Eosinophilic Esophagitis (EoE)

Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized by inflammation driven by an accumulation of eosinophils within the esophageal mucosa. Unlike gastroesophageal reflux disease (GERD), where eosinophils may be present in small numbers due to acid irritation, eosinophilic esophagitis (EoE) is defined by a significant and persistent eosinophilic infiltration. This inflammatory process results in esophageal dysfunction, leading to a variety of clinical symptoms.

Significance

Eosinophilic esophagitis (EoE) is increasingly recognized as a significant cause of esophageal morbidity, particularly in children and young adults. The prevalence of  eosinophilic esophagitis (EoE) has been steadily rising over the past few decades, likely due to increased awareness, improved diagnostic techniques, and potentially, environmental factors.

Understanding eosinophilic esophagitis (EoE) is crucial for medical practitioners as it requires a distinct diagnostic and management approach compared to other esophageal disorders.

The quality of life of patients with  eosinophilic esophagitis (EoE) can be severely impacted, so early diagnosis and treatment is very important.

Epidemiology

Prevalence and incidence

Eosinophilic esophagitis (EoE) is considered a relatively common esophageal disorder, although precise prevalence figures are challenging due to variations in diagnostic criteria and access to healthcare.

Estimates of prevalence range from approximately 10 to 50 cases per 100,000 individuals, but these numbers are likely underestimated. The incidence of eosinophilic esophagitis (EoE) is also increasing, reflecting greater awareness and improved diagnostic capabilities.

Demographics

Eosinophilic esophagitis (EoE) can affect individuals of all ages, but it is more commonly diagnosed in children and young adults. There is a significant male predominance, with males being affected approximately 2-4 times more often than females. The reason for this sex disparity is not fully understood.  While eosinophilic esophagitis (EoE) is observed in various racial and ethnic groups, studies suggest a higher prevalence in Caucasian populations.

Geographic distribution

Eosinophilic esophagitis (EoE) has been reported worldwide, but there appear to be regional variations in prevalence. Higher rates have been observed in developed countries, particularly in North America and Europe. This may reflect differences in environmental exposures, dietary habits, or access to diagnostic services. Environmental factors such as climate, and aeroallergen exposure may play a role in geographical distribution.

Pathogenesis of Eosinophilic Esophagitis (EoE)

Eosinophilic esophagitis (EoE) is fundamentally an immune-mediated disease, with a strong emphasis on Th2-type inflammation. Th2 lymphocytes play a central role in orchestrating the inflammatory response. Upon exposure to allergens (primarily food), Th2 cells release a cascade of cytokines that drive eosinophil recruitment and activation.

Cytokines and chemokines that are involved in EoE include:

• IL-4: Promotes Th2 differentiation and IgE production.  
• IL-5: Crucial for eosinophil maturation, recruitment, and survival.  
• IL-13: Induces eotaxin-3 production by epithelial cells, contributing to eosinophil chemotaxis, as well as promoting epithelial barrier dysfunction.
• Eotaxin-3: This chemokine is a key driver of eosinophil recruitment to the esophagus. It is upregulated in EoE, particularly in response to IL-13.

These and other cytokines contribute to the inflammatory cascade, leading to the characteristic eosinophilic infiltration of the esophageal mucosa. This chronic inflammation in eosinophilic esophagitis (EoE) then leads to structural changes in the esophagus.

Repeated cycles of inflammation and tissue repair result in the deposition of collagen and other extracellular matrix components, leading to fibrosis. Fibrosis can cause esophageal narrowing and stricture formation, contributing to dysphagia and food impaction. Esophageal motility can be impaired in eosinophilic esophagitis (EoE), further contributing to swallowing difficulties.

The esophageal epithelial barrier is vital for preventing the penetration of antigens. In eosinophilic esophagitis (EoE), this barrier is often compromised, allowing increased permeability to allergens.  This dysfunction is driven by cytokines like IL-13, and contributes to the ongoing inflammatory response. Dilated intercellular spaces are a histological hallmark of this dysfunction.

Causes and Risk Factors

A. Food Allergens

These are the most significant triggers for EoE. The reaction is typically a delayed hypersensitivity, not an immediate IgE-mediated allergy.

Common food triggers include:

• Milk (dairy)
• Wheat
• Soy
• Eggs
• Peanuts
• Tree nuts
• Seafood

Identifying specific food triggers can be challenging, often requiring elimination diets and allergy testing.

B. Environmental Allergens

Aeroallergens can exacerbate eosinophilic esophagitis (EoE) symptoms.

