E OSINOPHILIC E SOPHAGITIS O BJECTIVES  Identify the basic etiology and mechanism of EoE  Understand the relationship of EoE to food allergy  Discuss the pathogenesis, symptoms, diagnosis  Discuss current and future treatment strategies for EoE C ASE # 1  A 16y male is evaluated in the ED for chest discomfort of 2 hours duration that occurred after eating a large meal. He has difficulty swallowing and feels as though something is stuck in his chest. He is barely able to swallow his saliva and frequently spits into a cup. He has had 2 similar, but less severe, episodes in the past 6 months. He has a history of allergic rhinitis treated but no history of food allergy (anaphylaxis). Father has an esophageal stricture that requires repeat dilatation.  On PE, he is well developed and well nourished but uncomfortable. EGD shows multiple esophageal rings with raised white specks, longitudinal furrows, and friable esophageal mucosa. No strictures are detected. Histological exam of the mucosa shows intense inflammation of the lamina propria with more than 15 eosinophils per HPF. Q UESTION  Which of the following is the most appropriate management for this patient?  Endoscopic esophageal dilation  Leukotriene receptor antagonist therapy  Oral topical (swallowed) corticosteroids therapy  PPI therapy C ASE # 2  14 month F baby  Failure to thrive  Vomiting & refusal to take foods especially solids, on standard formula  Exclusive breastfed till 6 Mo, generally well other than moderate AD  OGD reveals thickened, furrowed esophageal mucosa with >50 Eos in proximal and distal Bx. W HAT TREATMENT WOULD YOU ADVISE  PPI  Predmix  Substitute formula with soy or protein hydrolysate  Elemental diet  Referral to Immunologist / allergist E OSINOPHILIC E SOPHAGITIS D EFINITION  A chronic, immune/antigen mediated esophageal disease characterized  clinically by symptoms related to esophageal dysfunction  histologically by eosinophil-predominant inflammation Liacouras C et al, J Allergy Clin Immunol 2011 A HISTORICAL PERSPECTIVE . . .  First described in 1978 but GORD was thought to be the driving force  More research done on GORD as the cause of EE   1982 Winter et al.  1985 Lee et al. Not until the 1990s was EoE described as a separate entity  1993 Attwood et al.  1995 Kelly et al E PIDEMIOLOGY  Mostly relegated to westernized world  More common in young males  50-70% with EoE also have atopy disease  Increasing in incidence   Not completely explained by increased awareness  May be associated with increased incidence of asthma, allergies Prevalence  0.5/100,000 in 1995  8.9/100,000 in 2004 E O E - N ATURAL H ISTORY  Lag of 4.3 years between onset of symptoms and diagnosis  Limited to the esophagus  Chronic disorder that cannot be outgrown  Chronic Persistent  Chronic Relapsing  Prolonged disease leads to remodeling of the esophagus  Not associated with premalignant or malignant transformation E O E - PATHOGENESIS E NVIRONMENTAL T RIGGERS  EoE association with atopic and allergic disorders  Seasonal variation in symptoms and diagnosis rates  Elemental diets result in clinical and histological improvement that reverse with reintroduction of foods  Priming with epicutaneous exposure to antigens can result in esophageal eosinophil recruitment in a mouse mode S EASONAL VARIATION IN D IAGNOSIS 150 eos/hpf 12 eos/hpf Adaptive Th2 cell mediated immune responses  Both IgE & non-IgE pathways involved  Principal Chemo attractants & cytokines involved  Eotaxin -3, IL-5, IL-13, GM-CSF, FGF-9  Patients with EoE have a striking increase in expression of eotaxin-3  Mice deficient in CCR3 were resistant to EoE  Eosinophils release major