Eosinophilic esophagitis: Pathogenesis, genetics, and therapy

doi:10.1016/j.jaci.2006.07.038

Journal of Allergy and Clinical Immunology

Volume 118, Issue 5, November 2006, Pages 1054-1059

https://doi.org/10.1016/j.jaci.2006.07.038 Get rights and content

Eosinophilic esophagitis (EE) is a recently recognized disorder characterized by the accumulation of eosinophils in the esophagus. Symptoms of EE frequently mimic those of gastroesophageal reflux disease, but the 2 diseases are quite distinct in terms of the histopathology and response to therapy. We demonstrate that EE involves the interplay of numerous genes, especially the eosinophil chemoattractant eotaxin-3, allowing molecular distinction from other forms of esophagitis and consideration of targeted therapeutic intervention.

Section snippets

Differential diagnosis

Unlike all other segments of the gastrointestinal tract, the esophagus is normally devoid of eosinophils, and therefore the finding of esophageal eosinophils denotes pathology. However, the presence of esophageal eosinophils is not specific for a particular disorder because eosinophil infiltration in the esophagus occurs in a variety of states, including eosinophilic esophagitis (EE), eosinophilic gastroenteritis, gastroesophageal reflux disease (GERD), chronic (noneosinophilic) esophagitis

Symptoms and disease characteristics

Patients with primary EE commonly report symptoms that include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.2, 3, 4, 5, 6 These symptoms appear to occur in a progressive order because they are the presenting symptoms from infancy into adulthood, respectively. Patients with EE are predominantly young males² and have relatively high levels of eosinophils (>20-24 peak eosinophils/×400 high-powered field [hpf])7, 8 in the esophageal

Epidemiology

Although the incidence of primary EE has not been rigorously calculated, an increasing number of cases have been noted over the last decade. Markowitz and Liacouras⁹ found that 8% to 10% of their pediatric patients with GERD-like symptoms who were unresponsive to acid blockade actually had EE. Fox et al¹⁰ also reported that 6% of their patients with esophagitis had EE. We found that EE occurred in approximately 1:1500 in the greater Cincinnati pediatric population over a 5-year time period

Esophageal eosinophil levels and histopathology

It has been proposed that the number and location of eosinophils is helpful when trying to differentiate EE from GERD. Up to 6 eosinophils/hpf (×400) might be mostly indicative of GERD, whereas more than 20 to 24 eosinophils/hpf appears to be mostly indicative of EE,6, 7, 8 especially when these levels are encountered while patients are receiving anti-GERD therapy. The level of eosinophils in the esophagus negatively correlates with response to conventional anti-GERD therapy. In particular,

Pathogenesis of EE

The cause of EE is poorly understood, but allergy has been implicated. The majority of patients have evidence of food and aeroallergen hypersensitivity, as defined by skin prick test responses, RAST results, or both; however, only a minority have a history of food anaphylaxis,¹⁰ indicating distinct mechanisms compared with classical IgE-mediated mast cell/basophil activation. Substantial evidence is accumulating that EE is associated with T_H2-type immune responses. In particular, increased

Genetics of EE

Over the past several years, evidence is accumulating that EE has a strong familial association.¹¹ In our own experience, nearly 10% of parents of patients with EE have a history of esophageal strictures, and approximately 8% have biopsy-proved EE.¹¹ Among approximately 300 pediatric probands we have recruited into a research databank to date, 26 of them have at least 1 sibling or parent with EE (data not published). In addition, Patel and Falchuk³³ have recently reported 3 adult brothers with

Association with the eotaxin-3 gene

Our genetic study on a single nucleotide polymorphism (SNP; +2496T>G, rs2302009) in the eotaxin-3 gene has shown association with EE by both population-based case-control comparison and family-based transmission disequilibrium testing.²¹ Of note, this SNP located in the 3′-untranslated region of the eotaxin-3 mRNA might affect mRNA stability. Notably, the induction of inflammatory cytokines is often controlled at the level of mRNA stability. Moreover, this SNP might disrupt a putative AU-rich

