Eosinophilic Esophagitis
No Relevant Disclosures
Rabindra R Watson, MD
Assistant Clinical Professor of Medicine
Director, Career Development in Advanced
Endoscopy
Division of Digestive Diseases
David Geffen School of Medicine
Objectives
• Discuss the rising prevalence of
eosinophilic esophagitis (EoE)
• Discuss the differentiation between EoE
and gastroesophageal reflux disease
• Discuss best treatment approaches for EoE
Definition
A primary clinicopathologic disorder of the esophagus, characterized by:
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Esophageal/Upper GI tract symptoms
>15 intraepithelial eosinophils/HPF on esophageal biopsy
Absence of GERD by either normal pH study or lack of response to high dose PPI therapy*
Furuta GT, et al, Gastro 2007
Definition
• "a chronic, immune/antigen-mediated,
esophageal disease characterized clinically
by symptoms related to esophageal
dysfunction and histologically by
eosinophil-predominant inflammation"
Names/Acronynms for EE
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Liacouras, et al, J Allergy Clin Immunol 2
Eosinophilic Esophagitis (EE or EoE)
Primary Eosinophilic Esophagitis (PEE)
Allergic Eosinophilic Esophagitis (AEE)
Idiopathic Eosinophilic Esophagitis (IEE)
Corrugated Esophagitis
Allergic Esophagitis
History of EE
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First described by Landres in 1978
Virtually no studies until the 1990’s
Marked increase in publications over last 5 years
Publications now number more than that for eosinophilic gastroenteritis
Initially described in children, but now increasingly being recognized in adults
Most studies single center with small numbers of patients
Dellon et al, AJG, 2007, pp. 2300‐2313
Epidemiology
EE>EG In Publication Numbers
• Diagnosis (?incidence) rising
• Straumann and Simon - 13.5 x increase in
Switzerland over 16 years
• Studies done in demographically stable area
with consistent recording -> suggesting real
increase not enhanced disease awareness
• Regional variations
• Urban > Rural
• Regional
• Incidence ~ 4 : 10,000
Spergel, et al, JPGN 2011;52: 300–30
Furuta et al, APT, 2006, pp. 173-182.
History of the Eosinophil
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G
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D
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Number of Publications on EE
But: Prevalence of GERD: 10-20%
Spergel, et al, JPGN 2011;52: 300–306
EOS = Greek for “goddess of
the dawn”
1879 - eosinophil named by
Paul Ehrlich because
cytoplasmic granules stained
red with eosin (like the
morning glow)
Pathophysiology
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Pathophysiology – Interleukins
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Allergen-induced
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Often related to food
? aeroallergen(s) in minority of people
Allergen (IgE) and non-allergic (non-IgE
mediated mechanisms
Why Esophagus?
Allergen
exposure
Eosinophilic
inflammation
Exposure to Antigens Æ Th2 response
Æ ÏIl-4, Il-5, Il-13
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Influences Eosinophil activation in bone
marrow
Release of Eotaxin-1 from esophageal
epithelial cells
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Dysphagia/foo
d impaction
Scarring
(fibrosis)
Potent promoter of eosinophil migration
Gene expression Ï53x in children with EoE
Blanchard C, et al. J Clin Invest 2006
Pathophysiology – Eosinophils
Presentation
Extracellular deposition of major basic
protein
Eosinophilic granules are toxic to
intestinal epithelium
Esophageal lymphocytes, mast cells,
fibroblasts are increased Æ remodeling
• Male predominance (65-71%)
• Age 20-40’s (mean 33.5)
• 52.8% with diagnosis of additional allergic
condition
• Dysphagia most common
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• 15% with EoE
• History of food impaction in 35-54%
Dellon ES, et al. Clin Gastro Hep; 2014
Prasad GA et al. Am J Gastro 2007
Mackenzie SH et al. Alim Pharm Therap 2008
Straumann A, et al. Clin Gastro Hep 2008
Symptoms
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Dysphagia to solid
foods
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Food impaction
Meat
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Heartburn (Refractory
GERD)
Bread
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Chest pain
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Abdominal pain
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Vomiting*
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Poor feeding*
*seen in younger children only
Differential Diagnosis
Rice
Rough-texture foods
Liacouras, et al, J Allergy Clin Immunol 2011
Laboratory Studies Suggestive of EE
Diagnostic Guidelines
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Clinical symptoms of esophageal dysfunction
>= 15 Eosinophils in 1 high‐power field
Lack of responsiveness to high‐dose proton pump inhibition (up to 2 mg/kg/day) or
Normal pH monitoring of the distal esophagus
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Making the diagnosis
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Requires an upper endoscopy (EGD)
and biopsies
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≥2-3 biopsies each from upper and
lower esophagus
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≥15 eosinophils per section under
microscope at high-level magnification
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Eosinophilic inflammation absent from
stomach and small intestine
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Negative pH study – no acid reflux
Eosinophilia
60% of children
5‐50% of of adults
Elevated serum IgE levels
Positive skin prick test
Radioallergosorbent tests (+ in 40‐73%)
Endoscopic findings
• 80%
• Rings
• Linear furrows
• Felinization
• Stricture
• White exudates
Note: None of these are pathognomonic for
EE
Histology
Variability in Histologic Criteria
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Review of literature through 2006 on EE
116 original articles, 39 abstracts, 69 reviews
Results showed 10 different histologic definitions
for EE (5-30 eosinophils/HPF)
35% of articles did not state diagnostic criteria
11% of original articles reported a high powered
field area
Eosinophil density per mm2 varied by factor of
23
Specific biopsy protocols reported in only 39% of
articles
Dellon et al, AJG, 2007, pp. 2300-2313.
