Slide 1

Paul J. Ufberg DO, MBA Maine Medical Center 3/22/15 8 AM

Slide 2

No conflicts to disclose NASPHAN Slides included in this presentation I like to treat EoE I think MMC should develop an Eoe Clinic with multi-specialty teams to include GI, Allergy, social workers and nutritionists

Slide 3

Recognize the increasing burden and significance of EoE Understand the criteria for diagnosis and basic pathophysiology of the disease Treatment options Discussion of future research

Slide 4

11 year old white male Chief complaint of abdominal pain Diffuse Always Worse for the last 6 month Food (?) are triggers Debilitating Limiting foods Nausea but no vomiting No diarrhea Seen by PCP multiple times Thought to be: Infection Post infection Reflux/gastritis Dyspepsia Functional pain Valley fever (AZ) Celiac disease Constipation Allergy

Slide 5

Always a difficult to feed child Labelled as GER at 6 months Never really spit up Weight gain at 10 th percentile throughout life Never sick but always run down Deteriorating in school work Eat and pain Dont eat and miserable ROS: Asthma Home inhaler never used Otherwise unremarkable Strong family history Asthma Atopy Exam: unremarkable

Slide 6

Lab workup was unremarkable CBC CMP Inflammatory markers Celiac panel Multiple RAST panels 2 to 3 panels Radiology unremarkable UGI SBFT CT Abdomen Trial of a PPI and miralax for 1 month with no improvement

Slide 7

Marked changes consistent with Eoe 60-80 Eoe/hpf in distal esophagus 40 Eoe/hpF in proximal esophagus Normal stomach 2-3 eosinophils/hpf in duodenum

Slide 8

Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:320.

Slide 9

Slide 10

Slide 11

Slide 12

Slide 13

Slide 14

Now what?

Slide 15

Slide 16

Slide 17

EoE first described in the late 1970s 1985 first case series By 1995 more robust description Distinct Triggers mechanisms explored Separate disease or part of a spectrum? Cincinnati Childrens retrospective 1991 2003 315 total cases of Eoe in one Ohio County Only 2.8 % were identified prior to 2000 From 2000-2003 Incidence 1 in 10,000 Prevalence 4.3 in 10,000 CHOP there was a 35- fold increase in newly diagnosed EE cases 1994 - 2 case 2003 - 72 cases

Slide 18

Slide 19

Slide 20

EE can present at any age ~50 cases/100,000 in patients under 20 years old Male predominant 3:1 More common in Non-Hispanic whites Atopy is common Food/environmental allergy Allergic rhinitis Eczema Asthma

Slide 21

Figure 1 Clinical Gastroenterology and Hepatology 2014 12, 589-596.e1DOI: (10.1016/j.cgh.2013.09.008)

Slide 22

Manifestations may vary with age Infants and toddlers may be poor feeders School aged children may have vomiting and pain Chest or abdominal pain Frequently appears like GER Vomiting tends to be random Adolescents tend to have dysphagia or food impaction Dysphagia is also most common in adults Choking, gagging, sticking Excessive drinking Impaction

Slide 23

103 Pediatric Patients with EoE SymptomMedian AgeNo. (%) Feeding disorder2.0 (1.26.2)14 (13.6) Vomiting8.1 (3.512.3)27 (26.2) Abdominal pain12.0 (9.615.2)27 (26.2) Dysphagia13.4 (10.016.7)28 (27.2) Food impaction16.8 (13.719.6)7 (6.8) Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004;351:9401.

Slide 24

Record review from 1993-2009 Radiology reports of food impaction UGI Esophogram Identified 43 patients with impaction 27/43 (63%) had an EGD 23 of 27 had EoE 28/43 (63%) - male Diniz, L Causes of Esophageal Food Bolus Impaction in the Pediatric Population Dig Dis Sci (2012) 57:690693

Slide 25

CHOP cohort of 620 patients 2/3 of Eoe patients had atopy Asthma - 231 (37%) Allergic rhinitis- 243 (39%) Atopic dermatitis - 78 (13%) Prevalences of atopy diseases 3X higher than expected in the general population 60-70% of Eoe have other atopic diseases Brown-Whitehorn, T, The link between allergies and eosinophilic esophagitis: implications for management strategies, Expert Rev Clin Immunol. 2010 January 1; 6(1): 101

