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Eosinophilic Esophagitis: An Allergy Perspective

Eosinophilic Esophagitis: An Allergy Perspective. Daniel DeMerell, MD. Eosinophilic Esophagitis: An Allergy Perspective. Disclosure- none. Eosinophilic Esophagitis ( EoE ): An Overview. Definition of EoE Epidemiology of EoE Etiology of EoE Role of allergies in EoE

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Eosinophilic Esophagitis: An Allergy Perspective

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  1. Eosinophilic Esophagitis: An Allergy Perspective Daniel DeMerell, MD

  2. Eosinophilic Esophagitis: An Allergy Perspective • Disclosure- none

  3. Eosinophilic Esophagitis (EoE): An Overview • Definition of EoE • Epidemiology of EoE • Etiology of EoE • Role of allergies in EoE • Diagnosis of EoE • Treatment of EoE • Prognosis of EoE

  4. Eosinophilic Esophagitis (EoE) • First described as distinct entity related to foods in 1995 in 10 children with esophageal eosinophilia, refractory to acid suppression who then responded to elemental diet (Kelley et al.) • 2007 expert panel released consensus recommendations for EoE in children and adults (Furuta GT et al.). • Presence of clinical symptoms related to esophageal dysfunction • Isolated esophageal eosinophilia • >15 eos/hpf • Absence of other causes of esophageal eosinophilia (especially GERD) • Normal pH monitoring study of distal esophagus • Lack of response to high-dose PPI

  5. Eosinophilic Esophagitis:2011 Updated Definition • In 2011, expert panel updated consensus recommendation for children and adults • “Eosinophilic esophagitis represents a chronic, immune/antigen mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation” • Infiltration of eosinophils not affecting other areas of GI tract Liacouras CA et al. J Allergy Clin Immunol2011

  6. Eosinophilic Esophagitis • Definition is limited because mechanism(s) of EoE still not fully understood • Challenging to design and compare studies • Diagnosis and treatment is evolving as we learn about the mechanisms

  7. Epidemiology of EoE • Prevalence and incidence of EoE increasing • Prevalence of EoE ranges from 6-60 cases per 100,000 (Dohil R et al., Prasad GA et al.- Olmstead County, MN) • Therefore prevalence of EoE likely comparable to that of IBD, but less than that of celiac disease (Rothenberg et al 2009 ) • Not clear how much is also related to increase in endoscopy • Males: females 3:1 (genetic variant of the TSLP receptor on the X-chromosome in males?) • Seen in all ages • More commonly diagnosed in urban and suburban areas than rural (Spergel JM et al 2011)

  8. Epidemiology of EoE • Veerappan et al- found EoE in 6.5% of adults undergoing endoscopy in outpatient US military hospital (included large percentage of black patients) • Genetics (gene locus identified on chromosome 5q22- Rothenberg M et al. 2010) • Commonly seen in atopic individuals (approximately 75%) • Timing of diagnosis (and exacerbations)- increased in pollen season in some patients

  9. Symptoms of EoE • Dysphagia and feeding dysfunction • Food impaction • GERD like symptoms • Chest pain • Abdominal pain • Vomiting • Anorexia/early satiety LiacourasCA et al. J Allergy Clin Immunol2011

  10. Kapel et al. Gastroenterology 2008;134:1316

  11. Findings Associated With EoE Endoscopic/Radiologic • Esophageal rings • Stricture • Linear furrows • Longitudinal narrowing • Longitudinal shearing (crepe paper esophagus) • White exudates Histologic • Mucosal eosinophilia • Eosinophil micro abscess • Superficial layering of eos • Extracellular eos granules • Epithelial desquamation • Basal zone hyperplasia • Dilated intercellular spaces • Sub epithelial fibrosis/sclerosis • Mastocytosis and MC degranulation • CD 8 lymphocytes and B cells LiacourasCA et al. J Allergy Clin Immunol2011

  12. Differential Diagnosis of EoE • GERD • Eosinophilic gastrointestinal diseases • Celiac disease • Crohn’s disease • Infection • Hypereosinophilic syndrome • Achalasia • Drug hypersensitivity • Vasculitis • Pemphigus vegetans • Connective tissue disease • Graft-versus-host disease LiacourasCA et al. J Allergy ClinImmunol 2011

