Eosinophilic Esophagitis (EoE)

Epidemiology

• Incidence: ~1.23 per 10,000 children in the U.S.
• Prevalence: ~4.3 per 10,000 and rising
• Gender ratio: Boys are affected 3x more than girls

Pathophysiology

• Chronic, antigen-driven immune disorder involving eosinophils, mast cells, and Th2 cytokines (especially IL-13)
• Long-term inflammation may lead to fibrostenosis and esophageal strictures

Clinical Presentation by Age

• Often associated with allergic conditions: asthma, eczema, food/environmental allergies

Diagnosis

• Requires clinical symptoms + histologic evidence: ≥15 eosinophils per high-power field (hpf) in ≥1 esophageal site
  
• Current ACG and NASPGHAN recommendations suggest performing initial EGD and Biopsies before trial of PPI
• If patient is symptomatic and cannot wean PPI, recommend performing initial EGD/Biopsies on PPI with understanding that it may affect biopsy results
  
• Endoscopic features: furrows, white plaques, edema, trachealization, strictures

Treatment Strategies

• Topical steroids (swallowed fluticasone or budesonide)
  • Fluticasone: 880–1760 mcg/day → 50–65% histologic remission
  • Budesonide: 1–2 mg BID → up to 87% efficacy with PPI
  • Eohilia (oral budesonide suspension): FDA-approved for patients ≥11 years (cherry? flavor)
    
• Proton Pump Inhibitors (PPIs)
  • A 8-12wk trial of PPI is recommended as first line in patients diagnosed with EoE
    
  • New study showing 50% remission rates (more likely if esophagus grossly normal and low initial Eos in Biopsies)
  • https://publications.aap.org/pediatrics/article/152/Supplement%203/S43/196042/Proton-Pump-Inhibitor-Therapy-in-Pediatric
    
  • 30–50% histologic response in PPI-naïve patients
  • omeprazole and other proton pump inhibitors (PPIs) can block eotaxin-3 expression, which in turn reduces eosinophil recruitment to the esophagus.
  • Mechanism of Action
  • Eotaxin-3 is a key chemokine that attracts eosinophils to inflamed esophageal tissue in EoE.
  • In esophageal cells stimulated by Th2 cytokines like IL-4, omeprazole inhibits the binding of STAT6 (a transcription factor) to the eotaxin-3 promoter, which reduces eotaxin-3 production.
  • This effect is independent of acid suppression—meaning PPIs have anti-inflammatory properties beyond just reducing stomach acid.
  • Clinical Implication
  • This helps explain why some patients with EoE-like symptoms respond to PPI therapy alone—a condition which was previously known as PPI-responsive esophageal eosinophilia (PPI-REE).
  • In these cases, PPIs may restore mucosal integrity and reduce eosinophilic inflammation by downregulating Th2 pathways, including eotaxin-3
  
  
• Biologics
  
• • Dupixent (dupilumab):
    • FDA-approved for children aged ≥1 year and ≥15 kg
    • Targets IL-4/IL-13 pathway to reduce type 2 inflammation
    • Shown to improve both symptoms and histology in Phase 3 trials
    • Recommended re-evaluation with endoscopy after 6 months of therapy

• Directed elimination diet: Based on allergy testing
• Empiric 6-/7-food elimination diet: Milk, soy, egg, wheat, peanut, tree nut, fish/shellfish
• Many experts are now recommending starting with just Milk (or milk and wheat)
  
• Elemental diet: Most effective (up to 98% remission), but least palatable and often poor adherence in certain ages
  

 Surveillance and Monitoring

• Repeat endoscopy after starting treatment: 8-12wks (PPI, Steroid, Diet)  6 months (especially with Dupixent) to assess histologic response
• Histologic remission goal: <1 eos/hpf on ≥4 biopsies
• Ongoing monitoring: Every 12–24 months or sooner if symptoms recur
• Use of EoE Endoscopic Reference Score (EREFS) is encouraged for standardized assessment

Complications

• Food impactions (due to inflammation or motility issues)
• Esophageal candidiasis (1% per patient-year with steroid use)

• Stricture formation:
  • 5% in children
  • Up to 71% in adults after 20 years of disease

• Chronic esophageal disorder with esophageal dysfunction and eosinophilic epithelial infiltration
• Strong link to Atopy, food allergy, or Fam Hx of allergies
  
• Incidence = 5 per 100k (1.23 / 10k  noted in fellows review)
  
• Prevalence = 29.5 per 100k (4.3 per 10k noted in fellows  review)
• Mean age at diagnosis is 7yr (range 1-17) with average duration of Sx = 3yr
• Most patients are Male
• 55% adult food impactions are related to EoE