Potential role of inflammatory cells in EE

Clinical investigations have demonstrated extracellular deposition of major basic protein in the esophagi of patients with EE.³⁶ In vitro studies have shown that eosinophil granule constituents are toxic to a variety of tissues, including intestinal epithelium.³⁶ Charcot-Leyden crystal (CLC) proteins, remnants of eosinophil degranulation, are the only eosinophil-associated mRNA strongly overexpressed in biopsy specimens of patients with EE.²¹ CLC protein is found on microscopic examination of

EE therapy

There is no uniformly agreed on therapy for EE, probably because of the lack of controlled clinical trials and studies on the natural history of the disorder. At present, therapy for EE is based on antigen elimination trials, anti-inflammatory approaches, and physical dilatation when strictures are present.³⁸ From the onset, anti-GERD therapy is indicated for the initial treatment of EE because acid can trigger esophageal eosinophilia, albeit generally of lower magnitude than that associated

Conclusion and future directions

It is now well accepted that atopic disorders, such as asthma and eczema, are complex diseases involving the interplay of multiple genes interacting with environmental factors, ultimately contributing to disease susceptibility. Initial analyses indicate a relatively strong genetic contribution in EE compared with other atopic diseases, indicating that fewer genes might be involved in disease pathogenesis compared with the more than 100 genes that have now been implicated in respiratory allergy.