basic protein causing inflammation  Chronically causes dysphagia G ENETIC P REDISPOSITION  Familial Clustering well recognized  Possible susceptibility locus 5q22  GWS - SNP in eotaxin-3 identified using microarray technology   50x more elevated than normal controls Defects in filaggrin,thymic stromal lymphopoeitin (TSLP) and TSLP receptor also implicated as genetic risk factors Current Opinion in Allergy and Clinical Immunology 2010, 10:231–237 E O E - CLINICAL FEATURES M OST Age COMMON CLINICAL MANIFESTATIONS Clinical presentation Infant and Toddlers feeding difficulties, feeding refusal or intolerance, irritability, vomiting, failure to thrive School-aged children Abdominal pain, vomiting, GERD-like symptoms, difficulty swallowing, food aversion/selflimited diet, failure to thrive Adolescents Dysphagia, esophageal food impactions, nausea, GERD-like symptoms, self-limited diet Adult Dysphagia, esophageal food impactions Mirna Chehade and Seema S. Aceves Current Opinion in Allergy and Clinical Immunology 2010, 10:231–237 C HILDREN V S A DULTS  “GORD” symptoms  Chest pain-”with alcohol”  Abdominal pain, vomiting  Food impaction  Feeding dysfunction  Dysphagia  Coping mechanisms- avoid highly textured and bulky foods, cut food into small pieces, lubricating foods, extensive chewing / long meals S YMPTOM PROGRESSION WITH AGE D IAGNOSIS  Symptoms related to esophageal dysfunction  One or more esophageal biopsy specimens show 15 Eos/hpf (peak value)  minimum threshold for a diagnosis of EoE  Disease is isolated to the esophagus  other causes of esophageal eosinophilia should be excluded  Disease remit with treatments of dietary exclusion, topical corticosteroids, or both O THER CAUSES EXCLUDED Liacouras, et al, J Allergy Clin Immunol 2011 E O E V S . GORD  GORD  EoE – male predominance, atopy, food impactions  Both have eosinophilia and basal zone hyperplasia  Lower number of eosinophils and concentrated more distally  EoE involves the mucosa, submucosa, muscularis while GORD does not  pH probe, response to treatments  “PPI responsive EoE” E NDOSCOPY IN E OE  Stacked circular rings ("feline" esophagus)  Strictures (particularly proximal strictures)  Attenuation of the subepithelial vascular pattern  Linear furrowing  Whitish papules (representing eosinophil microabscesses)  Small caliber oesophagus N ORMAL A BNORMAL Concentric Rings Loss of Vascularity “T RACHEATIZATION ” E XUDATES Clustered Eosinophils or micro abscesses breaking through mucosa A DVANCED E O E Longitudinal furrowing Erosions at GE junction Histological Findings Mucosal eosinophilia Eosinophil microabscess formation Superficial layering of eosinophils Typical finding associated with EoE > GERD Extracellular eosinophil granules Epithelial desquamation Basal zone hyperplasia Rete peg elongation Dilated intercellular spaces Subepithelial fibrosis/sclerosis–lamina propria fibrosis Mastocytosis and mast cell degranulation CD8+ lymphocytes and B cells Normal esophagous Superficial layering of surface Eo EoE Microabcess A. Superficial layering B. Large microabscess C. Small microabcess A LLERGIC E VALUATION  EoE is an antigen-driven allergic condition  EoE patient - 28% to 86% of adults - 42% to 93% of pediatric Have another allergic disease  50% to 60% of patients with EoE have a prior history of atopy  Major of patients have sensitization to food allergens, aeroallergens, or both (SPT or Specific IgE ) Studies Atopic disease Evidence of IgE to Evidence of IgE to Aeroallergen Food Aceves et al, Asthma 47% J Clin Gastroenterol AR 40 % Vol 41, No 3, March Eczema 4% 2007 + aeroallergen RAST 44% + food RAST 60% Collins et al, Asthma 52% Clin