Residency · Residency · Gastroenterology

Eosinophilic Esophagitis

Definition and Epidemiology

Diagnostic Criteria (Updated Guidelines 2023)

The updated 2023 diagnostic criteria for eosinophilic esophagitis require the presence of symptoms of esophageal dysfunction, which may include dysphagia, food impaction, heartburn, or chest pain, in combination with esophageal eosinophilia of at least 15 eosinophils per high-power field on esophageal biopsy. Importantly, the diagnosis should be made after evaluation of non-EoE disorders that may contribute to esophageal eosinophilia. A critical paradigm shift in recent guidelines is the recognition that proton pump inhibitor-responsive esophageal eosinophilia, previously classified as a separate entity, is now considered part of the EoE disease spectrum.

Epidemiology

Eosinophilic esophagitis has a prevalence of approximately 40 to 55 per 100,000 in adults, with a steadily increasing incidence that likely reflects both greater disease awareness and a true rise in disease burden. There is a notable male predominance, with a 3:1 ratio, and the peak incidence occurs between 30 and 40 years of age in adults and between 5 and 15 years in children. A strong association exists between EoE and atopic disease, with 30 to 50% of patients having comorbid asthma, 50 to 75% having allergic rhinitis, 20 to 30% having eczema, and 15 to 40% having food allergies. Familial clustering has been well documented, and genetic risk loci including TSLP at 5q22, calpain-14 at 2p22, and eotaxin-3 at 7q11 have been identified as contributors to disease susceptibility.

Pathophysiology

Immunologic Mechanisms

The pathophysiology of eosinophilic esophagitis is centered on a type 2 immune-mediated response driven by the Th2 pathway. Exposure to an offending antigen, typically a food protein or aeroallergen, triggers the release of thymic stromal lymphopoietin (TSLP) and interleukin-33 from esophageal epithelial cells. These alarmins activate Th2 cells, which in turn produce interleukin-4, interleukin-5, and interleukin-13, each of which plays a distinct role in the disease process.

Interleukin-5 is responsible for the recruitment and prolonged survival of eosinophils in the esophageal tissue, and this cytokine serves as the target for mepolizumab and reslizumab. Interleukin-13 drives epithelial barrier dysfunction by inducing dilated intercellular spaces and impairing expression of filaggrin and desmoglein, while simultaneously upregulating eotaxin-3 (CCL26) and promoting fibrosis through TGF-beta signaling. The IL-4 and IL-13 signaling pathways are the target of dupilumab, which blocks the IL-4 receptor alpha subunit shared by both cytokines. Eotaxin-3, encoded by CCL26, is the major eosinophil chemoattractant in EoE and represents the most highly upregulated gene in the EoE transcriptome.

Fibrostenotic Remodeling

Subepithelial fibrosis in EoE is driven by TGF-beta and interleukin-13 and represents a progressive process that, if left untreated, leads to transformation from an inflammatory phenotype characterized by rings, edema, and exudates to a fibrostenotic phenotype characterized by strictures and a narrow-caliber esophagus. Data from the functional lumen imaging probe (EndoFLIP) have demonstrated that reduced esophageal distensibility correlates with fibrostenotic disease and the risk of food impaction. A distensibility plateau below approximately 17 mm is associated with a significantly higher risk of food impaction events.

Clinical Presentation

Adults

The predominant symptom in adults with eosinophilic esophagitis is dysphagia to solids, present in 70 to 80% of patients. Many patients develop adaptive eating behaviors that may mask the severity of their disease, including slow eating, excessive chewing, chasing each bite with liquid, and outright avoidance of certain food textures. Food impaction is a frequent presentation, occurring in 33 to 54% of patients and sometimes serving as the initial presentation that brings the patient to medical attention, often requiring emergent endoscopy. Heartburn and chest pain are reported in 20 to 40% of patients and are often refractory to proton pump inhibitor therapy. The median duration of diagnostic delay from symptom onset is 4 to 6 years, underscoring the importance of maintaining clinical suspicion in patients with unexplained dysphagia.

Children

In children, the clinical presentation differs substantially from adults. Younger patients are more likely to present with vomiting, abdominal pain, feeding difficulties, and failure to thrive. Dysphagia is less commonly reported in younger children, largely because they may lack the language to articulate their swallowing difficulties.

