1. Eosinophilic Esophagitis
Sanford Pediatric Symposium
June 2018
Melissa Jensen, MD
Pediatric Gastroenterology, Hepatology, and Nutrition
Sanford Children’s Hospital

2. Disclosures
I have no financial disclosures

3. Outline Introduction Definition/Diagnosis Epidemiology Pathogenesis
Clinical symptoms
Endoscopic findings
Histopathologic findings
Treatment
Summary

4. Case #1 14 yo male, referral for dysphagia Occasional heartburn/reflux
No abdominal pain
“always” has congestion, cough, and throat clearing
Food gets stuck with swallowing, he has to wash it down with lots of fluids
Prescribed omeprazole but not taking it
Has seen an allergist with positive skin prick testing for: Chicken, egg white, cow's milk, orange, peanut, tomato, turkey, wheat, tree nut mix.
He was negative for beef, fish mix, pork, shellfish mix, soy

5. Case #2 15 month old male, referral for feeding difficulties
Gagging and vomiting with textures
Random vomiting episodes
Will get a “weird rash” on his face
Cough at night, emesis stains on the sheets in the morning
Allergy testing done with multiple food allergies positive: egg, milk, peanut, soybean, wheat
Although was currently drinking soy milk

6. Both patients were diagnosed with eosinophilic esophagitis (EoE)

7. Introduction
EoE is a CHRONIC immune and antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction
The diagnosis is clinico-pathological, thus based on:
Clinical symptoms
Endoscopic findings, and
Histologic criteria

8. History
The first case series were described in 1993 and 1994 in adults, and 1995 in children.
Prior to 1995, the literature contained only rare reports of individuals diagnosed with an isolated esophageal eosinophilia.
After 1995 and into the early 2000’s - Huge growth of literature about EoE
the development of the First International Gastrointestinal Eosinophilic Research Symposium (FIGERS) and the creation of The International Gastrointestinal Eosinophilic Researchers (TIGERS)
Increasing incidence and recognition

9. Clinical symptoms suggesting esophageal dysfunction
The definition and diagnostic criteria for EoE outlined by the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) in 2014 includes:
Clinical symptoms suggesting esophageal dysfunction
Histological presence of >15 intraepithelial eosinophils/HPF in at least 1 endoscopic esophageal mucosal biopsy taken at upper gastrointestinal endoscopy
Mucosal eosinophilia isolated to the esophagus that does not improve with Proton Pump Inhibitor (PPI) trial
Others causes of esophageal eosinophilia have been excluded
Response to treatment supports, but is not required, for diagnosis

10. American Gastroenterological association (aga) and North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)
Diagnostic guidelines
≥ 15 eosinophils in 1 high-power field
Lack of responsiveness to high-dose PPI (up to 2 mg/kg/day) OR
Normal pH monitoring of the distal esophagus

11. Conditions associated with esophageal eosinophilia
Gastroesophageal reflux disease (GERD)
Eosinophilic esophagitis (EoE)
Eosinophilic gastrointestinal diseases (EGIDs)
Celiac disease
Crohn's disease
Infection
Hypereosinophilic syndrome (HES)
Achalasia
Drug hypersensitivity
Vasculitis
Pemphigoid vegetans
Connective tissue disease
Graft versus host disease

12. PPI responsive eosinophilia (PPI-REE)
Estimated that 1/3 of patients may have remission of symptoms and histological findings with PPI use
Possibly a subtype of EoE rather than a distinct entity

13. Pathogenesis Mediated by Type 2 helper T cells (Th2)
Eosinophils, mast cells, and T cells
Proliferation and terminal differentiation of eosinophils depend critically on the presence of IL-5.
Eosinophil activation is regulated by multiple cytokines, including IL-5 and IL- 13 (involved in other allergic-mediated diseases such as asthma and rhinitis), IL-4, and TNF-α, which are produced by activated Th2 and mast cells
Several cells involved in Th2 inflammation express a chemoattractant receptor on their surface, called CRTH2, which mediates chemotaxis in response to prostaglandin D – a key prostanoid in allergic responses produced by mast cells
Induced primarily by food antigens, possible aeroallergens

