, GBS prophylaxis was not associated with the composite outcome in vaginal (odds ratio: 1.21, 95% CI: 0.96-1.52) or cesarean delivery (odds ratio: 1.17, 95% CI: 0.88-1.56) cohorts. Outcomes of asthma, eczema, food allergy, separately, and allergic rhinitis were also not associated with GBS prophylaxis.

Conclusions: Intrapartum GBS prophylaxis was not associated with subsequent diagnosis of asthma, eczema, food allergy, or allergic rhinitis in the first 5 years of age.
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http://dx.doi.org/10.1542/peds.2020-012187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085997PMC
May 2021

Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

Vaccine 2021 05 23;39(22):3053-3066. Epub 2021 Feb 23.

Center of Vaccinology, University of Geneva, Switzerland.

This is a Brighton Collaboration Case Definition of the term "Vaccine Associated Enhanced Disease" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901381PMC
May 2021

Reply.

J Allergy Clin Immunol 2021 04 23;147(4):1524-1525. Epub 2021 Feb 23.

Food Allergy Center, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine, Philadelphia, Pa. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.11.038DOI Listing
April 2021

Tolerability of and Adherence to Topical Treatments in Atopic Dermatitis: A Narrative Review.

Dermatol Ther (Heidelb) 2021 Apr 18;11(2):415-431. Epub 2021 Feb 18.

Department of Dermatology, Center for Dermatology Research, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1071, USA.

Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that oftentimes requires complex therapy. Poor adherence is a major barrier to AD treatment success. An interspecialty, virtual roundtable panel was held, through which clinical dermatologists, allergists, and behavioral and social psychologists discussed AD management and adherence. Relevant literature was reviewed, and the content of this article was organized based on the roundtable discussion. Current guidelines for AD treatment include maintenance and acute therapy for mild-to-severe AD. Therapy is often complex and requires significant patient involvement, which may contribute to poor treatment adherence. Behavioral and social psychology strategies that may help improve adherence include scheduling timely follow-up appointments, using a clearly written eczema action plan (EAP), reducing perceived treatment burden, utilizing anchoring techniques, sharing anecdotes, and rewarding children using positive reinforcement and stickers. There are multiple practical ways by which providers can improve both the management and treatment adherence of patients with AD.
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http://dx.doi.org/10.1007/s13555-021-00500-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019006PMC
April 2021

Integrated associations of nasopharyngeal and serum metabolome with bronchiolitis severity and asthma: A multicenter prospective cohort study.

Pediatr Allergy Immunol 2021 07 4;32(5):905-916. Epub 2021 Mar 4.

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: While infant bronchiolitis contributes to substantial acute (eg, severity) and chronic (eg, asthma development) morbidities, its pathobiology remains uncertain. We examined the integrated relationships of local (nasopharyngeal) and systemic (serum) responses with bronchiolitis morbidities.

Methods: In a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we applied a network analysis approach to identify distinct networks (modules)-clusters of densely interconnected metabolites-of the nasopharyngeal and serum metabolome. We examined their individual and integrated relationships with acute severity (defined by positive pressure ventilation [PPV] use) and asthma development by age 5 years.

Results: In 140 infants, we identified 285 nasopharyngeal and 639 serum metabolites. Network analysis revealed 7 nasopharyngeal and 8 serum modules. At the individual module level, nasopharyngeal-amino acid, tricarboxylic acid (TCA) cycle, and carnitine modules were associated with higher risk of PPV use (r > .20; P < .001), while serum-carnitine, amino acid, and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r < -.20; P < .05). The integrated analysis for PPV use revealed consistent findings-for example, nasopharyngeal-TCA (adjOR: 2.87, 95% CI: 1.68-12.2) and serum-GPC/GPE (adjOR: 0.54, 95% CI: 0.38-0.80) modules-and an additional module-serum-glucose-alanine cycle module (adjOR: 0.69, 95% CI: 0.56-0.86). With asthma risk, there were no individual associations, but there were integrated associations (eg, nasopharyngeal-carnitine module; adjOR: 1.48, 95% CI: 1.11-1.99).

Conclusion: In infants with bronchiolitis, we found integrated relationships of local and systemic metabolome networks with acute and chronic morbidity. Our findings advance research into the complex interplay among respiratory viruses, local and systemic response, and disease pathobiology in infants with bronchiolitis.
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http://dx.doi.org/10.1111/pai.13466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269431PMC
July 2021

Conserved IFN Signature between Adult and Pediatric Eosinophilic Esophagitis.

J Immunol 2021 03 8;206(6):1361-1371. Epub 2021 Feb 8.

Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue from pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA sequencing of paired human esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease. Unbiased analysis of differentially expressed genes in tissue revealed a strong IFN signature that was significantly enriched in EoE patients as compared with patients with gastroesophageal reflux disease. Both type I and type II IFN-responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of IFN gene sets was observed in pediatric EoE biopsies as compared with non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that human peripheral CD4 T cells from children with EoE produce IFN-γ upon activation with EoE-causal allergens. Together, this work identifies a conserved IFN signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process in humans.
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http://dx.doi.org/10.4049/jimmunol.2000973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946729PMC
March 2021

Severity grading system for acute allergic reactions: A multidisciplinary Delphi study.