Diagnostic Evaluation

Endoscopic Features (EREFS Classification)

The EREFS classification system provides a standardized approach to describing the endoscopic features of eosinophilic esophagitis. Edema manifests as loss of the normal vascular pattern, giving the mucosa a pale, featureless appearance. Rings may be fixed, creating the classic trachealized appearance of the esophagus, or transient, sometimes referred to as feline folds, and they correlate with underlying fibrosis. Exudates appear as white plaques or spots scattered across the mucosal surface and represent eosinophil microabscesses. Furrows are linear vertical lines running along the long axis of the esophagus and are highly specific for EoE. Strictures may present as focal or diffuse narrowing of the esophageal lumen.

The EREFS scoring system assigns a composite score of 0 to 9 for inflammatory features and 0 to 9 for fibrostenotic features, providing a useful tool for monitoring disease over time.

Biopsy Protocol

The recommended biopsy protocol calls for a minimum of 6 biopsies obtained from at least 2 esophageal levels, specifically including both proximal and distal locations. All biopsies must be taken from the esophageal body and not from the gastroesophageal junction or stomach. Given the patchy distribution of eosinophilic infiltration, the sensitivity of diagnosis increases with the number of biopsies obtained, reaching 97% with 6 biopsies. Beyond the peak eosinophil count, additional histologic features that support the diagnosis include basal zone hyperplasia, dilated intercellular spaces (spongiosis), eosinophil microabscesses, and subepithelial and lamina propria fibrosis.

<image>A detailed endoscopic image panel showing the five components of the EREFS scoring system for EoE, arranged in 5 labeled panels. Panel 1 "Edema": pale, edematous esophageal mucosa with loss of normal vascular pattern, compared with a small inset of normal vascular pattern. Panel 2 "Rings": concentric ring-like indentations creating a trachealized or corrugated appearance of the esophagus. Panel 3 "Exudates": white punctate spots and plaques scattered across the mucosal surface representing eosinophil microabscesses. Panel 4 "Furrows": vertical linear indentations running parallel to the long axis of the esophagus. Panel 5 "Stricture": narrowed esophageal lumen with difficulty passing standard adult endoscope. Use realistic endoscopic color tones with pink-red mucosa. Each panel should include a severity grade label (mild/moderate/severe) with corresponding EREFS sub-score.</image>

Functional Lumen Imaging Probe (FLIP) in EoE

The functional lumen imaging probe measures esophageal distensibility and diameter, providing an objective assessment of esophageal compliance that complements histologic and endoscopic evaluation. A distensibility index below 4.0 mm squared per mmHg suggests reduced esophageal compliance. The body distensibility plateau, defined as the diameter at which the esophagus reaches maximal distension, provides clinically actionable risk stratification: a plateau below 18 mm indicates high impaction risk, 18 to 21 mm indicates moderate risk, and above 21 mm indicates low risk.

Treatment

Goals of Therapy

The goals of treatment in eosinophilic esophagitis encompass both symptom resolution and histologic remission, defined as fewer than 15 eosinophils per high-power field and ideally fewer than 6 eosinophils per high-power field. Prevention of fibrostenotic progression is a critical long-term objective. It is essential to recognize that EoE is a chronic disease requiring ongoing maintenance therapy, as the disease recurs in more than 90% of patients after therapy is discontinued.

First-Line Options

Proton Pump Inhibitors

The recognition that PPI-responsive esophageal eosinophilia is part of the EoE disease spectrum, rather than a separate entity, has elevated proton pump inhibitors to a first-line treatment option. High-dose PPI therapy, such as omeprazole 20 to 40 mg twice daily or an equivalent regimen, achieves histologic response rates of 50 to 60%. The therapeutic benefit extends beyond acid suppression, as PPIs have been shown to reduce eotaxin-3 expression and restore epithelial barrier integrity through anti-inflammatory mechanisms. Patients who respond to PPI therapy should be maintained on the lowest effective dose.

