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 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: 351:940-41.
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 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; 351:940-41.
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 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
Endoscopy Normal esophagus EE Linear furrowing
Eosinophilic microabscesses “Crepe paper” esophagus Normal “Crepe paper” esophagus Furuta GT, Straumann A. Aliment Pharmacol Ther. 2006;24:173-82.
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: 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; 38:251-53.
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
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.
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: esophagitisringssmall caliberpermanent 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 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
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
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
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; 4:1077-1102. 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 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%
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