Overview of Eosinophilic Esophagitis

Gabriel Rendon, M.D.Texas Digestive Disease Consultants

Case Vignette

• CC: Dysphagia• HPI: 28 year old white man referred to the GI

clinic with three years of dysphagia. Intermittent, non-progressive, worse with solids; He also noted occasional sub-sternal chest pain. Denied heartburn, abdominal pain, weight loss, or change in bowel habits. Trial of Nexium was not helpful.

HPI (cont)

• PMH: Allergic rhinitis• Meds: Allegra, Nexium • NKDA• SH: Nonsmoker, rare EtoH use, no drug use.• FH: No significant GI diseases.

Physical Exam

• Vital signs: T 98.8 HR 86 BP 126/76 RR 16• GEN: WNWD, NAD;• HEENT: normal;• CHEST: CTA;• CV: RRR no M/R/G;• ABD: S, NABS, NT, ND;• EXT: normal;

LABS

• CBC: WBC 8.0 Hgb 14.6 PLT 288– 68 PMN 18 L 10 E 3 Mo

• Chem: WNL• LFT’s:

– AST 26 ALT 22 AlkPho 80 TB 0.6 DB 0.2

Endoscopy

Distal esophagus Mid esophagus

Pathology

Report: “Squamous mucosa with erosion, basal hyperplasia, increased papillae height, intercellular edema, and over 60 eosinophils per HPF. This is consistent with eosinophilic esophagitis.”

Eosinophilic Esophagitis

• Inflammatory disorder of the esophagus characterized by accumulation of eosinophils in the epithelium and a range of symptoms

• First reported in the 1978• Prior to 1995, there were only 12 manuscripts

about EoE• More than 250 articles written in the past 10

years

Definition1

• A clinicopathologic disorder of the esophagus characterized by a dense esophageal eosinophilia (>=15 eos/HPF) with severe squamous hyperplasia and upper GI symptoms

• Gastric and duodenal biopsies are normal• No response to PPI therapy or normal pH

monitoring

1. Furuta, et al. Eosinophilic Esophagitis in Children and Adults: A systematic review and Consensus recommendations for Diagnosis and Treatment. Gastroenterology 2007; 133: 1342-1363.

Pathogenesis

• Still poorly understood• The cellular and cytokine milieu similar to

bronchial asthma [8]• Food allergens and/or aeroallergens

– Recent study of 19 pts observed documented food and aero-allergies in 18/19 (94.8%) [30]

– seasonality and association with pollen count has been demonstrated [3]

– Evidence of disease remission in children fed an elemental diet [31]

Pathogenesis (cont)

• Association/Overlap with GERD– Eosinophil derived inflammatory proteins (Il-6,

PAF’s, vasoactive peptides) induce LES relaxations and decreased esophageal contractions [32]

– Acid/pepsin can damage tight junctions-> increased permeability->antigen exposure to deeper layers [33]

– Some cases of “classic” EoE have responded to dramatically to PPI’s [34]

Epidemiology

• Males affected more commonly than females1

– Adults: 76% male, mean age 38

• Can affect all races and ethnicities• In Olmsted county, prevalence 55/100,000

( 0.05%) [35]• Recent systematic review of 9 papers [36]:

• Population based prevalence of .03%• Symptom based prevalence of 2.8%

Prevalence in Selected Populations

• Solid Food dysphagia– Prasad27 prospectively studied 222 patients

undergoing endoscopy with biopsy for solid food dysphagia; Overall 33/222 (15%) had EE

– Mackenzie et al29 prospectively studied 94 pts presenting with dysphagia: 11/94 (11.7%) met histologic criteria for EE

• Food impaction– Desai et al5 reported 31 patients presenting with food

impaction over a 3 year period 17/31 (54%) had histology consistent with EE

Clinical Features

• Children– Feeding intolerance– Failure to Thrive– Heartburn– Emesis– Dysphagia/Food

impaction– Refractory GERD

• Adults– Intermittent dysphagia– Food impaction– Chest pain– Refractory GERD

Symptoms• Straumann8 prospectively re-examined 30 patients

with known EoE– 30/30 (100%) intermittent dysphagia with food impactions– 2/30 (6.7%) Heartburn

