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

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

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

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

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  Don’t eat and miserable  ROS:  Asthma –Home inhaler never used  Otherwise unremarkable  Strong family history  Asthma  Atopy  Exam: unremarkable

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

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

8. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:3–20.

14.  “Now what?”

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 Children’s 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

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

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

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

23.  103 Pediatric Patients with EoE SymptomMedian AgeNo. (%) Feeding disorder2.0 (1.2–6.2)14 (13.6) Vomiting8.1 (3.5–12.3)27 (26.2) Abdominal pain12.0 (9.6–15.2)27 (26.2) Dysphagia13.4 (10.0–16.7)28 (27.2) Food impaction16.8 (13.7–19.6)7 (6.8) Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004;351:940–1.

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) 57:690–693

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

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

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

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  Crohn’s 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: 1342–63. 133:1342-63, 2007

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

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

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

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%

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;128:3–20.

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

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

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

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

50. Straumann, Pediatric and adult eosinophilic esophagitis: similarities and differences Allergy Volume 67, Issue 4, pages 477–490, April 2012

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

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

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 don’t always correlate with each other

56.  PPI therapy  Diet changes  Focused  Empiric  Elemental Diet  Steroids  Other

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

59.  PPI therapy  Diet changes  Focused  Empiric  Elemental Diet  Steroids  Other

60.  Milk  Most common allergen  Consider avoiding

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

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

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

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

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

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

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

72.  PPI therapy  Diet changes  Focused  Empiric  Elemental Diet  Steroids  Other

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

74. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:3–20.

75.  OVB mixing instructions 0.5 mg Pulmicort Respule + 5 g (5 packets) of sucralose (Splenda) = 8–12 mL slurry  OVB 1–2 mg daily  No solid or liquid food for 30 minutes  <10 yo received OVB 1 mg/day  > 10 yr or over received 2 mg/day

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

77.  PPI therapy  Diet changes  Focused  Empiric  Elemental Diet  Steroids  Other

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

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 <0.5% (1 patient)  Perforation 0.8 % (3 patients)

80.  High dose PPI for minimum of 8 weeks  Discuss options for diet  Be honest  Be realistic  Consider ALL options  Include nutritionist and allergist in plan  Make decisions on testing as a team  Stress that this is a chronic condition

83.  Family considered options  Attempted 6 food elimination diet  Failed  Continued to lose weight  More fatigued  Allergy Testing

84.  Found to be allergic to many (most) foods  Restriction diet  Allowed between 9-12 foods  Symptoms improved  Weight loss persisted

88.  Majority of calories from Elecare  Able to eat and function “normally” on 12-15 foods  Food trial of 1-2 foods every month with EGD every 6-8 weeks.  He did gain weight

91.  Assessment of the impact of treatment on health related quality of life for patients with Eoe and their families.  4 centers, 97 patients (ages 2-18 years)  Screened at 0, 2, 6 months  HRQoL improved during evaluation and treatment, with positive changes strongest for patients with less symptom severity at baseline Klinnert, M; Health Related Quality of Life Over Time in Children with Eosinophilic Esophagitis (EoE) and their Families JPGN Accepted 6/2/14

92.  Change in the delivery method of steroids  Splenda – a story in serendipity  Antibodies directed specific interleukins  Focus on genetics  Change in testing  String and biomarker testing  Can we avoid more endoscopies?  Eoe multispecialty groups

96.  http://teamsupern8.com/ http://teamsupern8.com/  Diniz, L Causes of Esophageal Food Bolus Impaction in the Pediatric Population Dig Dis Sci (2012) 57:690–693  Management Guidelines of Eosinophilic Esophagitis in Childhood, Papadopoulou, JPGN Volume 58, Number 1, January 2014 107-118  Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007;133: 1342– 63.  Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:3–20.  Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004;351:940–1.  Dellon, E, Clinical Gastroenterology and Hepatology 2014 12, 589-596.e1DOI: (10.1016/j.cgh.2013.09.008)  Klinnert, M; Health Related Quality of Life Over Time in Children with Eosinophilic Esophagitis (EoE) and their Families JPGN Accepted 6/2/14  Brown-Whitehorn, T, The link between allergies and eosinophilic esophagitis: implications for management strategies, Expert Rev Clin Immunol. 2010 January 1; 6(1): 101  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  Straumann, Pediatric and adult eosinophilic esophagitis: similarities and differences Allergy Volume 67, Issue 4, pages 477–490, April 2012