1. What’s New in Eosinophilic Esophagitis and PPI-Responsive Esophageal Eosinophilia?
Stuart Jon Spechler, M.D.
Chief, Division of Gastroenterology,
VA North Texas Healthcare System;
Co-Director, Esophageal Diseases Center,
Professor of Medicine,
Berta M. and Cecil O. Patterson Chair in Gastroenterology,
UT Southwestern Medical Center

2. Eosinophilic Esophagitis (EoE)
Eosinophils infiltrate esophageal squamous epithelium, releasing secretory products that mediate:
Tissue damage
Tissue remodeling
Symptoms

3. Incidence of Eosinophilic Esophagitis (EoE) in Olmsted County, Minnesota12 10 8
Incidence per 100,000
(Age and Sex Adjusted) 6 4 2
1976-
1980
1981-
1985
1986-
1990
1991-
1995
1996-
2000
2001-
2005
Prasad. Clin Gastroenterol Hepatol 2009;7:1055.

4. EoE in the United States
Prevalence per 100,000
- Similar to ulcerative colitis
Dellon E. Clin Gastroenterol Hepatol 2014;12:589.
Most common cause of food impaction in patients seen in ER
Sperry S. Gastrointest Endosc 2011;74:985.
Health-care cost $ billion per year
Jensen E. Am J Gastroenterol 2015;110:626.

5. EoE Symptoms Symptoms are not specific. Adults Dysphagia Children
Food Impaction
Children
Vomiting
Feeding intolerance
Feeding aversion
Failure to thrive
Chest Pain
Heartburn
Upper abdominal pain
(CLICK) The most common clinical manifestations of EoE are dysphagia, or odynophagia.
(CLICK) Many EoE patients experience food impaction.
The other clinical manifestations of EoE vary between children and adults.
(CLICK) In children, because they can not verbalize their symptoms, often times they have vomiting, feeding intolerance or feeding aversion, and failure to thrive.
(CLICK) In adults, their symptoms are often chest pain, heartburn, epigastric pain; symptoms that all are very similar to GERD. These patients are often diagnosed with refractory “GERD” .
Symptoms are not specific.

6. EoE Endoscopic Reference Score (EREFS)
Exudates (plaques)
None of these findings are specific for EoE
Rings (trachealization)
Esophagus appears normal in ~10%
Edema (pallor)
Furrows (vertical lines)
Strictures
Hirano I.
Gut 2013;62:489.

7. EoE Histology ≥15 eosinophils per HPF Eosinophil microabscesses
Basal zone hyperplasia
Dilated intercellular spaces
Epithelium
Subepithelial fibrosis
Subepithelial
fibrosis
The finding of ≥15 eosinophils per HPF has no established biological importance.
Histological findings are not specific.

8. EoE Affects Children and Adults of All Ages in All Racial and Ethnic Groups
Reports of EoE from US, Canada, Australia, New Zealand, Europe, Mexico, India, Israel, Saudi Arabia, Iran, Japan, China

9. EoE Affects Both Sexes Male:Female = 3:1

10. Eosinophilic Esophagitis Conceptual Definition 2011
Eosinophilic esophagitis is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.
Liacouras CA et al. J Allergy Clin Immunol 2011;128:3-20.

11. Eosinophilic Esophagitis Consensus Diagnostic Guideline 2011
EoE is a clinicopathologic disease.
Clinico: Symptoms related to esophageal dysfunction
Pathologic: ≥1 esophageal biopsy shows eosinophil-predominant inflammation with ≥15 eos per HPF
(recommend 2-4 biopsy specimens from both proximal and distal esophagus)
Disease should be isolated to the esophagus
Disease should remit with treatments of dietary exclusion, topical corticosteroids or both
Liacouras CA et al. J Allergy Clin Immunol 2011;128:3-20.

12. Evidence that Eosinophilic Esophagitis is an Allergic Disorder
50-60% of patients have history of atopic disease (rhinitis, asthma, atopic dermatitis)
Most patients exhibit sensitization to food and/or aeroallergens
15% have food anaphylaxis
During oral immunotherapy for food allergy, 3% of patients develop EoE
In animal models, EoE can be induced by allergen sensitization
Dramatic response to elemental diet

13. If EoE is caused by food allergy, then why do eosinophils home to the esophagus?

14. RNA Microarray Analysis of Esophageal Biopsies
230 Genes
Downregulated
344 Genes
Upregulated
Eotaxin-3
(↑ >50-Fold)
A potent eosinophil chemoattractant 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 11 12 13
Controls
Pts. with EoE
Blanchard. J Clin Invest 2006;116:536

