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The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERs) organized a daylong symposium at the 2024 annual meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research as well as debates on the mechanisms and management of eosinophilic gastrointestinal diseases. Updates on recent clinical trials and consensus guidelines were also presented. We summarize the updates on eosinophilic gastrointestinal diseases presented at the symposium., Competing Interests: Disclosure statement Supported by U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and in part by the Division of Intramural Research, NIAID/NIH. CEGIR is also supported by patient advocacy groups including American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Diseases (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by the NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). B.L.W. was funded by NIH/NIAID (K23AI158813). E.M.A. was funded by the NIH (KL2TR002552, K12TR004410). S.S.A. was funded by NIH/NIDDK (R56AI092135). S.J.A. was funded by NIH/National Heart, Lung, and Blood Institute (NHLBI) (R01HL153170). D.A.H. was directly supported by the Hartwell Foundation, the Food Allergy Fund, and a faculty development award from the American Academy of Allergy, Asthma & Immunology. Allergy research in the Hill laboratory was supported by NIH/NHLBI (R01HL162715) and the Children’s Hospital of Philadelphia Research Institute. J.W.C. was supported by the NIH (K23DK129784). F.L.K. was funded by APFED HOPE Pilot Grant 2023 and NIH/NIAID K23AI171085. M.A.R. was funded by the NIH (K08AI148456). L.A.S. was supported by NIH/NIAID (R01AI168134). The contents are those of the authors and do not necessarily represent the official views or an endorsement by the NIH or other funders. None of the funding sources had a role in the design or conduct of the study. Disclosure of potential conflict of interest: B. L. Wright reports in-kind support from Regeneron in the form of study drug (dupilumab and placebo) for a clinical trial of milk oral immunotherapy. J. P. Abonia reports receipt of payment or honoraria for lectures from Takeda Global Research and Development; participation on a data safety monitoring board for OctaPharma USA; and receipt of grants or contracts from Cures Within Reach and Celgene. E. M. Abud is coinventor of patent WO/2018/160496 (microglia differentiation and use); serves as advisory board member and consulting agreements with StemPharm and Neucyte; and reports advisory board participation for Amgen and AstraZeneca. S. S. Aceves is coinventor of oral viscous budesonide, patented by the University of California, San Diego, and licensed by Takeda (oral budesonide suspension); has acted as speaker for Regeneron/Sanofi; and has received research funding from Bristol Myers Squibb. S. J. Ackerman is chief science officer and executive board member of EnteroTrack; has received patents on the Esophageal String Test (EST); has consulted for Areteia Pharmaceuticals; and has participated on the medical advisory panel of the American Partnership for Eosinophilic Disorders (APFED). M. Braskett reports acting as scientific advisor to Bryn Pharma; and receipt of royalties from UpToDate. J. W. Chang reports consulting for Regeneron/Sanofi, Takeda, and Bristol Myers Squibb. M. Chehade reports consulting for Regeneron/Sanofi, Adare/Ellodi, AstraZeneca, Bristol Myers Squibb, Allakos, Shire/Takeda, Phathom, and Recludix Pharma; and receipt of research funding from Regeneron, Allakos, AstraZeneca, Adare/Ellodi, Bristol Myers Squibb, Danone, and Shire/Takeda. G. M. Constantine reports speaker honoraria from PeerView CME. C. M. Davis reports research funding from NIH/NIAID, DBV, Regeneron, AstraZeneca, Takeda, and Allergenis; and educational funding from Genentech. E. S. Dellon reports research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; consulting for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; and receipt of educational grants from Allakos, Aqilion, Holoclara, and Invea. R. Durban reports consulting for Sanofi, AstraZeneca, Reckitt/Mead Johnson Nutrition, Abbott Nutrition, and Nutricia North America. D. A. Hill has received a patent related to the utilization of food-specific T-cell responses for the diagnosis and management of EoE. E. T. Jensen reports consulting fees from Regeneron, Jazz Pharmaceuticals, and TARGET-RWE. A. Kewalramani reports sitting on the Sanofi Mid-Atlantic Regional Respiratory Field medical advisory board. P. Khoury and A. D. Klion report royalties from UpToDate. F. L. Kuang reports research funding from AstraZeneca. E. C. McGowan reports funding from NIH/NIAID and American College of Gastroenterology; and consulting for Regeneron/Sanofi and Takeda. J. M. Spergel reports grant support from the NIH, Regeneron/Sanofi, and Novartis; and has consulted for Regeneron/Sanofi, Allakos, Readysetfood, Novartis, and Bristol Myers Squibb. A. M. Uchida reports consulting for Regeneron/Sanofi, Takeda, and AstraZeneca. J. B. Wechslerc reports consulting for Allakos, Ellodi, Regeneron/Sanofi/Genzyme, Bristol Myers Squibb, Invea Therapeutics, CellDex, and AstraZeneca; and clinical trial/research funding from Allakos and Regeneron/Sanofi. R. D. Pesek reports consulting for Regeneron. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Competing Interests: Disclosures The authors have no conflicts of interest to report.

