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Normodense human peripheral blood eosinophils were isolated under sterile conditions from the 22/23 and 23/24% interfaces and the cell pellet of metrizamide gradients. After culture for 7 d in RPMI media in the presence of 50 pM biosynthetic (recombinant) human granulocyte/macrophage colony-stimulating factor (rH GM-CSF), 43 +/- 7% (mean +/- SEM, n = 8) of the cells were viable; in the absence of rH GM-CSF, no eosinophils survived. The rH GM-CSF-mediated viability was concentration dependent; increased survival began at a concentration of 1 pM, a 50% maximal response was attained at approximately 3 pM, and a maximal effect was reached at concentrations of greater than or equal to 10 pM rH GM-CSF. In the presence of rH GM-CSF and mouse 3T3 fibroblasts, 67 +/- 6% (mean +/- SEM, n = 8) of the eosinophils survived for 7 d. In a comparative analysis, there was no difference in eosinophil viability after 7 and 14 d (n = 3) in the presence of 50 pM GM-CSF and fibroblasts. Culture with fibroblasts alone did not support eosinophil survival. The addition of fibroblast-conditioned media to rH GM-CSF did not further improve eosinophil viability, indicating a primary role for GM-CSF in supporting these eosinophil cell suspensions ex vivo and a supplementary role for 3T3 fibroblasts. Eosinophils cultured for 7 d localized on density gradient sedimentation at the medium/18, 18/20, and 20/21 interfaces of metrizamide gradients, indicating a change to the hypodense phenotype from their original normodense condition. In addition, the cultured eosinophils generated approximately 2.5-fold more LTC4 than freshly isolated cells when stimulated with the calcium ionophore A23187 and manifested sevenfold greater antibody-dependent killing of S. mansoni larvae than the freshly isolated, normodense cells from the same donor. Thus we demonstrate the rH GM-CSF dependent conversion in vitro of normodense human eosinophils to hypodense cells possessing the augmented biochemical and biological properties characteristic of the hypodense eosinophils associated with a variety of hypereosinophilic syndromes. In addition, these studies provide a culture model of at least 14 d suitable for the further characterization of hypodense eosinophils.

Rationale: Despite ongoing research, the molecular mechanisms controlling asthma are still elusive. CD48 is a glycosylphosphatidylinositol-anchored protein involved in lymphocyte adhesion, activation, and costimulation. Although CD48 is widely expressed on hematopoietic cells and commonly studied in the context of natural killer and cytotoxic T cell functions, its role in helper T cell type 2 settings has not been examined.Objectives: To evaluate the expression and function of CD48, CD2, and 2B4 in a murine model of allergic eosinophilic airway inflammation.Methods: Allergic eosinophilic airway inflammation was induced by ovalbumin (OVA)-alum sensitization and intranasal inoculation of OVA or, alternatively, by repeated intranasal inoculation of Aspergillus fumigatus antigen in wild-type, STAT (signal transducer and activator of transcription)-6-deficient, and IL-4/IL-13-deficient BALB/c mice. Gene profiling of whole lungs was performed, followed by Northern blot and flow cytometric analysis. Anti-CD48, -CD2, and -2B4 antibodies were administered before OVA challenge and cytokine expression and histology were assessed.Measurements and Main Results: Microarray data analysis demonstrated upregulation of CD48 in the lungs of OVA-challenged mice. Allergen-induced CD48 expression was independent of STAT-6, IL-13, and IL-4. Neutralization of CD48 in allergen-challenged mice abrogated bronchoalveolar lavage fluid and lung inflammation. Neutralization of CD2 inhibited the inflammatory response to a lesser extent and neutralization of 2B4 had no effect.Conclusions: Our results suggest that CD48 is critically involved in allergic eosinophilic airway inflammation. As such, CD48 may provide a new potential target for the suppression of asthma. [ABSTRACT FROM AUTHOR]

Summary T helper (Th)-2-derived cytokines and their involvement in the recruitment and activation of inflammatory cells crucially orchestrate asthma pathogenesis. A notable cellular component of this allergy-induced inflammation is the eosinophil. However, whether the eosinophil is an obligatory mediator for enhancing airways hyperreactivity (AHR) to cholinergic stimuli, a watershed of the asthmatic lung, is somewhat controversial. In this investigation we have endeavoured to define the spatial requirements for IL-4 and IL-13, and the downstream effector molecules, IL-5 and the CC chemokine eotaxin, for the recruitment of eosinophils and the development of AHR in a murine model of allergic pulmonary disease. These studies are of particular importance considering clinical trials, with either the soluble IL-4Rα subunit or a humanized anti-IL-5 antibody, are being conducted. Interestingly, our studies show that depletion of both IL-4 and IL-13 is necessary to ablate pulmonary eosinophilia and AHR, and that this may be attributed to the role these cytokines play in regulating the expression of the eosinophil- activating molecules, IL-5 and eotaxin. While it is clear that depletion of IL-5 diminishes pulmonary eosinophilia, we demonstrate in BALB/c mice that a deficiency in both IL-5 and eotaxin is necessary to abolish both the trafficking of eosinophils to the lung and AHR. However, in contrast to the neutrophil-rich inflammation observed in mice deficient in both IL-4 and IL-13, inflammation per se in mice deficient in both IL-5 and eotaxin is significantly attenuated. This suggests that asthma immunotherapy may be better directed towards the eosinophil- activating molecules IL-5 and eotaxin, rather than towards pleiotrophic molecules such IL-4 and IL-13, which are additionally important in modulating alternative inflammatory responses. [ABSTRACT FROM AUTHOR]

Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis, are not well understood. Herein, we report an ex vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant proinflammatory (IL-13) or profibrotic (TGF-β) cytokines. Compared with untreated cocultures, IL-13 increased expression of CD69 on eosinophils, whereas TGF-β increased expression of CD81, CD62L, and CD25. Eosinophils from IL-13-treated cocultures demonstrated increased secretion of GRO-α, IL-8, and macrophage colony-stimulating factor and also generated increased extracellular peroxidase activity following activation. Eosinophils from TGF-β-treated cocultures secreted increased IL-6 and exhibited increased chemotactic response to CCL11 compared with eosinophils from untreated or IL-13-treated coculture conditions. When eosinophils from TGF-β-treated cocultures were cultured with fibroblasts, they upregulated SERPINE1 expression and fibronectin secretion by fibroblasts compared with eosinophils that were cultured with granulocyte macrophage colony-stimulating factor alone. Translational studies revealed that CD62L was heterogeneously expressed by eosinophils in patient biopsy specimens. Our results demonstrate that disease-relevant proinflammatory and profibrotic signals present in the esophagus of patients with eosinophilic esophagitis cause distinct profiles of eosinophil activation and gene expression., Competing Interests: Conflict of interest statement. M.E.R. is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, Astra Zeneca, Pfizer, GlaxoSmith Kline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first 9 listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. M.E.R. is an inventor of patents owned by Cincinnati Children's Hospital., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Because young children cannot self-report symptoms, there is a need for parent surrogate reports. Although early work suggested parent-child alignment for eosinophil esophagitis (EoE) patient-reported outcomes (PROs), the longitudinal alignment is unclear., Objective: We sought to assess the agreement and longitudinal stability of PROs between children with EoE and their parents., Methods: A total of 292 parent-child respondents completed 723 questionnaires over 5 years in an observational trial in the Consortium of Eosinophilic Gastrointestinal Disease Researchers. The change in and agreement between parent and child Pediatric Eosinophilic Esophagitis Symptom Score version 2 (PEESSv2.0) and Pediatric Quality of Life Eosinophilic Esophagitis Module (PedsQL-EoE) PROs over time were assessed using Pearson correlation and Bland-Altman analyses. Clinical factors influencing PROs and their agreement were evaluated using linear mixed models., Results: The cohort had a median disease duration equaling 3.7 years and was predominantly male (73.6%) and White (85.3%). Child and parent PEESSv2.0 response groups were identified and were stable over time. There was strong correlation between child and parent reports (PEESSv2.0, 0.83;PedsQL-EoE, 0.74), with minimal pairwise differences for symptoms. Longitudinally, parent-reported PedsQL-EoE scores were stable (P ≥ .32), whereas child-reported PedsQL-EoE scores improved (P = .026). A larger difference in parent and child PedsQL-EoE reports was associated with younger age (P < .001), and differences were driven by psychosocial PRO domains., Conclusions: There is strong longitudinal alignment between child and parent reports using EoE PROs. These data provide evidence that parent report is a stable proxy for objective EoE symptoms in their children., Competing Interests: Disclosure statement CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is funded through a collaboration between NIAID, the National Institute of Diabetes and Digestive and Kidney Diseases, and NCATS and funded in part by the Division of Intramural Research, NIAID. CEGIR is also supported by patient advocacy groups including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Diseases, and Eosinophilic Family Coalition. As a member of the Rare Disease Clinical Research Network, CEGIR is supported by its Data Management and Coordinating Center (grant no. U2CTR002818). Funding support for the Data Management and Coordinating Center is provided by NCATS and the National Institute of Neurological Disorders and Stroke. G.S.H. is supported by a grant from the National Institutes of Health (NIH) (grant no. K23 DK131341). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first 9 listed; receives royalties from Teva Pharmaceuticals (reslizumab), Mapi Research Trust (PEESSv2.0), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital. J. M. Spergel is a consultant for ReadySetfood, Regeneron/Sanofi, and ARS Pharma; has grant support from Novartis, Regeneron/Sanofi, Bristol Myers Squibb, Food Allergy Research and Education (FARE), and NIH; receives royalties from UpToDate; and serves on the Data Safety and Monitoring Board for Alladapt and NIAID. M. H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, Robarts Clinical Trials, Inc/Alimentiv, Inc, and Shire/Takeda. S. S Aceves is a consultant and an educational speaker for Regeneron/Sanofi; has grant support from the NIH, Campaign Urging Research for Eosinophilic Diseases, Bristol Myers Squibb, and Implicit Biosciences; and is a coinventor of oral viscous budesonide patented by the University of California San Diego and licensed by Takeda. M. Pletneva is a consultant for Allakos. S. K. Gupta is a consultant and/or Data Safety and Monitoring Board member for Adare, Bristol Myers Squibb, QOL, Takeda, Medscape, PVI, ViaSkin, and UpToDate; and receives research support from Allakos, Ellodi, and AstraZeneca. J. B. Wechsler is a consultant for Bristol Myers Squibb, Ellodi, AstraZeneca, Allakos, and Regeneron/Sanofi; and receives research support from Regeneron. N. Gonsalves is a consultant for AstraZeneca, Allakos, Sanofi/Regeneron, AbbVie, Knopp, and Bristol Myers Squibb; is on the speaker bureau for Sanofi/Regeneron; and receives publication royalties from UpToDate. G. W. Falk is a consultant for Allakos, Bristol Myers Squibb/Celgene, Adare/Ellodi, Nexstone, Upstream Bio, and Sanofi/Regeneron; and receives research support from Allakos, Adare/Ellodi, Bristol Myers Squibb/Celgene, and Regeneron/Sanofi. I. Hirano has received research funding from Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, AstraZeneca, Meritage Pharma, Inc, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, and Shire/Takeda; and is a consultant for Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, Arena Pharmaceuticals, Aslan Pharmaceuticals, AstraZeneca, Calyx/Parexel, Celldex Therapeutics, Inc, Dermavant, EsoCap Biotech, Gossamer Bio, Eli Lilly, Nexstone, Meritage Pharma, Inc, Phathom Pharmaceuticals, Receptos/Celgene/Bristol Myers Squibb, Sanofi/Regeneron Pharmaceuticals, and Shire/Takeda. M. Chehade has received consultant fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Allakos, Shire/Takeda, and Phathom; and has received research support from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. C. M. Davis has received grant funding from DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, and Allergenis. E. S. Dellon is a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolo, and Shire/Takeda; and has received an educational grant from Allakos, Aqilion, Holoclara, and Invea. G. T. Furuta is Chief Medical Officer for EnteroTrack; and receives research funding from Arena/Pfizer. 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.)

