E OSINOPHILIC SOPHAGITIS

E OSINOPHILIC E SOPHAGITIS
O BJECTIVES

Identify the basic etiology and mechanism of
EoE

Understand the relationship of EoE to food
allergy

Discuss the pathogenesis, symptoms,
diagnosis

Discuss current and future treatment
strategies for EoE
C ASE # 1

A 16y male is evaluated in the ED for chest discomfort of 2 hours
duration that occurred after eating a large meal. He has difficulty
swallowing and feels as though something is stuck in his chest. He
is barely able to swallow his saliva and frequently spits into a cup.
He has had 2 similar, but less severe, episodes in the past 6 months.
He has a history of allergic rhinitis treated but no history of food
allergy (anaphylaxis). Father has an esophageal stricture that
requires repeat dilatation.

On PE, he is well developed and well nourished but uncomfortable.
EGD shows multiple esophageal rings with raised white specks,
longitudinal furrows, and friable esophageal mucosa. No strictures
are detected. Histological exam of the mucosa shows intense
inflammation of the lamina propria with more than 15 eosinophils
per HPF.
Q UESTION

Which of the following is the most appropriate
management for this patient?

Endoscopic esophageal dilation

Leukotriene receptor antagonist therapy

Oral topical (swallowed) corticosteroids therapy

PPI therapy
C ASE # 2

14 month F baby

Failure to thrive

Vomiting & refusal to take foods especially solids,
on standard formula

Exclusive breastfed till 6 Mo, generally well other
than moderate AD

OGD reveals thickened, furrowed esophageal
mucosa with >50 Eos in proximal and distal Bx.
W HAT TREATMENT WOULD YOU ADVISE

PPI

Predmix

Substitute formula with soy or protein
hydrolysate

Elemental diet

Referral to Immunologist / allergist
E OSINOPHILIC E SOPHAGITIS
D EFINITION

A chronic, immune/antigen mediated esophageal
disease characterized

clinically by symptoms related to esophageal
dysfunction

histologically by eosinophil-predominant
inflammation
Liacouras C et al, J Allergy Clin Immunol 2011
A HISTORICAL PERSPECTIVE . . .

First described in 1978 but GORD was thought to
be the driving force

More research done on GORD as the cause of EE


1982 Winter et al.

1985 Lee et al.
Not until the 1990s was EoE described as a
separate entity

1993 Attwood et al.

1995 Kelly et al
E PIDEMIOLOGY

Mostly relegated to westernized world

More common in young males

50-70% with EoE also have atopy disease

Increasing in incidence


Not completely explained by increased awareness

May be associated with increased incidence of asthma,
allergies
Prevalence

0.5/100,000 in 1995

8.9/100,000 in 2004
E O E - N ATURAL H ISTORY

Lag of 4.3 years between onset of symptoms and
diagnosis

Limited to the esophagus

Chronic disorder that cannot be outgrown

Chronic Persistent

Chronic Relapsing

Prolonged disease leads to remodeling of the
esophagus

Not associated with premalignant or malignant
transformation
E O E - PATHOGENESIS
E NVIRONMENTAL T RIGGERS

EoE association with atopic and allergic disorders

Seasonal variation in symptoms and diagnosis
rates

Elemental diets result in clinical and histological
improvement that reverse with reintroduction of
foods

Priming with epicutaneous exposure to antigens
can result in esophageal eosinophil recruitment
in a mouse mode
S EASONAL VARIATION IN
D IAGNOSIS
150 eos/hpf
12 eos/hpf
Adaptive Th2 cell mediated
immune responses

