1. Difficult Cases: EoE Ben Wright, MD and Jonathan Spergel, MD
AAAAI/WAO March
Orlando, FL

2. Disclosures Ben Wright, MD Jonathan Spergel, MD, PhD
No relevant disclosures
We will discuss off-label therapies that are not FDA- approved for EoE
Jonathan Spergel, MD, PhD
Grant support from:
Aimmune Therapeutics
Food Allergy Research Education (FARE)
DBV Technologies
National Institutes of Health (NIH)
Consultant for DBV Technologies

3. Case 1
HPI: 4 y/o female presents with intermittent vomiting and failure to thrive (<5%ile for weight).
Family has attempted feeding therapy and increasing caloric intake without improvement in weight gain.
Patient has been treated with lansoprazole 1mg/kg/dose BID x 3 months without improvement in symptoms.
PMHx: mild atopic dermatitis.

4. Case 1
EGD is normal
Esophageal biopsy was notable for 35 eos/hpf in the distal esophagus and 10 eos/hpf in the proximal esophagus.
Duodenal biopsy shows flattening and blunting of the intestinal mucosa with intraepithelial lymphocytosis.
Clinical symptoms and eosinophilia resolve completely following gluten elimination from the diet.

5. Question 1 What is the most likely diagnosis? Eosinophilic esophagitis
PPI-responsive esophageal eosinophilia
Celiac disease
GERD
Both A and D

6. Question 1 What is the most likely diagnosis? Eosinophilic esophagitis
PPI-responsive esophageal eosinophilia
Celiac disease
GERD
Both A and D

7. Symptoms of esophageal dysfunction Eosinophil-predominant inflammation
Definition
clinico – pathologic diagnosis
Symptoms of esophageal dysfunction
Children: reflux/vomiting, feeding disturbance, abdominal pain and failure to thrive
Adults: dysphagia, chest pain and food impaction
Eosinophil-predominant inflammation
Other diseases associated with esophageal eosinophilia must be excluded.
Consider alternative etiologies if other symptoms or pathologic findings are present.

8. Endoscopic Reference Score – EREFS
Slide courtesy of Dr. Hirano
Endoscopic Reference Score – EREFS
Major Criteria
Hirano et al. Gut. 2013

9. Endoscopic Reference Score – EREFS
Slide courtesy of Dr. Hirano
Endoscopic Reference Score – EREFS
Minor Criteria
Hirano et al. Gut. 2013

10. Histologic features Basal zone hyperplasia Eosinophil surface layering
Dilated intercellular spaces
Eosinophil abscesses
Thickened lamina propria fibers
Dyskeratotic epithelial cells and
Surface epithelial alteration not shown.
Collins et al. Dis Esophagus. 2017

11. Case 2
HPI: 25 y/o Caucasian male with 4 years of solid food dysphagia and several years of heartburn presents with food impaction.
Food passes in the ER and patient returns home.
PMHx: seasonal allergies and asthma. Uses ranitidine prn

12. Case 2 Esophagram shows rings and mid esophageal narrowing of 11mm.
EGD performed – esophagus with exudates, rings, furrows.
Dilation performed to 14mm with mid-esophageal tear visualized.
Path - hyperplastic squamous epithelium with a peak count of 35 eos/hpf.

13. Question 2
What is the next best step in the management of this patient?
Start budesonide 2mg PO BID.
Start omeprazole 40mg PO BID.
Start a six food elimination diet.
Start a two food elimination diet.
Any of the above.

14. Question 2
What is the next best step in the management of this patient?
Start budesonide 2mg PO BID.
Start omeprazole 40mg PO BID.
Start a six food elimination diet.
Start a two food elimination diet.
Any of the above.

15. Case 2 Treatment started with omeprazole 40mg PO BID
At 8 weeks follow-up
Dysphagia and heartburn resolved
Repeat EGD
Resolved exudates, furrows, improved rings
Pathology with 1 eos/hpf

16. Question 3
What percentage of patients with suspected EoE will respond to PPI therapy?
10%
30%
50%
80%

17. Question 3
What percentage of patients with suspected EoE will respond to PPI therapy?
10%
30%
50%
80%
Lucendo et al. Clin Gastroenterol Hepatol. 2016

18. EoE vs PPI-REE
Clinical, endoscopic, histologic, and gene expression features of EoE and PPI-REE are virtually indistinguishable.1
PPI should be considered first line therapy.
8 week course at regular dose twice daily for initial trial.2
Meta-analysis with non-statistically significant advantage of twice daily administration.
No differences between drugs.3
1. Dellon ES et al. Am J Gastroenterol 2013
2. Liacouras CA et al. J Allergy Clin Immunol 2011
3. Lucendo AJ et al. Clin Gastroenterol Hepatol 2015

19. AGREE Conference: New International Consensus Criteria

20. Case 3
HPI: 24 y/o male presents with a food impaction after eating steak. He has a history of food sticking in his throat, uses condiments to lubricate his foods, and drinks large quantities of water with meals.
EGD is notable for the food bolus, exudates, linear furrowing with rings and narrowing of the esophagus.
Esophageal biopsy shows > 100 eos/hpf in all segments of the esophagus.
The patient is started on high-dose PPI but his esophageal eosinophilia persists.