Background: IL-33 is a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of eosinophilic esophagitis (EoE) subjects. We previously developed a mouse model of EoE dependent on constitutive overexpression of IL-33 from the esophageal epithelium (EoE33)., Objective: Our objective was to develop an inducible, IL-33-dependent model of EoE and examine induction of EoE-associated pathology., Methods: We utilized a tetracycline-inducible system to express IL-33 in the esophagus by generating 2 transgenic mice. The first (iSophagus) expresses a reverse tetracycline transactivator from the esophageal epithelium. The second (TRE33) features a tetracycline response element driving expression of IL-33. When crossed, these mice generate an inducible model of EoE (iEoE33). Mice were administered doxycycline-infused chow for up to 2 weeks. Cytokines were assessed by ELISA or bead-based multiplex analysis. T cells were assessed by flow cytometry. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. iEoE33 was treated with steroids and crossed with IL-13 -/- mice., Results: Doxycycline-treated iEoE33 mice demonstrated expression of IL-33 in the esophageal epithelium, and esophageal pathology including eosinophilia, CD4 + cell infiltrate, basal zone hyperplasia, and dilated intercellular spaces. These findings became pronounced on day 7 of induction, were accompanied by weight loss and esophageal thickening, and were steroid responsive and IL-13 dependent., Conclusion: Inducible IL-33 expression in the esophageal epithelium elicited features pathognomonic of EoE. iEoE33 enables investigation of EoE disease mechanisms as well as initiation, progression, and resolution., Competing Interests: Disclosure statement Supported by the Donald and Kathy Levin Family Foundation, Mayo Clinic Foundation, and Phoenix Children’s Hospital Foundation. M.Y.M. is a member of the Immunology Graduate Program and is supported by the Mayo ClinicGraduate School of Biomedical Sciences. This work was also supported by NIH grants: R01DK114436 (H.N.), R37AI71106 (H.K.), R01AI128729 (H.K.), R01HL117823 (H.K.), and K23AI158813 (B.L.W.). iEoE33 mice were generated and characterized as an EoE model with funding support exclusively from the Donald and Kathy Levin Family Foundation. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Immunotherapy is a treatment approach based on the principle of incremental allergen exposure to achieve desensitization. Recently, oral immunotherapy has been introduced as a treatment of IgE-mediated food allergy. Some patients receiving oral immunotherapy for food allergy may develop eosinophilic esophagitis. Here, we summarize the literature examining this association, its treatment, and outcomes and discuss possible explanations for this clinical phenomenon. We further identify potential associations with aeroallergen sensitivity and other forms of immunotherapy including subcutaneous immunotherapy and sublingual immunotherapy. Finally, we discuss management of immunotherapy-induced eosinophilic esophagitis. Epicutaneous immunotherapy is highlighted as an area of therapeutic investigation., Competing Interests: Disclosure B.L. Wright has received in-kind support from Regeneron in the form of study drug for an ongoing clinical trial investigating the role of dupilumab as an adjunct to milk oral immunotherapy. J. Spergel has consulting agreements with Regeneron, Sanofi, Novartis, and Alladapt, and he has royalties with UpToDate. J. Spergel and N. Wolfset have received in-kind support from Regeneron, United States in the form of study drug for an ongoing clinical trial investigating the role of dupilumab in eosinophilic esophagitis. All other authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE., Objective: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE., Methods: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2 -/- , eosinophil-deficient, and IL-13 -/- mice. Finally, EoE33 mice were treated with dexamethasone., Results: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and T H 2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids., Conclusions: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The demographic characteristics of patients with eosinophilic gastrointestinal diseases (EGIDs) are poorly understood. Population-based assessments of EGID demographics may indicate health disparities in diagnosis., Objectives: We aimed to characterize the demographic distribution of EGIDs and evaluate the potential for bias in reporting patient characteristics., Methods: We conducted a systematic review, extracting data on age, sex, gender, race, ethnicity, body mass index, insurance, and urban/rural residence on EGID patients and the source population. Differences in proportions were assessed by chi-square tests. Demographic reporting was compared to recent guidelines., Results: Among 50 studies that met inclusion/exclusion criteria, 12 reported ≥1 demographic feature in both EGID and source populations. Except for age and sex or gender, demographics were rarely described (race = 4, ethnicity = 1, insurance = 1) or were not described (body mass index, urban/rural residence). A higher proportion of male subjects was observed for EoE or esophageal eosinophilia relative to the source population, but no difference in gender or sex distribution was observed for other EGIDs. "Sex" and "gender" were used interchangeably, and frequently only the male proportion was reported. Reporting of race and ethnicity was inconsistent with guidelines., Conclusion: Current data support a male predominance for EoE only. Evidence was insufficient to support enrichment of EGIDs in any particular racial, ethnic, or other demographic group. Population-based studies presenting demographics on both cases and source populations are needed. Implementation of guidelines for more inclusive reporting of demographic characteristics is crucial to prevent disparities in timely diagnosis and management of