Topical Corticosteroids

Topical corticosteroids represent a mainstay of EoE treatment. Budesonide is available as an oral viscous preparation (1 mg twice daily, mixed with sucralose or Neocate) or as an orodispersible tablet (Jorveza, 1 mg twice daily for induction and 0.5 mg twice daily for maintenance, approved in Europe). Fluticasone is administered as a swallowed metered-dose inhaler at 880 mcg twice daily (440 mcg per puff, 2 puffs twice daily), with explicit instructions for the patient not to inhale and to avoid eating or drinking for 30 minutes after administration. Histologic response rates with topical corticosteroids range from 60 to 75%. Oral candidiasis occurs in 5 to 15% of patients and can be treated with fluconazole, while esophageal candidiasis occurs in 3 to 10%. Adrenal suppression is rare with topical formulations but should be monitored with morning cortisol levels in patients on prolonged or high-dose therapy.

Dietary Elimination Therapy

Dietary elimination therapy offers a non-pharmacologic approach to EoE management. The traditional six-food elimination diet removes milk, wheat, eggs, soy, fish and seafood, and nuts, and achieves histologic response in approximately 72% of patients, with milk and wheat identified as the most common triggers. A step-up approach, now preferred over the traditional six-food elimination, begins with a two-food elimination diet removing only milk and wheat (response rate approximately 43%), then escalates to a four-food elimination diet (adding eggs and soy or legumes) and finally to a six-food elimination diet if needed.

Biologic Therapy

Dupilumab (FDA-approved for EoE, 2022)

Dupilumab is a monoclonal antibody targeting the IL-4 receptor alpha subunit, thereby blocking both IL-4 and IL-13 signaling pathways. The pivotal LIBERTY EoE TREET trial demonstrated that dupilumab 300 mg administered subcutaneously weekly achieved histologic response (defined as fewer than 6 eosinophils per high-power field) in 60% of patients compared to 5% with placebo at 24 weeks. Significant improvement was also observed in the Dysphagia Symptom Questionnaire score. The drug is well tolerated, with injection site reactions occurring in 13% and conjunctivitis in 2 to 3% of patients. Dupilumab is indicated for patients aged 12 years and older weighing at least 40 kg who are refractory to or intolerant of conventional therapies, though it may also be considered as a first-line option in appropriate clinical scenarios. Maintenance dosing is 300 mg subcutaneously weekly on an ongoing basis.

Emerging Biologics

Several additional biologic agents are in various stages of development for EoE. Cendakimab, an anti-IL-13 monoclonal antibody, has demonstrated positive results in phase 3 trials, achieving histologic remission in 48% of patients compared to 22% with placebo. Mepolizumab and reslizumab, both targeting IL-5, effectively reduce eosinophil counts but have shown limited improvement in symptoms and are not approved for EoE. Benralizumab, which targets the IL-5 receptor alpha subunit and depletes eosinophils, is currently in phase 3 trials. Lirentelimab, directed against Siglec-8 and targeting both eosinophils and mast cells, has produced mixed results in phase 2 and 3 studies.

Endoscopic Dilation

Endoscopic dilation is indicated for symptomatic strictures or a narrow-caliber esophagus that is refractory to medical therapy. Dilation may be performed using bougie dilators (Savary or Maloney) or through-the-scope balloon dilation. The traditional rule of three has been largely abandoned, and larger dilations are considered safe in experienced hands. The target diameter is 15 to 18 mm. The risk of perforation in modern series is less than 1%, which is substantially lower than historically estimated. Critically, dilation does not treat the underlying inflammation and must always be combined with anti-inflammatory therapy. FLIP-guided dilation, which targets the distensibility index rather than absolute diameter, is an emerging approach that may further refine dilation practice.

<image>A treatment algorithm flowchart for eosinophilic esophagitis management. Begin at top with "Confirmed EoE (>=15 eos/hpf + symptoms)." First tier shows three parallel first-line options: "PPI (high-dose BID)," "Topical corticosteroids (budesonide or fluticasone)," and "Dietary elimination (2-4-6 step-up)." Each option has an arrow to "Repeat EGD 8-12 weeks." Branch into "Histologic remission (<15 eos/hpf)" leading to "Maintenance therapy (lowest effective dose/diet)" and "Non-response" leading to "Switch or combine first-line therapies." If still non-responsive, arrow to "Dupilumab 300 mg SQ weekly." Side branch from any level for "Symptomatic stricture" leading to "Endoscopic dilation + anti-inflammatory therapy." Include FLIP distensibility index thresholds as a decision aid box (DI <4 = consider dilation). Use green for remission, yellow for partial response, red for non-response. Include response rates as percentages next to each treatment option.</image>