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The Role of the Environment in Eosinophilic Esophagitis
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EoE is a complex disease whereby environmental factors likely contribute to the expression of the disease in genetically predisposed individuals. These factors likely also contribute to the well-documented increase in the incidence and prevalence of EoE over the past 2 decades.6-14 Establishment of the gut microbiome in early life and factors that influence its development such as antibiotics, acid suppressants, and cesarean delivery are known to influence immune tolerance; these factors are the most studied environmental factors studied in EoE development, with generally consistent evidence of an association observed despite limitations of the studies conducted to date.24-28
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease clinicopathologically characterized by esophageal dysfunction. EoE is characterized by eosinophilic histologic inflammation indistinguishable from other atopic diseases such as asthma, eczema, or allergic rhinitis, which often co-occur in patients with EoE. This suggest a possible shared pathophysiology and triggers in the development of EoE with other atopic conditions. Although the evidence of EoE being linked to exposure to allergenic foods is strong, the connection between EoE and aeroallergens is less understood. In this review, we will discuss clinical, epidemiological, and animal studies that investigate how environmental allergens influence the clinical manifestations of EoE and its seasonality. It is also known that the developing immune system is significantly shaped by early-life exposures, pollution, climate change, and those factors that are known to influence development of asthma. We therefore also describe the evidence for and the gaps in our knowledge of the role of early-life exposures, pollution, and climate change in the development of EoE.
Very early onset eosinophilic esophagitis is common, responds to standard therapy, and demonstrates enrichment for CAPN14 genetic variants
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Eosinophilic esophagitis (EoE) is a chronic, food antigen–mediated disease characterized by esophageal dysfunction and intraepithelial eosinophil accumulation.
We hypothesized that very early onset EoE (V-EoE) would be enriched for early-life and genetic factors and have worse presentation and prognosis than later-onset pediatric EoE (L-EoE).
We conducted a single-site, retrospective review comparing patients diagnosed at age 12 months or less (V-EoE, n = 57) and age 14 to 18 years (L-EoE, n = 70). These patients underwent medical record, EoE Histology Scoring System, Endoscopic Reference Score, and EoE Diagnostic Panel assessment when sample availability permitted. Genetic association used 2 EoE genotype repositories. Data were analyzed using chi-square tests, t tests, Wilcoxon rank-sum tests, Spearman correlations, cluster analysis, and logistic regression.
Among pediatric patients with EoE, diagnosis most commonly occurred within early life (0-24 months, 17%). V-EoE was more likely to attain histologic remission via dietary restriction (P < .0001). Basal zone hyperplasia and eosinophil inflammation were greater in V-EoE (P < .05). Esophageal strictures more commonly occurred in L-EoE (P = .03). V-EoE had lower endoscopic scores (P < .05). Molecular expression was very similar between groups. Cesarean delivery was more common in patients with V-EoE (P = .03). Patients with V-EoE demonstrated enrichment of CAPN14 common genetic variants.
Early-life diagnosis of EoE is a common occurrence. V-EoE responds to standard therapy without early evidence for complications, suggesting a less severe prognosis than hypothesized. Molecular pathogenesis is preserved between V-EoE and L-EoE. Cesarean delivery and CAPN14 genetic variation likely promote earlier disease development.
Endoscopic and histological characteristics in patients with eosinophilic esophagitis responsive and non-responsive to proton pump inhibitors
2020, Jornal de Pediatria
To compare endoscopic and histologic features of pediatric patients with eosinophilic esophagitis (EoE) responding to proton pump inhibitor (PPI) to those not responding to PPI.
Endoscopic reports and photographs of patients with symptoms of esophageal dysfunction and ≥15 eosinophils per high-powered field (eos/hpf) in esophageal biopsies prior to PPI trial were reviewed. Patients were classified as responsive to PPI (PPIREoE) or non-responsive to PPI (PPINREoE) according to response totreatment (<15 eos/hpf) at second endoscopy after 8 weeks.
Of the 231 patients (72.3% male), 64 (27.7%) were responsive to the proton pump inhibitors. Edema (77.3% vs. 62.5%, p = 0.031) and vertical lines (69.5% vs. 51.6%, p = 0.014) were more frequent in PPINREoE patients. An eosinophil count in the mid-esophagus ≥ 35 eos/HPF (25.1% vs. 12.5%) was more frequent in these patients (p = 0.001). Those with eosinophil count < 15 eos/HPF in the mid-esophagus at the first endoscopy were more likely to respond to treatment with proton pump inhibitors compared to patients with 15-34 eos/HPF (p = 0.004, OR: 3.26, 95% CI: 1.46-7.24) and to patients with ≥ 35 eos/HPF (p = 0.006, OR: 3.20, 95% CI: 1.39-7.41).
Edema and vertical lines at the endoscopy and a higher eosinophil count in the mid-esophagus were more frequent in patients who were non-responsive to proton pump inhibitors. As there were no significant differences in the other findings between the groups, it cannot be affirmed that these characteristics are sufficient to differentiate between PPINREoE and PPIREoE patients.
Comparar características endoscópicas e histológicas entre pacientes com esofagite eosinofílica responsiva (EoERIBP) e não responsiva (EoENRIBP) ao tratamento com inibidores de bomba de prótons.
Avaliados laudos e imagens endoscópicas de pacientes com sintomas de disfunção esofágica associados a contagem ≥15 eosinófilos por campo de grande aumento (eos/CGA) em biópsia do esôfago. Os pacientes foram classificados em responsivos (EoERIBP) ou não responsivos (EoENRIBP) aos inibidores de bomba de prótons conforme resposta ao tratamento na segunda endoscopia (<15 eos/CGA) após 8 semanas.
