1. Eosinophilic Esophagitis
Ivan D. Cardona, M.D.
Allergy and Asthma Associates of Maine, P.A.

2. Objectives
To understand approaches for the diagnosis and management of eosinophilic esophagitis (EoE)
To understand the role of an allergy evaluation in the diagnosis of EoE
To understand the dietary management of EoE

3. Adverse Food Reactions
1Non-immunologic
Toxic / Pharmacologic /
Host independent
Non-Toxic / Intolerance /
Host dependent
Bacterial food poisoning
Heavy metal poisoning
Scombroid fish poisoning
Caffeine
Alcohol
Histamine
Tyramine (e.g. cheese, wine)
MSG (e.g. flushing, HA, abd pain)
Lactase deficiency
Galactosemia
Pancreatic insufficiency
Gallbladder / liver disease
Contact irritation (benzoic acid)
Gustatory rhinitis
Psychological/texture aversion
Adverse reactions to foods can be divided among those which are toxic and those that are non-toxic reactions1. Toxic reactions do not depend upon host factors and can be elicited by virtually anyone who ingests a sufficient quantity of the tainted food. Causes include bacterial food poisoning but can also include pharmacologic effects such as jitteriness from caffeine or itching and flushing from ingested histamine exemplified by scromboid poisoning. In contrast to the toxic reactions, nontoxic reactions are dependent upon host factors and can be divided among food intolerance and food allergy. Food intolerance is not mediated by the immune system. Examples include symptoms elicited from disaccharidase deficiency (lactose intolerance), metabolic disorders (galactosemia), pancreatic insufficiency, gallbladder or liver disease, anatomic defects (hiatal hernia), neuronally mediated illness (gustatory rhinitis-rhinorrhea from spicy or hot foods) and psychiatric disorders (anorexia nervosa). Examples of these are listed.
1Adapted from Sicherer S, Sampson H. J Allergy Clin Immunol 2006;117:S

4. Adverse Food Reactions
Immunologic
IgE-Mediated
(most common)
Non-IgE Mediated
Cell-Mediated
Systemic (Anaphylaxis)
Oral Allergy Syndrome
Immediate gastrointestinal allergy
Asthma/rhinitis
Urticaria
Morbilliform rashes and flushing
Contact urticaria
Food-dependent Exercise-induced Anaphylaxis
Delayed Anaphylaxis to Red Meat
Eosinophilic esophagitis
Eosinophilic gastritis
Eosinophilic gastroenteritis
Atopic dermatitis
Protein-Induced Enterocolitis
Protein-Induced Enteropathy
Eosinophilic proctitis
Dermatitis herpetiformis
Contact dermatitis
In contrast to food intolerance, food allergy defines adverse reactions to food protein mediated by the immune system. Food allergy can be further divided into those allergies that are mediated by IgE antibody and those which are not IgE mediated. The IgE mediated food allergies are typically acute in onset and examples include anaphylaxis or urticaria. The non-IgE mediated food allergies are generally slower in onset and primarily are gastrointestinal reactions.
Sampson H. J Allergy Clin Immunol 2004;113:805-9,
Chapman J et al. Ann Allergy Asthma & Immunol 2006;96:S51-68.

5. Food Allergic Disorders in Adults
Systemic IgE-mediated disease
Oral Allergy Syndrome
Food-dependent Exercise-induced Anaphylaxis
Delayed Anaphylaxis to Red Meat
Eosinophilic Esophagitis (mixed immunologic)
De novo?
But new onset EoE in up to 2.7%* who undergo IgE-mediated food oral immunotherapy
* Lucendo AJ et al. Ann Allergy Asthma Immunol. 2014;113(6):624-9

6. Conceptual Definition of EoE
Definition: Peak eosinophils of at least 15/hpf at 400x light microscopy (multiple biopsy specimens; 2-4 from distal and 2-4 from mid or proximal)
Symptoms related to esophageal dysfunction
Secondary causes of esophageal eosinophilia have been excluded
Response to dietary elimination and/or topical GC supports diagnosis but is not required
**Ruling out: PPI-Responsive Esophageal Eosinophilia** Mucosal esophageal eosinophilia persisting >2mo despite PPI trial
PPIs block STAT6, which is involved in the binding of the eotaxin-3 promoter in esophageal epithelial cells: suggesting PPIs may have an anti-eosinophil effect.
*Liacouras et al. JACI 2011

7. Not All Esophageal Eosinophilia is EoE
High dose
Proton pump inhibitor
Of course, not all esophageal eosinophilia automatically indicates EoE. Gastroesophageal reflux disease can also result in esophageal eosinophilia. This is an example of one of our patients, a 12 year old boy with dysphagia, who had furrows and white plaques on endoscopy, as well as eosinophilic infiltration of his esophageal mucosa. Upon therapy with a proton pump inhibitor at a dose close to 2 mg/kg/day, his symptoms resolved, and his endoscopic and histologic findings disappeared.
Therefore, gastroesophageal reflux disease can mimic EoE. It can also compound EoE, as a separate entity or secondary to EoE. Therefore, ruling out gastroesophageal reflux disease mimicking or compounding EoE by treating patients with a proton pump inhibitor prior to establishing the diagnosis of EoE is highly advisable.
GERD mimicking EoE
GERD compounding EoE
GERD secondary to EoE