J Allergy Clin Immunol 2021 Jul 19;148(1):173-181. Epub 2021 Jan 19.

Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.

Background: There is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research.

Objective: The aim of this study was to develop a severity grading system for acute allergic reactions for use in clinical care and research.

Methods: From May to September 2020, we convened a 21-member multidisciplinary panel of allergy and emergency care experts; 9 members formed a writing group to critically appraise and assess the strengths and limitations of prior severity grading systems and develop the structure and content for an optimal severity grading system. The entire study panel then revised the grading system and sought consensus by utilizing Delphi methodology.

Results: The writing group recommended that an optimal grading system encompass the severity of acute allergic reactions on a continuum from mild allergic reactions to anaphylactic shock. Additionally, the severity grading system must be able to discriminate between clinically important differences in reaction severity to be relevant in research while also being intuitive and straightforward to apply in clinical care. Consensus was reached for all elements of the proposed severity grading system.

Conclusion: We developed a consensus severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions. Successful international validation, refinement, dissemination, and application of the grading system will improve communication among providers and patients about the severity of allergic reactions and will help advance future research.
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http://dx.doi.org/10.1016/j.jaci.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273088PMC
July 2021

A Consensus Approach to the Primary Prevention of Food Allergy Through Nutrition: Guidance from the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and the Canadian Society for Allergy and Clinical Immunology.

J Allergy Clin Immunol Pract 2021 01 26;9(1):22-43.e4. Epub 2020 Nov 26.

Section of Allergy & Immunology, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colo. Electronic address:

Recently published data from high-impact randomized controlled trials indicate the strong potential of strategies to prevent the development of food allergy in high-risk individuals, but guidance in the United States at present is limited to a policy for only the prevention of peanut allergy, despite other data being available and several other countries advocating early egg and peanut introduction. Eczema is considered the highest risk factor for developing IgE-mediated food allergy, but children without risk factors still develop food allergy. To prevent peanut and/or egg allergy, both peanut and egg should be introduced around 6 months of life, but not before 4 months. Screening before introduction is not required, but may be preferred by some families. Other allergens should be introduced around this time as well. Upon introducing complementary foods, infants should be fed a diverse diet, because this may help foster prevention of food allergy. There is no protective benefit from the use of hydrolyzed formula in the first year of life against food allergy or food sensitization. Maternal exclusion of common allergens during pregnancy and/or lactation as a means to prevent food allergy is not recommended. Although exclusive breast-feeding is universally recommended for all mothers, there is no specific association between exclusive breast-feeding and the primary prevention of any specific food allergy.
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http://dx.doi.org/10.1016/j.jaip.2020.11.002DOI Listing
January 2021

Sustained milk consumption after 2 years post-milk epicutaneous immunotherapy for eosinophilic esophagitis.

Allergy 2021 05 28;76(5):1573-1576. Epub 2020 Nov 28.

Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/all.14659DOI Listing
May 2021

Is safe to eat in a restaurant if you have peanut allergy?

Ann Allergy Asthma Immunol 2020 11;125(5):499-500

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.08.024DOI Listing
November 2020

Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study.

J Allergy Clin Immunol 2020 11 24;146(5):1089-1096. Epub 2020 Aug 24.

Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Background: The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts.

Objective: Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis.

Methods: Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as "consensus reached." If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate de-identified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as "no consensus reached."

Results: The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system.

Conclusion: Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.
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http://dx.doi.org/10.1016/j.jaci.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006564PMC
November 2020

Sustained unresponsiveness to peanut after long-term peanut epicutaneous immunotherapy.

J Allergy Clin Immunol Pract 2021 01 22;9(1):524-526. Epub 2020 Aug 22.

DBV Technologies, Montrouge, France; Children's Hospital at Westmead, Sydney, NSW, Australia.

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http://dx.doi.org/10.1016/j.jaip.2020.08.017DOI Listing
January 2021

New issue of food allergy: Phobia of anaphylaxis in pediatric patients.

J Allergy Clin Immunol 2020 10 23;146(4):780-782. Epub 2020 Jul 23.

Food Allergy Center, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine, Philadelphia, Pa. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.07.010DOI Listing
October 2020

High Patient Disease Burden in a Cross-sectional, Multicenter Contact Registry Study of Eosinophilic Gastrointestinal Diseases.

J Pediatr Gastroenterol Nutr 2020 10;71(4):524-529

Department of Pediatrics, Cincinnati Children's Hospital Medical Center.

Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well-described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient-reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non-EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE.

Methods: We conducted a cross-sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi-square (categorical measures) and the Mann-Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation.

Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non-EoE EGID), a higher proportion of those with a non-EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating (P < 0.01 for all). Participants with a non-EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain (P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5--4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2--3.3 for elemental formula).

Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non-EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.
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http://dx.doi.org/10.1097/MPG.0000000000002817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574400PMC
October 2020
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