Dos 231 pacientes (72,3% masculino), 64 (27,7%) foram responsivos aos inibidores de bomba de prótons. Edema (77,3% vs. 62,5%, p = 0,031) e linhas verticais (69,5% vs. 51,6%, p = 0,014) foram mais frequentes nos EoENRIBP. A contagem de eosinófilos em esôfago médio ≥35 eos/CGA (25,1% vs. 12,5%) foi mais frequente nesses pacientes (p = 0,001). Os que apresentaram contagem de eosinófilos <15 eos/CGA no esôfago médio à primeira endoscopia apresentaram maior chance de responder ao tratamento com inibidores de bomba de prótons em comparação aos pacientes com 15-34 eos/CGA (p = 0,004; OR: 3,26; IC95%: 1,46 - 7,24) e aos pacientes com ≥35 eos/CGA (p = 0,006; OR: 3,20; IC95%: 1,39 - 7,41).
Edema e linhas verticais à endoscopia e maior contagem de eosinófilos em esôfago médio foram mais frequentes nos pacientes não responsivos aos inibidores de bomba de prótons. Uma vez que não houve diferenças significativas nos outros achados entre os grupos, não se pode afirmar que essas características sejam suficientes para distinguir pacientes com EoENRIBP dos pacientes com EoERIBP.
Correlation of endoscopic signs and mucosal alterations in children with eosinophilic esophagitis
2020, Gastrointestinal Endoscopy
Citation Excerpt :
In this retrospective study, we included children (1-18 years) diagnosed with EoE and undergoing endoscopic evaluation with biopsies at the Monroe Carell Jr Children’s Hospital at Vanderbilt between May 2017 and April 2018. EoE was defined according to the 2011 Consensus recommendations.15 Specifically, they were required to have symptoms of esophageal dysfunction and intense eosinophilic inflammation in at least one of multiple esophageal mucosal biopsy samples after an 8-week course of proton-pump inhibitor therapy in the absence of other causes of esophageal eosinophilia.
In children with eosinophilic esophagitis (EoE), the relationship among the endoscopic reference score (EREFS), the histology scoring system (EoEHSS), and the peak eosinophil count (PEC) is incompletely described. Our aim was to determine the relationship among EREFS, EoEHSS, and PEC and develop a predictive model using components of EREFS and EoEHSS for EoE activity.
We analyzed 189 paired EREFSs, EoEHSSs, and PECs. Active EoE (aEoE; n = 98) was defined as ≥15 eosinophils per high-power field and inactive EoE (iEoE; n = 91) as <15 eosinophils per high-power field. Spearman correlation (r) with Bonferroni correction was used to assess the relationship between EREFS, EoEHSS and PEC, and a back-transformed average Fisher test was used to determine the statistical significance of the differences. Receiver operating characteristic analysis was used to develop the predictive model.
The relationship between total EREFS and EoEHSS was modest (r = 0.61) but significantly stronger than the correlation between total EREFS and PEC (r = 0.55; P = .04). The relationship between total EREFS and EoEHSS tended to be stronger in aEoE compared with iEoE (r = 0.41 vs 0.24; P = .09). Compared with EREFS, EoEHSS had a significantly higher area under the curve (0.78 vs 0.92; P = .04) to predict aEoE. A combination of furrows, eosinophilic inflammation, basal cell hyperplasia, eosinophilic abscess, and dilated intercellular spaces had an area under the curve of 0.97, accuracy of 98%, sensitivity of 97%, and specificity of 98% to predict aEoE.
The endoscopy score modestly correlates with the histologic scoring system. Thus, the endoscopy score is not a reliable marker of tissue involvement in EoE. A panel of individual endoscopic and histologic signs hold promise to accurately predict EoE activity.
Eosinophilic esophagitis: Pathophysiology, diagnosis, and management
2019, Archives de Pediatrie
Citation Excerpt :
As filaggrin is part of EDC, a functional loss associated with single nucleotide polymorphisms (SNPs) results in epithelial barrier damage and increased antigen exposure. The eotaxin-3 gene, which allows eosinophil recruitment within esophageal mucosa, has the strongest transcriptome expression, 53 times more than in controls [19]. In mice, the absence of eotaxin-3 receptor protects from EoE [20].
Eosinophilic esophagitis (EoE) is a multifactorial esophageal inflammation, with a genetic predisposition, which combines a deficient esophageal mucosal barrier, an abnormal immune reaction to environmental allergens mediated by Th2 interleukins, immediate esophageal lesions and dysmotility, with secondary remodeling and fibrosis. Symptoms include reflux, abdominal pain, and food impaction, with a variation according to age. Fibroscopy shows major and minor endoscopic and histologic criteria, with a mucosal count ≥ 15 eosinophils/high power field (Eo/hpf). A new entity has been defined, where gastroesophageal reflux disease (GERD) and EoE share responsibility: the PPIs-sensitive form of EoE (PPI-REE). Children with fibroscopy showing ≥ 15 Eo/hpf need a second endoscopy following 8 weeks of PPI treatment. EoE has a strong association with other atopic disorders. Allergy testing (specific IgE blood test and skin prick tests [SPTs]) identifies patients at risk of anaphylaxis (14.8% of cases). The dietary therapy is based on a 4- to 12-week elimination test followed by endoscopy to check the disappearance of eosinophilic infiltration. The “dietary approaches are the amino acid-based formula, the allergy testing-based targeted diet, and the six-food elimination diet (empirical elimination of milk, wheat, soy, eggs, peanut/nuts, and fish/seafood). A recent first-line trial elimination of milk has been suggested, with wheat as a second elimination, if necessary. Dietary therapy allows remission and catch-up growth in 65% of cases. Swallowed topical steroids (budesonide in viscous gel or fluticasone propionate for nebulization) are an alternative, for which efficacy varies according to clinical and/or histological criteria and with relapses occurring at dosage tapering. Their use may be restricted by side effects, such as oral and/or esophageal candidiasis. The impact on long-term bone health and growth is unknown. Maintenance therapy is not standardized and is team-dependent, combining or not elimination diets and long-term steroids. The long-term risk of EoE is esophageal stenosis (25%) and endoscopic dilation may be repeated. Biotherapies have shown isolated histological improvement without significant clinical efficacy.