14. Epidemiology Incidence of 1/10,000 Prevalence of 4/10,000
Increasing incidence
Only partly due to increased recognition
Some studies have noted an incidence approaching or exceeding that of IBD
Males > females 3:1
More likely to be Caucasian
Often there is a personal history of atopic disease
An association with celiac disease has been reported in multiple studies
We are able to review UGI contrast series and biopsies from decades ago, and features of EoE are not present

15. Associations EoE is associated with:
Asthma
Allergic rhinitis
Atopic dermatitis
Food allergies
Study by Benninger et al showed that 63.5% of EoE patients suffered from at least 1 of these 4 diseases
3% of EoE patients suffered from all 4 of these

16. Clinical Manifestations
Vary by age group
Noel et al. NEJM 2004:
Feeding dysfunction (median age 2 years)
Vomiting (median age 8.1 years)
Abdominal pain (median age 12.0 years)
Dysphagia (median age 13.4 years)
Food impaction (median age 16.8 years)

17. Symptoms Suggestive of Eosinophilic Esophagitis
Children
Adult
Feeding aversion/intolerance
Vomiting/regurgitation
“GERD refractory to medical management”
“GERD refractory to surgical management”
Food impaction/foreign body impaction
Epigastric abdominal pain
Dysphagia
Failure to thrive
Dysphagia
Food impaction
“GERD refractory to medical management”

18. NAME that food!
Corn Dog (breading)

19. Diagnosis
Clinical symptoms, endoscopic appearance, and histologic findings
Requires an upper endoscopy (EGD) with esophageal biopsies
Ideally the patient has been on a high-dose PPI for several weeks already

20. Endoscopic Findings Longitudinal furrowing Friability Edema
Longitudinal shearing
Raised white specks
White exudates
Narrow caliber esophagus
Rings
Felinization/trachealization

21. Endoscopic Findings

23. Name that food!
Roast Beef

24. Histologic Findings Mucosal eosinophilia Eosinophilic microabscesses
Superficial layering of eosinophils
Extracellular eosinophil granules
Surface epithelial desquamation
Basal zone hyperplasia
Rete peg elongation
Dilated intercellular spaces
Subepithelial fibrosis/sclerosis/lamina propria fibrosis

25. Histological Findings
Above: normal esophagus
Right: increased mucosal eosinophils and basal zone hyperplasia

26. Peripheral eosinophilia
Typically no difference in peripheral eosinophilia between EoE and GERD patients.
More commonly seen with Eosinophilic Gastroenteritis
Publication in Journal of Gastroenterology and Hepatology in July 2017
Assessed activated eosinophils from peripheral blood samples
EoE vs control patients
Study showed a sensitivity of 100%

27. Name that food!
Watermelon

28. Food antigens as a mediator
In 1995, Kelly et al published their work showing that 10 children with GERD- like symptoms and esophageal eosinophilia despite reflux treatment, were treated with an elemental formula for 6 weeks had improved or complete resolution of symptoms. Biopsies also with significant decrease in eosinophils
Upon reintroduction of food, there was recurrence of both clinical symptoms as well as eosinophilic inflammation in the esophagus
Thus proving that food antigens are a primary mediator of EoE

29. Aeroallergens as mediator?
Given that there is a small subset of patients that do not respond to an elemental diet, this would give way to the possibility of aeroallergens as a mediator
There are some case reports and studies implying a seasonal affect on EoE symptoms and disease activity
Further evaluation is needed

30. Name that food!
Cantaloupe

31. Treatment options Dietary Medications Dilatation
Targeted elimination diet
Empiric (6 food) elimination diet
Elemental formula
Medications
PPI’s
Glucocorticoids
Dilatation

