Eosinophilic Esophagitis Nisha Patel, MD Eugene Vortia, MD Jonathan Moses, MD Cleveland Clinic Reviewed by Sandeep Gupta, MD of the Professional Education Committee

Definition Chronic immune and antigen mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation* * J Allergy Clin Immunol 2011;128:3–20

Epidemiology Male to Female ratio - 3:1 Familial clustering - 3% have an affected parent or sibling Overall prevalence 1:2000 Incidence - ~ 1: 10,000 per year* Among patients undergoing upper endoscopy for any indication, prevalence is ~ 7% * N Engl J Med 2004; 351:940-941, Gastroenterology 2008;134:1316-1321

Causes of Esophageal Eosinophilia Caustic injury Chronic (non-eosinophilic) esophagitis Churg-Strauss Syndrome Drugs (anti-convulsants, immunosuppressants) EoE Gastro-esophageal reflux disease Hypereosinophilic syndrome Inflammatory bowel disease Lymphoma Parasitic and fungal infections Scleroderma

Diagnostic Criteria* Clinical symptoms of esophageal dysfunction > 15 eosinophils per high-power field (eos/HPF) in biopsy specimens Exclusion of GERD by a normal pH probe study or lack of response to high-dose proton pump inhibitors Exclusion of other disorders associated with similar clinical, histological, or endoscopic features * NASPGHAN / AGA Consensus Recommendations- Gastroenterology 2007;133:1342-1363

Role of Food and Aeroallergens 50% have history of atopy * 2 out of 3 have food or aeroallergen sensitivity ** Milk, egg, soy, wheat, seafood and peanuts most frequently implicated foods ** JPGN 48:30– 36, 2009, * Curr Opin Allergy Clin Immunol 2007;7:264–268

Clinical Symptoms Symptoms vary according to age: Feeding dysfunction (median age 2 years) Vomiting (median age 8 years) Abdominal pain (median age 12 years) Dysphagia (median age 13 years) Food impaction (median age 17 years) Many patients develop strictures over several years N Engl J Med. 2004;351(9):940

Natural History Liacouras et al. JPGN 48:30– 36, 2009

Dysphagia and Food Impaction Dysphagia is the most frequent symptom in older children Other complications include Esophageal food impaction esophageal stricture formation Presence of food impaction among adults with EoE ranges from 30%–55% Gastrointest Endosc 2006;64:313–319 Clin Gastroenterol Hepatol 2008;6:598–600

Upper Endoscopy Findings Normal in 20%* Abnormal findings (80%) Linear furrowing (vertical lines) White exudates, white specks, nodules Circular rings (felinization, trachealization) Linear shearing, crepe-paper mucosa Stricture (in proximal, mid or distal esophagus) *Eur J Gastroenterol Hepatol. 2006 Feb; 18(2):211-7

Diagnosis Endoscopic pictures showing rings (trachealization), white exudates, linear furrowing Arch Pathol Lab Med. 2010;134:815–825

Biopsy Procurement EoE is a patchy disease and sensitivity of diagnosis varies based on number of biopsies Recommendation is to obtain 2-4 biopsies each from both mid and distal esophagus* Using 15 eos/hpf as the threshold, the sensitivity of 2, 3 and 6 biopsies was found to be 84%, 97% and 100%, respectively** *J Allergy Clin Immunol 2011;128:3-20 **Am J Gastroenterol 2009; 104:716–721

Histopathology Consensus criteria Other criteria Peak eos count of >15 per 40x eos/HPF Other criteria Eosinophilic micro-abscesses - cluster of > 4 eos Superficial layering - preferential distribution of eos in the upper ½ to ⅓ of epithelium Basal zone hyperplasia - > 20% of epithelium Papillary elongation Lack of correlation between symptoms and histologic findings

Histopathology Esophageal Eosinophilia Arch Pathol Lab Med. 2010;134:815–825

Schematic representation of the characteristic histology of EoE* Histopathology Schematic representation of the characteristic histology of EoE* *Arch Pathol Lab Med. 2010;134:815–825