Diagnostic challenges: PPI-REE
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PPI-responsive esophageal eosinophilia
(PPI-REE)
Initially thought that EoE and acid reflux
(GERD) were distinct entities
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???
Exclude GERD by trial of PPIs or reflux testing
EoE and GERD can co-exist
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Symptoms and EGD-findings suggestive of EoE
Microscopic requirements for EoE
Symptom and microscopic response to PPI
+/- abnormal reflux testing
Diagnostic challenges
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GERD predisposes to antigen exposure
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Decreased tight junction integrity, ?increase
antigen exposure
EoE may reduce LES pressure, promote
lamina propria fibrosis
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Role of allergy evaluation
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Recommended to evaluate for
concurrent atopic disorders
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Testing for immediate-type food,
environmental allergies
40% of EoE pts have motility abnormalities
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PPIs are anti-inflammatory
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Antioxidants
Ðcytokine production
Ðadhesion molecule producition
ÐIl-13, Il-4 stimulated eotaxin production
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Serum (IgE)
Skin prick and atopy patch testing
Usually not helpful for identifying EoErelated food allergies
Sgouros SN, et al. Eur J Gastro Hep 2006
Therapeutic Goals
Therapy
PPI
PPI
Treatment Impact
PPI
PPI
Therapeutic Response
PPI
PPI
Treatment Options – PPIs
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Proton Pump Inhibitors
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Topical Steroids
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Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Pantoprazole (Protonix)
Rabeprazole (AcipHex)
Esomeprazole (Nexium)
Dexlansoprazole (Dexilant)
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Mainstay of treatment
Inhaler (fluticasone) – swallowed
instead of inhaled
Viscous (budesonide) – mix with sugar
substitute
May have anti-inflammatory properties
33-50% of patients with EoE features
respond
Twice a day dosing x8 weeks to see if
PPI-REE
Topical Steroid Therapy
Topical Steroids
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Twice a day for 8-12 weeks
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Nothing to eat/drink for 30 minutes after
swallowing medication
Rinse, gargle and spit to clear residual
medicine from mouth
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Liacouras et al
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1% oral yeast infection (thrush)
5% esophageal yeast (usually
asymptomatic and probably not significant)
Faubion et al
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Arora et al
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Topical Steroid Therapy
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26 patients; 19 received fluticasone propionate
250 ug/puff; 2 puffs BID x 4 weeks
4 week trial of topical steroids
21/21 children with near total symptom relief in 1 week
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Side effects uncommon
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Complete symptoms relief in 1 week.
21 patients treated for 6 weeks
Complete symptom relief for 4 months
3 patients with relapse afer 4 months
About 1/2 of patients relapse within 12‐18 mos
Topical Therapy Improves Symptoms and Histology
Symptoms = Dysphagia, CP, Heartburn, Regurgiation,
Vomiting, Abdominal Pain
All treated patients with symptom
improvement and histologic improvement
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11 became asymptomatic
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Mean symptom score went from 5.4 to 0.7
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14/19 with recurrent symptoms at 3 months
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3 patients developed candidiasis
Remedios et al, GIE, 2006, pp. 3-1
Remedios, GIE, 2006, pp. 3-1
Budesonide for EoE
Budesonide for EoE
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RCT with placebo control of 1mg BID x 15d (N=36
total)
Primary outcome = # of mucosal eosinophils
Significant decrease in eosinophils (68.5 -> 5.5 hpf in
tx group); dysphagia improved as well (5.61 to 2.22);
p<0.0001 for both comparisons; no change in placebo
group
Also endoscopic improvement seen and no adverse
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RCT with placebo control of 1 or 2 (< or > 5 ft)
mg QD viscous budesonide x 3 mos (N=15
budesonide; N=9 placebo)
Primary outcome = # of mucosal eosinophils
Significant decrease in eosinophils (66.7 -> 4.8
hpf in tx group); eosinophilia decreased
throughout esophagus
Also endoscopic, symptom, and histologic
improvement
Oral Steroids
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Prednisone
May help if poor response to topical
steroids or in patients who need rapid
improvement in symptoms
Not commonly used
Numerous side effects from long-term use
Dietary Elimination
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Elemental (amino acid based) diet
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Most effective (>95% of patients respond)
Elemental formula is costly
Usually administered by feeding tube (not
palatable)
Elimination based on allergy testing
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Low predictive value for identifying EoEassociated allergen(s)
Markowitz, AJG, 2003
Elemental Diet Therapy in
Adults
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18 adults
Eosinophil count decreased
from 54 to 10/hpf
72% with near complete
response (<10 eos/hpf)
38% failed to adhere to diet
No symptom improvement