  13. Differentiating EoE From GERD • Difficult to separate into two distinct diseases • Possible relationships: • GERD causes esophageal injury with eosinophilia • EoE and GERD coexist but are unrelated • EoE causes or contributes to secondary GERD • GERD causes or contributes to EoE • A trial of PPIs, even when diagnosis of EoE is established, is recommended Spechleret al. Am J Gastroenterol2007

  14. Why The Increase In Allergic Diseases (Atopy)? • Genetics • Environment- allergen, pollution, chemical, pesticide, fertilizer exposure, environmental warming? • Hygiene hypothesis - Th1 vs. Th2 lymphocytes • Increased use of GERD medications- • Less acidic environment in gut leads to exposure to more intact proteins (altered mucosal absorption) which may affect processing of food antigens • Food antigen processing (i.e. cooking methods of peanuts can alter allergenicity)

  15. Hygiene Hypothesis:Why The Increase In Atopy Th2 cytokines- IL-4, IL-5, IL-13 Th1 cytokines- IFN-γ, IL-2, TNF-α www.fooddrugallergy.ucla.edu

  16. Why The Increase In Allergic Diseases (Atopy)? • Different routes of sensitization • Application of creams containing peanut oil to inflamed skin can sensitize to peanut (Lack G et al.) • Epicutaneous allergen sensitization potently primes for respiratory allergen-induced experimental EoE (Akei HS et al. Gastroenterology 2005) • Interesting in light of high percentage of EoE patients with atopic dermatitis • Connection between development of eosinophilic infiltration in respiratory tract and esophagus in response to external allergic triggers, but also to intrinsic Th2 cytokines(Rothenberg et al. Gastroenterology 2009)

  17. Why Are We Seeing An Increase In EoE? • Increased recognition • Chronic nature of EoE • Increasing atopic disease in general • Other as yet unknown factors

  18. Seasonal Distribution in Newly Diagnosed Cases of EoE in Adults • Retrospective review of newly diagnosed EoE patients 8/06-7/07 at Mayo Clinic • EoE more frequently diagnosed in spring (44%) and summer (24%) than fall (17%) and winter (15%) (in light of constant number of endoscopies done year round) • Also described in children (Wang FY et al.) • Implicates aeroallergens (and more specifically pollens) as potential etiologic factors in EoE • Patients with EoE have seasonal variations in symptoms (Onbasi K et al.) Almansa C et al.

  19. Food Allergy: Immunologic Spectrum • Anaphylaxis • Urticaria • Angioedema • Oral Allergy Syndrome IgE Mediated Mixed Non-IgE Mediated • Eosinophilicesophagitis • Atopic dermatitis (eczema) • Eosinophilicgastritis • Eosinophilic gastroenteritis • Celiac (IgA driven) • Food Protein Induced Proctitis • Food Protein Induced Enterocolitis • Food Protein Induced enteropathy Sampson H. et al.

  20. Mechanisms of EoE • EoE etiology- appears to be multifactorial • Immediate hypersensitivity(IgE against food/pollen proteins)(Gell and Coombs type I reaction) • Delayed type hypersensitivity (cellular- especially lymphocyte driven)(Gell and Coombs type IV reaction) • Mast cells have also been shown to play role • We don’t yet fully understand the complete mechanisms of EoE

  21. IgE Mediated Allergic Reactions:Require Sensitization and Re-exposure

  22. Food Allergies:The Facts On IgE Reactions • 6-7 million in U.S. suffer from food allergies • Food allergy is #1 cause of anaphylaxis in ED (over 50,000 cases anaphylaxis per year) • Estimated 180 deaths per year (majority to peanuts/tree nuts) • Almost a 20% increase in prevalence of food allergies from 1997-2007 • Peanut allergy affects >1% school aged children

  23. Oral Allergy Syndrome(Also Driven By IgE) • Oral pruritus with fresh raw fruits and vegetables (< 4% become systemic) • Occurs in subset of pollen allergic individuals • Birch- apple, apricots, peaches, carrots, cherries, kiwi, plums, hazelnuts • Ragweed- bananas, melons, cucumbers • Grasses- cherries, tomatoes, avocado, potatoes • Mugwort- melon, apple, peach, cherry • Very labile proteins- heating and gastric acid denature • Segment of EoE population has OAS (may be group with more relevant aeroallergen contribution, seasonal assoc.)