patients with EGIDs., Competing Interests: Supported by U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers), which is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Disease Research, National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases, NCATS, and patient advocacy groups including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). This work was also funded in part by the Division of Intramural Research, NIAID, National Institutes of Health. Disclosure of potential conflict of interest: M. Chehade served as consultant for Regeneron, Allakos, Adare/Ellodi, Shire/Takeda, AstraZeneca, Sanofi, Bristol Myers Squibb, Phathom, Recludix Pharma, and Nexstone Immunology; and received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Danone, and Bristol Myers Squibb. A. B. Muir has served on medical advisory board for Bristol Myers Squibb and Nexstone Immunology; and has received research funding from Morphic. M. H. Collins has received research funding from AstraZeneca, Ception, GSK, Meritage Pharma Inc, Receptos/Celgene/BMS, Regeneron Pharmaceuticals and Shire, a Takeda company; and is consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc/Alimentiv Inc and Shire, a Takeda company. C. M. Davis has received research funding from the National Institutes of Health/National Institute of Allergy and Infectious Disease (Consortium of Food Allergy Research/Consortium of Eosinophilic Gastrointestinal Researchers), DBV Technologies, DBV, Aimmune Therapeutics, Regeneron Pharmaceuticals, and Allergenis. G. T. Furuta is chief medical officer at EnteroTrack; consultant for Shire/Takeda; and has received grant funding from Arena and Holoclara. S. Gupta is consultant/data safety and monitoring board member or author for Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate; and has received research support from Allakos, Ellodi, and AstraZeneca. P. Khoury has received research funding from American Partnership for Eosinophilic Disorders. K. A. Peterson is consultant or served as advisor for AGA, Alladapt, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Lucid, Nexstone, Peerview, Regeneron, Takeda, and WebMD; has received research support from AstraZeneca, Allakos, Adare, Regeneron-Sanofi, and Revolo; served as speaker for AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; received grant support (unrestricted) from Allakos and Chobani; and holds equity in Nexeos Bio. E. T. Jensen has received consultant fees from Regeneron, Jazz Pharmaceuticals, and TARGET-RWE. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

Although eosinophilic gastrointestinal diseases, including eosinophilic esophagitis, have been described over the past 2 to 3 decades, barriers to diagnosis and treatment are common and compounded by issues related to social determinants of health, race, ethnicity, and access to care. These barriers contribute to delays in diagnosis, resulting in persistent inflammation in the gastrointestinal tract, which can have significant consequences, including fibrostenotic complications in adults, failure to thrive in children, and decreased quality of life in all affected patients. In this commentary, we summarize gaps in knowledge regarding the epidemiology of eosinophilic gastrointestinal diseases, highlight barriers to diagnosis, discuss potential approaches based on best practices in other atopic and chronic gastrointestinal diseases, and provide recommendations for reducing barriers to timely diagnosis of eosinophilic gastrointestinal diseases in underserved populations., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Introduction: Eosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4 + T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing., Methods: In this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus., Results: Our results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4 + T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4 + and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4 + T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE., Discussion: Herein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gruden, Kienzl, Ristic, Kindler, Kaspret, Schmid, Kargl, Sturm, Doyle, Wright, Baumann-Durchschein, Konrad, Blesl, Schlager and Schicho.)

Background: Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored., Objective: We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE., Methods: We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation., Results: RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6)., Conclusions: These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1 + esophageal epithelial cells with the proinflammatory and epithelial remodeling response in EoE., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease requiring maintenance therapy. Traditionally, EoE has been a contraindication to oral immunotherapy (OIT) and a rationale for discontinuing treatment because OIT may induce EoE. Most, but not all patients with OIT-induced EoE experience symptom resolution and histologic remission after discontinuing OIT. Recent studies report OIT continuation even after EoE onset, despite the previously accepted standard of care. This creates clinical as well as ethical challenges for allergists treating these patients. Considering the published literature on EoE and OIT and the primary medical ethics principles of beneficence, nonmaleficence, autonomy, and justice, we discuss the ethical implications of pursuing desensitization despite the potential complications associated with EoE. When ethical principles are in opposition, shared decision-making should be employed to determine whether OIT should be continued after an EoE diagnosis. This article highlights the ethical dilemmas allergists face when determining whether patients with a diagnosis of EoE should continue OIT., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-β, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.