Gastro and AR 68 % Hepato Vol. 6, No. 6 Eczema 44% AC 56 % + SPT aeroallergen 71% + SPT food 76% ROY–GHANTA et al, Asthma 26% Clin Gastro and AR 78% Hepato Vol. 6, No. 5 AD 4% Specific IgE Specific IgE for food aeroallergen 83% 86% ( Birch pollen ,Timothy ryegrass pollen Ragweed pollen , dust mite Pet dander ) Atopic disease Aeroallergen Specific IgE Food specific IgE Aceves et al J Clin Gastroenterol Vol 41, No 3, March 2007 Asthma 47% AR 40 % Eczema 4% + aeroallergen RAST 44% + food RAST 60% COLLINS ET AL Clin Gastro and Hepato Vol. 6, No. 6 Asthma 52% AR 68 % Eczema 44% AC 56 % + SPT aeroallergen 71% + SPT food 76% ROY–GHANTA ET AL Clin Gastro and Hepato Vol. 6, No. 5 Asthma 26% AR 78% AD 4% Specific IgE aeroallergen 86% ( Birch pollen ,Timothy ryegrass pollen Ragweed pollen , dust mite Pet dander ) Specific IgE for food 83% TOOLS FOR TESTING ALLERGIES   Skin prick testing (IgE mediated)  Standardized and very consistent results  Commonly identifies egg, milk, soy, wheat, peanuts, beans, rye, and beef Atopy patch testing (non-IgE mediated)  More variable in preparations and methodologies  Identifies corn, soy and wheat SPT + APT NPV PPV Peanut, beef, corn, chicken, potato and pork >96%  Milk 82%  Egg 61%  Egg and soy 93%  Other 17-42%  Wheat 88%  Milk 41%  Spergel JM et al.J Allergy Clin Immunol. 2012;130(2):461. P REDICTIVE VALUES FOR SKIN PRICK TEST AND ATOPY PATCH TEST FOR EOE  The combination of the 2 testing methods had an excellent NPV (88% to 100%) for all foods except milk, which was very low at 41%  Combination of SPT and APT in designing a diet plan has a high success rate for food elimination or food reintroduction in EE with the exception of milk. J Allergy Clin Immunol. 2012;130(2):461. S ERUM I G E MEASUREMENT AND DETECTION OF FOOD ALLERGY IN PEDIATRIC PATIENTS WITH E O E • serum IgE measurement detected more positive results than did skin prick testing. Specific IgE to milk was most common (43%) • low-titer IgE antibody may be useful in identifying relevant food sensitivities making a more directed approach to food avoidance possible Ann Allergy Asthma Immunol. 2010;104:496 –502. 10 M OST COMMON FOODS  Milk  Potato  Egg  Beef  Soy  Chicken  Wheat  Pork  Corn A EROALLERGENS Outdoor Allergens Indoor Allergens  64-93%  16 – 69%  Grass and tree pollen  Dust mites  Moulds  Dog, cat  Weeds  Cockroach E O E - M ANAGEMENT T REATMENTS  Dietary Management  Pharmacotherapy  Repeated dilatations FOR E OE D IET EXCLUSIONS IN  Elemental Diet  Elimination Diet E OE  Tailored – based on SPT+APT  Empirical – SFED (milk, egg, soy, wheat, nuts, fish)  Modifications or combinations of above E LEMENTAL  Gold standard  95-100% response rates  Unpalatable  Costly  Low in micronutrients, fiber  Many times tube feeding DIET S IX FOOD ELIMINATION DIET Gonsalves et al, Gastroenterology 2012  50 adults with EoE  6 weeks of SFED resulted in clinicopathological remission  Eosinophilia returned when diet liberalized S IX FOOD ELIMINATION DIET Lucendo AJ et al, JACI Feb 2013  67 adult patients, SFED induced remission 73.1%  Food triggers identified by sequential reintroduction and endoscopic biopsy  Most common food triggers- Milk, egg and wheat  Offending foods eliminated maintaining remission over 3 years  Little correlation between S.IgE/SPT and subsequent identification of offending food Lucendo AJ et al, JACI Feb 2013 Spergel et al, J Allergy Clin Immunol Jun 2012 P HARMACOTHERAPY  Topical corticosteroids  Montelukast  Fluticasone  Azathioprine  Budesonide  Biological agents  Oral Prednisolone  Anti – IL5  PPIs  Anti –TNF Study Design & No. of Pt Medication and Dosage Outcome Konikoff et al, 2006 RDBPC