15. Immune System Activation Th1 and Th2 Differentiation
Antigen
Antigen Presenting Cell
Activate Immune System
Naive CD4+ T Cells
EoE is due to the infiltration of the esophagus by eosinophils.
A number of cytokines have been indentified as chemotactic signals for eosinophils. Cytokines are produced from inflammatory cells.
(CLICK) Infection, injury, allergens activate (CLICK) the immune system including CD4 lymphocytes.
If these lymphocytes secret (CLICK) predominantly TNF-b, IFN-g, they are classified (CLICK) as Th1 cells.
However if these same CD4+ helper cells secrete (CLICK) predominantly IL-4 or IL-13 they are classified (CLICK) as Th2 cells which are often involved in allergic disease.
In EoE, (CLICK) the secretion of IL-4 and IL-13 by Th2 cells is thought to play a role.
Allergic
Disorders
Th1
(T-helper 1)
Th2
(T-helper 2)
TNF-β, IFN-Ɣ
IL-4, IL-5, IL-13

16. *
IL-13 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients
Eotaxin-3 is a potent eosinophil chemoattractant
Unstimulated
IL-13 (10 ng/ml) *
(pg/ml per 250,000 cells)
Eotaxin-3
*p<0.001 *
Recently, our group published these data on how the Th2 cytokine IL-13 and IL-4 stimulates eotaxin-3 secretion in esophageal squamous cells from EoE patients. EoE1-T and EoE2-T are esophageal squamous cell lines established from biopsy specimens taken from EoE patients. Unstimulated, these cells secrete very little eotaxin-3. But when you treat them with IL-13, their production of eotaxin-3 increases dramatically.
EoE1-T
EoE2-T
Cheng E et al. Gut 2013;62:824.

17. IL-4 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients
Eotaxin-3 is a potent eosinophil chemoattractant *
Unstimulated
IL-4 (10 ng/ml)
*p<0.001
(pg/ml per 250,000 cells)
Eotaxin-3
Similarly, when you treat the EoE cells with IL-14, their production of eotaxin-3 also increases dramatically. *
EoE1-T
EoE2-T
Cheng E et al. Gut 2013;62:824.

18. Eosinophilic Esophagitis Pathogenesis Model (Genetically-Susceptible Individual)
Food allergen activates immune system
Th2 Response
↑↑↑ esophageal production of eotaxin-3
↑ IL-5
↑ IL-13
↑ IL-4
↑ eosinophil production, activation, recruitment
↑↑↑eotaxin-3

19. GERD Eosinophilic Esophagitis
AGA Institute 2007 Definition of EoE
Gastroenterology 2007;133:1342.
A primary disorder of the esophagus characterized by
UGI symptoms, esophageal biopsy ≥15 eos/hpf,
and the absence of pathologic GERD
GERD
Eosinophilic
Esophagitis
EoE
GERD

20. help these EoE patients
Possible Reasons for the Association of GERD and Esophageal Eosinophils
GERD causes mild eosinophilia (<7 eos/hpf)
GERD and EoE co-exist but are unrelated
GERD
EoE
EoE contributes to or causes GERD
Eosinophil secretory products alter esophageal motility and permeability, and induce remodeling
GERD
EoE
GERD contributes to or causes EoE
Reflux might cause esophageal mucosa to produce chemokines that attract eosinophils
Increased esophageal permeability might expose deep layers of esophageal epithelium to antigens
GERD
EoE
PPIs might
help these EoE patients
Spechler, Genta, Souza. Am J Gastroenterol 2007;102:1301.

21. “A trial of PPI therapy is recommended for patients with eosinophilic esophagitis, even if the diagnosis seems clear-cut.”
Spechler S, Genta R, Souza R. Am J Gastroenterol 2007;102:1301.

22. Only acid-peptic disease can respond to PPIs
Rationale for a Trial of PPI Therapy in Patients with Esophageal Eosinophilia
PPIs only affect gastric acid secretion
Only acid-peptic disease can respond to PPIs
Response to PPIs = GERD

23. PPI-Responsive Esophageal Eosinophilia (PPI-REE)
Reflux
Have typical EoE symptoms and histology
Do not have GERD by endoscopy or pH monitoring
Exhibit a clinical and histological response to PPIs
30% to 50% of patients with symptomatic esophageal eosinophilia respond to PPIs

24. Possible Explanations for PPI-Responsive Esophageal Eosinophilia (PPI-REE)
Pts have subclinical GERD, not Ag-driven eosinophilia Responds to anti-secretory effects of PPIs
Non-Erosive
Reflux Disease
(NERD)
Pts have Ag-driven eosinophilia (EoE), not GERD
Responds to anti-inflammatory effects of PPIs
Patients have GERD exacerbating Ag-driven EoE Responds to both anti-secretory and
anti-inflammatory effects of PPIs