32. Targeted Elimination Diet
Allergy-test directed elimination
Difficult, as EoE involves both IgE-mediated and cell-mediated allergic mechanisms
Serum testing (minimal data in this situation)
Skin prick testing - assesses food-specific IgE bound to mast cells in the skin
Sensitivity “low”
Specificity ≥86%
Atopy patch testing – non-IgE, cell-mediated allergic reactions
Specificity ≥82%
Combined skin prick/patch testing
Sensitivity ≥81%
Specificity 72-90%

33. Targeted Elimination Diet
Overall efficacy (when combining skin prick and patch testing)
45%
Advantage is that it includes the fewest foods removed

34. Empiric 6-food Elimination Diet
Removes the top 6 known allergens in EoE
Milk
Wheat
Soy
Egg
Fish and shellfish
Peanuts and tree nuts

35. Empiric 6-food elimination diet
72% of patients with 1 food antigen trigger
The rest of patients had 2-3 food antigen triggers
Minimally triggered by peanuts/nuts and fish/seafood
Response rate is ~70-80%
Cow’s milk elimination ONLY
65% achieved a complete or partial remission
Patients were typically younger and with lower pretreatment eosinophil counts

36. Elemental Diet (i.e. Formula)
Typically done if previous treatments have been unsuccessful
All foods and beverages are removed from the diet
Allowed to have an elemental (amino acid) formula and water
Removes the intact protein, which eliminates potential food antigen triggers
Complete source of nutrition
Examples include Neocate, Neocate Jr, EO28 Splash, Neocate Nutra, Elecare, or Elecare Jr.
May require assistance of NG or G-tube
83-97% of children will respond to this diet
Potential role of aeroallergens

37. Food Reintroduction
If a patient responds to the 6 food elimination diet or the elemental diet, then the eliminated foods may be reintroduced
One or two foods at a time
6-8 week trial, then repeat EGD
If biopsies are normal, then may continue eating those foods plus addition of another 1-2 food items
If biopsies are abnormal, then will again need to eliminate those foods from the diet

38. Table 2 Start (least allergenic) End (most allergenic) A B C D
Food reintroduction approach in eosinophilic esophagitis
Start (least allergenic)
End (most allergenic) A B C D
Vegetables (nonlegume) Carrots, squash (all types), sweet potato, white potato, string beans, broccoli, lettuce, beets, asparagus, cauliflower, Brussels sprouts Fruit (noncitrus, nontropical) Apple, pear, peaches, plum, apricot, nectarine, grape, raisins Vegetables Tomatoes, celery, cucumber, onion, garlic, any other vegetables
Citrus fruit Orange, grapefruit, lemon, lime Tropical fruit Banana, kiwi, pineapple, mango, papaya, guava, avocado Melons Honeydew, cantaloupe, watermelon Berries Strawberry, blueberry, raspberry, cherry, cranberry Grains Rice, millet, quinoa
Legumes Lima beans, chickpeas, white/black/red beans Grains Oat, barley, rye other grains Meat Lamb, chicken, turkey, pork
Fish/Shellfish Corn Peas Peanut Wheat Beef Soy Egg Milk

39. Name that food!
Grape

40. Medications Swallowed steroids
Fluticasone propionate
Budesonide respules
Eliminate symptoms and inflammation while on the medication, but does not cure the disease
When a patient stops the medication, the clinical symptoms and the tissue eosinophils typically return
Asthma medications that are swallowed instead of inhaled

41. Allergy treatments? Antihistamines, cromolyn sodium, montelukast
Little benefit
May help with symptom reduction
May improve peripheral eosinophilia
No improvement in tissue eosinophil counts

42. Swallowed steroids Swallowed fluticasone Swallowed budesonide “slurry”
Metered-dose-inhaler
Hold your breath, spray, swallow
Swallowed budesonide “slurry”
Budesonide liquid respules
Liquid is mixed with sucralose