8. EoE: Endoscopic Findings
normal
furrows
Strictures
AND/OR
Small
caliber
esophagus
The diagnosis of EoE relies on performing an endoscopy with biopsies. Upon endoscopy, one may find a variety of features, including rings, furrows, or white plaques, as shown in this slide. The presence of rings reminds the endoscopist of the trachea, hence the name trachealization of the esophagus to this appearance. Rings are thought to be due to esophageal dysmotility from prolonged disease. White plaques, while they can be mistaken by appearance to for a candidal infection, they are rather caused by eosinophilic microabscesses in the esophageal epithelium associated with surface epithelial desquamation, resulting in this appearance.
A combination of two or more of these features is often present in the same patient.
Note that some patients with EoE can have a normal looking esophageal mucosa, hence the importance of obtaining biopsies to establish the diagnosis, looking for esophageal eosinophilic infiltration.
rings
plaques
Lieberman JA and Chehade M. Immunol Allergy Clin North Am 2012;32(1):67-81.

9. EoE: Clinical Manifestations
% Patients
Common symptoms of EoE vary between adults and children. In this figure, blue bars represent adults, and red bars represent children. While adults commonly present with dysphagia and food impactions, children present mostly with abdominal pain and reflux symptoms including emesis. Note that last bar on the graph: up to 30% of children with EoE can present with failure to thrive. Therefore, growth failure in an atopic child with gastroesophageal reflux symptoms warrants further investigation for EoE among other etiologies. Failure to thrive typically reverses with adequate therapy for EoE.
Chehade M et al. J Pediatr Gastroenterol Nutr 2007;45:
Gonsalves N et al. Gastrointest Endosc 2006;64:

10. EoE: Demographical Characteristics
Male predilection
– 60-80%
Age at diagnosis
– Adults: 3rd and 4th decades of life
– Children: No recognized peak
Atopic predisposition
– More common in patients with food allergies
– >50% have asthma, allergic rhinitis and/or atopic dermatitis
So which patients are more likely to have EoE?
EoE is more common in males than females, with 60-80% of patients being male.
In adults, EoE is more common in the 3rd and 4th decades of life, whereas in children, there is no recognized peak, as it can occur at any age.
EoE seems to be more common in patients with food allergies and history of atopy. More than 50% of patients with EoE have history of asthma, allergic rhinitis, and/or atopic dermatitis.
There are no large genetic studies yet on EoE. However, the disease seems to run in families. In a pediatric study by Liacouras and colleagues, the authors found that 7% of their children had parents with a history suspicious for EoE, and 5% of their children had siblings with EoE.
One widely used measure of familial aggregation is the sibling recurrence risk ratio, which compares disease rates among siblings with the prevalence in the general population. The estimated sibling recurrence risk ratio For EoE is approximately 80. Compared with other allergic disorders with such as asthma, with a sibling recurrence ratio of 2, 80 indicates that EoE likely has a large genetic component.

11. Management of EoE Treatment: Topical corticosteroids
Fluticasone HFA swallowed mcg BID
Budesonide respules po 2 mg/day (mix ten 1gm packets of Splenda per 1 mg of Budesonide)
Esophageal dilation
Chronic dietary elimination
other than CHOP, no Patch at Sinai, Cincinatti, or NJ
*Liacouras et al. JACI 2011

12. Management of EoE Evaluation of allergies:
SPT may help with management of concomitant IgE-mediated disease (food and environmental allergies)
Patch testing for non-IgE mediated food sensitivities
Six food Elimination Diet Approach (for motivated adults)
Or modified approach: wheat and milk top 2
other than CHOP, no Patch at Sinai, Cincinatti, or NJ
*Liacouras et al. JACI 2011

13. Management of EoE Future Treatments: Aero-allergen immunotherapy?
(More on that later)
Anti IL-5 therapy (recently approved for asthma)
Non-controlled retrospective trial: N=43 peds pts and 40% had <15 eos/hpf and 77% had significantly fewer mast cells1
Two RCT, one peds and one adult study: Mild to moderate improvement in Eos counts, but no change in symptoms compared to placebo2,3
Targeting other molecules in the pathogenesis
other than CHOP, no Patch at Sinai, Cincinatti, or NJ
1Otani et al., JACI 2013; 131(6): Straumann et al.,Gut 2010;59: Spergel et al., JACI 2012;129:456-63