• Croese6 reviewed 31 patients with EoE in Australia– 27/29 (93%) Dysphagia– 19/27 (70%) Food Impactions – 13/27 (48%) Heartburn– 13/27 (48%) Chest Pain– 1/27 (3.7%) Abdominal pain– Symptoms fluctuated over time; long symptom free

intervals

6.Croese et al. Clinical and endoscopic features of eosinophilic esophagitis in adults. Gastrointestinal endosc 2003;58:516-22.8. Straumann et al. Eosinophilic esophagitis: red on microscopy, white on endoscopy. Digestion 2004;70:109–116.

Symptoms (cont)• Kaplan4 reviewed 8 cases of EoE over 10 year period

– 8/8 (100%) has dysphagia• Potter13 retrospectively reviewed 29 patients with EoE

– 24/29 (83%) had dysphagia– 8/29 (28%) had food impaction– 9/29 (31%) had refractory GERD

• Remedios9 prospectively studied 26 patients with EoE– 26/26 (100%) reported dysphagia– 17/26 (65%) reported food impaction– 17/26 (65%) were previously dx with GERD– 2/26 (7.6%) reported chest pain

4. Kaplan et al. Endoscopy in eosinophilic esophagitis. Clinical gastroenterology and hepatology 2003;1:433– 437.9 . Remedios et al. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment

with fluticasone propionate. Gastrointestinal Endosc 2006;63:3-12.13. Potter et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointestinal

endosc 2004;59:355-61

Natural History

• Straumann et al3 (2003) prospectically studied 30 adults with EoE– Mean follow up 7.2 years (1.4-11.5)

• Dysphagia– 7/30 (23.3%) reported increasing– 11/30 (36.7%)reported stable persisting– 11/30 (36.7%)improving– 1/30 (3.4%) asymptomatic

3. Straumann, et al. Natural history of primary eosinophilic esophagitis. Gastroenterology 2003; 125:1660-69.

Natural History (cont)

• BMI and nutritional status maintained• Endoscopic findings remained stable• Laboratory values remained stable (peripheral

eosinophilia, IgE, albumin)• Histology improved over time

– 6/7 subjects with subepithelial tissue sampling had significant fibrosis and sclerosis

• Response to therapy– 11/30 underwent dilation

• 10/11 responded well

Natural History (cont)

Diagnosis

Endoscopy

• Endoscopic findings can be subtle– Linear furrowing– Ringed or corrugated (trachealization or felinization)– White exudates, specks or nodules– Linear shearing/crepe paper mucosa– Stricture– Small caliber esophagus– Solitary ring– Normal

Endoscopy

• Desai et al5 identified 17/31 (54%) presenting with food impaction with histology consistent with EoE– 17/17 (100%) had rings and furrows– 5/17 (29%) strictures (4 proximal, 1 distal)

• Croese et al6 retrospectively reviewed 31 patients diagnosed with EoE– 30/31 (97%) had furrows (with or without rings)– 17/31 (54%) had strictures

5. Desai et al. Association of eosinophilic inflammation with esophageal food impaction in adults. Gastrointestinal endoscopy 2005; 61: 795-801.

Endoscopy• Straumann et al8 retrospectively reviewed 30 adult patients

with EoE– 16/30 (53%) had white exudates

– 13/30 nodules– 12/30 plaques

– 15/30 (50%) had concentric rings– 13/30 (43%) had stricture– 11/30 (38%) had a solitary ring– 4/30 (13%) had crepe paper mucosa

• Straumann et al7 reported a series of 5 patients with EoE and mucosal friability– 5/5 (100%) had “crepe-paper mucosa” leading to lacerations– Postulated that mucosal fragility is pathognomonic for EoE

7. Straumann et al. Fragility of the esophageal mucosa: A pathognomonic endoscopic sign of primary eosinophilic esophagitis? Gastrointestinal endosc 2003; 59: 407-412.

