2. 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

3. 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

4. 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:
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

5. Epidemiology PREVALENCE Incidence rising Family history
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:

6. Clinical Features of EE
CHILD
Vomiting
Heartburn
ADOLESCENT
Heartburn
Dysphagia
ADULT
Dysphagia
Stricture
Yan B, Shaffer EA. World J Gastroenterol. 2006

7. Pediatric Series N = 381 66% male 85% GER sx Endoscopy N = 103
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
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
Liacouras CA et al. Clin Gastroenterol Hepatol. 2005; 3:1198.
Noel R et al. N Engl J Med. 2004; 351:

8. Clinical Features of Pediatric EE
Noel R et al. N Engl J Med. 2004: 351:
Represents median age of presentation

9. EE vs. GER

10. Diagnosis of EE Requires endoscopy and histology Adjunctive modalities
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

11. Endoscopy
Normal esophagus EE
Linear furrowing

12. Eosinophilic microabscesses “Crepe paper” esophagus
Normal
“Crepe paper” esophagus
Furuta GT, Straumann A. Aliment Pharmacol Ther. 2006;24:

13. EE Trachealization Contrast UGI series
Fox VL et al, Gastrointestinal Endosc. 2002

14. EGD: Mucosal pallor UGI: Stricture EUS: Submucosal thickening
Fox VL et al, Gastrointestinal Endosc. 2002

15. 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.

16. 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:

17. Pathogenesis Present understanding: Th-2 response
“An immune disorder that results from a mixed allergic response” to dietary and possibly other environmental antigens*
Th-2 response
IL-5 key for eosinophil differentiation, activation
Eotaxins, IL-4, IL-13 recruit eos to GI tract
Chronic allergy
Kay AB. New Engl J Med. 2001
*Markowitz JE, Liacouras CA. Dig Liver Dis. 2006; 38:

18. Pathogenesis
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
Rothenberg ME. New Engl J Med. 1998

19. 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 STAT-6 protected mice vs. EE
Mishra A et al. J Clin Invest. 2001; 107:83-90.
Rothenberg ME. FIGERS and NASPGHAN Annual Meeting 2006.

20. Blanchard C et al. J Allergy Clin Immunol. 2006; 118: 1054-9.

21. Rothenberg ME. J Allergy Clin Immunol. 2004; 113:11-28.

22. 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

23. 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

24. 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
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

25. Fluticasone 880 mcg/d PO X 3 months
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

26. Dietary Therapy Kelly & Sampson, 1995 Markowitz et al., 2003
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

27. Dietary Therapy Six Food Elim. SPT/APT- Directed Elemental Kagalwalla
Spergel
N = 146
Elemental
Liacouras
N = 160
Kagalwalla A et al. Clin Gastroenterol Hepatol. 2006; 4:
Spergel JM et al. Ann Allergy Asthma Immunol. 2005; 95:
Liacouras CA et al. Clin. Gastroenterol. Hepatol. 2006; 3:1198.

28. Role of SPT/APT Combination testing
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%

30. Khan S, Henderson N (2002)
Current Treatment Options
in Gastroenterologyg

31. 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?

32. Paul Ehrlich
Eos
GREEK GODDESS OF DAWN