Slide 26

EE and Atopic disease US prevalence of asthma and atopic dermatitis in the 1990s and 2000s, expressed as a percentage Brown-Whitehorn, T, The link between allergies and eosinophilic esophagitis: implications for management strategies, Expert Rev Clin Immunol. 2010 January 1; 6(1): 101

Slide 27

Slide 28

Slide 29

Long term outcome of EoE is still unclear Concern for fibrosis and subsequent strictures due to remodeling of the esophagus Adult study of patients with EoE 29 of 30 patients had dysphagia 11 of 30 needed dilations All had persistent Eosinophilia 86% of adults had esophageal structural changes. 67% had narrowing on radiographic studies

Slide 30

Slide 31

Slide 32

Slide 33

Slide 34

Slide 35

Slide 36

Initial guidelines mainly by pediatric specialists Diagnostic guidelines Clinical symptoms of esophageal dysfunction 15 Eosinophils in 1 high- power field Lack of responsiveness to high-dose proton pump inhibition (up to 2 mg/kg/day) Normal pH monitoring of the distal esophagus Rule out other causes of Eosinophilia Gastroesophageal reflux disease Crohns disease Connective tissue disease Hypereosinophilic syndrome Infection Drug hypersensitivity response Furuta GT, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007;133: 134263. 133:1342-63, 2007

Slide 37

Doubling of papers on Eoe over 4 years Poor use of the recommendations from 2007 1/3 of physicians were following guidelines Many doctors not using clinical criteria Time to consider a revision

Slide 38

Larger physician panel with more adult and pediatric representation 33 physicians 6 months Focus on the chronicity of disease Change of Term EE becoming Eoe Maintain threshold number of 15 eosinophils/hpf In most cases Therapeutic approaches Recognition of PPI Responsive disease

Slide 39

What is Eosinophilic Esophagitis (Eoe)? EoE is a chronic immune or antigen mediated disorder causing esophageal inflammation. It is associated with esophageal dysfunction resulting from severe eosinophil-predominant inflammation. Gastric and duodenal mucosa - normal Esophageal eosinophilia and symptoms do not respond to high dose Proton Pump Inhibitor (PPI) therapy

Slide 40

Esophageal biopsy is needed for diagnosis Pathologically 1 or more biopsy containing 15 eosinophils/hpf is considered threshold Earlier literature considered 20 Eos/hpf More biopsies the better 1 biopsy -sensitivity 73 % 2 biopsies 84% 3 biopsies 97%

Slide 41

Slide 42

Peak eosinophil count Eosinophilic granules Layering of eosinophils Micro abscesses Basal cell hypertrophy Fibrotic changes These findings may be consistent with EoE without 15 Eos/Hpf Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:320.

Slide 43

Considered to be distinct from EoE Possibly a subset of the disease Progression? Treated with high dose PPI Thought to be related to: GERD treated with acid suppression Anti-inflammatory effect from PPI Some combination of multiple factors

Slide 44

Slide 45

Slide 46

Slide 47

Familial clusters of Eoe and atopy Increased incidents in 1 st degree relatives 50-90% of patients with Eoe have atopy ~ 75% have a family history of atopic disease Chromosome loci identified 5q22 Harbors the Thymic stromal lymphopoietin (TSLP) Genetic variant of TSLP was found on X chromosome Increased atopic disease with 5q22 changes

Slide 48

Chromosome 2p23 - CAPN14 region 2 fold increase expression in patients with Eoe specifically in esophagus Up regulated in disease states Induced by IL-13 Kottyan, Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease, Nature Genetics, doi:10.1038/ng.3033; July 2014

Slide 49

Eoe Vs. GERD Increased Eotaxin-3 and Interleukin-5 (IL-5) Eotaxin-3 is a chemoattractant for Eosinophils IL-13 likely stimulants the Eotaxin T-Helper Cells 2 and multiple IL involved IL-5 and IL-13 has been shown to cause esophageal inflammation in mouse models Collagen deposition component as well TGF-B is involved

Slide 50

Straumann, Pediatric and adult eosinophilic esophagitis: similarities and differences Allergy Volume 67, Issue 4, pages 477490, April 2012