21. Question 4
The patient is not interested in diet elimination and wishes to start swallowed budesonide but is concerned about the risks of long-term steroid use. Which of the following statements is true?
Only systemic steroids cause adrenal insufficiency.
Topical steroids induce histologic remission in 50 to 90% of patients with EoE.
Once remission is achieved, steroids may be discontinued.
The most common side effect of swallowed budesonide is oral candidiasis.

22. Question 4
The patient is not interested in diet elimination and wishes to start swallowed budesonide but is concerned about the risks of long-term steroid use. Which of the following statements is true?
Only systemic steroids cause adrenal insufficiency.
Topical steroids induce histologic remission in 50 to 90% of patients with EoE.
Once remission is achieved, steroids may be discontinued.
The most common side effect of swallowed budesonide is oral candidiasis.

23. Treatments for EoE
Elimination diet (dairy, egg, wheat, soy, nuts, and seafood)
Swallowed steroids
Elemental formula
Esophageal dilation

24. Case 3
HPI: The patient returns for a surveillance endoscopy after 2 years of treatment with oral viscous budesonide (2mg PO BID).
EGD is remarkable for exudates and a fungal stain shows hyphae and pseudohyphae consistent with candidal infection.

25. Question 5
What is the incidence of esophageal candidiasis in EoE subjects treated with swallowed topical steroids?
< 1%
5-10%
20-25%
50%
75%

26. Question 5
What is the incidence of esophageal candidiasis in EoE subjects treated with swallowed topical steroids?
< 1%
5-10%
20-25%
50%
75%

27. Adverse effects of swallowed steroids
Esophageal candidiasis
Usually not oropharyngeal.
Often discovered incidentally.
Treat with oral nystatin/fluconazole.
No difference in risk using nebulized vs. viscous topical budesonide.
Adrenal suppression
Some evidence in children (10%).

28. Budesonide
Shire - Multi-center, phase 2, DBPC, clinical trial with 2 mg BID dosing
93 patients; ages 11-40
Variable
Budesonide
Placebo
Dysphagia Scale
Eosinophils/hpf to
Histological Response Rate (eos <6/hpf)
39% 3%
Endoscopy Score
-3.8
-0.3
Decrease in AM Cortisol (change from baseline, mg/dL, mean ± SD)
After 4 wks of study drug
-0.3 ± 5.0
1.2 ± 3.0
End of treatment
-0.7 ± 4.4
0.4 ± 4.2
Growth velocity (cm/yr)
Total number 17 14
Mean ± SD
4.0 ± 4.8
5.8 ± 3.4
Median (range)
4.1 (-5.8 to 12.0)
5.1 (0.7 to 13.7)
Dellon et al. Gastroenterology

29. Case 3
The patient is treated successfully with fluconazole but is reluctant to resume swallowed budesonide and wishes to pursue dietary therapy.
He is started on a six food elimination diet but wishes to know which foods are triggering his EoE so he can reintroduce some foods back into his diet.

30. Question 6
What is the next best step in the management of this patient?
Repeat endoscopy after 2 months to confirm resolution of esophageal eosinophilia.
Perform skin testing and introduce the foods with the smallest wheal diameter.
Perform serum IgE testing and introduce foods with undetectable levels of specific IgE.
Introduce foods one at a time and monitor for recurrence of symptoms to confirm food triggers.

31. Question 6
What is the next best step in the management of this patient?
Repeat endoscopy after 2 months to confirm resolution of esophageal eosinophilia.
Perform skin testing and introduce the foods with the smallest wheal diameter.
Perform serum IgE testing and introduce foods with undetectable levels of specific IgE
Introduce foods one at a time and monitor for recurrence of symptoms to confirm food triggers

32. Step up vs. step down
Identification of food triggers may be accomplished by two means:
Provoking eosinophilia by single food group reintroduction after broad elimination.
Resolving eosinophilia by single food group elimination.
Because most patients have 1-2 food triggers, this can be accomplished with the least number of endoscopies by a “step up approach”.
Zhan et al Clin Gastroenterol Hepatol. 2018

33. Step up vs. step down 80% SFGED SFGED 80% 60% FFGED FFGED 60% 40%
TFGED
TFGED
40%
Step-wise progression shows approximate rates of resolution of esophageal eosinophilia with various empiric dietary elimination strategies.
TFGED – two food group elimination diet (milk, gluten containing cereals including oat)
FFGED – four food group elimination diet (TFGED + egg and legumes)
SFGED – six food group elimination diet (SFGED + tree nuts and seafood)
Molina-Infante et al. J Allergy Clin Immunol. 2017

34. Food reintroduction approach in EoE
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
Spergel et al. Gastrointest Endosc Clin N Am. 2008

35. Question 7
Which of the following statements is true regarding allergy test-directed diets?
Atopy patch testing reliably identifies triggers because EoE is T-cell mediated.
Skin prick testing for milk has a high NPV (> 90%).
Skin prick testing is more useful in adults than children.
With exception of milk, SPT generally has a low PPV and a high NPV.

