6/9/215 Eosinophilic Esophagitis: The New Kid on the Block Consultant: Takeda Disclosures Stuart Jon Spechler, M.D. Chief, Division of Gastroenterology, VA North Texas Healthcare System; Co-Director, Esophageal Diseases Center, Professor of Medicine, Berta M. and Cecil O. Patterson Chair in Gastroenterology, UT Southwestern Medical Center Eosinophilic Esophagitis (EoE) Eosinophils infiltrate esophageal squamous epithelium, releasing secretory products that mediate: Tissue damage Tissue remodeling Symptoms Incidence of Eosinophilic Esophagitis (EoE) in Olmsted County, Minnesota Incidence per 1, (Age and Sex Adjusted) 12 1 8 6 4 2 1976-198 1981-1985 1986-199 1991-1995 1996-2 21-25 Prasad. Clin Gastroenterol Hepatol 29;7:155. 1
6/9/215 EoE in the United States Prevalence 5-1 per 1, - Similar to ulcerative colitis Dellon E. Clin Gastroenterol Hepatol 214;12:589. Most common cause of food impaction in patients seen in ER Sperry S. Gastrointest Endosc 211;74:985. Health-care cost $.5-1.4 billion per year Jensen E. Am J Gastroenterol 215;11:626. There Is No Diagnostic Gold Standard for Eosinophilic Esophagitis No single clinical, laboratory, endoscopic, or histological feature establishes the diagnosis of EoE. Children Vomiting Feeding intolerance Feeding aversion Failure to thrive EoE Symptoms Adults Dysphagia Food Impaction Chest Pain Heartburn Upper abdominal pain Symptoms are not specific. EoE Endoscopic Reference Score (EREFS) Exudates (plaques) None of these findings are specific for EoE Rings Esophagus (trachealization) appears normal in ~1% Edema (pallor) Furrows (vertical lines) Strictures Hirano I. Gut 213;62:489. 2
6/9/215 EoE Histology 15 eosinophils per HPF Eosinophil microabscesses Basal zone hyperplasia Dilated intercellular spaces Subepithelial fibrosis Epithelium Subepithelial fibrosis The finding of 15 eosinophils per HPF has no established biological importance. Histological findings are not specific. EoE Affects Children and Adults of All Ages in All Racial and Ethnic Groups Earlier studies suggested a predilection for whites Recent studies suggest whites and African Americans affected with similar frequency Sperry SLW. Am J Gastroenterol 212;17:215. Furrows, rings uncommon in blacks Bohm M. J Clin Gastroenterol 211. Reports of EoE from US, Canada, Australia, New Zealand, Europe, Mexico, India, Israel, Saudi Arabia, Iran, Japan, China EoE Affects Both Sexes Male:Female = 3:1 Eosinophilic Esophagitis Conceptual Definition 211 Eosinophilic esophagitis is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Liacouras CA et al. J Allergy Clin Immunol 211;128:3-2. 3
6/9/215 Eosinophilic Esophagitis Consensus Diagnostic Guideline 211 EoE is a clinicopathologic disease. Clinico: Symptoms related to esophageal dysfunction Pathologic: 1 esophageal biopsy shows eosinophilpredominant inflammation with 15 eos per HPF (recommend 2-4 biopsy specimens from both proximal and distal esophagus) Disease should be isolated to the esophagus Disease should remit with treatments of dietary exclusion, topical corticosteroids or both Liacouras CA et al. J Allergy Clin Immunol 211;128:3-2. Incidence of Eosinophilic Esophagitis (EoE) in Olmsted County, Minnesota Incidence per 1, (Age and Sex Adjusted) 12 1 8 6 4 2 1976-198 1981-1985 1986-199 1991-1995 1996-2 21-25 Prasad. Clin Gastroenterol Hepatol 29;7:155. Hypotheses Proposed to Explain Recent Appearance and Rising Incidence of EoE Hygiene Hypothesis encounters with infectious stressors in childhood leads to allergies in adults Changes in Food Composition Pesticides, fungicides, fertilizers, additives, processing, packaging Changes in Environmental Exposures Pollution Antisecretory Medications Incidence of Eosinophilic Esophagitis (EoE) in Olmsted County, Minnesota Incidence per 1, (Age and Sex Adjusted) 12 1 8 6 4 2 1976-198 1981-1985 1986-199 Proton Pump Inhibitor (PPI) Use Becomes Widespread 1991-1995 1996-2 21-25 Prasad. Clin Gastroenterol Hepatol 29;7:155. 4