  24. EoE Mechanisms:Delayed Type Hypersensitivity (DTH) • Primarily lymphocyte driven (rather than antibody) • Atopy Patch Testing (APT) is used to identify delayed reactions to foods • Other examples of DTH include PPD used to test for TB, allergic contact dermatitis (nickel or poison oak reactions)

  25. EoE Mechanism:Delayed Type Hypersensitivity

  26. Mechanisms of EoE: Mast Cells • Esophageal mastocytosis and degranulation in EoE • Lead to dysmotility in children and adults associated with dysphagia • Produce cytokines that activate eosinophils and promote tissue remodeling • Mast cell-associated transcriptome may distinguish EoE patients from controls (future marker?) • Increased TGF-β1 associated with esophageal remodeling and fibrosis as well as dysmotility • Potential therapeutic target Aceves S et al. J Allergy Clin Immunol2010 AboniaJP et al. J Allergy ClinImmunol 2010

  27. Esophageal Cytokine Profile in EoE • Thus far, no reliable, noninvasive biomarkers for EoE, however: • Eotaxin-3– mRNA expression increased in EoE patients vs. controls (89% sensitivity with single biopsy) • Signals migration of eosinophils from vascular space into tissue • strongly correlated with tissue eosinophilia and mastocytosis • IL-13 • Tissue and serum expression levels of IL-13 correlate with tissue eosinophilia in EoE (and disease activity) • One of the most promising potential biomarkers for the disease • Induces eotaxin-3 production • IL-5 • Produced by mast cells, promote maturation and activation of eosinophils • Absence leads to deficiency of eosinophil number and function Blanchard C et al. Bhardwaj et al.

  28. The molecular pathogenesis of EoE. An allergic insult by either food antigens or aeroallergens initiates the transition of the esophagus from a normal (NL) to an EoE phenotype through the production of TSLP by the esophageal epithelium. TSLP-activated dendritic cells induce a robust TH2 response and enhanced IL-13, which in turn mediates marked dysregulation of gene expression (the EoE transcriptome). Enhanced eotaxin-3 (CCL26) secretion by the esophageal epithelium promotes eosinophil migration from the blood into the tissue. Eosinophil- and mast cell–derived TGF-β along with IL-13 and IL-5 act on fibroblasts and mast cells and stimulate the fibrotic response. Loss of FLG expression, partially because of IL-13 overproduction, genetic variants, or both, might further enhance or even predispose patients with EoE to antigen exposure and exacerbate TH2 inflammation (and promote food allergen uptake) Sherill JD et al.

  29. Esophageal Remodeling In EoE • Esophageal biopsies show increased TH2 cytokines (IL-5, IL-4, IL-13) and TH1 cytokines (IFN-γ) • Also increased eosinophil chemo attractants • eotaxin-1, eotaxin-3, and TNF-α • Esophageal remodeling in EoE is similar to allergen induced airway remodeling in patients with asthma • EoE patients- increased fibrosis and vascularity vs. controls and patients with GERD • TGF-β(expressed by eosinophils) promotes fibrosis and remodeling in sub epithelia in EoE AcevesS et al. J Allergy Clin Immunol2007

  30. Diagnosis of Food Allergy • Detailed history and PE • possible causal foods, quantity ingested, time course, other contributing factors (exercise, ASA, EtOH), possible cross contamination • Food specific IgE testing • Skin testing • Serum specific testing • Basophil activation/release assays • Atopy patch testing (eosinophilic GI diseases, AD) • Oral Challenge (DBPCOC, Single blinded, or open)

  31. Diagnosis Food Allergy (IgE Mediated): Skin Prick Testing • Small amount of the allergen is placed on top of the skin • Skin is “scratched” to introduce allergen percutaneously • Wheal and flare is measured using positive and negative controls with results in 20 minutes • Skin prick tests (SPT) generally have better sensitivity and predictability than serum specific testing and are the preferred initial diagnostic approach (Bernstein IL et al.) • For IgE food allergy- NPV>95%, PPV 50% • For EoE- NPV 58-95%, PPV 33-95%

  32. Skin Testing

  33. Delayed Reactions To Foods:Patch Testing (APT): • Measures delayed type hypersensitivity (allergic contact dermatitis) • Food slurry is prepared and placed in shallow aluminum wells (Finn Chambers) and taped on back touching the skin for. • The patches are removed at 48 hours (preliminary read) and measured at 72 hours (final read) using standard patch test protocols. • Turjanmaa K et al. • Spergal JM et al. Ann Allergy, Asthma, Immunol 2005