Straumann et al8

8. Straumann et al. Eosinophilic esophagitis: red on microscopy, white on endoscopy. Digestion 2004;70:109–116.

Endoscopy

• Remedios et al9 prospectically enrolled 26 patients with histopathologic EoE (>15 eos/HPF)– 20/26 (77%) had linear furrows– 16/26 (61%) had mucosal rings– 7/26 (27%) had narrow esophagus– 4/26 (15%) had white papules/plaques

Linear Furrows

Mucosal Rings

White Exudates

Crepe Paper Mucosa

Biopsy Procurement

• Gonsalves et al10 reviewed 66 patients (341 specimens) with EoE– Number of biopsies needed varied with threshold

• >15 eos/HPF: 5 biopsies had sensitivity 100%– 1 biopsy had sensitivity of 55%

• >30 eos/HPF: 5 biopsies had sensitivity 89%– 20 patients had biopsies from both proximal and distal sites

• Mean 68 eos/HPF proximally, 82 eos/HPF distally (NS)• 16/20 patients had distal eosinophilia and no proximal eosinophilia

• Remedios reported 1 patient with proximal eosinophilia (25 eos/HPF) and no distal eosinophilia

10. Gonsalves et al. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointestinal Endosc 2006;64:313-9.

Radiology

• Upper GI contrast studies may demonstrate strictures, rings, corrugations

• May show small caliber esophagus not readily appreciated by endoscopy

• Zimmerman et al10 reviewed 14 pts with EoE– 10/14 had strictures

• Mean length of 5.1 cm• 7/10 had concentric rings along the stricture

10. Zimmeman et al. Idiopathic eosinophilic esophagitis in adults. Radiology 2005; 236:159 –165 .

Radiology

Histology• Historically, esophageal eosinophilia thought

secondary (pathognomonic) to GERD1

• 1995, Kelly et al14 described 10 children with GERD type symptoms, intense esophageal eosinophilia and no response to acid suppressive therapy

• Several more studies described patients with refractory GERD symptoms and eosinophilia1

• In GERD, eosinophilia is mild, usually <10 eos/HPF and confined to distal esophagus

• In EoE, the eosinophilia is more intense, >15 eos/HPF (often much greater) and throughout the esophagus

14. Kelly KJ et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109:1503–1512.

Histology Features

• Markedly increased intraepithelial eosinophils• Superficial layering• Basal zone/papillary hyperplasia• Eosinophilic micro-abscesses• Degranulation (MBP)• Edema• Other cells (Lymphocytes, PMN, Mast cells)• Subepithelial fibrosis

Histologic Features

• Gonsalves10 studied 66 patients with 341 biopsy specimens– Median count was 107 eos/HPF (0-557)– 93% Epithelial hyperplasia– 90% Superficial layering– 75% eosinophilic microabscess– 52% degranulation

Histologic Features

• Straumann et al (peak method)– Mean count in proximal esophagus was 78

eos/HPF– Mean count in distal esophagus was 117 eos/HPF– Papillary hyperplasia was seen in 80%– Basal zone hyperplasia was seen in 65%

• Remedios et al (mean method)– Mean count in proximal esophagus was 25– Mean count in distal esophagus was 39

Histology

• Parfitt15 studied biopsied from 41 pts with EE (>15 eos/HPF x2) and 116 pts with GERD:

15. Parfitt et al. Eosinophilic esophagitis in adults: distinguishing features from gastroesophageal reflux disease: a study of 41 patients. Modern pathology (2006) 19, 90–96.

Histology

Histology

Association with Allergies

History of Allergy or Atopy

• Remedios9 et al reviewed 26 pt with EoE– 20/26 (77%) patients had an atopic history

(Asthma, hay fever, rhinitis, food allergy or atopic dermatitis)

• Straumann et al11

– 18/30 (60%) had history of atopy

• Croese et al6

– 28/30 (93%) had an allergic history

Peripheral Eosinophilia

• Peripheral eosinophilia associated with atopic conditions

• Problematic in that there was a difference in thresholds

• Straumann3 reported 12/24 (50%) with mild elevation (350-1500 cells/mm3)