Common environmental triggers:

• Pollen
• Dust mites
• Animal dander

The role of environmental allergens may explain seasonal variations in EoE symptoms.

C. Genetic Factors

Eosinophilic esophagitis (EoE) has a strong genetic component, as evidenced by familial clustering and association with specific gene variants.

• TSLP (Thymic Stromal Lymphopoietin): This gene encodes a cytokine that initiates Th2 immune responses. Variations in TSLP may increase susceptibility to eosinophilic esophagitis (EoE) by promoting eosinophilic inflammation.
• FLG (Filaggrin): This gene encodes a protein crucial for maintaining the skin and esophageal epithelial barrier. Mutations in FLG can lead to barrier dysfunction, increasing permeability to allergens and contributing to eosinophilic esophagitis (EoE) development. This gene is also heavily implicated in Atopic dermatitis, which is a common comorbidity.

The genetic component helps to explain why some individuals develop eosinophilic esophagitis (EoE) in response to allergens, while others do not. Atopic conditions such as asthma, eczema, and allergic rhinitis are risk factors, and share some genetic links with eosinophilic esophagitis (EoE). Family history of eosinophilic esophagitis (EoE) or other atopic diseases increases the risk.

D. Male Predominance

Eosinophilic esophagitis (EoE) is more common in males than females. The reason for this sex disparity is not fully understood. Hormonal influences and sex-specific differences in immune responses may play a role.

E. Pediatric vs. Adult Presentation Differences

Children are more likely to present with feeding difficulties, abdominal pain, and vomiting. Adults typically experience dysphagia, food impaction, and chest pain.

Clinical Presentation and Symptoms of Eosinophilic Esophagitis (EoE)

Eosinophilic esophagitis (EoE) symptoms can vary significantly between individuals, and some patients may be asymptomatic or have only mild symptoms. The overlap of symptoms with other esophageal disorders, such as GERD and achalasia, can make diagnosis challenging. It is crucial to consider EoE in patients with persistent dysphagia or other esophageal symptoms, even if they have a history of GERD.

A. Symptoms in Adults

• Dysphagia (Solid Food): This is the hallmark symptom in adults. Difficulty swallowing solid foods, particularly dry or dense foods like bread or meat, is very common.  
• Food Impaction: Episodes of food getting lodged in the esophagus, requiring emergency intervention, are frequent and distressing. This is a key distinguishing symptom.  
• Chest Pain: Non-cardiac chest pain, often described as a burning or squeezing sensation, can occur. This can sometimes be confused with cardiac chest pain.  
• Heartburn/Reflux-like Symptoms: While EoE is distinct from GERD, some patients may experience heartburn, regurgitation, or other reflux-like symptoms. It’s important to note that these symptoms are due to esophageal dysfunction caused by eosinophilic inflammation, not necessarily acid reflux.  
• Upper abdominal pain
• “Compensatory eating behaviors”: Some patients will modify their diet, eating only soft foods, or eating very slowly, in order to avoid symptoms.  

B. Symptoms in Children

• Feeding Difficulties: Infants and young children may exhibit poor feeding, food refusal, or selective eating.  
• Abdominal Pain: This is a common complaint, often described as a vague or diffuse discomfort.  
• Vomiting: Frequent vomiting or regurgitation can occur, particularly after meals.  
• Failure to Thrive: In severe cases, chronic inflammation and reduced food intake can lead to poor growth and weight gain.  
• Reflux like symptoms
• Irritability around meal times  

Children with eosinophilic esophagitis (EoE) may develop learned food avoidance behaviors due to negative experiences with eating. They may become anxious or fearful around mealtimes, leading to further feeding difficulties. These behavioral changes can significantly impact their quality of life and nutritional status. Children may learn to drink excessive amounts of fluids with their meals to help with swallowing.

Laboratory Investigations and Diagnostic Procedures

A. Endoscopy

This is the cornerstone of eosinophilic esophagitis (EoE) diagnosis.  

• Visual Findings:
  • Esophageal Furrows: Linear or circular grooves running along the esophageal mucosa.  
  • Esophageal Rings: Concentric, fixed rings that narrow the esophageal lumen.  
  • White Plaques/Specks: Small, raised white areas representing eosinophil aggregates.  
  • Crepe Paper Esophagus: A fragile, corrugated appearance of the esophageal mucosa.  
  • Edema: Swelling of the esophageal walls.  

These visual findings, while suggestive, are not pathognomonic for EoE and require histological confirmation.  

B. Histopathology

At least 6 biopsies from different locations within the esophagus are recommended. This is due to the patchy nature of eosinophilic infiltration. Taking biopsies from both the proximal and distal esophagus increases diagnostic yield.  