Treatment Acid suppression Dietary elimination Elemental diet Allergy evaluation Topical steroids Leukotriene inhibitors Systemic steroids and Biologics Esophageal dilatation

Acid Suppression Useful part of diagnostic evaluation GERD can coexist with EoE May help with symptoms Some patients have PPI-responsive esophageal eosinophilia and so EoE can be excluded in these patients* *J Allergy Clin Immunol 2011;128:3-20

Food Elimination Empiric 6 food elimination diet Based on milk, soy, eggs, wheat, peanuts/tree nuts, and seafood (6 most common foods) Foods are reintroduced with monitoring of symptoms and endoscopy/hisstopathology Skin prick and atopy patch-directed elimination Culprit foods identified and then eliminated 6-food elimination diet or targeted elimination leads to complete histologic remission in 50% of patients * A food was considered to cause EoE if its elimination led to resolution of esophageal eosinophilia or reintroduction led to reoccurrence of EoE. *J Allergy Clin Immunol 2012 Aug; 130 (2): 461 – 467. e500 18

Elemental diet Elemental amino acid-based diet Superior at inducing histologic remission compared with 6-food elimination and skin test–directed diets. Remission occurred in 96%, 81%, and 65% of patients on elemental, 6-food elimination, and directed diets. J Allergy Clin Immunol 2012;129:1570-8

Allergy evaluation and avoidance Evaluation by an allergist and/or immunologist recommended for all patients Skin prick testing (SPT) and atopy patch testing (APT) useful in effective avoidance/elimination strategies Evidence does not currently support serum specific IgE-based food allergen testing J Allergy Clin Immunol 2012 Aug; 130 (2): 461 – 467. e5 20

Topical Steroids Provide short term resolution of clinical and pathologic features Small risk of systemic side effects (1% absorbed) Esophageal candidiasis occurs in 15-20% after 3 months of therapy Fluticasone (MDI) and Budesonide (viscous) are most commonly used

Fluticasone Propionate Shown to be safe and effective in Pediatric randomized controlled trials ±* Dose: 220 - 440μg MDI swallowed daily without the use of a spacer No rinsing, eating or drinking for 30 minutes afterward, and then drink small amount of liquid *Gastroenterology 2006;131:1381–1391 ± Clinical Gastroenterology and Hepatology 2008;6: 165–73

Oral viscous Budesonide Good option in younger children (<4 yrs) Dosing: 1 mg - 2 mg of 0.5 mg/2ml Budesonide nebulizer suspension mixed with 10 gm of sucralose (Splenda® – 1 gm/packet) orally at bedtime Dosed according to height <5ft (1mg) or >5ft (2mg) No eating, drinking or rinsing mouth for 30 minutes, and then drink small amount of liquid * Gastroenterology 2010;139:418-429

Leukotriene Inhibitors May help symptoms in some patients Studies show no impact on esophageal eosinophilia Symptoms usually recur on discontinuation * Gut 2003 Feb; 52(2): 181-5

Oral Steroids and Biologics Systemic corticosteroids may be used for emergent situations (severe dysphagia, hospitalization, weight loss)* Chronic use of steroids in management of EoE results in systemic side effects, sometimes severe Mepolizumab and Reslizumab (anti-IL5) are biologics studied in trials for treatment of EoE Safety and sustained efficacy of biologics not fully established J Allergy Clin Immunol 2011;128:3-20

Esophageal Dilatation Used in symptomatic patients who have strictures with critical esophageal narrowing Increased risk of mucosal tearing and rarely, perforation during procedure After dilation, strictures with dysphagia recurs in half of the patients after 2 years* * Gastroenterology 2003;125:1660-1669

Summary EoE is an increasingly recognized esophageal disorder characterized dysphagia and in severe cases food impaction; characteristic endoscopic findings; and intraepithelial eosinophilia not responsive to PPI therapy Exact pathogenesis remains under investigation, but food allergens, aeroallergens, genetics and acid exposure have been implicated Accepted treatments include allergy testing/dietary changes, topical steroids, dilation, and PPI. Complications include esophageal strictures Based on current evidence, there does not appear to be malignant potential