  34. Patch Testing (APT)

  35. Allergy Testing For EoE • Skin testing (combination of SPT and APT to foods and SPT to aeroallergens best) • General screen includes- cow’s milk, hen’s egg, soy, wheat, rice, corn, oat, barley, potato, beef, chicken, pork, turkey, peanut, peas, green beans, squash, carrots, peach, apple (+/- fish, shellfish, tree nuts, and other foods that are common part of individual's diet) Spergel JM et al. J Allergy Clin Immunol2007;119:509-11 Bernstein IL et al. Ann Allergy Asthma Immunol 2008;100:s1-148

  36. Food Allergy Tests That Are Unproven or Disproved • Food specific IgG or IgG4 (IgG “RAST”) • May actually be more representative of foods the gut has recently seen or tolerates • Provocation/neutralization • Cytotoxic tests/ hair analysis • Applied kinesiology (muscle response testing) • Electro-dermal testing Bernstein IL et al.

  37. Treatment Of EoE • What are goals of treatment? • clinical improvement • histological normalcy • reversal of fibrosis (remodeling) • prevention of disease progression • Drugs, diet, and dilation

  38. Treatment of EoE- Medications • Medications • Corticosteroids • Proton pump inhibitors • Anti-IL-5 mAb- (reslizumab and mepolizumab) decreased esophageal eosinophilia but limited clinical response (studies ongoing) • Also suggests that eosinophilia may not be the key pathologic effector (?part of a larger Th2 response) • Medications not recommended • Cromolyn sodium- mast cell stabilizer • Leukotriene receptor antagonists (monteleukast, zafirlukast) • Immunosuppressants (azothiaprine, 6-MP)- risks outweigh benefits • Spergel JM et al. J Allergy Clin Immunol2012 • Assa’ad et al. Gastroenterology 2011 • Straumann et al. Gut 2010

  39. Treatment of EoE • Food elimination (elemental diet vs. targeted food diet) • Esophageal dilation- can provide immediate and long-lasting relief of dysphagia in patients with stricture (doesn’t address esophageal inflammation)- more data needed

  40. Treatment of EoE: Corticosteroids • Systemic corticosteroids- for severe dysphagia, hospitalization, inability to eat, weight loss • Significant long term risks- infection (esp fungal), HTN, osteopenia/osteoporosis, glucose intolerance, cataracts, adrenal suppression • Localized corticosteroids • Swallowed fluticasone 220 mcg- 1-2 puffs bid or viscous budesonide 1 mg bid • Disease recurs with drug cessation • Patients with more significant atopy may be less responsive • Steroid resistance in minority of patients (as seen with other atopic diseases like asthma)

  41. Treatment of EoE: Proton Pump Inhibitors • Cohort of unselected adults referred for endoscopy due to upper GI symptoms with proximal esophageal eosinophilic infiltrate • Baseline endoscopy followed by Rabeprazole 20 mg bid for 2 months, then endoscopy repeated • 75% achieved clinicopathological remission with PPIs • 50% of patients with EoE phenotype responded to PPIs • Interestingly, pH monitoring was poorly predictive of PPI response. • Potential mechanisms of PPI response • Placebo effect • Treat concurrent GERD • Acid hypersensitivity • Anti-inflammatory effect of PPIs Molina-Infante J et al.

  42. Treatment of EoE:Dietary Intervention • Elemental Diet-restricted to amino-acid based formula (Elecare, Neocate, or Eo28 Splash) • Targeted elimination diet • Based on allergy testing (SPT/patch testing (APT)) • Empiric elimination diet • Also called 6 Food Elimination Diet (SFED) • Avoidance of most common food allergens • milk, egg, wheat, soy, nuts (peanuts/tree nuts), and seafood(fish and shellfish)

  43. Treatment of EoE: Dietary Intervention • Remember to stop topical corticosteroids before starting diet to allow recurrence of symptoms in order to document clinical effectiveness of diet • Complete removal of the food(s) for 8-12 weeks • If possible, repeat endoscopy at end of elimination trial (consideration of cost, coverage, risk) • If clinicopathologic improvement, then add foods back one at a time • Clinical trials often repeat endoscopy after each food reintroduced, but not always practical

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