The diagnostic hallmark of eosinophilic esophagitis (EoE) is the presence of ≥15 eosinophils per high-power field (HPF) in at least one biopsy specimen. This threshold distinguishes EoE from other conditions with mild esophageal eosinophilia.  

Other Histological Features:

• Basal Cell Hyperplasia: Increased thickness of the basal layer of the esophageal epithelium.
• Surface Layering of Eosinophils: Eosinophils clustered along the epithelial surface.  
• Dilated Intercellular Spaces (DIS): Widening of the spaces between epithelial cells, reflecting epithelial barrier dysfunction.  
• Eosinophil microabscesses: Clumps of eosinophils within the epithelium.  
• Fibrosis of the lamina propria.  

C. Allergy Testing

These tests help identify potential food triggers.

• Skin Prick Tests: Detect immediate IgE-mediated allergies, but may not be as sensitive for delayed hypersensitivity reactions in EoE.
• Atopy Patch Tests: Assess delayed hypersensitivity reactions by applying allergen patches to the skin.
• Food Elimination Diets: Empiric or targeted elimination of common food allergens, followed by reintroduction to identify triggers.  
• Component Resolved Diagnostics: This advanced form of allergy testing can help determine specific protein components of foods that a patient is reacting to.  

D. Blood Tests

• Complete Blood Count (CBC) with Differential: May show mild eosinophilia in the peripheral blood, but this is not a consistent finding.
• IgE Levels: Total IgE levels may be elevated, especially in patients with atopic comorbidities, but are not specific for eosinophilic esophagitis (EoE).

E. Esophageal Manometry

This test is used to assess esophageal motility and identify any abnormalities. Findings may reveal impaired esophageal peristalsis or other motility disturbances in patients with eosinophilic esophagitis (EoE), especially those with strictures. This test is more useful in the differential diagnosis of other motility disorders such as achalasia.

F. pH Monitoring

pH monitoring helps to differentiate eosinophilic esophagitis (EoE) from GERD. A 24-hour pH monitoring assesses the amount of acid reflux in the esophagus. Although there can be an overlap of GERD and EoE, it is important to try and distinguish if the eosinophilia is caused by acid reflux. pH monitoring is useful to detect if a patient has abnormal acid reflux. It is also of value when evaluating PPI responsive esophageal eosinophilia.

Differential Diagnosis

Feature	Eosinophilic Esophagitis (EoE)	Gastroesophageal Reflux Disease (GERD)	Achalasia	Crohn’s Disease (Esophageal)	Celiac Disease (Esophageal)	Pill Esophagitis	Hypereosinophilic Syndrome (HES)
Primary Symptom	Dysphagia, food impaction	Heartburn, regurgitation	Dysphagia	Dysphagia, abdominal pain	Abdominal pain, diarrhea	Chest pain, dysphagia	Systemic symptoms, organ involvement
Endoscopy	Furrows, rings, white plaques, edema	Erythema, erosions, ulceration	Bird’s beak, dilated esophagus	Patchy inflammation, ulceration	Mucosal atrophy, scalloping	Localized ulceration	Variable, may show esophageal involvement
Histology	≥15 eosinophils/HPF, DIS, fibrosis	Mild eosinophilia, basal hyperplasia	Normal	Granulomas, inflammation	Increased intraepithelial lymphocytes	Localized inflammation, ulcer	Eosinophilic infiltration in multiple organs
Allergy Testing	Positive for food/environmental allergies	Negative	Negative	Variable	Variable	Negative	Variable, may be positive
pH Monitoring	Normal or mildly abnormal	Abnormal (acid reflux)	Normal	Normal	Normal	Normal	Normal
Manometry	May show motility abnormalities	Normal or mild abnormalities	Aperistalsis, increased LES pressure	Variable	Normal	Normal	Variable
Response to PPI	Variable, often limited	Good response	None	Variable	None	None	Variable
Age of Onset	Children, young adults	Any age	Any age	Any age	Any age	Any age	Any age
Other Features	Atopic comorbidities (asthma, eczema)	May have hiatal hernia	Weight loss	Other GI involvement, fistulas	Other GI involvement, dermatitis herpetiformis	History of pill ingestion	Organ damage (heart, lungs, etc.)
Eosinophil Count	High esophageal eosinophils	Low esophageal eosinophils	Normal esophageal eosinophils	Variable esophageal eosinophils	Normal esophageal eosinophils	Variable esophageal eosinophils	High peripheral eosinophils

Treatment and Management

The goals of eosinophilic esophagitis (EoE) treatment are to alleviate symptoms, improve esophageal function, and prevent complications such as strictures. Treatment strategies typically involve a combination of dietary, pharmacological, and endoscopic therapies.  