The interplay between genetic and environmental factors during pregnancy can predispose to inflammatory diseases postnatally, including eosinophilic esophagitis (EoE), a chronic allergic disease triggered by food. Herein, we examined the effects of amniotic fluid (AF) on esophageal epithelial differentiation and responsiveness to proallergic stimuli. Multiplex analysis of AF revealed the expression of 66 cytokines, whereas five cytokines including IL-4 and thymic stromal lymphopoietin (TSLP) were not detected. Several proinflammatory cytokines including TNFα and IL-12 were highly expressed in the AF from women who underwent preterm birth, whereas EGF was the highest in term birth samples. Exposure of esophageal epithelial cells to AF resulted in transient phosphorylation of ERK1/2 and the transcription of early response genes, highlighting the direct impact of AF on esophageal epithelial cells. In a three-dimensional spheroid model, AF modified the esophageal epithelial differentiation program and enhanced the transcription of IL-13-target genes, including CCL26 and CAPN14 , which encodes for a major genetic susceptibility locus for eosinophilic esophagitis. Notably, CAPN14 exhibited upregulation in spheroids exposed to preterm but not term AF following differentiation. Collectively, our findings call attention to the role of AF as a potential mediator of the intrauterine environment that influences subsequent esophageal disorders. NEW & NOTEWORTHY The interaction between amniotic fluid and the esophageal epithelium during pregnancy modifies esophageal epithelial differentiation and subsequent responsiveness to inflammatory stimuli, including interleukin 13 (IL-13). This interaction may predispose individuals to inflammatory conditions of the esophagus, such as eosinophilic esophagitis (EoE), in later stages of life.

Background: Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion., Objective: Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo., Methods: A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti-IL-5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines., Results: Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric T H 2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients., Conclusion: We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of T H 2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders., Competing Interests: Disclosure statement Supported by a grant from AstraZeneca. Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Uniquity Bio, Santa Ana Bio, EnZen Therapeutics, Bristol-Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint; has an equity interest in the first 9 of the aforementioned companies; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. V. A. Mukkada is a consultant for Takeda Sanofi, Regeneron, Phantom, and Allakos and serves on an adjudication board for Alladapt. M. H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso, Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc/Alimentiv Inc, and Shire, a Takeda company. The rest of 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.)

Atopic dermatitis (AD) is a chronic itchy inflammatory disease of the skin. Genetic studies have identified multiple risk factors linked to the disease; however, most of the studies have been derived from European and East Asian populations. The admixed African American (AA) genome may provide an opportunity to discovery ancestry-specific loci involved in AD susceptibility. Herein, we present joint analysis of ancestry and genotype effects followed by validation using differential gene expression analysis on AD using 726 AD-affected individuals and 999 non-AD control individuals from the AA population, genotyped using Multi-Ethnic Global Array (MEGA) followed by imputation using the Consortium on Asthma among African Ancestry Populations in the Americas (CAAPA) reference panel. The joint analysis identified two novel AD-susceptibility loci, rs2195989 in gene ANGPT1 (8q23.1) and rs62538818 in the intergenic region between genes LURAP1L and MPDZ (9p23). Admixture mapping (AM) results showed potential genomic inflation, and we implemented genomic control and identified five ancestry-of-origin loci with European ancestry effects. The multi-omics functional prioritization of variants in AM signals prioritized the loci SLAIN2, RNF39, and FOXA2. Genome-wide association study (GWAS) identified variants significantly associated with AD in the AA population, including SGK1 (rs113357522, odds ratio [OR] = 2.81), EFR3A (rs16904552, OR = 1.725), and MMP14 (rs911912, OR = 1.791). GWAS variants were common in the AA but rare in the European population, which suggests an African-ancestry-specific risk of AD. Four genes (ANGPT1, LURAP1L, EFR3A, and SGK1) were further validated using qPCR from AD and healthy skin. This study highlighted the importance of genetic studies on admixed populations, as well as local ancestry and genotype-ancestry joint effects to identify risk loci for AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) Study is a prospective, multicity, 6-month incidence study conducted from May 2020 to February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other National Institutes of Health-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics, and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5598 individuals, including 1913 principal participants (children), 1913 primary caregivers, 729 secondary caregivers, and 1043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research. Trial registration: ClinicalTrials.gov. Identifier: NCT04375761., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Background: Eosinophils are elusive cells involved in allergic inflammation. Single-cell RNA-sequencing (scRNA-seq) is an emerging approach to deeply characterize cellular properties, heterogeneity, and functionality., Objectives: We sought to comprehensively characterize the transcriptome and biological functions of human eosinophils at a site of severe allergic inflammation in the esophagus (ie, eosinophilic esophagitis [EoE])., Methods: We employed a gravity-based scRNA-seq methodology to sequence blood eosinophils from patients with EoE and control individuals compared to a reanalyzed public scRNA-seq dataset of human esophageal eosinophils of EoE patients. We used flow cytometry, immunostaining, and a stimulation assay to verify mRNA findings., Results: In total, scRNA-seq was obtained from 586 eosinophils (188 from blood [n = 6 individuals] and 398 from esophagus [n = 6 individuals]). The esophageal eosinophils were composed of a population of activated eosinophils (enriched in 659 genes compared with peripheral blood-associated eosinophils) and a small population of eosinophils resembling peripheral blood eosinophils (enriched in 62 genes compared with esophageal eosinophils). Esophageal eosinophils expressed genes involved in sensing and