1. Eosinophilic Esophagitis in children
LMEF Pediatric Conference
06/20/2017
Emily C. Hon, M.D.

2. I have no disclosures

3. Objectives Define eosinophilic esophagitis (EoE)
Describe clinical presentation of EoE patients
Learn how EoE is diagnosed
Understand treatment options for EoE

5. Eosinophils White blood cells responsible for fighting parasites
Increased in allergic disorders
Do not exist in the esophagus under normal conditions

6. What is Eosinophilic Esophagitis (EoE)?
2nd most common cause of chronic esophagitis (after GERD)
Leading cause of dysphagia and food impaction in children
Chronic, antigen-mediated (food)
TH-2 pathway, non IgE mediated
First defined in early 1990s
Evolving definition
EoE is thought to be a chronic, antigen (primarily food-derived) mediated disease.
As this is a relatively new entity, the definition has been evolving.
It currently requires both clinical and histological findings
1. Esopahgeal dysfunction characterized by dysphagia, vomiting, feeding difficulties, abd pain
2. Histological findings: an eosinophil- predominant inflammation isolated to the esophagus.
-where current controversy exists is how we exclude other causes of esophageal eosinophilia such as GERD and PPI-responsive esophageal eosinophilia.

7. What is EoE? Requires both of the following: Clinical Histological
Esophageal dysfunction
Dysphagia, vomiting, feeding difficulties, abdominal pain
Histological
Eosinophil-predominant inflammation (>15 eosinophils per field) isolated to the esophagus
Need to exclude other causes of esophageal eosinophilia
Persists after a high dose Proton Pump Inhibitor (PPI) trial
Clinical AND Histological. Path should not be used to dx EoE in isolation.

8. Eosinophils and acid in the esophagus
Winter- Eos in the esophagus are related to GERD. Eos/hpf were usually <10, and concentrated in the distal esophagus
Attwood: Described 12 patients with high esophageal eosinoiphilia, dysphagia, 11/12 had normal pH probes, and normal endoscopy.
Several papers to follow described more patients with this distinct entity, response to elemental diet, topical steroid.
Steiner: Denser infiltrates of eos does not correlate with increased GERD. The finding of >20eos/hpf is likely associated with normal reflux indesx and a nonacid-related cause of esophagitis
If eos/hpf >20, these patients were just as likely as completely normal EGDs to have abnormal JD scores. This study helped “confirm the minimal role that acid reflux has in eosinophilic esophagitis)
The EoE consensus statement in 2007 clear stated that the esophageal abnormalities do not respond to treatment with high-dose proton pump inhibitor therapy.
Then in 2011 consensus we have developed a new term called PPI-responsive esophageal eosinophilia… could be GERD, could be EoE 
So now our definition of EoE or perhaps classic EoE depends on whether a pt. responds to HDPPI.

9. Current controversy- 2017 European Guidelines
“…PPI-REE and EoE are virtually indistinguishable from one another, even at the genetic level, and very different from GERD... Therefore, the main novelty in these guidelines is the retraction of the term PPI-REE and the consideration of PPI therapy not as a diagnostic criterion for EoE, but rather as a therapeutic agent.”

10. Other Causes of Esophageal Eosinophilia
GERD
Achalasia
PPI-responsive esophageal eosinophilia
Drug hypersensitivity
Vasculitis
Eosinophilic gastrointestinal diseases
Connective tissue disease
Graft-versus-host disease
Celiac Disease
Crohn disease
Infectious esophagitis
Hypereosinophilic syndrome
Pemphigoid vegetans is an extremely rare variant of bullous pemphigoid by vegetative and purulent lesions in the groin, axillae, thighs, hands, eyelids, and perioral lesions. Skin lesions with path c/w eosinophilic spongiosis as well as pemphigoid. Only few cases reported.

11. Epidemiology Prevalence in US: 56.7/100,000 (Dellon, 2014)
Risk factors:
Male predominance (2-3x)
Personal or family history of atopy
More common in non-Hispanic whites, but occurs in all racial / ethnic groups
Dellon prevalence study looked at 35M pts from database of commercially insured population using ICD9 code This would have been before PPIREE definition.

12. Clinical Presentation
Age-dependent
Infants / toddlers:
Persistent reflux symptoms
Vomiting
Feeding difficulties
Refusal to eat
School-age:
Abdominal pain

13. Clinical Presentation
Adolescents and adults:
Dysphagia (solids)
Food impactions
Chest pain
Globus sensation
Throat-clearing

14. ENT symptoms?

15. True or False? All patients with dysphagia have EoE. FALSE
All patients with EoE have dysphagia.

16. Compensating Behaviors
Adaptations to esophageal dysfunction:
Drinking plenty of liquids with all meals
Prolonged chewing
Avoiding bulky foods, meats, breads
Slow or picky eaters
Parents cut food into very small pieces
High index of suspicion needed!
May diagnose other family members
However, many children have adapted to the esophageal dysfunction with the following compensating behaviors. So they don’t vomit or think they have trouble swallowing but…

17. Physical Exam Non-diagnostic for EoE
Growth parameters can be low, normal, or high
Find co-morbid allergic diseases
Allergic shiners
Rhinorrhea with pale boggy turbinates
Eczema, urticaria
Wheezing, prolonged expiration
Non-diagnostic- They can be FTT, obese, epigastric tenderness?