• Parfitt15 reported 1/10 (10%) with >800 cells/mm3

Atopic/Allergy TestingSkin prick test and atopic patch test have been

used in children in 2 published studies17,18

– Resolution of symptoms and histology in 77% with elimination diet in identified allergens

– Elemental diets effective in the rest• Recent study of 19 adult pts observed

documented food and aero-allergies in 18/19 (94.8%) [30]

17. Spergel Et Al. Treatment Of Eosinophilic Esophagitis With Specific Food Elimination Diet Directed By A Combination Of Skin Prick And Patch Tests. Ann Allergy Asthma Immunol 2005;95:336 –343.

18. Spergel Jm, Beausoleil Jl, Mascarenhas M, Et Al. The Use Of Skin Prick Tests And Patch Tests To Identify Causative Foods In Eosinophilic Esophagitis. J Allergy Clin Immunol 2002;109:363–368.

EoE vs GERDEoE GERD

Age Younger Older

Gender M>>>F M>F

Atopic/Allergic +++ +

Dysphagia +++ +

Food Impaction +++ +

Peripheral Eosinophilia ++ -

Rings, Furrows +++ +

Hiatal Hernia + +++

Mean Eos/HPF 76 16

Degranulation, microabscess

+++ +

Treatment

Treatment

• PPI• Topical steroids• Endoscopic dilation• LT receptor antagonists and mast cell

stabilizers• Dietary changes

PPI

• Can be part of diagnosis– Lack of a clinicopathologic response in patients with

esophageal eosinophilia virtually diagnostic of EoE– Can be used in lieu of 24 hr pH monitoring1

• Concomitant therapy– Remedios9 showed pts with EE, 10/26 had abnormal

24 hr pH probes– Recent study in press reported 75% (26/35) response

rate in unselected patients with eosinophilic infiltration

Topical Steroids• First reported use in 19981

• Arora22 identified 21 patients with EoE and treated them with swallowed FP 220 ug bid x6 weeks– All had resolution of their solid food dysphagia– Rapid relief within several days– Recurrences occurred 12-18 months later– Histology was not assessed– No oral candidiasis

22. Arora As, Perrault J, Smyrk Tc. Topical Corticosteroid Treatment Of Dysphagia Due To Eosinophilic Esophagitis In Adults. Mayo Clin Proc 2003;78:830 – 835

Remedios et al• 19/26 subjects were treated with swallowed FP 440 ug bid x 4 weeks

– All 19 had symptom relief– 18/19 histologic improvement– Mean proximal eosinophil count decreased from 24.98 to 4.46– Mean distal eosinophil count decreased from 39.3 to 3.8– 3 patients developed asymptomatic esophageal candidiasis

Topical Steroids

• Pediatric randomized double blind placebo controlled trial by Konikoff23 et al– 31 patients randomized to swallowed FP 440 bid x 3

months or placebo• 10/20 (50%) had histologic resolution in the FP group• 1/11 (9%) histologic resolution in placebo group (P =.047)

• Recent randomized double blind placebo controlled trial of oral budesonide [37]– 13/18 resonse rate; 4/18 placebo– Mean eosinophil count 66->5

Swallowed FP (Flovent)

• 2 puffs swallowed twice daily• Take after meals• Do not use a spacer• Deep breath, hold depress inhaler and

swallow aerosol with each puff• Rinse mouth• No food or drink for 30-60 minutes

Dilation• Small case series by Morrow [20] and Straumann [8] reported

15/16 and 11/19 patients treated with dilation had symptom improvement

• Recently, Dellon [38] reviewed 36 patients undergoing dilation– 83% response rate– 7% complication rate: deep tears and chest pain– Size improved from 12 to 16mm– No perforations

• Schoepfer [39] reviewed 207 pts undergoing dilation for EoE– Significant improvement in dysphagia– Mean duration 15-17 months– No perforations– 7% post procedural chest pain

Dilation

• May be considered in symptomatic patients with fixed narrowing or persistent dysphagia (with or without histologic remission)– Role for primary therapy?