responding to diverse stimuli, most notably IFN-γ, IL-10, histamine and leukotrienes, and succinate. Esophageal eosinophils were most distinguished from other esophageal populations by gene expression of the receptors CCR3, HRH4, SUCNR1, and VSTM1; transcription factors CEBPE, OLIG1, and OLIG2; protease PRSS33; and the hallmark eosinophil gene CLC. A web of bidirectional eosinophil interactions with other esophageal populations was derived. Comparing esophageal eosinophils and mast cells revealed that esophageal eosinophils expressed genes involved in DNAX-activation protein-12 (also known as TYROBP) interactions, IgG receptor-triggered events, immunoregulation, and IL-10 signaling., Conclusions: In EoE, esophageal eosinophils exist as 2 populations, a minority population resembling blood eosinophils and the other population characterized by high de novo transcription of diverse sensing receptors and inflammatory mediators readying them to potentially intersect with diverse cell types., Competing Interests: Disclosure statement Funding for this study was derived from National Institutes of Health grant R01 AI045898 and the Campaign Urging Research for Eosinophilic Diseases (CURED) awarded to M.E.R. This project was supported in part by National Institutes of Health grant P30 DK078392 (Gene Expression Core, Research Flow Cytometry Core) of the Digestive Diseases Research Core Center in Cincinnati. Disclosure of potential conflict of interest: M.E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, Enzen Pharmaceuticals, Bristol Myers Squibb, Astra Zeneca, Pfizer, GlaxoSmith Kline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first 9 listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. M.E. Rothenberg is an inventor of patents owned by Cincinnati Children’s Hospital. 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.)

Background: A 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively affect quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy., Objective: We performed a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE., Methods: Patients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary end points were proportion experiencing histologic remission (<15 eosinophils per high-power field); change in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome (EoE diagnostic panel), and QoL scores; and predictors of remission., Results: Sixty-three patients were randomly assigned to 1FED (n = 38) and 4FED (n = 25). In 4FED versus 1FED, mean PEESS improved -25.0 versus -14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (-0.25 vs -0.29; P = .77), endoscopic reference score (-1.10 vs -0.58; P = .47), and QoL scores were similar between groups. The EoE transcriptome normalized in those with histologic response to both diets. Baseline peak eosinophil count predicted remission (odds ratio, 0.975 [95% confidence interval, 0.953-0.999], P = .04; cutoff ≤42 eosinophils per high-power field). The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496)., Conclusions: Although 4FED moderately improved symptoms compared with 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first-choice therapy for pediatric EoE, given its effects, tolerability, and relative simplicity., Competing Interests: Disclosure statement Funded through a Patient-Centered Outcomes Research Institute (PCORI) award (CER-1403-11593). The statements presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its board of governors, or its methodology committee. Additional funds for the study were provided by the Division of Allergy and Immunology at Cincinnati Children’s Hospital Medical Center. Disclosure of potential conflict of interest: J. P. Abonia has received payment or honoraria for lectures from Takeda Global Research and Development; has participated on a data safety monitoring board for OctaPharma USA Inc; and has received grants or contracts from Cures Within Reach and Celgene. S. S. Aceves has received consultant fees from Regeneron Pharmaceuticals, AstraZeneca, and Bristol Myers Squibb; has received research funding from Implicit Biosciences; is coinventor of oral viscous budesonide University of California, San Diego, patent Takeda license; and has received educational speaker fees from Sanofi/Genzyme and Regeneron Pharmaceuticals. K. E. Capocelli is employed by and has an equity interest in Alnylam. M. Chehade has served as a consultant for Regeneron Pharmaceuticals, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Nexstone Immunology, Allakos, Shire/Takeda, and Phathom; and has received research funding from Regeneron Pharmaceuticals, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Danone, and Bristol Myers Squibb. M. H. Collins 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/Takeda. E. S. Dellon is a consultant for 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, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and has received educational grants from Allakos, Aqilion, Holoclara, and Invea. G. T. Furuta serves as CMO for EnteroTrack LLC; and has received research funding from Arena/Pfizer, Holoclara, and the National Institutes of Health (NIH). S. K. Gupta is a consultant for Abbott, Allakos, Adare Pharmaceuticals, DBV Technologies, Gossamer Bio, QOL Medical, Medscape, Receptos/Celgene, and UpToDate; and has received research support from Shire/Takeda. J. Leung is a consultant for Adare, Eli Lilly, AbbVie, Genzyme, Regeneron, Sanofi, and Shire/Takeda; and has received research funding from Adare, Allakos, Celgene, Regeneron, AstraZeneca, and Shire/Takeda. V. A. Mukkada has received consulting fees from Allakos, Regeneron, Sanofi, and Shire/Takeda; has received honoraria for lectures from the American Gastroenterological Association; and serves on an adjudication board for Alladapt. R. D. Pesek is a consultant for Regeneron Pharmaceuticals. T. Shoda has funding from the NIH and is a coinventor of patents owned by Cincinnati Children’s Hospital Medical Center. J. M. Spergel has received grant support from Regeneron Pharmaceuticals/Sanofi, Novartis, the NIH, and Food Allergy Research and Education; is a consultant for Regeneron Pharmaceuticals, Sanofi, Alladapt, Readysetfood, and ARS Pharmacy; and has received royalties from UpToDate. J. B. Wechsler is a consultant for Allakos, Ellodi, Regeneron Pharmaceuticals, Sanofi/Genzyme, AstraZeneca, Celldex, and Invea Therapeutics; and has received clinical trial/research funding from Allakos, Invea Therapeutics, and Sanofi/Regeneron. M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, Astra Zeneca, Pfizer, GlaxoSmith Kline, Sanofi/Regeneron, Revolo Biotherapeutics, and Guidepoint; and has an equity interest in the first nine listed, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. M. E. Rothenberg is an inventor of patents owned by Cincinnati Children’s Hospital. The rest of 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.)