25. Omeprazole Blocks Th2 Cytokine-Stimulated Eotaxin-3 Secretion in Squamous Cells from EoE Patients
Unstimulated
Omeprazole (50μM)
*p<0.05 compared to IL-13 alone
# p<0.05 compared to IL-4 alone
IL-13 (50ng/ml)
IL-4 (10ng/ml)
IL-13+Omeprazole (OME)
Eotaxin-3 (pg/ml/250K cells)
IL-4+Omeprazole (OME) * #
OME
OME
Recently, we published data showing that PPIs might have direct eosinophil-reducing effects in the esophagus. Esophageal squamous cells can produce eotaxin-3, which is a potent eosinophil chemoattractant that draws eosinophils to the esophagus in EoE. This slide shows eotaxin-3 secretion by EoE1-T and EoE2-T, which are two esophageal squamous cell lines from EoE patients. At baseline, these cells make very little eotaxin-3, and omeprazole treatment, shown here in yellow, has no apparent effect on their eotaxin-3 production. When the cells are stimulated with Th2 cytokines, IL-13 and IL-4, their expression of eotaxin-3 increases dramatically. However, that cytokine-stimulated eotaxin-3 secretion can be blocked by treatment with the PPI omeprazole. We have proposed that this acid-independent PPI effect of blocking Th2 cytokine-stimulated eotaxin-3 production by esophageal squamous cells might explain the phenomenon of PPI-responsive esophageal eosinophilia. # *
OME
OME
EoE1-T
EoE2-T
Cheng E et al. Gut 2013;62:824.

26. Effects of Lansoprazole on IL-4-Stimulated Eotaxin-3 Protein Secretion in EoE Squamous Cell Lines
EoE1-T + *
EoE2-T *
Inhibition of IL-4-stimulated eotaxin-3 secretion may be a class effect of PPIs.
Eotaxin-3 (pg/ml)
To see if this inhibitory effect was unique to omeprazole, we treated our EoE cell lines with another PPI, lansoprazole. Similar to omeprazole, lanoprazole at concentrations of 10 and 50 uM significantly decreased IL-4-stimulated eotaxin-3 protein secretion. This suggests that the inhibition of IL-4-stimulated eotaxin-3 secretion may be a class effect of the PPIs. + +
Control IL µM µM
Control IL µM µM
IL-4 +Lansoprazole
IL-4 +Lansoprazole
Zhang X et al. PLoS One 7:e50037, 2012

27. PPIs and Esophageal Eosinophilia in GERD and in EoE
Reflux
PPIs have anti-secretory (gastric acid inhibitory) effects that might be beneficial both for GERD and for EoE.
PPIs have anti-inflammatory effects (independent of their anti-secretory effects) that might be beneficial both for GERD and for EoE.
For patients with esophageal symptoms and eosinophilia, a clinical and/or histological response to PPIs…
- Does not rule in GERD
- Does not rule out EoE

28. A trial of PPI therapy is recommended for patients with symptomatic esophageal eosinophilia, even if the diagnosis of eosinophilic esophagitis seems clear-cut.
A trial of PPI therapy is recommended for patients with eosinophilic esophagitis, even if the diagnosis seems clear-cut.
Cheng E, Souza R, Spechler S. Gastroenterol Clin North Am 2014;43:243.
Spechler S, Genta R, Souza R. Am J Gastroenterol 2007;102:1301.

29. Topical Steroid Therapy for EoE (Fluticasone, Oral Viscous Budesonide)
RCTs show that topical steroids significantly reduce esophageal eosinophil levels
Most patients experience symptomatic relief during treatment with steroids
Symptoms recur frequently when steroids are stopped
Limited data on efficacy and safety of long-term steroid therapy for EoE

30. Topical Steroid Therapy for EoE in Adults
Fluticasone 2-4 puffs (220μg/puff)
BID, after breakfast and dinner
Do not use spacer (designed for lung delivery)
Inspire deeply first, depress inhaler, swallow
Do not eat or drink for at least 30 minutes

31. Approaches to Diet Therapy for EoE
Directed elimination diet
Based on skin prick testing
46% success (95% CI, 35-56%)
Empiric elimination diet
Prohibit most common food allergens (milk, soy, eggs, wheat, nuts, seafood)
72% success (95% CI, 66-78%)
Prohibit 4 foods – 54% success
Molina-Infante. Rev Esp Enferm Dig 2015;107:1639.
Elemental diet
Use amino acid-based formulas
91% success (95% CI, 85-96%)
Arias A. Gastroenterology 2014;146:1639.

32. Management of EoE 2015
Patient with Esophageal Symptoms and Esophageal Eosinophilia
Symptoms
Resolve
Trial of PPI BID 4-8 weeks
Dx: GERD or PPI-REE
Continue PPI Rx
Symptoms
Persist
Dx: EoE
Empiric Elimination Diet
Symptoms
Resolve
Symptoms
Persist
Patient Declines
Diet Therapy
Continue Diet Rx
Topical Steroids 6-8 weeks
Symptoms
Resolve
Symptoms
Persist
Follow, Resume Steroids PRN
Rule Out Infection
(Candida, HSV)
Dysphagia Persists
Esophageal Stenosis
Esophageal Dilation
Modified from Aceves, Furuta, Spechler. Gastrointest Endosc Clin N Am 2008;18:195

33. Photo by S. Spechler