• Impressive mucosal tears and chest pain• Bougie preferred over balloon; goal to 15-16

mm• Good durable response in most patients

Mast Cell Stabilizers and LTRA’s

• Cromolyn Sodium– No direct studies have been reported– 14 patients reported by Liacouras with no

response

• LTRA– Attwood26 reported 7/8 patients had symptomatic

improvement, but no histologic remission

26. Attwood et al. Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 2003;52:181– 185.

Dietary Changes

• No studies in adults• Specific food elimination as directed by APT or

skin test– 112/146 (77%) patients responded both clinically

and histologically19

• Removal of most common agents– Kagalwalla25 reported that 74% improved

• Amino acid formulas– Resolution in 92-98% of patients1

25. Kagalwalla AF, Sentongo TA, Ritz S, Et Al. Effect Of Six-food Elimination Diet On Clinical And Histologic Outcomes In Eosinophilic Esophagitis. Clin Gastroenterol Hepatol 2006;4:1097–1102

Other Treatment Options

• Systemic steroids• Immunomodulators

– 1 case report of a patient treated with azathioprine

• Mepolizumab (Il-5 Mab)– Not FDA approved– Phase 3 trials in HES

Unresolved Issues

• Etiology and pathogenesis• Increased recognition vs true increased

incidencce• Association/overlap with GERD• Treatment duration and endpoints• How to best identify possible aero or food

allergens• Long term esophageal sequalae

Summary• EoE is an increasingly recognized, male predominant

disorder characterized dysphagia and food impaction; characteristic but sometimes subtle endoscopic findings; and intraepithelial eosinophilia not entirely responsive to PPI

• Exact pathogenesis remains unknown, but food allergens, aeroallergens, genetics and acid exposure have been implicated

• The usual accepted treatments include PPI, topical steroids, dilation, and allergy testing/dietary changes

• There appears to be no malignant potential and patients remained nutritionally replete

• Still alot being learned about this disease

References1. Furuta, et al. Eosinophilic esophagitis in children and

adults: A systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342-1363.

2. Noel et al. Eosinophilic esophagitis. N England J of medicine 2004; 351:940-941.

3. Straumann, et al. Natural history of primary eosinophilic esophagitis. Gastroenterology 2003; 125:1660-69.

4. Kaplan et al. Endoscopy in eosinophilic esophagitis. Clinical gastroenterology and hepatology 2003;1:433– 437.

References (cont)5. Desai et al. Association of eosinophilic inflammation with

esophageal food impaction in adults. Gastrointestinal endoscopy 2005; 61: 795-801.

6.Croese et al. Clinical and endoscopic features of eosinophilic esophagitis in adults. Gastrointestinal endosc 2003;58:516-22.

7. Straumann et al. Fragility of the esophageal mucosa: A pathognomonic endoscopic sign of primary eosinophilic esophagitis? Gastrointestinal endosc 2003; 59: 407-412.

8. Straumann et al. Eosinophilic esophagitis: red on microscopy, white on endoscopy. Digestion 2004;70:109–116.

References (cont)9. Remedios et al. Eosinophilic esophagitis in adults:

clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointestinal Endosc 2006;63:3-12.

10. Gonsalves et al. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointestinal Endosc 2006;64:313-9.

11. Zimmeman et al. Idiopathic eosinophilic esophagitis in adults. Radiology 2005; 236:159 –165 .

12. Fox et al. High-resolution EUS in children with eosinophilic “allergic” esophagitis. Gastrointestinal Endosc 2003;57:30-6.

References (cont)13. Potter et al. Eosinophilic esophagitis in adults: an emerging

problem with unique esophageal features. Gastrointestinal endosc 2004;59:355-61

14. Kelly KJ et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109:1503–1512.

15. Parfitt et al. Eosinophilic esophagitis in adults: distinguishing features from gastroesophageal reflux disease: a study of 41 patients. Modern pathology (2006) 19, 90–96.

16. Straumann et al. Idiopathic eosinophilic esophagitis is associated with a th2-type allergic inflammatory response. J of ALLERGY CLIN IMMUNOL 108: 954-61.