14. Allergy Skin Prick Testing

15. Food Patch Testing

16. Food Patch Testing Problems
Reagents are not standardized
Limited studies with inconsistent results
Application is time consuming
Preparation requires practice and used fresh
Value compared to Six Food Elimination Diet may not be as accurate

17. Food Elimination in Adults
50 adults completed SFED
74% had ≤15 eos/hpf
94% had dec. sxs score
26% non-responders
Comparable to peds study*
74% histologic response;
97% symptom response
20 patients reintroduced
100% causative food found
60% Wheat and 50% Milk
13% of foods predicted by SPT
Gonsalves et al. Gastroenterology 2012;142:1451-9
*Kagalwalla et al. Clin Gastroentero Hepatol 2006:

18. Histologic Remission Rates for Different Dietary Treatment Options
Meta-analysis by Aries et al. Gastroenterology 2014;146:

19. EoE and Aeroallergens? What about the ~1/3 of Non-SFED-responders?
Aeroallergens through PND or inhalation? 1
Mouse models show increases eos in esophagus after nasal challenge with dust mite and roach Ag2
Correlation between EoE dx/flares and pollen counts3
Case reports of aeroallergen immunotherapy associated with improvement of EoE1,4
1Ramirez RM et al. JACI 2013:132(2):503-4
2Rayapudi M, et al. J Leukoc Biol 2010:88:337-46
3Moawad FJ, et al. Aliment Pharmacol Ther 2010;31:509-15
4Perez J, et al. Ann Allergy Asthma Immunol 2011;107:A59

20. Role of the Allergist in EoE
Managing the high rates of co-morbid atopic conditions including asthma, allergic rhinitis, atopic dermatitis, and food allergy
Helping determine dietary management
Maximizing treatment of potential aeroallergen sensitivities
So where does allergy fit in to EoE? Well, depending upon the study, reports generally show a high rate of concurrent atopic disease such as asthma, allergic rhinitis, atopic dermatitis and food allergy. This means that an allergist is likely needed for management of co-morbid conditions. But moreover, as we will discuss, diet appears to be the main trigger of EoE, and so the allergist is essential in determining dietary management. There is also evidence that environmental allergens play a role in EoE, because some patients show seasonality of symptoms with pollen seasons despite dietary therapy, and evaluation and management of those allergies is also necessary.
Liacouras CA et al. JACI 2011;128(1):3-20.

21. EoE: Collaborative Effort
Patient/Family
Internist
Pediatrician
Physician Assistant
Gastroenterologist
Allergist
Pathologist
Dietitian
We believe that the management of EoE requires collaborative efforts. Diagnosis of the disorder clearly requires a biopsy, and so a gastroenterologist and pathologist are essential. But their role extends well beyond simply performing an endoscopy and reading pathology slides, as you will see later in the talk. Since dietary management is typically needed, a registered dietitian is a key professional who can provide advice and guidance for successful management, as you will hear later in the program.
And the allergist plays a key role because many people with EoE have co-existing allergic disorders, often food allergies, and these typically play a role in EoE as well. But we also want to underscore that EoE is a medical condition that often requires complicated empiric therapeutic trials, repeated procedures, and a number of options for diagnosis and treatment. Therefore, patient and family preferences are a central aspect of management. The patient, family and primary care doctors are truly a guiding force in the collaborative team.

22. Example of a Collaborative Effort
MMC Pediatric GI and Allergy and Asthma Associates of Maine
Algorithm for the Evaluation of Children and Adolescents with
Symptoms Suggestive of Eosinophilic Esophagitis (EoE)
Adapted in 2015
(modified from recent guidelines, taking into account
individual experience and concerns about safety)
This effort came about due to significant variability
in diagnosis and management among specialties and providers

23. Symptoms Suggestive of EoE
Start High-Dose PPI 1mg/kg BID for 2 months
Symptomatic
After 2 months
Of High-Dose PPI
Asymptomatic
After 2 months
Of High-Dose PPI
EGD with Biopsies
Follow like GERD; Wean PPI when appropriate
 15 eos/hpf
≥ 15 eos/hpf
If Break-Through Symptoms on PPI,
EGD with Biopsies,
Follow Algorithm on Left
Eosinophilic Esophagitis
Offer Treatment Options Below and Activate Dietician Kay Mullin for #1-3:
1.Skin Test-Directed Diet (Allergy referral for SPT ± Patch Test)
2.Six Food Elimination
3.Elemental Diet
4.Topical Steroid
Follow symptoms and repeat EGD at GI’s Discretion
Consider other Diagnoses

24. SUMMARY Wide spectrum of adverse food reactions in adults
Most well understood is IgE-mediated disease
Not all esophageal eosinophilia is classic EoE
Consider consultation with allergist for evaluation of concomitant food/environmental allergies
Collaborative approach to EoE, especially if concomitant atopy, can be helpful

25. THANK YOU !!!!