In response to the social inequities that exist in health care, the NIH-funded Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee to examine systemic racism and implicit bias in the care and research of eosinophilic gastrointestinal diseases (EGIDs). Herein, we describe our process, highlighting milestones and issues addressed since the committee's inception, which we hope will inspire other researchers to enhance diversity, equity, inclusion, and accessibility (DEIA) in their fields. Our journey began by establishing mission and vision statements to define the purpose of the committee. Regular discussion of diversity-related topics was incorporated into existing meetings and web-based materials were shared. This was followed by educational initiatives, including establishing a library of relevant publications and a speaker series to address DEIA topics. We then established a research agenda focused on the following actionable items: (1) to define what is known about the demographics of EGIDs by systematic review of population-based studies; (2) to develop a practical tool for reporting participant demographics to reduce bias in EGID literature; (3) to examine health disparities in the care of individuals with eosinophilic esophagitis who present to the emergency department with an esophageal food impaction; (4) to examine how access to a gastroenterologist affects the conclusions of published research examining the prevalence of pediatric eosinophilic esophagitis; and (5) to develop a model for examining the dimensions of diversity, and provide a framework for CEGIR's ongoing projects and data capture. In addition to promoting consciousness of DEIA, this initiative has fostered inclusivity among CEGIR members and will continue to inspire positive changes in EGID care and research., Competing Interests: MC received consultant fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Allakos, Shire/Takeda, Phathom, and received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Danone. GFuruta serves as CMO for EnteroTrack and received research funding from Arena/Pfizer, Holoclara, and NIH. JPA received payment or honoraria for lectures from Takeda Global Research and Development, participated on a Data Safety Monitoring Board for OctaPharma USA, Inc., and received grants or contracts from Cures Within Reach and Celgene. SA received consultant fees for Regeneron, AstraZeneca, Bristol Meyers Squibb, research funding from Implicit Biosciences, is co-inventor of oral viscous budesonide UCSD patent Takeda license, and received educational speaker fees from Sanofi/Genzyme, Regeneron. MHC received research funding from AstraZeneca, Ception, GlaxoSithKline, Meritage Pharma Inc., Receptos/Celgene/BMS, Regeneron Pharmaceuticals and Shire, a Takeda company, and is a consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc./Alimentiv, Inc. and Shire, a Takeda company. ESD received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda, consultant fees from Abbott, Abbvie, Adare/ Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio, and educational grants from Allakos, Holoclara, Invea. GFalk received consultant fees for Adare/Ellodi, Allakos, Bristol Myers Squibb/Celgene, Lucid, Nexstone, Phathom, Regeneron/Sanofi, Shire/Takeda, Upstream Bio, and research support from Adare/Ellodi, Allakos, Arena/Pfizer, Bristol Myers Squibb/Celgene, Lucid, Nexteos, Regeneron/Sanofi, Shire/Takeda. SG is a Consultant/DSMB member/author for Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate, and received research support from Allakos, Ellodi, AstraZeneca. ETJ received consulting fees for Regeneron Pharmaceuticals and Jazz Pharmaceuticals. PK received funding from APFED. DM has received past honoraria from GSK for awareness activities unrelated to this publication and/or disease state. MR is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, Bristol Myers Squibb, Astra Zeneca, Ellodi Pharma, GlaxoSmith Kline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first seven listed, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. MR is an inventor of patents owned by Cincinnati Children’s Hospital. JS received grant support from Regeneron/Sanofi, Novartis, NIH, FARE, consulting fees from Regeneron, Sanofi, Alladapt, Readysetfood, ARS Pharmacy, and royalties from Uptodate. ABM received research funding from Morphic and served on medical advisory board for Bristol Myers Squib and Nextone Immunology. VM received consultant fees from Allakos, Regeneron, Sanofi, and Shire/Takeda, and served on an adjudication board for Alladapt. CD received research funding from DBV Technologies, Food Allergy Research and Education, Allergenis, Regeneron Pharmaceuticals, Pfizer, and consultant or advisory board fees for Aimmune Therapeutics. JBW has received consultant fees from Allakos, Ellodi, Regeneron, Sanofi/Genzyme, AstraZeneca, and Invea Therapeutics, and clinical trial/research funding from Allakos, Invea Therapeutics, and Sanofi-Regeneron. BLW, DDB, AK, GE, GH, KK, EK, SKyle, PM, PM-K, CS, MJS, G-YY, KS, NM, SKesh, PB, MS, AZ, AP, AH, and GF have no conflicts of interest to declare., (© The Author(s), 2023.)