6/9/215 Peptic Digestion of Potential Protein Allergens Undigested Protein Allergen Delivered to Duodenum PPI Pepsin (Acid) PPI Pepsin (Acid)? Allergic Response? Protein Allergen Protein Allergen Untersmayr. J Allergy Clin Immunol 28;121:131. Hypothesis: Acid reducing medications contribute to the development of eosinophilic esophagitis Raise gastric ph pepsin not active Allergenic peptides not degraded in the stomach PPIs increase gastric mucosal permeability - Facilitates uptake of undegraded peptide allergens and exposure to immune cells Effects on gut microbiome Merwat and Spechler. Am J Gastroenterol 29;14:1897. Evidence that Eosinophilic Esophagitis is an Allergic Disorder 5-6% of patients have history of atopic disease (rhinitis, asthma, atopic dermatitis) Most patients exhibit sensitization to food and/or aeroallergens - 15% have food anaphylaxis During oral immunotherapy for food allergy, 3% of patients develop EoE In animal models, EoE can be induced by allergen sensitization Dramatic response to elemental diet 5
6/9/215 If EoE is caused by food allergy, then why do eosinophils home to the esophagus? RNA Microarray Analysis of Esophageal Biopsies EoE Patients Abnormally Express 1% of Genome 23 Genes Downregulated 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 1 11 12 13 Controls Pts. with EoE 344 Genes Upregulated Eotaxin-3 ( >5-Fold) Blanchard. J Clin Invest 26;116:536 Immune System Activation Th1 and Th2 Differentiation Antigen Activate Immune System Naive CD4+ T Cells Th1 (T-helper 1) TNF-β, IFN-Ɣ Antigen Presenting Cell Allergic Th2 Disorders (T-helper 2) IL-4, IL-5, IL-13 IL-13 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients Eotaxin-3 (pg/ml per 25, cells) Eotaxin-3 is a potent eosinophil chemoattractant Unstimulated IL-13 (1 ng/ml) EoE1-T p<.1 EoE2-T Cheng E et al. Gut 213;62:824. 6
6/9/215 IL-4 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients Eotaxin-3 (pg/ml per 25, cells) Eotaxin-3 is a potent eosinophil chemoattractant Unstimulated IL-4 (1 ng/ml) p<.1 Eosinophilic Esophagitis Pathogenesis Model (Genetically-Susceptible Individual) eosinophil production, activation, recruitment Food allergen activates immune system Th2 Response IL-5 IL-13 IL-4 esophageal production of eotaxin-3 eotaxin-3 EoE1-T EoE2-T Cheng E et al. Gut 213;62:824. AGA Institute 27 Definition of EoE Gastroenterology 27;133:1342. A primary disorder of the esophagus characterized by UGI symptoms, esophageal biopsy 15 eos/hpf, and the absence of pathologic EoE Eosinophilic Esophagitis Possible Reasons for the Association of and Esophageal Eosinophils causes mild eosinophilia (<7 eos/hpf) and EoE co-exist but are unrelated EoE contributes to or causes Eosinophil secretory products alter esophageal motility and permeability, and induce remodeling contributes to or causes EoE EoE Reflux might cause esophageal mucosa to produce chemokines that attract eosinophils PPIs might Increased esophageal permeability might expose help these deep layers of esophageal epithelium to antigens EoE patients Spechler, Genta, Souza. Am J Gastroenterol 27;12:131. EoE EoE 7
6/9/215 A trial of PPI therapy is recommended for patients with eosinophilic esophagitis, even if the diagnosis seems clear-cut. Spechler S, Genta R, Souza R. Am J Gastroenterol 27;12:131. Rationale for a Trial of PPI Therapy in Patients with Esophageal Eosinophilia PPIs only affect gastric acid secretion Only acid-peptic disease can respond to PPIs Response to PPIs = PPI-Responsive Esophageal Eosinophilia Reflux Have typical EoE symptoms and histology Do not have by endoscopy or ph monitoring Exhibit a clinical and histological response to PPIs Possible Explanations for PPI-Responsive Esophageal Eosinophilia 1) Patients have with acid reflux causing esophageal eosinophilia, even though endoscopy and ph monitoring are normal. Non-Erosive Reflux Disease (NERD) 2) Patients have EoE (or an EoE-like disorder) that responds to anti-inflammatory effects of PPIs (independent of their effects on acid inhibition). 8