Both IgE & non-IgE pathways involved

Principal Chemo attractants & cytokines involved

Eotaxin -3, IL-5, IL-13, GM-CSF, FGF-9

Patients with EoE have a striking increase in expression
of eotaxin-3

Mice deficient in CCR3 were resistant to EoE

Eosinophils release major basic protein causing
inflammation

Chronically causes dysphagia
G ENETIC P REDISPOSITION

Familial Clustering well recognized

Possible susceptibility locus 5q22

GWS - SNP in eotaxin-3 identified using
microarray technology


50x more elevated than normal controls
Defects in filaggrin,thymic stromal lymphopoeitin
(TSLP) and TSLP receptor also implicated as
genetic risk factors
Current Opinion in Allergy and Clinical Immunology 2010, 10:231–237
E O E - CLINICAL FEATURES
M OST
Age
COMMON CLINICAL MANIFESTATIONS
Clinical presentation
Infant and Toddlers
feeding difficulties, feeding refusal or
intolerance, irritability, vomiting,
failure to thrive
School-aged children
Abdominal pain, vomiting, GERD-like
symptoms,
difficulty swallowing, food aversion/selflimited diet, failure to thrive
Adolescents
Dysphagia, esophageal food impactions,
nausea,
GERD-like symptoms, self-limited diet
Adult
Dysphagia, esophageal food impactions
Mirna Chehade and Seema S. Aceves Current Opinion in Allergy and Clinical Immunology 2010, 10:231–237
C HILDREN V S A DULTS
 “GORD” symptoms

Chest pain-”with alcohol”
 Abdominal pain, vomiting

Food impaction
 Feeding dysfunction

Dysphagia
 Coping mechanisms- avoid
highly textured and bulky
foods, cut food into small
pieces, lubricating foods,
extensive chewing / long
meals
S YMPTOM PROGRESSION WITH
AGE
D IAGNOSIS

Symptoms related to esophageal dysfunction

One or more esophageal biopsy specimens show
15 Eos/hpf (peak value)

minimum threshold for a diagnosis of EoE

Disease is isolated to the esophagus

other causes of esophageal eosinophilia should
be excluded

Disease remit with treatments of dietary
exclusion, topical corticosteroids, or both
O THER
CAUSES EXCLUDED
Liacouras, et al, J Allergy Clin Immunol 2011
E O E V S . GORD

GORD

EoE – male predominance, atopy, food impactions

Both have eosinophilia and basal zone hyperplasia

Lower number of eosinophils and concentrated
more distally

EoE involves the mucosa, submucosa, muscularis while
GORD does not

pH probe, response to treatments

“PPI responsive EoE”
E NDOSCOPY
IN
E OE

Stacked circular rings ("feline" esophagus)

Strictures (particularly proximal strictures)

Attenuation of the subepithelial vascular pattern

Linear furrowing

Whitish papules (representing eosinophil
microabscesses)

Small caliber oesophagus
N ORMAL
A BNORMAL
Concentric Rings
Loss of Vascularity
“T RACHEATIZATION ”
E XUDATES
Clustered Eosinophils or
micro abscesses breaking
through mucosa
A DVANCED E O E
Longitudinal furrowing
Erosions at GE junction
Histological Findings
Mucosal eosinophilia
Eosinophil microabscess formation
Superficial layering of eosinophils
Typical finding
associated with
EoE > GERD
Extracellular eosinophil granules
Epithelial desquamation
Basal zone hyperplasia
Rete peg elongation
Dilated intercellular spaces
Subepithelial fibrosis/sclerosis–lamina propria fibrosis
Mastocytosis and mast cell degranulation
CD8+ lymphocytes and B cells
Normal esophagous
Superficial layering of surface Eo
EoE
Microabcess
A.
Superficial
layering
B.
Large
microabscess
C.
Small
microabcess
A LLERGIC E VALUATION

EoE is an antigen-driven allergic condition

EoE patient
- 28% to 86% of adults
- 42% to 93% of pediatric
Have another allergic
disease