Background: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined., Objective: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro., Methods: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of type 2 airway inflammation, such as inhalation of IL-33. Eosinophil-specific IL-4/13-deficient mice were used to address the specific roles for eosinophil-derived cytokines. Direct cell interactions between ILC2s and eosinophils were assessed by in vitro culture experiments., Results: Targeted depletion of eosinophils resulted in significant reductions of total and IL-5 + and IL-13 + lung ILC2s in all models of respiratory inflammation. This correlated with reductions in IL-13 levels and mucus in the airway. Eosinophil-derived IL-4/13 was necessary for both eosinophil and ILC2 accumulation in lung in allergen models. In vitro, eosinophils released soluble mediators that induced ILC2 proliferation and G protein-coupled receptor-dependent chemotaxis of ILC2s. Coculture of ILC2s and IL-33-activated eosinophils resulted in transcriptome changes in both ILC2s and eosinophils, suggesting potential novel reciprocal interactions., Conclusion: These studies demonstrate that eosinophils play a reciprocal role in ILC2 effector functions as part of both adaptive and innate type 2 pulmonary inflammatory events., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The prevalence and incidence of allergic disease have been rising in Westernized countries since the twentieth century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease., Recent Findings: Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release. Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Since the onset of the COVID-19 pandemic, economic crisis, and persistent systemic and structural racism have plagued Black communities. The continued physical and symbolic violence and murders of Black bodies are undeniable. As White institutions, schools are definite contributors to this brutality as they center the culture and realities of White children while ignoring or denigrating Black children. This is even evident in the undermining of Black families' efforts to prepare their children to face the inequities and injustices they experience in the U.S. In this article, we discuss Black families' engagement in their children's education amid threats through racial socialization research aimed at developing and validating Black children's perspectives, experiences, and realities in Black identity to promote their positive social-emotional and psychological development. Black families must know how to cultivate their child's healthy self-identity, voice, and agency, along with academic achievement. Schools should learn from these practices. Schools that choose to ignore these concepts will continue contributing to trauma and violence against Black children and maintain deficit-oriented views. The article includes examples and implications for teaching and supporting the well-being of Black children, and concludes with practical ideas that educators can learn from and integrate into their practices., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Food-specific immunoglobulin G4 (FS-IgG4) is associated with eosinophilic esophagitis (EoE); however, it is not clear whether production is limited to the esophagus., Aims: To assess FS-IgG4 levels in the upper gastrointestinal tract and plasma and compare these with endoscopic disease severity, tissue eosinophil counts, and patient-reported symptoms., Methods: We examined prospectively banked plasma, throat swabs, and upper gastrointestinal biopsies (esophagus, gastric antrum, and duodenum) from control (n = 15), active EoE (n = 24), and inactive EoE (n = 8) subjects undergoing upper endoscopy. Patient-reported symptoms were assessed using the EoE symptom activity index (EEsAI). Endoscopic findings were evaluated using the EoE endoscopic reference score (EREFS). Peak eosinophils per high-power field (eos/hpf) were assessed from esophageal biopsies. Biopsy homogenates and throat swabs were normalized for protein content and assessed for FS-IgG4 to milk, wheat, and egg., Results: Median FS-IgG4 for milk and wheat was significantly increased in the plasma, throat swabs, esophagus, stomach, and duodenum of active EoE subjects compared to controls. No significant differences for milk- or wheat-IgG4 were observed between active and inactive EoE subjects. Among the gastrointestinal sites sampled, FS-IgG4 levels were highest in the esophagus. Esophageal FS-IgG4 for all foods correlated significantly across all sites sampled (r ≥ 0.59, p < 0.05). Among subjects with EoE, esophageal FS-IgG4 correlated significantly with peak eos/hpf (milk and wheat) and total EREFS (milk). EEsAI scores and esophageal FS-IgG4 levels did not correlate., Conclusions: Milk and wheat FS-IgG4 levels are elevated in plasma and throughout the upper gastrointestinal tract in EoE subjects and correlate with endoscopic findings and esophageal eosinophilia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation., Methods: Immortalized esophageal epithelial cells (EPC2) were cultured in air-liquid interface (ALI) and exposed to SDS. Barrier function/activity was assessed by transepithelial electrical resistance (TEER), FITC-dextran flux, and RT-PCR. Additionally, SDS-treated mouse esophageal organoids were evaluated for morphology. To investigate the effects of SDS in vivo, mice were treated with 0.5% SDS in drinking water for 14 days. Esophagi were assessed by gross morphology, histopathology, protein expression, and bulk RNA sequencing., Results: When EPC2 