Eosinophil count increased
back to previous in 3-7
days
Dietary Elimination
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Six-food elimination
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Wheat, dairy (including milk proteins), soy,
nuts, egg, seafood
64-94% resolution (depending on
parameter assessed)
Acceptable first-line therapy for EoE
>
Petersen et al, Am Jl Gastro, 2013, pp 1-8
>
=
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Markowitz, AJG, 2003
Issues with SFED
Six-food elimination diet (SFED)
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Avoid foods listed in the SFED x6 weeks
Assess if endpoints met
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Symptom resolution
Improvement of endoscopic appearance
Appropriate reduction in esophageal eosinophils
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If endpoints met, reintroduce food groups one
at a time every 2 weeks to identify trigger(s)
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Wheat (60%)
Dairy (50%)
Soy, nuts (10% each)
Eggs (5%)
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Some patients’ symptoms may not occur so
frequently
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Up to ~35% of patients may not respond to
SFED
„ Another food? (rice, corn, legumes)
„ Can be time consuming and still at “square
one”
Can be difficult to eliminate all 6 food groups
Four-food elimination maybe as effective (nuts and
seafood OK)
Wh t b t j t li i ti
h t d d i (t i
Leukotriene D4 Receptor Inhibitors
Six food elimination diet (SFED)
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Longer duration on SFED before recognizing
symptom response
Longer duration for each food reintroduction before
determining whether each food is a trigger
50 adults
6 weeks
Clinicopathological remission with SFED
Eosinophilia returned when diet liberalized
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Cromolyn - mast cell inhibitor
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Montelukast
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Single study of 14 pts showed no benefit
Has been used to treat asthma
Needs to be given daily rather than in a pulse manner
Attwood et al
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8 patients treated with 10 mg/day
Adjusted dose up to 100 mg/day
7/8 with symptom resolution, although not histologic
resolution
Adverse events: nausea and myalgia
75% recurred within 3 weeks of stopping drug
Gonsalves et al, Gastroenterology 2012
Biological- Reslizumab-(anti-IL-5
antibody)
Interleukin‐5 Inhibitors
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Mepolizumab - IL-5 monoclonal antibody
Reported for adult EoE (Garrett, J. All Clin Imm,
2004)
4 patients with hypereosinophilic syndromes
1 patient with EE
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Unresponsive to diet, topical/oral steroids
Given study drug 3 x at 10 mg/kg every 4 wks
Symptomatic, endoscopic, and histologic
improvement seen.
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226 children
(mean age-12 +/1 4)
3 doses and placebo
12 weeks
Histological response with
treatment
Treatment and placebo
symptom response
Spergel JM et al, J Allerg Clin Immunol 2012
Endoscopic Dilation
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Breaks up scar tissue
Useful for treating very tight strictures
Feasible in absence of prior medical
therapy
Effective for quick relief of dysphagia
Does not treat the underlying inflammation
Risks
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Indications for Dilation
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Chest pain (75%) – usually resolves within 2-3 days
Clinically significant bleeding (only 1 case report in
literature)
Perforation (0 3% in academic medical centers)
Known EE with dysphagia that fails to
respond to medical therapy
Severely symptomatic strictures
Defer dilation at initial endoscopy if EE is
suspected
About 80% will have immediate response
to dilation
Symptoms tend to recur, but relief usually
lasts at least 3-8 months
Endoscopic Dilation
Dilation is Safe – But Painful
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207 dilations
Mean recurrence in
dysphagia at 23 mos
in dilation only group
and 20 mos in dilation
and med tx (p=NS)
No perforations; 74%
with chest pain
Symptom relief
despite no change in
eosinophil counts
Maintenance
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Stopping therapy will lead to relapse in
>90% of patients by 9 months
Prognosis
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Maintenance therapies
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Indicated particularly for patients with highgrade strictures and rapid relapse
Topical steroids used at 25-50% of the
initial dose
Long-term elimination of dietary trigger(s)
On-demand esophageal dilation
Little data to date on this important issue
Long term prognosis of pediatric EE unknown
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? If similar to food allergy/atopic dermatitis which
abate with age
Strautman et al, Gastroenterology, 2003
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Followed 30 adults with EE
Mean f/u of 7.2 years
Dysphagia persisted in 97%
Strictures in 13/30
No progression of eosinophilic infiltration
No malignancies/hypereosinophilic syndromes
Only 3% with a major negative impact on activity
Conclusions
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EoE is a chronic immune disorder of the
leading to esophageal dysfunction
Pathophysiology is unclear, ?asthma of
esophagus
Rising incidence in parallel with allergic
disorders
EoE and GERD can coexist: PPI trial
Therapy is multifaceted: steroids,
elimination, endoscopic dilation
Insufficient data to determine long term
outcomes
Questions?
"I wanted you to meet our endoscopy specialist before we miniaturized him."
rwatson@mednet.ucla.edu