N = 36 Fluticasone propionate 2 puffs twice daily : All subjects received 220 mcg/puff( total 880mcg/d) * 3 mo (Ages 3–16 y) 1 o outcome : Prox EsoEo 65.9 + - 25.3 vs 1.4 + -1.1 eos/hpf [P =0.03] :Dist EsoEo 84.6 + -19.7 vs 19.6 + - 12.9 eos/hpf [P=0.04 ] 2o outcome :Resolution of vomiting FP vs placebo 67% vs 27%; [P =0 .04] :Improve endocopic finding (Furrow) [P=0.047] : reduce epithelial hyperplasia [ P= 0.01] :FP decreased the number of CD8 & mast cells in proximal and distal esophagus (P=0 .05) F LUTICASONE Alexander JA et al Clin Gastro Hepatol 2012 S UBEPITHELIAL F IBROSIS R EVERSAL WITH F LUTICASONE J. Allergy Clin. Immunol. 128(5), 1037–1046 (2011) B UDESONIDE Dohil et al Gastroenterology 2010  “Oral viscous” budesonide  Randomized placebo controlled study  OVB=15, placebo-9  Significant reduction in symptoms and eosinophilia Study Design Medication and & No. of Dosage Pt Outcome Dohil et al,2010 RDBPC N = 24 1 o outcome In OVB gr 87.6%  responder Reduce peak EsoEo all esophageal Levels proximal (P=0.0024), mid (P =0 .0001), and distal (P=0 .0001) when compared to baseline 2o outcome Upper gastrointestinal endoscopy score reduced 4.6 1.5 [P=0.0005] :Symptom score decrease from 3.51.2 [p=0.0007] : Epithelial &Lamina propria Eosinophilia & Fibrosis reduced [P=0.0035] Oral viscous budesonide * 3 mo Subjects <5 ft tall : 1 mg daily Subjects >5 ft tall : 2 mg daily (Age 1–17 mean 7.8 yr) M AINTENANCE STEROIDS  After induction of clinicopathological remission, topical corticosteroid therapy might need to be maintained  long-term therapy must be individualized for each patient  When topical steroids used chronically : side effects, growth should be carefully monitored  Candidiasis 15%, growth stunting in children (J Allergy Clin Immunol 2011;128:3-20.) A NTI – IL 5 T REATMENT Anti-interleukin-5 antibody treatment (mepolizumab) eosinophilic oesophagitis: a randomized, placebo controlled, double-blind trial in active  11 adult patients were randomized to mepolizumab (n = 5) or placebo (n = 6)  Mepolizumab gr. decrease mean EsoEo 54% vs placebo 5 %  But no complete resolution in any subject, no significant symptom improvement Gut 2010 ;59(1):21-30 R ESLIZUMAB  226 children (mean age-12 +/1 4)  3 doses and placebo  12 weeks  Histological response with treatment  Treatment and placebo symptom response Spergel JM et al, J Allerg Clin Immunol 2012 O THER TREATMENTS  Treatment of EoE with cromolyn sodium, leukotriene receptor antagonists, and immunosuppressive agents (azathioprine or 6MP) is not recommended  Anti–tumor necrosis factor (TNF) : one case report  Anti-IgE therapy (omalizumab) : no publish study, one case report (J Allergy Clin Immunol 2011;128:3-20.) E SOPHAGEAL D ILATION  Provides good relief from dysphagia  Reserve for those with strictures or rings  Downsides  High risk of perforation or tear  Does not treat the underlying cause  Repeat procedures often required T REATMENT S TRATEGIES  Induce clinical remission - yes  Induce histological remission   ?yes  What defines histological remission?  Does this prevent complications? Balance benefits of treatment (disease complications) with treatment complications and impact of treatment on quality of life. U NRESOLVED ISSUES  Importance of treating asymptomatic patients  Natural history of EoE and rates and predictive indexes of complications  Accuracy of skin prick and patch testing  Optimal end points of treatment  Biomarkers and molecular signatures that aid in the diagnosis of EoE  Lack of non-invasive or minimally invasive methods for diagnosis and follow up CME ACTIVITY  Please answer MCQs at the end of session  Self assessment exercise