Background: Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven esophageal disorder. Connective tissue disorders (CTDs) and esophageal connective tissue alterations are associated with EoE. Therefore, angiotensin II type 1 receptor blockade with losartan, an accepted CTD treatment, is a potential EoE treatment., Objective: We evaluated losartan's effects on esophageal pathology, symptoms, and safety in patients with EoE with and without a CTD in an open-label, non-placebo controlled multisite study., Methods: Fifteen participants with EoE, aged 5 to 23 years, underwent treatment with per-protocol titrated doses of losartan in an open-label, 16-week pilot trial. Losartan was added to standard of care therapy and 14 patients completed the study. Eosinophil counts served as the primary end point, whereas we also assessed the EoE Histology Scoring System, Endoscopic Reference Scores, EoE Diagnostic Panel, and patient-reported outcomes., Results: Esophageal eosinophilia was not reduced after losartan. The peak eosinophil count was not reduced for the proximal (median [interquartile range]: -3 [-22 to 3]; P = .49) and distal esophagus (median [interquartile range]: -18 [-39 to -1]; P = .23). There were no differences in losartan response in EoE with or without CTD (n = 7 and 8, respectively). Regardless, in a small subset of four participants esophageal eosinophilia was resolved with a concomitant reduction in EoE Histology Scoring System score and Endoscopic Reference Score. Across all subjects, the Pediatric EoE Symptom Score, Pediatric Quality of Life Inventory EoE Module, and EoE Diagnostic Panel improved after losartan (P < .05)., Conclusions: Losartan treatment was associated with improved patient-reported outcome scores and EoE Diagnostic Panel biomarkers although without a reduction in esophageal eosinophilia overall. A subset of patients demonstrated improved histopathologic and endoscopic features that could not be tied to a specific feature predicting response to treatment., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE)., Objective: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both., Methods: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed., Results: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity., Conclusions: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation., Competing Interests: Disclosure statement Supported by National Institutes of Health (NIH) grant K99/R00 AI158660 (to T.S.) and the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR, U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is cofunded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and in part by the Intramural Research Program of NIAID. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (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 NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). This project was supported in part by NIH P30 DK078392 (Gene Expression Core, Pathology Research Core, and Confocal Imaging Core) of the Digestive Diseases Research Core Center in Cincinnati. Disclosure of potential conflict of interest: E. S. Dellon is consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Meyers Squibb (BMS), Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. E. S. Dellon has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and has received educational grants from Allakos, Holoclara, and Invea. S. S. Aceves is disease state awareness speaker and consultant for Sanofi/Regeneron, consultant for Ferring Pharma; has research funding from Implicit Biosciences and BMS; and is a coinventor of oral viscous budesonide UCSD patent, Takeda license. M. Chehade served as consultant for Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, BMS, Allakos, Shire/Takeda, Phathom, Recludix Pharma, Nexstone Immunology; and received research funding from Regeneron, Allakos, AstraZeneca, Adare/Ellodi, BMS, Danone, and Shire/Takeda. M. H. Collins is consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, BMS, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene, Regeneron Pharmaceuticals, Robarts Clinical Trials/Alimentiv, Sanofi, and Shire/Takeda. C. M. Davis receives research funding from the NIH/NIAID (U01AI126614, UM2AI130836, U54AI117804), DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, Takeda, and Allergenis. G. W. Falk is consultant for Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Ubiquity Bio, and Phathom Pharmaceuticals; and receives research funding from Arena/Pfizer, Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Allakos, Nexteos, and Celldex Therapeutics. G. T. Furuta receives research funding from Pfizer/Arena; is consultant for Sanofi/Regeneron and BMS; and is chief medical officer for EnteroTrack. N. P. Gonsalves is consultant for Allakos, AstraZeneca, BMS, and Sanofi/Regeneron; is speaker for Sanofi/Regeneron; and receives publication royalties from UpToDate. S. K. Gupta is consultant/data safety monitoring board member of Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate; and receives research funding from Allakos, Ellodi, and AstraZeneca. I. Hirano has received research funding from Ellodi/Adare, Allakos, Pfizer/Arena Pharmaceuticals, AstraZeneca, Meritage Pharma, Receptos/Celgene, Sanofi, Regeneron, and Shire/Takeda; and is is consultant for Ellodi/Adare, Allakos, AstraZeneca, BMS/Receptos/Celgene, Calyx/Parexel, EsoCap Biotech, Gossamer Bio, Lilly, Meritage Pharma, Pfizer/Arena Pharmaceuticals, Phathom, Sanofi/Regeneron, and Shire/Takeda. K. A. Peterson is consultant/advisory for AGA, Alladapt, AstraZeneca, Allakos, BMS, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, Takeda, and WebMD; receives research funding from AstraZeneca, Allakos, Regeneron-Sanofi, Revolo, Adare, Ellodi, BMS, and Celldex; is speaker for AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; has grant support (unrestricted) from Allakos; and has equity in Nexeos Bio. M. A. Pletneva is consultant for Allakos and Sanofi/Regeneron. J. M. Spergel is consultant for Novartis, Regeneron, and Sanofi; and receives grant support from Regeneron and Sanofi. J. B. Wechsler is speaker for Sanofi/Regeneron; and consultant for Sanofi/Regeneron, Celldex, Celgene/Receptos/BMS, Allakos, Ellodi, and AstraZeneca. M. E. Rothenberg is consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, BMS, AstraZeneca, Ellodi Pharma, Glaxo Smith Kline, Sanofi/Regeneron, Revolo Biotherapeutics, and Guidepoint; has equity interest in the first 6 listed; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. T. Shoda is a coinventor of patents owned by Cincinnati Children’s Hospital Medical Center. 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.)

