Esophageal Eosinophilia
Is it due to...?
• severe GERD
– Intraepithelial eos correlate
w/reflux esophagitis
– but..
• Normal esophageal pH
studies
• Poor response to acid
blockade
• subset of eosinophilic
gastroenteritis
• manifestation of IBD or
other autoimmune
disorder
• a new separate disease
Eosinophilic Esophagitis
• Isolated eosinophilic infiltration of
esophageal mucosa
• Digestive symptoms
– Dyspepsia, dysphagia
– Can mimic GE reflux
– Unresponsive to acid suppression therapy
• Emerging disease
– Increasing incidence
Chronology
• 1953: Schatzki’s ring reported
– Possible association with EE
• 1970s: “Felinized” esophagus reported
– Multiple concentric rings attributed to GERD or congenital anomaly
• 1978: First report of “eosinophilic esophagitis” as separate entity
– Landres et al, Gastroenterology 74:1298.
• 1982: Correlation established between eos and reflux esophagitis
• 1995: Kelly and Sampson demonstrate link between persistent EE and
dietary antigens
– Improvement with an elemental formula; Gastroenterology 109:1503-12.
• 1998: First reports of successful treatment of EE with oral or topical
corticosteroids
• 2003: First study of natural history of EE in adults published
• 2006: First randomized controlled trial of pharmacologic therapy in EE
(swallowed fluticasone) published
• 2006: First Int’l. Gastrointestinal Eosinophil Research Symposium
(FIGERS) begins developing guidelines for diagnosis and
management of EE in children
Epidemiology
• PREVALENCE
– 1.5-3/10000 adults
– 4.3/10000 children
• Incidence rising
– Approaching that of
IBD
• Family history
– 6.8% of patients
• Male predilection
Noel R et al. N Engl J Med. 2004: 351:940-41.
Clinical Features of EE
CHILD
Vomiting
Heartburn
ADOLESCENT
Heartburn
Dysphagia
ADULT
Dysphagia
Stricture
Yan B, Shaffer EA. World J Gastroenterol. 2006
Pediatric Series
• N = 381
– Age 9 +/- 3 y
• 2 cases in 1994, vs.
• 72 cases reported in 2003
• 66% male
• 85% GER sx
– 18% dysphagia
• Endoscopy
– Normal in 32%
• Despite clearly abnormal
histology
Liacouras CA et al. Clin Gastroenterol Hepatol. 2005;
3:1198.
• N = 103
– Only 3% identified prior to
2000
• Atopic history
–
–
–
–
Rhinoconj. 57%
Food allergy sx 46%
Wheezing 37%
Fam hx atopy 74%
• Age-dependent clinical
features
Noel R et al. N Engl J Med. 2004; 351:940-41.
Clinical Features of Pediatric EE
Noel R et al. N Engl J Med. 2004: 351:940-41.
Represents median age of
presentation
EE vs. GER
Diagnosis of EE
• Requires endoscopy and histology
– Strictly defined as dense eosinophilia confined to the esophagus
– Eosinophilia also in stomach, small bowel, colon may be due to
another EGID, IBD, parasitic or fungal infection, connective tissue
disease, neoplasm
• Adjunctive modalities
–
–
–
–
–
Contrast UGI series: eval. dysphagia
Esophageal pH-metry: exclude acid GER
CBC/d: periph. eosinophil count
Serum IgE level
Future: biomarkers
Endoscopy
Normal esophagus
EE
Linear furrowing
Eosinophilic microabscesses
Furuta GT, Straumann A. Aliment
Pharmacol Ther. 2006;24:173-82.
Normal
“Crepe paper” esophagus
EE
Trachealization
Contrast UGI series
Fox VL et al, Gastrointestinal Endosc. 2002
EGD:
Mucosal pallor
UGI: Stricture
EUS: Submucosal
thickening
Fox VL et al, Gastrointestinal Endosc. 2002
Histology
• Eosinophils in the esophagus are never normal
• Eosinophil count (eos/hpf) alone is not enough to establish dx of EE
• >15 eos/hpf suggests EE in the proper clinical context
• Pathology report should quantify eos in the most dense field
•
Multiple biopsies should be taken from distal and proximal sites in esophagus
• GERD esophagitis is typically localized to distal esophagus
• Inflammation may have “patchy” distribution
Ruchelli E, Antonioli D, FIGERS/NASPGHAN Annual Meeting 2006 .
Proposed Biomarkers
• Non-invasive
• Reproducible and predictive
• Based on pathophysiology
– Sputum eosinophils
– Serum CD23 levels
– Plasma eotaxin-3 and eosinophil-derived neurotoxin (EDN) levels
• Correlated strongly, along with peripheral eosinophil count, with mean
esophageal eosinophil density*
– mRNA or gene microarray for eotaxins and cytokines (IL-5, IL-13,
RANTES)
Gupta SK. FIGERS 2006.
*Konikoff MR et al. Clin Gastroenterol Hepatol. 2006; 4:1328-36.
Pathogenesis
Present understanding:
Chronic allergy
“An immune disorder
that results from a
mixed allergic
response” to dietary
and possibly other
environmental
antigens*
Kay AB. New Engl J Med. 2001
Th-2 response
IL-5 key for eosinophil
differentiation, activation
Eotaxins, IL-4, IL-13 recruit
eos to GI tract
*Markowitz JE, Liacouras CA. Dig Liver Dis. 2006; 38:251-53.