Slide 51

Majority of patients with Eoe have food allergy (s) Often not IgE mediated 5.7-24% have food induced anaphylaxis Average 4-5 foods (categories) Typical allergens Milk # 1 Egg and Soy Wheat, Corn and Beef Chicken Peanuts, Rice, Potato Oat, Barley, Turkey, Pea

Slide 52

Seasonal variation of Eoe Decreased Eoe in the winter Increase during grass and pollen season In adults increased new diagnosed Eoe in spring Aeroallergens with age Mold, dust mites and cockroaches

Slide 53

Slide 54

Slide 55

What is the goal of therapy? Clinical improvement Improve symptoms and Quality of life Histologic improvement Prevent complications/remodeling of esophagus Multiple endoscopies and medications Endoscopic improvement Prevent complications Multiple endoscopies and medications All Three?? End points are not clear End points dont always correlate with each other

Slide 56

PPI therapy Diet changes Focused Empiric Elemental Diet Steroids Other

Slide 57

Distinguish Eoe from PPI RE GERD can cause eosinophilia but not as severe as Eoe GERD and Eoe are not mutually exclusive Symptomatic patients should be given a trial of PPI High dose PPI up to 1mg/kg BID 3 months of therapy PPI therapy alone is insufficient to treat Eoe

Slide 58

Slide 59

PPI therapy Diet changes Focused Empiric Elemental Diet Steroids Other

Slide 60

Milk Most common allergen Consider avoiding

Slide 61

Strong association with food allergies Remove likely trigger foods Trial and Error Self directed Clinical experience Allergy testing Skin prick Patch testing RAST testing inaccurate

Slide 62

Pros Keep most of the diet intact More specific Effective Cons Delayed reactions to foods Persistence of reactions Testing can be difficult to interpret Confounding variables

Slide 63

Removal of most common food allergens Six food elimination diet Milk, Soy, Wheat, Egg, Peanuts/Nuts and Fish Studies have demonstrated a 75% improvement Consider nutritionist to assist with these changes

Slide 64

PROS Fairly easy to initiate No testing needed Good results CONS Hard to maintain May be removing unnecessary foods May not be removing all triggers Nutritional issues

Slide 65

Amino acid based formula alone Can be flavored Some beverages allowed Dum Dum or Smarties - OK Symptomatic improvement in the first 3-6 weeks 95% response histologically and clinically No medications needed May be able to reintroduce foods slowly back into the diet Symptoms may return

Slide 66

Slide 67

PROS Full nutrition Effective No medications Can get creative CONS No foods Quality of life issues Bad taste Often requires alternative feeding option Expensive

Slide 68

Slide 69

Nutritionist involvement is important Repeat endoscopy timing Variable Usually need frequent follow ups Reintroduction of foods can be considered after normal biopsy Patients usually have multiple (4-5) allergies 25% may be severe and react to most (ALL) foods Keep in mind the seasons

Slide 70

Slide 71

Slide 72

PPI therapy Diet changes Focused Empiric Elemental Diet Steroids Other

Slide 73

Improve the clinicopathologic features of EoE Effective therapy as topical therapy Systemic steroids in emergencies When discontinued symptoms usually recur Multiple options for delivery Good short term safety Except for fungal infection Variability in dosing

Slide 74

Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:320.

Slide 75

OVB mixing instructions 0.5 mg Pulmicort Respule + 5 g (5 packets) of sucralose (Splenda) = 812 mL slurry OVB 12 mg daily No solid or liquid food for 30 minutes 10 yr or over received 2 mg/day

Slide 76

PROS Effective Multiple delivery systems Inhaler Slurry options or mixing Can be used in an emergency CONS Recurrence with cessation Not studied for maintenance therapy Concern for long term steroid effect

Slide 77

PPI therapy Diet changes Focused Empiric Elemental Diet Steroids Other

Slide 78

Cromolyn Sodium mast cell stabilizer no apparent benefit Limited to a small study Leukotriene receptor agonist - Singulair no apparent benefit Anti TNF agents showed no benefit IL-5 antagonist Cytokine inhibitor Pending

Slide 79

Not a first line treatment option Still controversial Does not address the inflammation Complications not as great as once believed 404 patients 839 dilations. Chest pain 5% Bleeding