Background: Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS)., Methods: The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P  ≤ .05 was considered significant., Results: Median age ( P  = .82) or height ( P  = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm 2 ) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P  < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P  = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P  = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P  = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P  = .15), and non-eosinophil-related individual EoEHSS scores did not differ., Conclusions: TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.L.N. None. A.B. None. K.K. None. P.K. None. S.B. None. V.A.M. has been a consultant for Regeneron, Sanofi, Allakos, and Shire/Takeda; and serves on an adjudication committee for Alladapt. R.S. None. C.W. None. M.E.R. has received research support from AstraZeneca, Regeneron-Sanofi, GlaxoSmithKline, the CURED Foundation, the Food Allergy Fund, NIH grants, and a US–Israel Binational Grant (number 2019016); receives royalties from Ception Therapeutics (for reslizumab), Mapi Research Trust (for the Pediatric Eosinophilic Esophagitis Symptom Score version 2), and UpToDate; is a consultant for AstraZeneca, Bristol Myers Squibb, Regeneron-Sanofi, Revolo Biotherapeutics, Celldex, Nexstone One, and Guidepoint; has received payment for expert testimony from Tucker Ellis; is an inventor on patents owned by Cincinnati Children’s Hospital Medical Center; has a leadership role in the International Eosinophil Society; has equity interest in PulmOne Therapeutics, Spoon Guru, ClostraBio, Serpin Pharm, Celldex, Nextstone One, and Allakos; and has received equipment from Phadia. M.H.C. is a consultant for Allakos; Arena/Pfizer; AstraZeneca; Calypso Biotech; EsoCap Biotech; GlaxoSmithKline; Receptos/Celgene/Bristol Myers Squibb; Regeneron Pharmaceuticals; Robarts Clinical Trials, Inc./Alimentiv, Inc; and Shire, a Takeda company; and has received license fees for use of the Eosinophilic Esophagitis Histology Scoring System (EoEHSS).

Eosinophilic gastrointestinal diseases (EGIDs) are chronic, immune-mediated disorders, characterized clinically by gastrointestinal (GI) symptoms and histologically by eosinophil-predominant infiltration in ≥1 GI tract segment. 1 A recent, international consensus by 91 experts proposed a new framework for EGID nomenclature to establish updated terms, designations, and conventions. 2 Although this framework offers a standardized starting point for the field, debate is ongoing regarding the appropriate terminology for cases involving multiple areas, such as "non-eosinophilic esophagitis (EoE) EGID and EoE" or "non-EoE EGID with esophageal involvement (EI)." Notably, in a survey of these experts, 61% agreed with the later term "non-EoE EGID with EI," because EoE is isolated to the esophagus by current diagnostic criteria. 3 However, limited molecular and pathogenic data exist to support the distinction. Furthermore, disease burden of symptoms and comorbidities generally is higher in non-EoE EGIDs than EoE. 4 Presently, there is no screen to predict non-EoE EGID concomitance in EoE; therefore, decision-making to further explore other GI segment involvement is clinically challenging. We aimed to answer 2 fundamental questions in the field (Figure 1A): Is there a shared or distinct pathogenesis between patients with isolated EoE and non-EoE EGIDs with EI as assessed by patient characteristics and molecular profiles? Can we predict concomitant non-EoE EGIDs when EoE exists? Herein, we report a similar molecular signature between EoE and EI and a potential predictive model to identify concomitant non-EoE EGIDs in patients with EoE., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents., Methods: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically., Results: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B., Conclusions: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear., Methods: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24., Results: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events., Conclusions: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.)., (Copyright © 2024 Massachusetts Medical Society.)

Eosinophilic gastrointestinal diseases (EGIDs) are a group of diseases characterized by selective eosinophil infiltration of the gastrointestinal (GI) tract in the absence of other causes of eosinophilia. These diseases are generally driven by type 2 inflammation, often in response to food allergen exposure. Among all EGIDs, the clinical presentation often includes a history of atopic disease with a variety of GI symptoms. EGIDs are traditionally separated into eosinophilic esophagitis (EoE) and non-EoE EGIDs. EoE is relatively better understood and now associated with clinical guidelines and 2 US Food and Drug Administration-approved treatments, whereas non-EoE EGIDs are rarer and less well-understood diseases without US Food and Drug Administration-approved treatments. Non-EoE EGIDs are further subclassified by the area of the GI tract that is involved; they comprise eosinophilic gastritis, eosinophilic enteritis (including eosinophilic duodenitis), and eosinophilic colitis. As with other GI disorders, the disease presentations and mechanisms differ depending on the involved segment of the GI tract; however, the differences between EoE and non-EoE EGIDs extend beyond which GI tract segment is involved. The aim of this article is to summarize the commonalities and differences between the clinical presentations and disease mechanisms for EoE and non-EoE EGIDs., Competing Interests: Disclosure statement Supported by the National Institutes of Health (grant K99/R00 AI158660 [to T.S.] and grants R01 AI045898, R01 AI124355, and U19 AI070235 [to M.E.R.]); the Digestive Health Center (Pilot and Feasibility Program; grant P30 DK078392 [to T.S.]); Cincinnati Children's Trustee Award (to T.S.); the Campaign Urging Research for Eosinophilic Disease (CURED) (to M.E.R.); the Sunshine Charitable Foundation and its supporters Denise A. Bunning and David G. Bunning (to M.E.R.); and CEGIR (U54 AI117804 to M.E.R.), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, NCATS. CEGIR is also supported by patient advocacy groups including the Campaign Urging Research for Eosinophilic Diseases (CURED), American Partnership for Eosinophilic Disorders (APFED), 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 National Center for Advancing Translational Sciences (NCATS) and the National Institute of Neurological Disorders and Stroke (NINDS). Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Celldex, Uniquitybio, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmith Kline, Regeneron/Sanofi, and Guidepoint and has an equity interest in the first 8 listed plus Allakos and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate. In addition, T. Shoda and M. E. Rothenberg are inventors of patents owned by Cincinnati Children’s Hospital. 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.)