Monitoring and Follow-Up

Assessment of Remission

Monitoring the response to therapy in EoE involves multiple complementary measures. The Dysphagia Symptom Questionnaire provides a symptom-based score on a 0 to 84 scale, although symptoms do not always correlate with histologic activity. Histologic assessment relies on peak eosinophil count and can be comprehensively evaluated using the EoE Histologic Scoring System (EoE-HSS). Endoscopic assessment is performed using the EREFS score, and FLIP distensibility provides an objective measure of esophageal compliance. The frequent discordance between symptoms and histology underscores that histologic monitoring through repeat biopsies is essential for guiding treatment decisions.

Long-Term Considerations

Eosinophilic esophagitis is a chronic disease that requires maintenance therapy, and patients must be counseled about the lifelong nature of their condition. Untreated disease progresses from an inflammatory to a fibrostenotic phenotype, with an estimated 2.3% of patients developing a stricture per year of untreated disease. Unlike Barrett esophagus, there is no proven increased risk of esophageal cancer associated with EoE. However, the quality of life impact is significant, with many patients experiencing food anxiety, social isolation, and substantial psychosocial burden.

Special Considerations

EoE and Concomitant GERD

Eosinophilic esophagitis and gastroesophageal reflux disease can coexist and are not mutually exclusive conditions. GERD may lower the eosinophilic threshold for an EoE flare, and when both conditions are present, treatment should address both pathologies.

EoE at the GEJ

Eosinophilic gastrointestinal diseases extend beyond the esophagus and may include eosinophilic gastritis and eosinophilic duodenitis, which can overlap with EoE. While dupilumab is currently approved for eosinophilic esophagitis, investigation is ongoing for its application in other eosinophilic gastrointestinal diseases.

<image>A histopathological illustration comparing normal esophageal mucosa with EoE. Left panel: normal squamous epithelium with thin basal zone, regular papillae, intact intercellular spaces, and no eosinophils. Right panel: EoE showing markedly thickened basal zone (>15% of epithelial thickness), elongated papillae, dilated intercellular spaces (spongiosis), surface eosinophilic microabscess (cluster of >=4 eosinophils), scattered intraepithelial eosinophils with degranulation (extracellular eosinophil granules visible), and subepithelial fibrosis in the lamina propria with collagen deposition highlighted. Label all features with leader lines. Use H&E stain color scheme: pink epithelium, red eosinophil granules, blue nuclei, pale pink collagen. Include a magnified inset of an eosinophil showing bilobed nucleus and eosinophilic granules. Indicate the ">15 eos/hpf" counting threshold with a representative HPF circle overlay.</image>

Key Clinical Pearls

• PPI-responsive esophageal eosinophilia is now classified as part of EoE, not a separate entity
• Always take >= 6 biopsies from >= 2 levels — EoE is patchy; normal-appearing esophagus does not exclude EoE
• Food allergy testing (skin prick, IgE panels) does NOT predict EoE food triggers — empiric elimination is preferred
• Dupilumab is the first FDA-approved biologic for EoE (2022); consider for refractory patients or those preferring non-dietary, non-steroid approach
• Untreated EoE progresses to fibrostenotic disease — early and sustained treatment prevents stricture formation
• FLIP distensibility is an emerging objective endpoint; distensibility plateau <18 mm predicts food impaction risk
• Esophageal dilation is safe (<1% perforation) and effective for strictures but must be combined with anti-inflammatory therapy
• Symptoms do not reliably predict histologic activity — repeat biopsies are essential for monitoring

References

1. Dellon ES, et al. ACG Clinical Guideline: Evidence-Based Approach to the Diagnosis and Management of Esophageal Eosinophilia and Eosinophilic Esophagitis. Am J Gastroenterol. 2023;118(3):424-444.
2. Dellon ES, et al. Dupilumab in adults and adolescents with eosinophilic esophagitis (LIBERTY EoE TREET). N Engl J Med. 2022;387(25):2317-2330.
3. Hirano I, et al. AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis. Gastroenterology. 2020;158(6):1776-1786.
4. Schoepfer AM, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology. 2013;145(6):1230-1236.
5. Molina-Infante J, et al. Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study. J Allergy Clin Immunol. 2018;141(4):1365-1372.

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