36. Question 7
Which of the following statements is true regarding allergy test-directed diets?
Atopy patch testing reliably identifies triggers because EoE is T-cell mediated.
Skin prick testing for milk has a high NPV (> 90%).
Skin prick testing is more useful in adults than children.
With exception of milk, SPT generally has a low PPV and a high NPV.

37. Diet vs. steroids
Discussion of treatment should take into account the following:
Age (e.g. elemental diet may not be appropriate or realistic beyond infancy).
Medical history (e.g. patients with osteoporosis, adrenal insufficiency may be at higher risk for complications of steroid therapy).
Extent of disease activity (e.g. “step up” approach to empiric elimination diet may take longer to achieve histologic remission).
Quality of life
Patients and providers may choose to alter initial treatment approach in the future based on these factors.

38. Case 4
HPI: 10 y/o male with EoE presents with chronic dysphagia, vomiting and poor weight gain.
He has failed treatment with swallowed budesonide and empiric six food elimination (milk, wheat, egg, soy, nuts and seafood).

39. Question 8
Which of the following biologic medications is most likely to results in an improvement in clinical symptoms?
Omalizumab
Infliximab
Mepolizumab
Dupilumab

40. Question 8
Which of the following biologic medications is most likely to results in an improvement in clinical symptoms?
Omalizumab
Infliximab
Mepolizumab
Dupilumab

41. Biologics agents for treatment of EoE*
Mepolizumab (anti-IL-5) – variable results. Induces histologic resolution in most but may not improve clinical symptoms.
Reslizumab (anti-IL-5) – reduces eosinophil counts but in RCT clinical symptoms improved in active and placebo groups.
Omalizumab (anti-IgE) – overall appears to be ineffective. Possible benefit in small subset.
Infliximab (anti-TNFα) – ineffective.
*Off-label use. There are no medications FDA-approved for treatment of EoE.
Reviewed by Ko et al. Clin Rev Allergy Immunol. 2018

42. Biologics agents for treatment of EoE*
QAX576 (anti-IL13)1 - mean esophageal eosinophil count decreased by 60% vs increase of 23% with placebo (P = .004) with a trend towards improved symptoms.
Dupilumab (anti-IL4Rα)2 - improvements noted for :
symptoms (SDI and EEsAI) and endoscopy findings (EREF) active: -1.9 vs placebo: -0.3; p=0.0006
histology (peak-Eos/hpf, active -91.8% vs placebo -7.4%; p < )
*Off-label use. There are no medications FDA-approved for treatment of EoE.
Rothenberg et al. J Allergy Clin Immunol. 2015
Hirano et al Late breaking Abstract DDW 2017

43. Symptoms of possible EoE
Standard of Care
EGD 3
EoE steroid responder
EGD 2
EoE (steroid tx)
≥ 15 eos/hpf?
EGD 1
EoE
tx preference
EoE steroid
non-responder
6-8 wk PPI
≥ 15 eos/hpf?
EoE diet responder
Symptoms of possible EoE
≥ 15 eos/hpf?
PPI-REE
≥ 15 eos/hpf?
GERD
EoE (diet tx)
EoE diet
non-responder
reflux sxs?
EGD
(multiple)
Normal vs. other

44. Role of the allergist in EoE
EoE is an atopic disease.
Assist with food trigger identification, especially when food trigger is not part of SFED.
Manage atopic comorbidities (i.e. atopic dermatitis, asthma and allergic rhinitis)
Treat seasonal allergic rhinitis (e.g. intranasal steroids, AIT) particularly if pollens are triggering EoE.
In the future allergists may suggest biologic therapies currently used for other atopic disorders.

45. Role of the allergist in EoE
The following is evidence that aeroallergens may play a role in EoE pathogenesis1:
Case reports of aeroallergen-induced EoE.
Esophageal eosinophilia in patients with allergic rhinitis during the pollen season.
Decreases in EoE diagnoses during winter.
Case reports of aeroallergen SLIT inducing EoE.
AIT in conjunction with diet/steroids may improve histologic response2 but there are also case reports of AIT inducing recurrence of EoE.3
The role AIT in EoE needs to be elucidated.
Reviewed in Spergel JM Best Pract Res Clin Gastroenterol. 2015
Commins et al. Abstract AAAAI/WAO 2018
Wells et al. Ann Clin Case Rep. 2017;2:1227.