Background: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood., Objective: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis., Methods: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms., Results: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden., Conclusion: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Climate change is not just jeopardizing the health of our planet but is also increasingly affecting our immune health. There is an expanding body of evidence that climate-related exposures such as air pollution, heat, wildfires, extreme weather events, and biodiversity loss significantly disrupt the functioning of the human immune system. These exposures manifest in a broad range of stimuli, including antigens, allergens, heat stress, pollutants, microbiota changes, and other toxic substances. Such exposures pose a direct and indirect threat to our body's primary line of defense, the epithelial barrier, affecting its physical integrity and functional efficacy. Furthermore, these climate-related environmental stressors can hyperstimulate the innate immune system and influence adaptive immunity-notably, in terms of developing and preserving immune tolerance. The loss or failure of immune tolerance can instigate a wide spectrum of noncommunicable diseases such as autoimmune conditions, allergy, respiratory illnesses, metabolic diseases, obesity, and others. As new evidence unfolds, there is a need for additional research in climate change and immunology that covers diverse environments in different global settings and uses modern biologic and epidemiologic tools., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Eosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis., Objectives: Using machine learning, we localized and characterized esophageal mast cells (MCs) to decipher their potential role in disease pathology., Methods: Esophageal biopsy samples (EoE, control) were stained for MCs by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize MCs, designated Mast Cell-Artificial Intelligence (MC-AI)., Results: MC-AI enumerated cell counts with high accuracy. During active EoE, epithelial MCs increased and lamina propria (LP) MCs decreased. In controls and EoE remission patients, papillae had the highest MC density and negatively correlated with epithelial MC density. MC density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater MC degranulation in the epithelium, papillae, and LP in patients with EoE compared with control individuals. MCs were localized further from the basement membrane in active EoE than EoE remission and control individuals but were closer than eosinophils to the basement membrane in active EoE., Conclusions: Using MC-AI, we identified a distinct population of homeostatic esophageal papillae MCs; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial MC levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of MCs in EoE and other disorders., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Eosinophilic esophagitis (EoE) is characterized by persistent or relapsing allergic inflammation, and both clinical and histologic features of esophageal inflammation persist over time in most individuals. Mechanisms contributing to EoE relapse are not understood, and chronic EoE-directed therapy is therefore required to prevent long-term sequelae., Objective: We investigated whether EoE patients in histologic remission have persistent dysregulation of esophageal gene expression., Methods: Esophageal biopsy samples from 51 pediatric and 52 adult subjects with EoE in histopathologic remission (<15 eosinophils per high-power field [eos/hpf]) and control (48 pediatric and 167 adult) subjects from multiple institutions were subjected to molecular profiling by the EoE diagnostic panel, which comprises a set of 94 esophageal transcripts differentially expressed in active EoE., Results: Defining remission as <15 eos/hpf, we identified 51 and 32 differentially expressed genes in pediatric and adult EoE patients compared to control individuals, respectively (false discovery rate < 0.05). Using the stringent definition of remission (0 eos/hpf), the adult and pediatric cohorts continued to have 18 and 25 differentially expressed genes (false discovery rate < 0.05). Among 6 shared genes between adults and children, CDH26 was upregulated in both children and adults; immunohistochemistry demonstrated increased cadherin 26 staining in the epithelium of EoE patients in remission compared to non-EoE controls. In the adult cohort, POSTN expression correlated with the endoscopic reference system score (Spearman r = 0.35, P = .011), specifically correlating with the rings' endoscopic reference system subscore (r = 0.53, P = .004)., Conclusion: We have identified persistent EoE-associated esophageal gene expression in patients with disease in deep remission. These data suggest potential inflammation-induced epigenetic mechanisms may influence gene expression during remission in EoE and provide insight into possible mechanisms that underlie relapse in EoE., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: With more than 103 million cases and 1.1 million deaths, the COVID-19 pandemic has had devastating consequences for the health system and the well-being of the entire US population. The Rare Diseases Clinical Research Network funded by the National Institutes of Health was strategically positioned to study the impact of the pandemic on the large, vulnerable population of people living with rare diseases (RDs)., Objective: This study was designed to describe the characteristics of COVID-19 in the RD population, determine whether patient subgroups experienced increased occurrence or severity of infection and whether the pandemic changed RD symptoms and treatment, and understand the broader impact on respondents and their families., Methods: US residents who had an RD and were <90 years old completed a web-based survey investigating self-reported COVID-19 infection, pandemic-related changes in RD symptoms and medications, access to care, and psychological impact on self and family. We estimated the incidence of self-reported COVID-19 and compared it with that in the US population; evaluated the frequency of COVID-19 symptoms according to self-reported infection; assessed infection duration, complications and need for hospitalization; assessed the influence of the COVID-19 pandemic on RD symptoms and treatment, and whether the pandemic influenced access to care, special food and nutrition, or demand for professional psychological assistance., Results: Between May 2, 2020, and December 15, 2020, in total, 3413 individuals completed the survey. Most were female (2212/3413, 64.81%), White (3038/3413, 89.01%), and aged ≥25 years (2646/3413, 77.53%). Overall, 80.6% (2751/3413) did not acquire COVID-19, 2.08% (71/3413) acquired it, and 16.58% (566/3413) did not know. Self-reported cases represented an annual incidence rate of 2.2% (95% CI 1.7%-2.8%). COVID-19 cases were more than twice the expected (71 vs 30.3; P<.001). COVID-19 was associated with specific symptoms (loss of taste: odds ratio [OR] 38.9, 95% CI 22.4-67.6, loss of smell: OR 30.6, 95% CI 17.7-53.1) and multiple symptoms (>9 symptoms vs none: OR 82.5, 95% CI 29-234 and 5-9: OR 44.8, 95% CI 18.7-107). Median symptom duration was 16 (IQR 9-30) days. Hospitalization (7/71, 10%) and ventilator support (4/71, 6%) were uncommon. Respondents who acquired COVID-19 reported increased occurrence and severity of RD symptoms and use or dosage of select medications; those who did not acquire COVID-19 reported decreased occurrence and severity of RD symptoms and use of medications; those who did not know had an intermediate pattern. The pandemic made it difficult to access care, receive treatment, get hospitalized, and caused mood changes for respondents and their families., Conclusions: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary., (©Maurizio Macaluso, Marc E Rothenberg, Thomas Ferkol, Pierce Kuhnell, Henry J Kaminski, David W Kimberlin, Michael Benatar, Mirna Chehade, The Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 14.02.2024.)

Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation, that develops in a small subset of people with food allergies. Genome-wide association studies (GWASs) have identified 9 independent EoE risk loci reaching genome-wide significance (p < 5 × 10 -8 ) and 27 additional loci of suggestive significance (5 × 10 -8  < p < 1 × 10 -5 ). In the current study, we perform linkage disequilibrium (LD) expansion of these loci to nominate a set of 531 variants that are potentially causal. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their genomic sequence context cloned into a GFP reporter library. Analysis of reporter gene expression in TE-7, HaCaT, and Jurkat cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants, representing 6 genome-wide significant EoE loci and 7 suggestive EoE loci, that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in individuals with EoE. Transcription factor enrichment analyses reveal possible roles for cell-type-specific regulators, including GATA3. Our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing functional insights into the effects of genetic variation in this disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Atopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD; however, the mechanism by which AHR partially ameliorates AD is not well known., Methods: Gene expression data from human biopsies were analyzed, and compared to gene expression from RNA-sequencing in our in-vitro HaCaT cell model system. Western blot, ELISA qRT-PCR were used to further explore the relationship between AHR and IL-13 signaling in HaCaT cells., Results: The AHR target gene CYP1A1 was decreased in lesional skin compared with healthy control skin ( p  = 4.30 × 10 -9 ). Single-cell RNA sequencing (scRNAseq) demonstrated increased AHR expression ( p  < 1.0 × 10 -4 ) and decreased CYP1A1 expression in lesional AD keratinocytes compared with healthy control keratinocytes ( p  < 0.001). Activation of AHR by AHR agonists in HaCaT cells reversed IL-13-dependent gene expression of several key genes in AD pathogenesis, most notably the eosinophil chemoattractant CCL26 (eotaxin-3). Differentially expressed genes in keratinocytes of patients with AD substantially overlapped with genes regulated by AHR agonists from HaCaT cells by RNAseq, but in reverse direction. Mechanistically, there was evidence for direct transcriptional effects of AHR; AHR binding motifs were identified in the differentially expressed genes from lesional AD keratinocytes compared to control keratinocytes, and AHR activation did not modify IL-13-dependent signal transducer and activator of transcription 6 (STAT6) translocation to the nucleus., Discussion: Together, these data suggest that the AHR pathway is dysregulated in AD and that AHR modulates IL-13 downstream signaling in keratinocytes through genome-wide, transcriptional regulatory effects., Competing Interests: AB is a co-founder of Datirium, LLC, the developer of https://scidap.com/ data analysis platform, and a member of Scientific Advisory Board of LDRTC, LLC. AB and MK developed CWL-Airflow, which is licensed to Datirium, LLC. The remaining 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., (© 2024 Proper, Dwyer, Appiagyei, Felton, Ben-Baruch Morgenstern, Marlman, Kotliar, Barski, Troutman, Rothenberg, Mersha and Azouz.)

Introduction: Eosinophilic gastrointestinal disorders beyond eosinophilic esophagitis (non-EoE EGIDs) are rare chronic inflammatory disorders of the gastrointestinal (GI) tract. Diagnosis is based on clinical symptoms and histologic findings of eosinophilic inflammation after exclusion of a secondary cause or systemic disease. Currently, no guidelines exist for the evaluation of non-EoE EGIDs. Therefore, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed a task force group to provide consensus guidelines for childhood non-EoE EGIDs., Methods: The working group was composed of pediatric gastroenterologists, adult gastroenterologists, allergists/immunologists, and pathologists. An extensive electronic literature search of the MEDLINE, EMBASE, and Cochrane databases was conducted up to February 2022. General methodology was used in the formulation of recommendations according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to meet current standards of evidence assessment., Results: The guidelines provide information on the current concept of non-EoE EGIDs, disease pathogenesis, epidemiology, clinical manifestations, diagnostic and disease surveillance procedures, and current treatment options. Thirty-four statements based on available evidence and 41 recommendations based on expert opinion and best clinical practices were developed., Conclusion: Non-EoE EGIDs literature is limited in scope and depth, making clear recommendations difficult. These consensus-based clinical practice guidelines are intended to assist clinicians caring for children affected by non-EoE EGIDs and to facilitate high-quality randomized controlled trials of various treatment modalities using standardized, uniform disease definitions., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)