50% to 60% of patients with EoE have a prior
history of atopy

Major of patients have sensitization to food
allergens, aeroallergens, or both (SPT or
Specific IgE )
Studies
Atopic
disease
Evidence of IgE to Evidence of IgE to
Aeroallergen
Food
Aceves et al,
Asthma 47%
J Clin Gastroenterol AR 40 %
Vol 41, No 3, March Eczema 4%
2007
+ aeroallergen RAST
44%
+ food RAST 60%
Collins et al,
Asthma 52%
Clin Gastro and
AR 68 %
Hepato Vol. 6, No. 6 Eczema 44%
AC 56 %
+ SPT aeroallergen
71%
+ SPT food 76%
ROY–GHANTA et al, Asthma 26%
Clin Gastro and
AR 78%
Hepato Vol. 6, No. 5 AD 4%
Specific IgE
Specific IgE for food
aeroallergen
83%
86%
( Birch pollen ,Timothy
ryegrass pollen
Ragweed pollen , dust
mite Pet dander )
Atopic disease
Aeroallergen Specific IgE
Food specific IgE
Aceves et al
J Clin Gastroenterol Vol
41, No 3, March 2007
Asthma 47%
AR 40 %
Eczema 4%
+ aeroallergen RAST 44%
+ food RAST 60%
COLLINS ET AL
Clin Gastro and Hepato
Vol. 6, No. 6
Asthma 52%
AR 68 %
Eczema 44%
AC 56 %
+ SPT aeroallergen 71%
+ SPT food 76%
ROY–GHANTA ET AL
Clin Gastro and Hepato
Vol. 6, No. 5
Asthma 26%
AR 78%
AD 4%
Specific IgE aeroallergen
86%
( Birch pollen ,Timothy
ryegrass pollen
Ragweed pollen , dust mite
Pet dander )
Specific IgE for food 83%
TOOLS FOR TESTING
ALLERGIES


Skin prick testing (IgE mediated)

Standardized and very consistent results

Commonly identifies egg, milk, soy, wheat,
peanuts, beans, rye, and beef
Atopy patch testing (non-IgE mediated)

More variable in preparations and methodologies

Identifies corn, soy and wheat
SPT + APT
NPV
PPV
Peanut, beef, corn,
chicken, potato and pork
>96%

Milk 82%

Egg 61%

Egg and soy 93%

Other 17-42%

Wheat 88%

Milk 41%

Spergel JM et al.J Allergy Clin Immunol.
2012;130(2):461.
P REDICTIVE
VALUES FOR SKIN PRICK TEST AND
ATOPY
PATCH TEST FOR
EOE

The combination of the 2 testing methods had an
excellent NPV (88% to 100%) for all foods except
milk, which was very low at 41%

Combination of SPT and APT in designing a diet
plan has a high success rate for food elimination
or food reintroduction in EE with the exception
of milk.
J Allergy Clin Immunol. 2012;130(2):461.
S ERUM I G E MEASUREMENT AND DETECTION OF
FOOD ALLERGY IN PEDIATRIC PATIENTS WITH E O E
• serum IgE measurement
detected more positive results
than did skin prick testing.
Specific IgE to milk was most
common (43%)
• low-titer IgE antibody may be
useful in identifying relevant
food sensitivities making a more
directed approach to food
avoidance possible
Ann Allergy Asthma Immunol.
2010;104:496 –502.
10 M OST
COMMON FOODS

Milk

Potato

Egg

Beef

Soy

Chicken

Wheat

Pork

Corn
A EROALLERGENS
Outdoor Allergens
Indoor Allergens

64-93%

16 – 69%

Grass and tree pollen

Dust mites

Moulds

Dog, cat

Weeds

Cockroach
E O E - M ANAGEMENT
T REATMENTS

Dietary Management

Pharmacotherapy

Repeated dilatations
FOR
E OE
D IET
EXCLUSIONS IN

Elemental Diet

Elimination Diet
E OE

Tailored – based on SPT+APT

Empirical – SFED (milk, egg, soy, wheat, nuts, fish)

Modifications or combinations of above
E LEMENTAL

Gold standard

95-100% response rates

Unpalatable

Costly

Low in micronutrients,
fiber

Many times tube feeding
DIET
S IX FOOD ELIMINATION DIET
Gonsalves et al, Gastroenterology 2012

50 adults with EoE

6 weeks of SFED resulted in clinicopathological remission

Eosinophilia returned when diet liberalized
S IX FOOD ELIMINATION DIET
Lucendo AJ et al, JACI Feb 2013

67 adult patients, SFED induced remission 73.1%

Food triggers identified by sequential reintroduction and endoscopic biopsy

Most common food triggers- Milk, egg and wheat

Offending foods eliminated maintaining
remission over 3 years

Little correlation between S.IgE/SPT and
subsequent identification of offending food
Lucendo AJ et al, JACI Feb 2013
Spergel et al, J Allergy Clin Immunol Jun 2012
P HARMACOTHERAPY