References (cont)17. Spergel Et Al. Treatment Of Eosinophilic Esophagitis With Specific

Food Elimination Diet Directed By A Combination Of Skin Prick And Patch Tests. Ann Allergy Asthma Immunol 2005;95:336 –343.

18. Spergel Jm, Beausoleil Jl, Mascarenhas M, Et Al. The Use Of Skin Prick Tests And Patch Tests To Identify Causative Foods In Eosinophilic Esophagitis. J Allergy Clin Immunol 2002;109:363–368.

19. Spergel Et Al. Treatment Of Eosinophilic Esophagitis With Specific Food Elimination Diet Directed By A Combination Of Skin Prick And Patch Tests. Annals Of Allergy, Asthma And Immunology 2005, Vol. 95, No. 4, Pp. 336 – 343.

20. Morrow Et Al. The Ringed Esophagus: Histological Features Of GERD. THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 4, 2001: 984-989.

References (cont)21. Cohen At Al. An Audit Of Endoscopic Complications In Adult Eosinophilic

Esophagitis. Clinical Gastroenterology And Hepatology 2007;5:1149 –1153.

22. Arora As, Perrault J, Smyrk Tc. Topical Corticosteroid Treatment Of Dysphagia Due To Eosinophilic Esophagitis In Adults. Mayo Clin Proc 2003;78:830 – 835.

23. Konikoff Mr, Noel Rj, Blanchard C, Et Al. A Randomized, Double- Blind, Placebo-controlled Trial Of fluticasone Propionate For Pediatric Eosinophilic Esophagitis. Gastroenterology 2006;131: 1381–1391.

24. Fang Et Al. Comparison Of Esomeprazole To Aerosolized, Swallowed Fluticasone For Eosinophilic Esophagitis. Gie 2007; 65:ab131

25. Kagalwalla AF, Sentongo TA, Ritz S, Et Al. Effect Of Six-food Elimination Diet On Clinical And Histologic Outcomes In Eosinophilic Esophagitis. Clin Gastroenterol Hepatol 2006;4:1097–110

References (cont)

26. Attwood et al. Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 2003;52:181– 185.

27. Prasad et al. Prevalence and predictive factors of eosinophilic esophagitis. A J of Gastroenterology. 2007; 102:2627-2632.

28. Straumann et al. Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response. J Allergy Clin Immunol 2001;108:954 – 961.

29. Mackenzie et al. Prospective Analysis of Eosinophilic Esophagitis in Patients Presenting with Dysphagia. A J of Gastroenterology 2006; 101:S47.

References (cont)30. Del Robledo et al. Defining the role of Food Allergy in a population of Adult

Patients with EoE. Inflamm and Allergy Drug Targets Nov 2010 epub.31. Chehade et al. Food Allergy and eosinophilic esophagitis. Current opinion in

Allergy and Clinical Immunology. June 2010 3:231-7.32. Lamouse-Smith et al. Eosinophils in the GI tract. Current Gastroenterol Rep. 2006;

8:390-5.33. Barlow et al. The pathogenesis of heartburn in non-erosive disease.

Gastroenterology 2005;128:771-8. 34. Ngo P et al. Eosinophils in the esophagus--peptic or allergic eosinophilic

esophagitis? Case series of three patients with esophageal eosinophilia. Am J Gastroenterol. 2006 Jul;101(7):1666-70

35. Prasad et al. Epidemiology of EoE over three decades in Olmsted county. Clinical gastro and hep. Oct 2009; 10:1055-61.

36. Sealock et al. Systematic Review: the epidemiology of EoE in adults. Aliment Pharmaco Ther Sept 2010; 6:712-9.

References (cont)37. Straumann et al. Budesonide is Effective in Adolescent and Adult Patients

With Active Eosinophilic Esophagitis. Gastro, epub.38. Dellon et al. Esophageal dilation in eosinophilic esophagitis: safety and

predictors of clinical response and complications. Gastrointest Endosc 2010;71:706-12.

39. Am J Gastroenterol 2010; 105:1062–1070; doi:10.1038/ajg.2009.657; published online 24 November 2009.