• Mixed IgE and non-IgE mediated allergic response to suspected aeroallergens or food allergens. causative agent is not always identified
  
• Non IgE pathogenesis involves mostly T-helper type 2 cytokine-mediated (IL 5 & IL 13) pathways producing potent eosinophil attractant (Eotaxin-3) in epithelium of esophagus
• Eotaxin 1 & 2 also involved (proinflammatory / chemoattractant)
• Chonic EoE leads to tissue remodeling and collagen deposition in the Lamina propria
  

• Infants
• vomiting / feeding concerns/ poor weight gain
• Children
• Solid food dysphagia with occasional/recurring food impactions,
  
• Strictures,
  
• Heartburn
  
• GERD unresponsive to acid suppressing therapy
• Chronic abdominal pain

• Requires:
• Symptoms of esophageal inflammation
• Esophageal mucosal Biopsy while on PPI
  
• >15 Eosinophils per high powered field (HPF, 40x or ~60 eos per mm squared) at > 1 esophageal site
• If not on PPI at time of Bx,
• Start PPI
• Rescope to differentiate between EoE and PPI responsive EoE (PPI-REE)
  
• Exclusion of other d/o assoc w/ similar clinical, histological, or endoscopic features
• Endoscopy
• EREFS score
• Edema
• Rings
• Exudates
• Furrows
• Strictures
• Up to 30% of children may have normal esophageal mucosa
• Trachealization (circumferential ridges) may be seen
• Labs may include:
• Peripheral eosinophilia
• Elevated IgE

• Hyperplasia of basal zone of esophageal mucosa beyond 1/3rd the total mucosal thickness
• Increased height of papillae beyond 1/3rd the total mucosal thickness
• Superficial eosinophilic microabscesses
• Eosinophilic inflammatory infiltrate with eosinophils count >15/hpf

• GERD
• IBD
• Celiac
• Viral Esophagitis
• Parasitic infection
• Drug Allergy
• Hypereosinophilic Syndrome
• Churg-Strauss

• Treatment prevents fibrosis and stricture formation
  
• Diet
• Elimination diet guided by history and results of food alergy testing
• 71-74% histologic response to empiric dietary elimination
• 75% improvement if guided by skin prick or allergy patch testing
  
• 91-98% response on elemental diet (amino-acid based formula)
• 6 food elimination diet removes: (mnemonic MS SWEPT)
  
• Milk
• Soy
• Seafood
• Wheat
• Egg
• Peanuts
• Tree nuts
• Empiric food elimination and diets based on multimodal allergy testing are comparable in results
• NOTE: dietary therapy can be costly and difficult for some patients to obtain, in addition, many patients feel that some of these diets lower their quality of life. All of these factors affect patients adherence and outcome
  
• Steroids
• Topical - Swallowed, for those who fail to adhere to or have a poor response to diet therapy
  
• Fluticasone - without spacer
  
• 880mcg/day 50% histologic remission, 67% Sx remission
• 1760mcg/day 65% remission rate
  
• Budesonide - viscous suspension
• 1-2mg BID 53% efficacy, 87% if combined with PPI
  
• Histologic remission seen in 50-77% after 3mo treatment
• Recurrence common (90%) after discontinuation of therapy
• Watch for bone demineralization, Fungal infection/Candidiasis, adrenocortical insufficiency
• Monoclonal Ab therapy targeting IL-5, IL-13
  
• mepolizumab
• reslizumab
• Follow up with periodic endoscopy and histologic reassessment

• Stricture Formation
• 5% overall prevalence in children
• 17% at 2yrs of disease
• 71% at 20yrs of disease in adults
  

1. Kliegman, Robert. Nelson Textbook of Pediatrics. Edition 21. Philadelphia, PA: Elsevier, 2020.
2. Tortora, Gerard J. Principles of Anatomy and Physiology. 15th ed. Hoboken, NJ: J. Wiley, 2009. Print.
3. Moore, Keith L.,, Arthur F. Dalley, II, and Keith L Moore. Clinically Oriented Anatomy. Fifth edition. Baltimore: Wolters Kluwer Health, 2009. Print.
4. Kleinman RE, Goulet O, Mieli-Vergani G, et al, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, and Management. 5th ed. Hamilton, Ontario: BC Decker; 2008.
5. The NASPGHAN fellows concise review of pediatric gastroenterology, hepatology, and nutrition. 1st edition (2011)
6. Wyllie, Robert & Hyams, J.S.. (2011). Pediatric Gastrointestinal and Liver Disease. 10.1016/C2009-0-53242-4.  (Accessed online Feb 2020)