18. Diagnosis
How do we diagnose EoE?

19. Upper Endoscopy and Biopsies
Only reliable diagnostic test
Abnormal findings:
Pallor
Longitudinal furrowing
White exudates
Crepe paper mucosa
Rings
Felinization (transient)
Trachealization (permanent)
Strictures
None are pathognomonic for EoE
Once we have the clinical findings of esophageal dysfunction, we move on to EGD and biopsies.
A normal esophagus has a smooth, pale pink mucosa, and visible vessels. In EoE, most commonly see pallor with poor visualization of the vessels. This photo also shows longitudinal furrowing. White exudates or specks can be seen representing eosinophilic microabscesses. This can look similar to candidal esophagitis so a fungal brushing may be sent., crepe paper mucosa, is rare but is seen when we are coming out of the EGD It’s a sign of longitudinal shearing. Last is ringing of the esophagus (transient ringing is felinization and permanent ringing is trachealization), strictures
Liacouras, 2011

20. Histology
≥15 eosinophils per field in esophageal biopsy specimen after a PPI trial
Isolated to the esophagus
Other findings:
Eosinophilic microabscesses
Surface layering of eosinophils
Eosinophil degranulation
Basal cell hyperplasia
Lamina propria fibrosis
Other causes ruled out.
With few exception,, 15 eos/hpf (peak value) is considered a minimum threshold for a diagnosis of EoE if other associated findings are seen.
Eosinophilia should be isolated to the esophagus, otherwise we need to think of other etiologies such as EGE, EC, Crohn’s disease, etc.
A shows a normal esophageal epithelial layer. In B, you can see the many eosinophils which is much >15 eos/hpf. In C the arrow is pointing nicely to just layers of eosinophils on the surface of the mucosa. D points to an eosinophilic microabscess. Basal cell hyperplasia refers to expansion of this basal cell layer
Liacouras, 2011

21. PPI-Responsive Esophageal Eosinophilia
GERD
Usually <10 eos/hpf in distal esophagus
pH Probe, PPI trial
PPI-responsive esophageal eosinophilia
Considered distinct from EoE, but not necessarily a manifestation of GERD
Resolution of esophageal eosinophilia with high dose PPI.
PPI 1mg/kg dose BID x 2 months prior to EGD
Anti-inflammatory mechanism?

22. Treatment

23. Therapies Goals: Food elimination diets: Topical steroids
Reduced symptoms and improved histology
Prevent feeding dysfunction
Prevent fibrosis and stricture formation
Food elimination diets:
Elemental
Empiric elimination
Allergy testing-based
Topical steroids
Prednisone for rapid improvement in symptoms
Esophageal dilation
We don’t know who will continue to have ongoing esophageal injury, so hard to determine how/who to treat and monitor. Defining endpoints also difficult.

24. Elemental Diet Disadvantages: Amino-acid based formula1
Up to 96% histologic remission rate2
Disadvantages:
Poor tasting, expensive formula
Development of solid food aversion
NGT or GT
Long food reintroduction process, many endoscopies
Kelly, 1995
Henderson, 2012

25. Six-Food Elimination Diet (SFED)
Wheat
Ignore
Nuts/peanuts
Soy
Fish/seafood
Eggs
Dairy
When working with these diets, it’s important for families to work with a nutritionist to ensure they are still getting good nutrition while restricting these groups.
Kagalwalla, 2006-
85% clinical and histological remission
Variety of table foods, less cost
Still socially difficult for children
Requires endoscopy with each food introductions, separated by at least 6 weeks.
Dietician
Prevent contamination
Prevent iatrogenic malnutrition
Kagalwalla, 2006

26. 4-Food Elimination Diet
Milk
Wheat
Egg
Soy
Milk Elimination diet: 65% clinical and histological remission (95% CI 42-88%)
Milk Elimination Diet (65%)
Kagalwalla, 2012

27. Empiric Elimination + Meat
Beef
Chicken
Pork
Turkey

28. Allergy Testing Based Elimination
Results similar to empiric food elimination
Disadvantages:
Requires painful testing
Skin prick testing (IgE)
Atopy patch testing (non-IgE, high variability)
ADT similar to empiric food elimination: Spergel et al, 2012: SPT/APT directed + milk elimination  77%
Spergel, 2012

29. Allergy Dietician Prevent iatrogenic malnutrition
Prevent contamination

30. Topical Steroids Not FDA-approved for EoE
50-80% histologic remission, common recurrence
Swallowed fluticasone:
Metered dose inhaler without spacer
Oral viscous budesonide:
10 packets of Splenda per 2 respule (0.5 mg/2 ml)
Neocate Nutra ½ tsp per 2 respules
Small amount applesauce
No drinking or eating for 30 minutes, then drink water
Can swish and spit with water
Possible adrenal insufficiency
Update on adrenal insufficiency concerns- look at Roma’s paper.

31. Esophageal Dilations Mostly in adolescents and adults
Treats strictures, but not underlying inflammation
3% risk for significant adverse effect same as non-EoE (Menard-Katcher, 2017)
15% chest pain.
Menard-Katcher- retrospective study of all children undergoing esophageal dilation at academic children’s hospital: “significant’= requiring some medical attention/intervnetion more than reassurance. No association with # eosinophils.

32. Epinephrine injection and allergy shots are NOT part of EoE treatment.

33. Figure 1. PPI- nonresponsive EoE diagnosis confirmed
Dietary And Pharmacologic Treatments Discussed
Pharmacotherapy chosen FP
OVB
Diet Elimination chosen
Empiric, allergy testing not needed
Empiric Milk
Empiric Four-food
Empiric Four-food + Meat (beef, chicken, pork, and turkey)
Empiric Six-food
Allergy Skin Test Guided + Milk Elimination (work with Allergists)
Figure 1.

34. Questions?