44. Potential side effects of swallowed steroids
Similar side effect profile as when used for asthma
Concerns for opportunistic fungal and viral esophagitis
Potential impact of longer-term steroid administration on bone mineral density and linear growth
Concerns for adrenal suppression/insufficiency
Systematic review April 2018 that included 17 publications
596 patients with EoE
Abnormal adrenal testing of ~15.8%
None of the 7 RCT’s demonstrated statistical significance between placebo and treatment groups

45. New treatment options?
Based on the understanding of EoE’s immunopathogenic mechanisms, as well as on the results of in vitro studies, animal models, and clinical trials, the Th2 cytokines, IL-13 and IL-4, the CRTH2 receptor, and the eosinophil-specific chemokine, eotaxin-3, are currently the most promising targets for discovering new antieosinophil drugs
Currently under investigation:
CRTH2 antagonist (oral)
IL-13 antagonist (fully human monoclonal antibody, biologic, infusion)

46. Name that food!
Steak

47. Other/New diagnostic options?
Transnasal endoscopy
Potential alternatives:
Minimally invasive esophageal string test
Cytology brushing
Published on June 14, 2018 with Dr. Yamen Smadi as an author
Esophageal brushing thru a Cortrack nasogastric tube
Measured eosinophil-derived neurotoxin via ELISA, significantly higher in active EoE patients compared to patients with GERD
Description esophageal string test: “There was an old test developed in the 70s,” Dr. Furuta says. “You had a capsule filled with string, and you would tape one end of the string to your cheek and swallow the capsule, and the string would go all the way down to the small intestine.” Doctors would then pull the string out and check for intestinal parasites. “We wondered if you could do a similar thing and check the portion of string from the esophagus for the unique proteins of eosinophils.”
Measured against endoscopy, the results of the string test were “remarkably consistent” — enough so that Dr. Furuta’s team, with his collaborator Steven Ackerman, M.D., at the University of Illinois at Chicago, knew they’d produced a new treatment standard. With help from a grant and seed capital from Children’s Colorado, the team is developing a commercial version of the test, now undergoing trials, that it hopes to introduce to the market soon.
eosinophil-derived proteins in luminal secretions is reflective of mucosal inflammation in children with EoE
Feces test ***

48. Transnasal endoscopy

49. Dilatation
Potential complications (low) include chest pain, perforation, or hemorrhage
Will fix a stricture or narrowing, but will not treat the underlying disease process or prevent it from happening again

50. Why Treat? Clinical symptoms Prevent long term complications
At risk for food impactions and esophageal tissue injury
Dysphagia has a negative impact on the quality of life
Prevent long term complications
What are the complications and long term outcomes of untreated eoe?

51. Long Term Complications
Tissue remodeling
Primarily fibrostenotic changes, which include esophageal narrowing, dysmotility, and stricture formation
Risk of fibrostenotic disease doubles for every 10 years of disease
Repeated dilations increases risk for perforation and morbidity
Successful therapy has been show to prevent tissue remodeling and strictures

52. Chronic disease Limited data regarding the natural history of EoE
In a report by Spergel et al. of 620 children over a 14-year period, only 10% developed tolerance to their food allergies
EoE does not evolve into other GI diseases

53. Cases, wrap up
14 yo male, referral for dysphagia. Has congestions, cough, throat clearing. Food gets stuck. Multiple food allergies.
15 month old male, referral for feeding difficulties. Gagging and vomiting with textures, random vomiting episodes, “weird rash” on his face, cough at night. Multiple food allergies.
Both diagnosed with EoE
Both treated with swallowed budesonide
One is doing well, re-scope with no/minimal eos
Teenager with no symptoms but continued eos, trying a different budesonide formulation

54. Take home points
EoE is a clinical and histological diagnosis that currently requires endoscopy/biopsy for diagnosis
Potential for multiple GI symptoms depending on the age group, but including feeding difficulties, abdominal pain, vomiting, dysphagia, and food impaction
More common in families with a history of atopy
This is a chronic condition that requires medication and/or strict dietary elimination to prevent long term complications such as esophageal strictures
Recommendations for PCP’s: Start your patient on a PPI, and if symptoms are not resolved then they should be referred to a Peds GI for further evaluation