cells were exposed to SDS (5 μg/ml) for 96 h, TEER decreased (p = 0.03), and FITC-dextran flux increased (p = 0.0002). mRNA expression of IL-33 increased 4.5-fold (p = 0.02) at 6 h and DSG1 decreased (p < 0.0001) by 72 h. Disrupted epithelial integrity was noted in SDS-treated esophageal organoids. When mice were exposed to SDS, they showed increased esophageal width, chemokine, and metalloprotease levels. Mice treated with SDS also showed increased IL-33 protein expression, basal zone hyperplasia, CD4 + cell infiltration, and esophageal eosinophilia. RNA sequencing revealed upregulation of immune response pathway genes., Conclusion: Exposure to SDS decreases esophageal barrier integrity, stimulates IL-33 production, and promotes epithelial hyperplasia and tissue eosinophilia. Detergents may be a key environmental trigger in EoE pathogenesis., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Eosinophilic esophagitis (EoE) is a chronic allergy-mediated condition with an increasing incidence in both children and adults. Despite EoE's strong impact on human health and welfare, there is a large unmet need for treatments with only one recently FDA-approved medication for EoE. The goal of this study was to establish swine as a relevant large animal model for translational biomedical research in EoE with the potential to facilitate development of therapeutics. We recently showed that after intraperitoneal sensitization and oral challenge with the food allergen hen egg white protein (HEWP), swine develop esophageal eosinophilia-a hallmark of human EoE. Herein, we used a similar sensitization and challenge treatment and evaluated immunological and pathological markers associated with human EoE. Our data demonstrate that the incorporated sensitization and challenge treatment induces (i) a systemic T-helper 2 and IgE response, (ii) a local expression of eotaxin-1 and other allergy-related immune markers, (iii) esophageal eosinophilia (>15 eosinophils/0.24 mm 2 ), and (iv) esophageal endoscopic findings including linear furrows and white exudates. Thereby, we demonstrate that our sensitization and oral challenge protocol not only induces the underlying immune markers but also the micro- and macro-pathological hallmarks of human EoE. This swine model for EoE represents a novel relevant large animal model that can drive translational biomedical research to develop urgently needed treatment strategies for EoE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Cortes, Brodsky, Chen, Pridgen, Odle, Snider, Cruse, Putikova, Masuda, Doyle, Wright, Dawson, Blikslager, Dellon, Laster and Käser.)

Background & Aims: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature., Methods: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement., Results: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When &gt;2 GI tract areas are involved, the name should reflect all of the involved areas., Conclusions: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: We aimed to assess the diagnostic utility of eosinophil peroxidase (EPX) staining on Cytosponge (CS) samples in eosinophilic esophagitis (EoE)., Methods: Esophageal biopsy (BX) samples from adult subjects with EoE were assessed using peak eosinophils per high-power field (eos/hpf), EPX, and the EoE histologic scoring system. EPX staining and eos/hpf were compared (BX vs CS)., Results: CS EPX positivity correlated with eos/hpf (CS [ r = 0.82, P < 0.0001]; BX [ r = 0.65, P < 0.0001]) and EoE histologic scoring system (grade [ r = 0.62, P < 0.00001]; stage [ r = 0.61, P < 0.0001]). CS EPX identified subjects with active EoE (area under the curve = 0.86, P < 0.0001)., Discussion: The correlation of CS EPX with eosinophilic inflammation and histologic disease severity supports its diagnostic utility in EoE., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Purpose: The incidence of severe combined immunodeficiency (SCID) in the USA was reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn screening would identify two to four cases of SCID per year. This estimate did not consider ethnic nuances in Arizona, with higher percentages of Native American and Hispanic populations compared to national percentages. The true incidence of SCID and non-SCID T cell lymphopenia has not previously been reported in Arizona., Methods: A retrospective chart review was performed on all abnormal SCID newborn screening (NBS) tests in Arizona from January 1, 2018, to December 31, 2019, using data from the Arizona Department of Health Services and the Phoenix Children's Hospital's electronic medical record [IRB# 20-025]., Results: Seven infants were diagnosed with SCID, yielding an incidence of 1 in 22,819 live births. Four of these infants had Artemis-type SCID. Thirteen infants were identified with an abnormal initial NBS which ultimately did not lead to a diagnosis of SCID. Four of these infants were diagnosed with congenital syndromes associated with T cell lymphopenia. Infants of Hispanic ethnicity were over-represented in this cohort., Conclusion: Over 2 years, NBS in Arizona confirmed an incidence more than 2.5 times that reported nationally. This increased incidence is likely reflective of Arizona's unique population profile, with a higher percentage of Native American population. The findings in our non-SCID cohort are in alignment with previously published data, except for an increased percentage of infants of Hispanic/Latino ethnicity, possibly reflecting Arizona's increased percentage of Hispanic/Latino population compared to the general US population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Diagnosis