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Supported in part by the Burroughs Wellcome Fund (M.E.R), National Institutes of Health grants R01 AI45898 (M.E.R.) and R21 DK074626-01 (N.W.), the CURED (Campaign Urging Research for Eosinophilic Disease) Foundation, and the Food Allergy and Anaphylaxis Network (M.E.R.).

Disclosure of potential conflict of interest: M. E. Rothenberg has consultant arrangements with GlaxoSmithKline, Ception Therapeutics, Cambridge Antibody Technology, and MedaCorp; owns stock in Ception Therapeutics; has received grant support from Cambridge Antibody Technology; is on the speakers' bureau for Merck; and has received honorarium from GlaxoSmithKline, Ception Therapeutics, Merck, and Tanox. The rest of the authors have declared that they have no conflict of interest.

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Mechanisms of asthma and allergic inflammationEosinophilic esophagitis: Pathogenesis, genetics, and therapy

Section snippets

Differential diagnosis

Symptoms and disease characteristics

Epidemiology

Esophageal eosinophil levels and histopathology

Pathogenesis of EE

Genetics of EE

Association with the eotaxin-3 gene

Potential role of inflammatory cells in EE

EE therapy

Conclusion and future directions

Am J Gastroenterol

Gastrointest Endosc

J Allergy Clin Immunol

Gastroenterol Clin North Am

Gastrointest Endosc

J Allergy Clin Immunol

Mod Pathol

Gastrointest Endosc

J Allergy Clin Immunol

J Allergy Clin Immunol

Gastroenterology

Gastroenterology

Gastrointest Endosc

Clin Gastroenterol Hepatol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Clin Gastroenterol Hepatol

J Allergy Clin Immunol

J Allergy Clin Immunol

Reflux esophagitis: sequelae and differential diagnosis in infants and children including eosinophilic esophagitis

Pediatr Dev Pathol

Allergic esophagitis in children: a clinicopathological entity

Am J Surg Pathol

Eosinophilic esophagitis

Curr Opin Pediatr

Eosinophilic esophagitis in children: symptoms, histology and pH probe results

J Pediatr Gastroenterol Nutr

Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy

Pediatr Dev Pathol

Mechanisms of asthma and allergic inflammation
Eosinophilic esophagitis: Pathogenesis, genetics, and therapy