6/9/215 Eotaxin-3 (pg/ml/25k cells) Omeprazole Blocks Th2 Cytokine-Stimulated Eotaxin-3 Secretion in Squamous Cells from EoE Patients 4 35 3 25 2 15 1 5 Unstimulated Omeprazole (5µM) IL-13 (5ng/ml) IL-4 (1ng/ml) IL-13+Omeprazole (OME) IL-4+Omeprazole (OME) OME EoE1-T # OME p<.5 compared to IL-13 alone # p<.5 compared to IL-4 alone OME EoE2-T Cheng E et al. Gut 213;62:824. # OME Effects of Lansoprazole on IL-4-Stimulated Eotaxin-3 Protein Secretion in EoE Squamous Cell Lines Eotaxin-3 (pg/ml) 4 3 2 1 EoE1-T 2 a class effect of PPIs. + + 4 3 Inhibition of IL-4-stimulated eotaxin-3 secretion may be Control IL-4 1 µm 5 µm 1 IL-4 +Lansoprazole EoE2-T Control IL-4 1 µm 5 µm + + IL-4 +Lansoprazole Zhang X et al. PLoS One 7:e537, 212 Topical Steroid Therapy for EoE (Fluticasone, Oral Viscous Budesonide) RCTs show that topical steroids significantly reduce esophageal eosinophil levels Most patients experience symptomatic relief during treatment with steroids Symptoms recur frequently when steroids are stopped Limited data on efficacy and safety of long-term steroid therapy for EoE Topical Steroid Therapy for EoE in Adults Fluticasone 2-4 puffs (22µg/puff) BID, after breakfast and dinner Do not use spacer (designed for lung delivery) Inspire deeply first, depress inhaler, swallow Do not eat or drink for at least 3 minutes 9
6/9/215 Randomized Trial: 8 weeks of Fluticasone (44 µg BID) or Esomeprazole (4 mg QD) for Esophageal Eosinophilia 42 adults with 1 symptom (dysphagia, food impaction, heartburn) 15 eosinophils per high power field on esophageal biopsy 24-hour esophageal ph monitoring 8 patients with Eosinophils/HPF 1 8 6 4 2 P=.12 No P=.174 P=.174 1 8 6 4 2 Dysphagia Score Before After Before After Before After Before After Fluticasone Esomeprazole Fluticasone Esomeprazole 8 6 4 2 P=.162 No 8 6 4 2 P=.1 Moawad FJ. Am J Gastroenterol 213. Randomized Trial: 8 weeks of Fluticasone (44 µg BID) or Esomeprazole (4 mg QD) for Esophageal Eosinophilia Fluticasone and esomeprazole have similar effects on esophageal eosinophilia. Esomeprazole is superior to fluticasone for dysphagia. Eosinophils/HPF 1 8 6 4 2 P=.12 No P=.174 P=.174 1 8 6 4 2 Dysphagia Score Before After Before After Before After Before After Fluticasone Esomeprazole Fluticasone Esomeprazole 8 6 4 2 P=.162 No 8 6 4 2 P=.1 Moawad FJ. Am J Gastroenterol 213. Reflux Proton Pump Inhibitors (PPIs) and Esophageal Eosinophilia in and in Eosinophilic Esophagitis (EoE) PPIs have anti-secretory (gastric acid inhibitory) effects that might be beneficial both for and for EoE. PPIs have anti-inflammatory effects (independent of their anti-secretory effects) that might be beneficial both for and for EoE. For patients with esophageal symptoms and eosinophilia, a clinical and/or histological response to PPIs - Does not rule in - Does not rule out EoE A trial of PPI therapy is recommended A trial of PPI therapy is for patients with symptomatic recommended for patients with esophageal eosinophilia, even if the eosinophilic esophagitis, even if diagnosis of eosinophilic esophagitis the diagnosis seems clear-cut. seems clear-cut. Cheng Spechler E, Souza S, Genta R, Spechler R, Souza S. Gastroenterol R. Am J Gastroenterol Clin North 27;12:131. Am 214;43:243. 1
6/9/215 Approaches to Diet Therapy for EoE Directed elimination diet Based on skin prick testing 46% success (95% CI, 35-56%) Empiric elimination diet Prohibit most common food allergens (milk, soy, eggs, wheat, nuts, seafood) 72% success (95% CI, 66-78%) Prohibit 4 foods 54% success Molina-Infante. Rev Esp Enferm Dig 215;17:1639. Elemental diet Use amino acid-based formulas 91% success (95% CI, 85-96%) Arias A. Gastroenterology 214;146:1639. Management of EoE 215 Suspected EoE ( 15 eos/hpf) Symptoms Resolve Trial of PPI BID 4-8 weeks Dx: or PPI- Symptoms Persist Responsive Eosinophilia Dx: EoE Continue PPI Rx Stop PPI or consider ph testing Directed or Empiric Elimination Diet Symptoms Symptoms Resolve Persist Continue Diet Rx Symptoms Topical Steroids 6-8 weeks Resolve Symptoms Persist Follow, Resume Steroids PRN Rule Out Infection Dysphagia Persists (Candida, HSV) Esophageal Stenosis Esophageal Dilation Modified from Aceves, Furuta, Spechler. Gastrointest Endosc Clin N Am 28;18:195 Photo by S. Spechler 11