Topical corticosteroids

Montelukast

Fluticasone

Azathioprine

Budesonide

Biological agents

Oral Prednisolone

Anti – IL5

PPIs

Anti –TNF
Study
Design &
No. of Pt
Medication and
Dosage
Outcome
Konikoff et al,
2006
RDBPC
N = 36
Fluticasone propionate 2
puffs twice daily : All subjects
received 220
mcg/puff( total 880mcg/d)
* 3 mo
(Ages 3–16 y)
1 o outcome
: Prox EsoEo 65.9 + - 25.3 vs
1.4 + -1.1 eos/hpf [P =0.03]
:Dist EsoEo 84.6 + -19.7 vs
19.6 + - 12.9 eos/hpf
[P=0.04 ]
2o outcome
:Resolution of vomiting FP vs
placebo 67% vs 27%;
[P =0 .04]
:Improve endocopic finding
(Furrow) [P=0.047]
: reduce epithelial
hyperplasia [ P= 0.01]
:FP decreased the number of
CD8 & mast cells in proximal
and distal esophagus
(P=0 .05)
F LUTICASONE
Alexander JA et al Clin Gastro Hepatol 2012
S UBEPITHELIAL F IBROSIS R EVERSAL
WITH F LUTICASONE
J. Allergy Clin. Immunol. 128(5), 1037–1046 (2011)
B UDESONIDE
Dohil et al Gastroenterology 2010

“Oral viscous” budesonide

Randomized placebo controlled study

OVB=15, placebo-9

Significant reduction in symptoms and eosinophilia
Study
Design Medication and
& No. of Dosage
Pt
Outcome
Dohil et
al,2010
RDBPC
N = 24
1 o outcome
In OVB gr 87.6%  responder
Reduce peak EsoEo all esophageal
Levels proximal (P=0.0024),
mid (P =0 .0001), and
distal (P=0 .0001) when compared to baseline
2o outcome
Upper gastrointestinal endoscopy score
reduced 4.6 1.5 [P=0.0005]
:Symptom score decrease from 3.51.2
[p=0.0007]
: Epithelial &Lamina propria Eosinophilia &
Fibrosis reduced [P=0.0035]
Oral viscous
budesonide * 3 mo
Subjects <5 ft tall
: 1 mg daily
Subjects >5 ft tall
: 2 mg daily
(Age 1–17 mean 7.8
yr)
M AINTENANCE
STEROIDS

After induction of clinicopathological remission,
topical corticosteroid therapy might need to be
maintained

long-term therapy must be individualized for
each patient

When topical steroids used chronically : side
effects, growth should be carefully monitored

Candidiasis 15%, growth stunting in children
(J Allergy Clin Immunol 2011;128:3-20.)
A NTI –
IL 5
T REATMENT
Anti-interleukin-5 antibody treatment (mepolizumab)
eosinophilic oesophagitis:
a randomized, placebo controlled, double-blind trial
in
active

11 adult patients were randomized to mepolizumab (n = 5) or
placebo (n = 6)

Mepolizumab gr. decrease mean EsoEo 54% vs placebo 5 %

But no complete resolution in any subject, no significant symptom
improvement
Gut 2010 ;59(1):21-30
R ESLIZUMAB

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
O THER
TREATMENTS

Treatment of EoE with cromolyn sodium,
leukotriene
receptor
antagonists,
and
immunosuppressive agents (azathioprine or 6MP) is not recommended

Anti–tumor necrosis factor (TNF) : one case
report

Anti-IgE therapy (omalizumab) : no publish study,
one case report
(J Allergy Clin Immunol 2011;128:3-20.)
E SOPHAGEAL D ILATION

Provides good relief from dysphagia

Reserve for those with strictures or rings

Downsides

High risk of perforation or tear

Does not treat the underlying cause

Repeat procedures often required
T REATMENT S TRATEGIES

Induce clinical remission - yes

Induce histological remission


?yes

What defines histological remission?

Does this prevent complications?
Balance benefits of treatment (disease complications)
with treatment complications and impact of
treatment on quality of life.
U NRESOLVED
ISSUES

Importance of treating asymptomatic patients

Natural history of EoE and rates and predictive
indexes of complications

Accuracy of skin prick and patch testing

Optimal end points of treatment

Biomarkers and molecular signatures that aid in
the diagnosis of EoE

Lack of non-invasive or minimally invasive
methods for diagnosis and follow up
CME
ACTIVITY

Please answer MCQs at the end of session

Self assessment exercise