of non-esophageal eosinophilic gastrointestinal disorders requires quantification of tissue eosinophils. Our objective was to evaluate eosinophil peroxidase (EPX) immunohistochemistry (IHC) as a method for histologic diagnosis of eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD)., Methods: We performed a retrospective analysis of biopsies from pediatric EG/EoD cases and controls. Subjects with EG or EoD had ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpf in the stomach and/or ≥3 hpf in the duodenum, respectively. Controls had no histopathologic diagnosis recorded. Tissue eosinophil counts were assessed by hematoxylin & eosin stains. EPX stains were assessed using a unique histopathologic scoring system. Slides were digitized and EPX+ staining area/mm 2 was quantified by image analysis., Results: Twenty-six EG/EoD cases and 40 controls were analyzed. EPX scores and EPX/mm 2 levels were markedly elevated in EG/EoD (p ≤ 0.0001). Eosinophil density (eos/mm 2 ) correlated strongly with EPX scores and EPX/mm 2 levels in the stomach (r ≥ 0.77) and moderately with EPX scores and EPX/mm 2 levels in the duodenum (r ≥ 0.52); (p < 0.0001). EPX quantification identified EG/EoD subjects with high diagnostic accuracy (EPX score: AUC = 1 for EG and EoD; EPX/mm 2 : AUC = 0.98 (95%CI 0.96-1) for EG, AUC = 0.91 (95%CI 0.81-1) for EoD)., Conclusion: EPX-based assessment of eosinophilic inflammation may facilitate automated histologic diagnosis.

Background & Aims: Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time., Methods: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis., Results: At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia., Conclusions: In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E mediated food allergy that typically presents with repetitive emesis and may be associated with lethargy, marked pallor, hypotension, hypothermia, and/or diarrhea. Although many foods are known to cause FPIES, peanut-triggered FPIES is emerging due to changes in the feeding practice guidelines, which recommends early peanut introduction in infants., Objective: We aimed to characterize peanut-triggered acute FPIES cases in our pediatric population and to describe their attributes, treatment, and outcomes. We hypothesized that increases in the incidence of peanut-triggered FPIES coincided with implementation of the guidelines for early peanut introduction., Methods: A retrospective chart review was conducted of pediatric patients who presented to Phoenix Children's Hospital Emergency Department and subspecialty clinics during a 6-year period (January 2013 to September 2019)., Results: Thirty-three cases of patients with acute FPIES were identified, five of which were peanut triggered. In those patients with peanut-triggered FPIES, the median age for peanut introduction was 7 months (range, 5-24 months). Two patients had positive peanut skin-prick test results. All five cases were identified in the past 2 years (2018 to 2019). No peanut-triggered reactions were documented in the preceding 4-year period (2013 to 2017)., Conclusion: Peanut may be an emerging trigger of acute FPIES, coinciding with an earlier introduction of peanut in the infant diet after implementation of the new addendum guidelines for the prevention of peanut allergy. Oats and rice were the most common triggers of acute FPIES in our cohort. Further study will help clarify the significance and reproducibility of these findings., Competing Interests: The authors have no conflicts of interest to declare pertaining to this article. Catherine M. Freeman and Juan Carlos Murillo are co-first authors, (Copyright © 2021, The Author(s). Published by OceanSide Publications, Inc., U.S.A.)

Background: Diagnosis of eosinophilic esophagitis (EoE) requires manual quantification of tissue eosinophils. Eosinophil peroxidase (EPX) is an eosinophil-specific, cytoplasmic granule protein released during degranulation., Aims: The objective of this study was to evaluate image analysis of EPX immunohistochemistry as an automated method for histologic diagnosis of EoE., Methods: We performed a secondary analysis of prospectively collected esophageal biopsies obtained from adult subjects with EoE and controls. Tissue sections were stained with hematoxylin and eosin (H&E) and evaluated for peak eosinophils per high power field (eos/hpf). The same slides were de-stained and re-stained to detect EPX for direct comparison. Slides were digitized, and EPX staining area/mm 2 was quantified using image analysis. Paired samples were compared for changes in EPX staining in treatment responders and non-responders., Results: Thirty-eight EoE cases and 49 controls were analyzed. Among EoE subjects, matched post-treatment biopsies were available for 21 responders and 10 non-responders. Baseline EPX/mm 2 was significantly increased in EoE subjects and decreased in treatment responders. EPX quantification correlated strongly with eos/hpf (r = 0.84, p < 0.0001) and identified EoE subjects with high diagnostic accuracy (AUC 0.95, p < 0.0001). The optimal diagnostic EPX-positive pixel/area threshold was 17,379 EPX/mm 2 . Several controls (5/49) with < 15 eos/hpf on H&E staining exceeded this cutoff., Conclusions: EPX/mm 2 correlates strongly with eos/hpf, accurately identifies subjects with EoE, and decreases in treatment responders. Automated quantification of intact eosinophils and their degranulation products may enhance pathologic assessment. Future studies are needed to correlate EPX/mm 2 with symptoms, endoscopic findings, and esophageal distensibility.