Pathogenesis
Rothenberg ME. New Engl J Med. 1998
• Once in GI tract, eos
release eotaxins, IL-5,
GM-CSF, PAF and attract
more eos
• Eos cause local
inflammation by releasing
MBP, cytotoxic granule
contents, more cytokines
• Ongoing inflammation
can lead to fibrosis,
stenosis, morphologic
alteration
Role of Environmental Allergens
•
•
•
•
Seasonal exacerbation in some cases
Association with pollen allergy
Atopic background of many EE patients
Experimental EE (mouse models)
– Respiratory allergens induced EE while oral or
intragastric ones did not
– Intratracheal IL-13 induced EE
– Deficiency in IL-5, eotaxin-3 and its receptor, and STAT6 protected mice vs. EE
Mishra A et al. J Clin Invest. 2001; 107:83-90.
Rothenberg ME. FIGERS and NASPGHAN Annual Meeting 2006.
Blanchard C et al. J Allergy Clin Immunol. 2006; 118: 1054-9.
Rothenberg ME. J Allergy Clin Immunol. 2004; 113:11-28.
Natural History
• In general, the disease “stays around”
– No mortality but persistent morbidity
– No evidence of dysplasia or malignant transformation
• Complications of untreated EE
–
–
–
–
–
–
–
Esophageal stricture
Food impaction
Sliding hiatal hernia (esoph. shortening)
Tracheal edema
Subglottic stenosis
Superinfection with Candida or CMV
Risk of emesis-induced or endoscopic perforation
Natural History
•
Based on limited data
– 30 adult patients followed for up to 11 years*
• No adverse impact on nutritional status
• No worsening of sx, but no histologic improvement
– 24 pediatric patients who refused tx or were lost to follow-up**
• Mean follow-up 6 yrs later
• All had persistent eosinophilia
• 20 who had presented with GER sx came back with dysphagia
– N=89 (CCH 8 yr retrospective): of 66% of the patients who had initial resolution, 79%
later relapsed***
•
Chronic disease at best, progressive at worst
– Progression: esophagitisringssmall caliberpermanent fibrosis and stricture
•
•
•
Histologic relapse off therapy is common
Absence of sx does not predict absence of inflammation
Effectively treated patients have not been observed to develop dysphagia or
fibrosis
* Straumann A et al. Gastroenterology 2003.
** Liacouras CA, Putnam P. FIGERS 2006.
***Assa’d A et al. J Allergy Clin Immunol. 2007.
Treatment Options
Intervention
Advantages
Drawbacks
Cromolyn
Safe
Limited efficacy
Montelukast
Convenient
Clinical response without
histologic improvement
Topical
corticosteroid
Efficacious, easy
Relapse off therapy
Potential adverse effects
Systemic
corticosteroid
Efficacious, easy
Relapse off therapy
Established adverse
effects
Elimination diet
Non-pharmacologic
alternative in select pts
Difficult, may induce food
aversions
Efficacy variable
Elemental diet
Efficacious
May prevent relapse
Very difficult
Usually requires feeding
tube
• 31 children with EE
• Fluticasone 880 mcg/d PO X 3
months
– Induced remission (lowered peak
eos ct to <1)
– Improved endoscopic and
histologic features
– Reduced vomiting
– Reduced esoph. CD8+ T cells
and mast cells
– Was safe
• Responders
– Non-allergic (neg. SPT)
– Younger, shorter, lighter
Dietary Therapy
– Kelly & Sampson, 1995
• N = 10 children
• Strict AA formula X 6 w
– 100% clin/histol response
– 80% remission
– Markowitz et al., 2003
• N = 51 children, 48/51
responded to AA-based
formula (Neocate 1+)
– NG tube in all but 3
– Liacouras et al., 2006
• N = 381 over 10 years
• 172 tx’d with AA-based
formula
– 128 required NGT
– Eos/hpf
» Pre-diet: 38.7
» Post: 1.1
• 75 tx’d with elimination
diet based on SPT/APT
– Spergel et al., 2005
• Elim. Diet based on
SPT/APT
– Kagalwalla et al., 2006
• Six food elimination diet
– CMP, soy, egg, wheat,
peanut, seafood
Dietary Therapy
100
90
80
70
60
50
40
30
20
10
0
95
% responders
77
74
Post-diet eos/hpf
13.8
12.8
1.1
Six Food
Elim.
SPT/APTDirected
Kagalwalla
N = 35
Spergel
N = 146
Elemental
Liacouras
N = 160
Kagalwalla A et al. Clin Gastroenterol Hepatol.
2006; 4:1077-1102.
Spergel JM et al. Ann Allergy Asthma Immunol.
2005; 95:336-43.
Liacouras CA et al. Clin. Gastroenterol. Hepatol.
2006; 3:1198.
Role of SPT/APT
Spergel JM et al., 2007
• Combination testing
– Can identify correct
elimination diet in 70%
• Resolution of sx/bx
• Specific foods were definitely
identified as the cause of EE
in 39/146
– On elimination bx
normalized
– Reintroduction of the
causative foods
» relapse of symptoms
» Bx: return of
eosinophilic
inflammation
• 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%
Khan S, Henderson N (2002)
Current Treatment Options
in Gastroenterologyg
• Do children with EE grow up to be adults with EE?
• What is the role in EE pathogenesis of...
– food and aeroallergen cross-reactivity?
– IgE?
• Is there a genetic or phenotypic difference between
atopic and non-atopic EE?
• What is the prevalence of EE among highly atopic pts?
• What is the value of RAST, skin prick testing, and
atopic patch testing in dx of EE?
• Therapeutic prospective comparisons:
– Elemental diet vs. elimination diet vs. corticosteroids
• Should endpoint of treatment be...
– clinical remission, OR...
– normalization of histology?
Paul Ehrlich
1854-1915
Eos
GREEK GODDESS OF DAWN