A. Dietary Therapy

This is a cornerstone of EoE management, especially for identifying and eliminating food triggers. Dietary therapy requires close monitoring with repeat endoscopies to ensure efficacy.

• Elemental Diet: This involves consuming a formula containing amino acids, carbohydrates, and fats, completely eliminating intact proteins. Highly effective but can be challenging to adhere to long-term. Often used for initial induction of remission, especially in children.  
• Empiric Elimination Diet (6-Food Elimination Diet): Involves eliminating the six most common food triggers: milk, wheat, soy, eggs, peanuts/tree nuts, and seafood.  After a period of elimination, foods are reintroduced one at a time to identify triggers.  It is a common first line approach.
• Targeted Elimination Diet: Based on allergy testing (skin prick tests, atopy patch tests, component resolved diagnostics). It eliminates only those foods identified as triggers. This can be more practical for long-term management.

B. Pharmacological Therapy

• Topical Corticosteroids: Fluticasone propionate and budesonide are commonly used.  It is administered as swallowed aerosols or viscous slurries to coat the esophageal mucosa.  It reduces eosinophilic inflammation and improves symptoms. Long-term use can have potential side effects, such as oral candidiasis.  
• Proton Pump Inhibitors (PPIs): PPIs are often used as a first-line treatment, even before a definitive EoE diagnosis.  While not directly targeting the allergic inflammation, they can reduce symptoms and, in some cases, resolve esophageal eosinophilia. PPI-responsive esophageal eosinophilia must be ruled out before the final diagnosis of EoE can be established.  
• Biologics: Dupilumab is a monoclonal antibody that blocks IL-4 and IL-13 signaling. It has been shown to be effective in reducing eosinophilic inflammation and improving symptoms. It offers a systemic treatment option for patients who do not respond to topical corticosteroids or dietary therapy.

C. Endoscopic Dilation

It is used to treat esophageal strictures that cause dysphagia and food impaction. A balloon dilation or bougie dilation can widen the esophageal lumen. This carries a risk of esophageal perforation, so it should be performed by experienced endoscopists.  It is not a treatment for the underlying disease process, but rather a treatment of a complication of the disease.

D. Long-Term Management and Monitoring

A regular follow-up with a gastroenterologist and allergist is essential.  Follow-up endoscopies with biopsies are necessary to monitor disease activity and treatment response. Dietary maintenance is also crucial for preventing symptom recurrence. Constant monitoring for complications such as strictures and food impaction is vital and patient education is a large component of long term management.

Complications of Eosinophilic Esophagitis (EoE) 

• Food Impaction: This is a common and distressing complication, especially in adults. Esophageal narrowing and strictures make it difficult for food to pass, leading to impaction. So this requires urgent endoscopic intervention to remove the impacted food. Recurrent food impactions can significantly impact quality of life.  
• Esophageal Strictures and Narrowing:nChronic inflammation leads to fibrosis and remodeling of the esophageal wall. This results in the formation of strictures, which progressively narrow the esophageal lumen. Strictures contribute to dysphagia and increase the risk of food impaction.  Long term unchecked inflammation almost always leads to some form of esophageal remodeling. 
• Esophageal Perforation (Rare): While rare, esophageal perforation can occur during endoscopic procedures, particularly dilation.  It is a serious complication that requires immediate medical attention.  Also, in rare cases, a food impaction can lead to perforation.  
• Impact on Quality of Life: EoE can significantly affect patients’ quality of life due to dysphagia, food avoidance, and anxiety related to eating. Children may experience social isolation and nutritional deficiencies. While adults may struggle with work productivity and social activities. The constant need for dietary restrictions can cause increased anxiety.

Prognosis

EoE is a chronic disease that typically requires long-term management.  While symptoms can be effectively controlled with treatment, relapse is common if treatment is discontinued.  Most patients respond well to dietary therapy, topical corticosteroids, or biologics. Early diagnosis and intervention can prevent or minimize complications such as strictures.  Adherence to treatment is crucial for long-term symptom control.

With appropriate management, most patients can lead relatively normal lives. Regular monitoring and follow-up are essential to detect and treat complications.  

Early diagnosis and treatment can prevent long term complications such as stricture formation.  Early treatment can also prevent the development of compensatory eating behaviors in children.

While not always a cure, long term remission is a realistic goal for many patients. Remission can be histological, symptomatic, or both. Maintaining remission often requires continued dietary or pharmacological therapy.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

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