55. Education, advocacy, and/or research support resources:
American Academy of Allergy, Asthma, and Immunology:
American Partnership for Eosinophilic Disorders:
Campaign Urging Research for Eosinophilic Disorders:
Children's Digestive Health and Nutrition Foundation:
Food Allergy & Anaphylaxis Network:
North American Society of Pediatric Gastroenterology and Nutrition:
Registry for Eosinophilic Gastrointestinal Disorders: Registry

56. References
Papadopoulou A, Koletzko S, Heuschkel R, Dias JA, Allen KJ, Murch SH, et al. Management Guidelines of Eosinophilic Esophagitis in Childhood. Journal of Pediatric Gastroenterology and Nutrition. 2014; 58(1): p Spergel J, Brown-Whitehorn T, Beausoleil J, Franciosi J, Shuker M, Verma R, et al. 14 Years of Eosinophilic Esophagitis: Clinical Features and Prognosis. Journal of Pediatric Gastroenterology and Nutrition. 2009; 48(1). Adamiak T. Pediatric Eosinophilic Esophagitis: Increasing Incidence or Growing Awareness. Furuta GT, Katzka D. Eosinophilic Esophagitis. New England Journal of Medicine. 2015; 373(17). Lee T, Meyer G, Brennan T. Eosinophilic Esophagitis. The New England Journal of Medicine. 2004; 351(9). Wechsler J, Schwartz S, Amsden K, Kagalwalla A. Elimination diets in the management of eosinophilic esophagitis. Journal of Asthma and Allergy Schroeder S, Atkins D, Furata G. Recent advances in the treatment of eosinophilic esophagitis. Expert Rev Clin Immunol CA L. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol Dec; 3(12). JE M. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol April; 98(4). Delton E, Gonsalves N, Hirano I. ACG Clinical Guideline: Evidenced Based Approach to the Diagnosis and Management of Esophageal Eosinophilic Esophagitis. Nature Noel RJ, Putnam PE, Rothenberg ME. N Engl J Med. Eosinophilic esophagitis. 2004;351(9):940. Y Smadi, C Deb, J Bornstein, S Safder, K Horvath, D Mehta; Blind esophageal brushing offers a safe and accurate method to monitor inflammation in children and young adults with eosinophilic esophagitis, Diseases of the Esophagus, , doy056,

57. References
Liacouras C.A., Markowitz J.E. (2012) A History of Eosinophilic Esophagitis. In: Liacouras C., Markowitz J. (eds) Eosinophilic Esophagitis. Clinical Gastroenterology. Humana Press
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128:3.
Kagalwalla AF, Akhtar N, Woodruff SA, et al. Eosinophilic esophagitis: epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment. J Allergy Clin Immunol. 2012;129(5):1387–1396.e7.
Lieberman JA, Morotti RA, Konstantinou GN, Yershov O, Chehade M. Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort. Allergy. 2012;67(10):1299–1307.
Straumann A. The natural history and complications of eosinophilic esophagitis. Thorac Surg Clin. 2011;21(4):575– 587.
Schoepfer AM, Safroneeva E, Bussmann C, et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology. 2013;145(6):1230–1236. e1–2.
Dellon ES, Kim HP, Sperry SL, Rybnicek DA, Woosley JT, Shaheen NJ. A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc. 2014;79(4):577–585.e4.
Wechsler JB, Schwartz S, Amsden K, Kagalwalla A. Elimination diets in the management of eosinophilic esophagitis. J Asthma Allergy. 2014; 7: 85–94.
Spergel, Jonathan & F Brown-Whitehorn, Terri & L Beausoleil, Janet & Franciosi, James & Shuker, Michele & Verma, Ritu & Liacouras, Chris. (2009). 14 Years of Eosinophilic Esophagitis: Clinical Features and Prognosis. Journal of pediatric gastroenterology and nutrition /MPG.0b013e