As the awareness among gastroenterologists regarding endoscopic features suggesting eosinophilic esophagitis is increasing, individuals without symptoms of esophageal dysfunction are increasingly being found to have esophageal eosinophilia on biopsies performed during upper gastrointestinal endoscopies. However, the course of disease and the management of these asymptomatic individuals with esophageal eosinophilia remain elusive. In this review, we propose a definition of asymptomatic individuals with esophageal eosinophilia and discuss the prevalence, risk factors, and course of disease of this specific patient group. Furthermore, we have established a diagnostic and therapeutic pathway based on the most recent available data., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Eosinophilic esophagitis (EoE) is an antigen-driven disease associated with epithelial barrier dysfunction and chronic type 2 inflammation. Eosinophils are the defining feature of EoE histopathology but relatively little is known about their role in disease onset and progression. Classically defined as destructive, end-stage effector cells, eosinophils (a resident leukocyte in most of the GI tract) are increasingly understood to play roles in local immunity, tissue homeostasis, remodeling, and repair. Indeed, asymptomatic esophageal eosinophilia is observed in IgE-mediated food allergy. Interestingly, EoE is a potential complication of oral immunotherapy (OIT) for food allergy. However, we recently found that patients with peanut allergy may have asymptomatic esophageal eosinophilia at baseline and that peanut OIT induces transient esophageal eosinophilia in most subjects. This is seemingly at odds with multiple studies which have shown that EoE disease severity correlates with tissue eosinophilia. Herein, we review the potential role of eosinophils in EoE at different stages of disease pathogenesis. Based on current literature we suggest the following: (1) eosinophils are recruited to the esophagus as a homeostatic response to epithelial barrier disruption; (2) eosinophils mediate barrier-protective activities including local antibody production, mucus production and epithelial turnover; and (3) when type 2 inflammation persists, eosinophils promote fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Doyle, Masuda, Kita and Wright.)

Objectives: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy., Methods: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index)., Results: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 (P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively)., Discussion: We successfully developed a new testing approach using CD4 T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro , that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD., Competing Interests: Conflict of interest: A.D. Doyle reports grants from NIH (F31HL124959), donor money paid to the Mayo Clinic from Donald R. Levin Family Foundation, and a scholarship at the Mayo Clinic from Mayo Clinic Sidney Luckman Family Predoctoral Fellowship, during the conduct of the study. Conflict of interest: M. Mukherjee has nothing to disclose. Conflict of interest: W.E. LeSuer has nothing to disclose. Conflict of interest: T.B. Bittner has nothing to disclose. Conflict of interest: S.M. Pasha has nothing to disclose. Conflict of interest: J.J. Frere has nothing to disclose. Conflict of interest: J.L. Neely has nothing to disclose. Conflict of interest: J.A. Kloeber has nothing to disclose. Conflict of interest: K.P. Shim has nothing to disclose. Conflict of interest: S.I. Ochkur has nothing to disclose. Conflict of interest: T. Ho has nothing to disclose. Conflict of interest: S. Svenningsen has nothing to disclose. Conflict of interest: B.L. Wright reports donor money paid to the Mayo Clinic from Donald R. Levin Family Foundation, during the conduct of the study. Conflict of interest: M.A. Rank has nothing to disclose. Conflict of interest: J.J. Lee received grants from NIH (HL058723), NIH NCRR (K26 RR0109709) and the Mayo Foundation for Medical Education and Research, during the conduct of this study; J.J. Lee is deceased and this statement was made on behalf of the author by the corresponding author. Conflict of interest: P. Nair reports grants and personal fees for consultancy and lecturing from AstraZeneca and Teva, grants from Boehringer Ingelheim, grants and personal fees for lecturing from Novartis, grants and personal fees for consultancy from Sanofi and GSK, and personal fees for consultancy from Theravance and Knopp, outside the submitted work. Conflict of interest: E.A. Jacobsen reports grants from NIH (HL065228), and donor money paid to the Mayo Clinic from Donald R. Levin Family Foundation, during the conduct of the study., (Copyright ©ERS 2019.)

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE.