Biology and Treatment of Eosinophilic Esophagitis
2009; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2009.07.007
ISSN1528-0012
Autores Tópico(s)Eosinophilic Disorders and Syndromes
ResumoEosinophilic esophagitis is a recently recognized but expanding disorder characterized by antigen-driven eosinophil accumulation in the esophagus. Symptoms frequently mimic those of gastroesophageal reflux disease, but the diseases are distinct in their histopathology, gene expression signature, response to therapy, hereditary risk, and association with allergies. The pathogenesis of eosinophilic esophagitis involves environmental and genetic factors, particularly food antigens and expression level of the eosinophil chemoattractant eotaxin-3, respectively. Analyses of gene expression signatures and animal models have indicated the importance of adaptive T-cell immunity that involves interleukin-5 and interleukin-13–induced esophageal epithelial cell responses. Symptoms, dysregulation of esophageal gene expression, and pathology are largely reversible following reduced exposure to specific food antigens as well as anti-inflammatory therapy, but chronic treatment is necessary to prevent relapse. Therefore, eosinophilic esophagitis is a disease with unique features that include chronic esophagitis, atopy, immune sensitization to oral antigens, reversibility, and familial association. Eosinophilic esophagitis is a recently recognized but expanding disorder characterized by antigen-driven eosinophil accumulation in the esophagus. Symptoms frequently mimic those of gastroesophageal reflux disease, but the diseases are distinct in their histopathology, gene expression signature, response to therapy, hereditary risk, and association with allergies. The pathogenesis of eosinophilic esophagitis involves environmental and genetic factors, particularly food antigens and expression level of the eosinophil chemoattractant eotaxin-3, respectively. Analyses of gene expression signatures and animal models have indicated the importance of adaptive T-cell immunity that involves interleukin-5 and interleukin-13–induced esophageal epithelial cell responses. Symptoms, dysregulation of esophageal gene expression, and pathology are largely reversible following reduced exposure to specific food antigens as well as anti-inflammatory therapy, but chronic treatment is necessary to prevent relapse. Therefore, eosinophilic esophagitis is a disease with unique features that include chronic esophagitis, atopy, immune sensitization to oral antigens, reversibility, and familial association. Unlike all other segments of the gastrointestinal tract, the esophagus is normally devoid of eosinophils,1Mishra A. Hogan S.P. Lee J.J. et al.Fundamental signals that regulate eosinophil homing to the gastrointestinal tract.J Clin Invest. 1999; 103: 1719-1727Google Scholar so the finding of esophageal eosinophilia denotes pathology. However, the mere presence of esophageal eosinophils is not specific for a particular disorder because eosinophil accumulation in the esophagus occurs in a variety of states, including eosinophilic esophagitis (EE, also referred to as EoE), eosinophilic gastroenteritis, gastroesophageal reflux disease (GERD), chronic (noneosinophilic) esophagitis, parasitic and fungal infections, inflammatory bowel disease, hypereosinophilic syndrome, scleroderma, drug and/or iatrogenic-induced states such as caustic injury,2Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-28Google Scholar multiple convulsive therapy syndrome,3Balatsinou C. Milano A. Caldarella M.P. et al.Eosinophilic esophagitis is a component of the anticonvulsant hypersensitivity syndrome: description of two cases.Dig Liver Dis. 2008; 40: 145-148Google Scholar and immunosuppression, especially following solid organ transplantation (see Supplementary Table 1).4Noble C. Francis L. Withers G.W. et al.Audit of eosinophilic oesophagitis in children post-liver transplant.Pediatr Transplant. 2008 Nov 1; ([Epub ahead of print])Google Scholar As part of a spectrum of eosinophilic gastrointestinal disorders, it is notable that EE can evolve into and/or be associated with eosinophilic gastritis, enteritis, and/or colitis.2Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-28Google Scholar The diagnosis of EE requires elimination of other causes of esophagitis, especially GERD; EE is generally distinguished from GERD by persistent esophageal eosinophilia despite adequate acid neutralization therapy before endoscopy.5Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google Scholar EE can be associated with other diseases such as Rubinstein–Taybi syndrome6Noble A. Drouin E. Faure C. Eosinophilic esophagitis and gastritis in Rubinstein-Taybi syndrome.J Pediatr Gastroenterol Nutr. 2007; 44: 498-500Google Scholar and celiac disease.7Kagalwalla A.F. Shah A. Ritz S. et al.Cow's milk protein-induced eosinophilic esophagitis in a child with gluten-sensitive enteropathy.J Pediatr Gastroenterol Nutr. 2007; 44: 386-388Google Scholar, 8Quaglietta L. Coccorullo P. Miele E. et al.Eosinophilic oesophagitis and coeliac disease: is there an association?.Aliment Pharmacol Ther. 2007; 26: 487-493Google Scholar, 9Verzegnassi F. Bua J. De Angelis P. et al.Eosinophilic oesophagitis and coeliac disease: is it just a casual association?.Gut. 2007; 56: 1029-1030Google Scholar, 10Heine R.G. Eosinophilic esophagitis in children with celiac disease: new diagnostic and therapeutic dilemmas.J Gastroenterol Hepatol. 2008; 23: 993-994Google Scholar, 11Ooi C.Y. Day A.S. Jackson R. et al.Eosinophilic esophagitis in children with celiac disease.J Gastroenterol Hepatol. 2008; 23: 1144-1148Google Scholar The similarities between EE and celiac disease provide insight into possible pathogenic mechanisms of EE. Celiac disease is a prototypic T-cell–mediated immune disease triggered by an oral antigen (gliadin). Although celiac disease has a significant autoimmune component that has not yet been associated with EE, both diseases are associated with immune cell–mediated epithelial cell abnormalities and can be reversed by a food elimination diet, although EE does not typically respond to gliadin avoidance. The EE transcriptome (genes that are up-regulated or down-regulated in esophageal tissue of patients with EE compared with normal esophageal tissue)12Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Google Scholar includes genes that regulate the immune response and have been associated with celiac disease. The transcriptome includes overexpression of genes that encode MICA and MICB (ligands that activate NKG2D) and the cytokine interleukin (IL)-15; all have been shown to induce intraepithelial lymphocyte activation.13Hue S. Mention J.J. Monteiro R.C. et al.A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.Immunity. 2004; 21: 367-377Google Scholar, 14van Heel D.A. Interleukin 15: its role in intestinal inflammation.Gut. 2006; 55: 444-445Google Scholar, 15Caillat-Zucman S. How NKG2D ligands trigger autoimmunity?.Hum Immunol. 2006; 67: 204-207Google Scholar, 16Koning F. Gilissen L. Wijmenga C. Gluten: a two-edged sword Immunopathogenesis of celiac disease.Springer Semin Immunopathol. 2005; 27: 217-232Google Scholar Genetic studies of celiac disease have identified the HLA class II genes (encoding DR HLA-DQ2 or -DQ8 molecules), whose products function in the adaptive immune system, as main risk factors along with environmental factors.17Stepniak D. Koning F. Celiac disease—sandwiched between innate and adaptive immunity.Hum Immunol. 2006; 67: 460-468Google Scholar Genome-wide association studies of celiac disease have identified genes that regulate immunity, including IL18RAP, IL12A, and CCR3 (encodes the receptor for the chemokine eotaxin), and genetic variants in the IL2/IL21 locus.18van Heel D.A. Franke L. Hunt K.A. et al.A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.Nat Genet. 2007; 39: 827-829Google Scholar, 19Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Google Scholar A recent study linked blood eosinophilia with several genes including celiac disease locus that contains SH2B3 (also known as LNK),20Gudbjartsson D.F. Bjornsdottir U.S. Halapi E. et al.Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.Nat Genet. 2009; 41: 342-347Google Scholar providing further support for a connection between eosinophils and celiac disease.Symptoms and Disease CharacteristicsEE has many different presentations; patients commonly have difficulty eating, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.21Orenstein S.R. Shalaby T.M. Di Lorenzo C. et al.The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children.Am J Gastroenterol. 2000; 95: 1422-1430Google Scholar, 22Walsh S.V. Antonioli D.A. Goldman H. et al.Allergic esophagitis in children: a clinicopathological entity.Am J Surg Pathol. 1999; 23: 390-396Google Scholar, 23Liacouras C.A. Spergel J.M. Ruchelli E. et al.Eosinophilic esophagitis: a 10-year experience in 381 children.Clin Gastroenterol Hepatol. 2005; 3: 1198-1206Google Scholar These symptoms appear to occur in a progressive order, presenting from infancy into adulthood in the order listed,24Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Google Scholar, 25Noel R.J. Rothenberg M.E. Eosinophilic esophagitis.Curr Opin Pediatr. 2005; 17: 690-694Google Scholar so this could be the natural history of EE. Adult patients typically have recurrent dysphagia and food impactions that are refractory to anti-GERD therapy; in fact, recent studies indicate that 10%–50% of adult male patients with these symptoms have EE.26Desai T.K. Stecevic V. Chang C.H. et al.Association of eosinophilic inflammation with esophageal food impaction in adults.Gastrointest Endosc. 2005; 61: 795-801Google Scholar, 27Mackenzie S.H. Go M. Chadwick B. et al.Eosinophilic oesophagitis in patients presenting with dysphagia—a prospective analysis.Aliment Pharmacol Ther. 2008; 28: 1140-1146Google Scholar Although a fixed stricture could account for the esophageal dysphagia and food impaction observed in some patients with EE,28Bassett J. Maydonovitch C. Perry J. et al.Prevalence of esophageal dysmotility in a cohort of patients with esophageal biopsies consistent with eosinophilic esophagitis.Dis Esophagus. 2009; 6: 543-548Google Scholar evidence is mounting that the esophagus displays impaired smooth muscle function, likely from asynchrony of circular and longitudinal muscle contraction during swallowing.29Korsapati H.R. Babaei A. Bhargava V. et al.Dysfunction of the longitudinal muscles of the oesophagus in eosinophilic esophagitis.Gut. 2009; 58: 1056-1062Google Scholar A variety of motor disturbances that are reversible with therapy have been reported in patients with EE.30Lucendo A.J. Castillo P. Martin-Chavarri S. et al.Manometric findings in adult eosinophilic oesophagitis: a study of 12 cases.Eur J Gastroenterol Hepatol. 2007; 19: 417-424Google Scholar, 31Nurko S. Rosen R. Esophageal dysmotility in patients who have eosinophilic esophagitis.Gastrointest Endosc Clin North Am. 2008; 18 (ix): 73-89Google Scholar EE patients are predominantly young males24Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Google Scholar who have a high rate of atopic disease and normal esophageal pH compared with patients with GERD. Although EE was originally recognized in pediatric patients, it has similar characteristics (including atopic sensitization) and occurrence rates in adults.32Roy-Ghanta S. Larosa D.F. Katzka D.A. Atopic characteristics of adult patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2008; 6: 531-535Google Scholar EE frequently presents during infancy,33Assa'ad A.H. Putnam P.E. Collins M.H. et al.Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.J Allergy Clin Immunol. 2007; 119: 731-738Google Scholar but the disease has also been recognized in patients older than 90 years.34Kapel R.C. Miller J.K. Torres C. et al.Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups.Gastroenterology. 2008; 134: 1316-1321Google Scholar EE is a chronic disorder that has no significant evidence of spontaneous remission, even over a 14-year period,35Spergel J.M. Brown-Whitehorn T.F. Beausoleil J.L. et al.14 years of eosinophilic esophagitis: clinical features and prognosis.J Pediatr Gastroenterol Nutr. 2009; 48: 30-36Google Scholar but some patients have seasonal variations in symptoms,36Almansa C. Krishna M. Buchner A.M. et al.Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.Am J Gastroenterol. 2009; 104: 828-833Google Scholar consistent with an etiology related to airborne allergen exposure.EpidemiologyEE has been reported from all continents except Africa.37Croese J. Fairley S.K. Masson J.W. et al.Clinical and endoscopic features of eosinophilic esophagitis in adults.Gastrointest Endosc. 2003; 58: 516-522Google Scholar, 38Cherian S. Smith N.M. Forbes D.A. Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia.Arch Dis Child. 2006; 91: 1000-1004Google Scholar, 39Cury E.K. Schraibman V. Faintuch S. Eosinophilic infiltration of the esophagus: gastroesophageal reflux versus eosinophilic esophagitis in children—discussion on daily practice.J Pediatr Surg. 2004; 39: e4-e7Google Scholar, 40Attwood S.E. Smyrk T.C. Demeester T.R. et al.Esophageal eosinophilia with dysphagia A distinct clinicopathologic syndrome.Dig Dis Sci. 1993; 38: 109-116Google Scholar, 41Cantu P. Velio P. Prada A. et al.Ringed oesophagus and idiopathic eosinophilic oesophagitis in adults: an association in two cases.Dig Liver Dis. 2005; 37: 129-134Google Scholar, 42Shitrit A.B. Reinus C. Zeides S. et al.Eosinophilic esophagitis.Isr Med Assoc J. 2006; 8: 587Google Scholar, 43Fujiwara H. Morita A. Kobayashi H. et al.Infiltrating eosinophils and eotaxin: their association with idiopathic eosinophilic esophagitis.Ann Allergy Asthma Immunol. 2002; 89: 429-432Google Scholar, 44Munitiz V. Martinez de Haro L.F. Ortiz A. et al.Primary eosinophilic esophagitis.Dis Esophagus. 2003; 16: 165-168Google Scholar, 45Lucendo Villarin A.J. Carrion Alonso G. Navarro Sanchez M. et al.Eosinophilic esophagitis in adults, an emerging cause of dysphagia Description of 9 cases.Rev Esp Enferm Dig. 2005; 97: 229-239Google Scholar, 46Straumann A. Spichtin H.P. Bucher K.A. et al.Eosinophilic esophagitis: red on microscopy, white on endoscopy.Digestion. 2004; 70: 109-116Google Scholar, 47Molina-Infante J. Hernandez-Alonso M. Perez-Gallardo B. et al.The first Asian case report of eosinophilic esophagitis in an asymptomatic adult: what about a proton pump inhibitor trial?.J Chin Med Assoc. 2009; 72: 166-167Google Scholar Although the exact incidence of EE has not been determined, a mini-epidemic has been noted over the past decade. Liacouras et al found that ∼10% of pediatric patients with GERD-like symptoms are unresponsive to acid blockade and have EE.48Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Dev Pathol. 1999; 2: 15-18Google Scholar, 49Markowitz J.E. Liacouras C.A. Eosinophilic esophagitis.Gastroenterol Clin North Am. 2003; 32: 949-966Google Scholar Furuta et al reported that 6% of patients with esophagitis have EE.50Fox V.L. Nurko S. Furuta G.T. Eosinophilic esophagitis: it's not just kid's stuff.Gastrointest Endosc. 2002; 56: 260-270Google Scholar Over a 16-year observation period, Straumann and Simon documented a prevalence of ∼1:4000 adults in Switzerland.51Straumann A. Simon H.U. Eosinophilic esophagitis: escalating epidemiology?.J Allergy Clin Immunol. 2005; 115: 418-419Google Scholar Croese et al reported EE to be present in 1:70,000 adults in an Australian provincial city,37Croese J. Fairley S.K. Masson J.W. et al.Clinical and endoscopic features of eosinophilic esophagitis in adults.Gastrointest Endosc. 2003; 58: 516-522Google Scholar and another study revealed a ∼0.4% prevalence in a random adult Swedish population.52Ronkainen J. Talley N.J. Aro P. et al.Prevalence of eosinophilia and eosinophilic esophagitis in adults in the community: a random population based study (Kalixanda) (abstr).Gastroenterology. 2006; 130: A575Abstract Full Text Full Text PDF Google Scholar EE was identified in 0.1% of children in the Cincinnati metropolitan area over a 9-year time period24Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Google Scholar (M. Rothenberg, unpublished findings). In an outpatient US-based military hospital, EE was identified in 6.5% of adult patients undergoing endoscopy53Veerappan G.R. Perry J.L. Duncan T.J. et al.Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study.Clin Gastroenterol Hepatol. 2009; 7 (426 e1–2): 420-426Google Scholar; this study was notable because the EE population included a large percentage of black patients, suggesting that the predominance of EE in white patients reported in other studies might be due to patient referral patterns. These epidemiology studies indicated that EE has a prevalence that is comparable to that of inflammatory bowel disease but less than that of celiac disease.54Bousvaros A. Morley-Fletcher A. Pensabene L. et al.Research and clinical challenges in paediatric inflammatory bowel disease.Dig Liver Dis. 2008; 40: 32-38Google Scholar, 55Catassi C. Fasano A. Celiac disease.Curr Opin Gastroenterol. 2008; 24: 687-691Google Scholar Although EE has only been appreciated as a separate disease entity in the past 10 years, it was probably previously unrecognized among patients diagnosed with reflux esophagitis.56Whitney-Miller C.L. Katzka D. Furth E.E. Eosinophilic esophagitis: a retrospective review of esophageal biopsy specimens from 1992 to 2004 at an adult academic medical center.Am J Clin Pathol. 2009; 131: 788-792Google ScholarEsophageal Numbers of Eosinophils and HistopathologyIt is important to emphasize that there is currently no diagnostic test for EE; instead, diagnosis depends on coordinated clinical and pathologic data. Although a minimum level of 15 eosinophils/high-power field (hpf) has been proposed to be part of the diagnostic criteria of EE,5Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google Scholar any level has to be interpreted in the context of clinical data. Determination of the number and location of eosinophils is helpful in trying to differentiate EE from GERD. As many as 6 eosinophils/hpf (400×) might indicate GERD, whereas more than 20–24 eosinophils/hpf appear to indicate EE,48Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Dev Pathol. 1999; 2: 15-18Google Scholar, 57Rothenberg M.E. Mishra A. Collins M.H. et al.Pathogenesis and clinical features of eosinophilic esophagitis.J Allergy Clin Immunol. 2001; 108: 891-894Google Scholar especially when these levels are encountered in patients who receive anti-GERD therapy. The number of eosinophils in the esophagus is negatively correlated with response to conventional anti-GERD therapy.48Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Dev Pathol. 1999; 2: 15-18Google Scholar In particular, numbers of esophageal eosinophils ≥24/hpf have been correlated with lack of responsiveness to anti-GERD therapy. These levels might indicate EE rather than GERD or chronic esophagitis, especially in patients who are already on anti-GERD therapy. Patients with intermediate levels of eosinophils (7–15/hpf) often present a diagnostic dilemma for several reasons. First, the exact cutoff eosinophil concentration value used in the diagnosis of EE has not been determined. Second, EE is often a patchy disease; diagnosis varies based on the number of biopsy specimens obtained, and the maximum level of eosinophils can vary.58Shah A. Kagalwalla A.F. Gonsalves N. et al.Histopathologic variability in children with eosinophilic esophagitis.Am J Gastroenterol. 2009; 104: 716-721Google Scholar In 2007, an expert panel stated that EE is a clinicopathologic disease that should be considered in patients (1) with symptoms including but not restricted to food impaction and dysphagia (in adults) and feeding intolerance and GERD symptoms (in children); (2) with >15 eosinophils/hpf; and (3) in whom other disorders associated with similar clinical, histologic, or endoscopic features, especially GERD with sustained esophageal eosinophilia (peak numbers of eosinophils >15/400× hpf) after adequate GERD therapy (eg, proton pump inhibitors), have been excluded.5Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google Scholar For research studies, a higher threshold (≥24 eosinophils/hpf) has been recommended.5Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google Scholar Based on histologic analysis of a large cohort of adult patients and the performance of esophageal pH monitoring, 1, 2, 3, and 6 esophageal biopsy specimens from the mid and distal esophagus provide sensitivity levels of 73%, 84%, 97%, and 100%, respectively, using 15 eosinophils/hpf.58Shah A. Kagalwalla A.F. Gonsalves N. et al.Histopathologic variability in children with eosinophilic esophagitis.Am J Gastroenterol. 2009; 104: 716-721Google Scholar Therefore, at least 3 biopsy specimens are recommended for the diagnosis of EE.5Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google ScholarIn addition to high numbers of eosinophils, other features distinguish EE from GERD (see Supplementary Table 2). The presence of eosinophils in both the proximal and the distal esophagus typically denotes EE, whereas the accumulation of eosinophils mainly in the distal esophagus is typical, but not specific, for GERD.59Collins M.H. Histopathologic features of eosinophilic esophagitis.Gastrointest Endosc Clin North Am. 2008; 18 (viii–ix): 59-71Google Scholar In addition, esophageal tissue from patients with EE typically contains a thickened mucosa with basal layer hyperplasia (assessed by Ki-67 antigen staining) and papillary lengthening59Collins M.H. Histopathologic features of eosinophilic esophagitis.Gastrointest Endosc Clin North Am. 2008; 18 (viii–ix): 59-71Google Scholar, 60Noel R.J. Putnam P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Google Scholar; this appears to be more pronounced than in GERD.61Steiner S.J. Kernek K.M. Fitzgerald J.F. Severity of basal cell hyperplasia differs in reflux versus eosinophilic esophagitis.J Pediatr Gastroenterol Nutr. 2006; 42: 506-509Google Scholar Consistent with increased proliferation of the basal cells in response to allergen provocation, rather than acid exposure, biopsy specimens from patients with EE demonstrate down-regulation of cyclooxygenase-2.62Lewis C.J. Lamb C.A. Kanakala V. et al.Is the etiology of eosinophilic esophagitis in adults a response to allergy or reflux injury? Study of cellular proliferation markers.Dis Esophagus. 2009; 22: 249-255Google Scholar Furthermore, esophageal biopsy specimens from patients with EE can have eosinophil surface layering and eosinophilic microabscesses, processes rarely associated with GERD.63Parfitt J.R. Gregor J.C. Suskin N.G. et al.Eosinophilic esophagitis in adults: distinguishing features from gastroesophageal reflux disease: a study of 41 patients.Mod Pathol. 2006; 19: 90-96Google Scholar In addition to eosinophils, esophageal biopsy specimens from patients with EE have increased numbers of dendritic cells and mast cells, generally more than in patients with GERD.64Teitelbaum J.E. Fox V.L. Twarog F.J. et al.Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate.Gastroenterology. 2002; 122: 1216-1225Google Scholar, 65Konikoff M.R. Noel R.J. Blanchard C. et al.A randomized double-blind-placebo controlled trial of fluticasone proprionate for pediatric eosinophilic esophagitis.Gastroenterology. 2006; 131: 1381-1391Google Scholar, 66Lucendo A.J. Navarro M. Comas C. et al.Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology: an analysis of the cellular mechanisms of the disease and the immunologic capacity of the esophagus.Am J Surg Pathol. 2007; 31: 598-606Google Scholar It was recently proposed that extracellular deposition of the granule protein eosinophil-derived peroxidase (EPO) occurs in the esophagus of patients with EE; this might be more closely correlated with clinical features than eosinophil number.67Protheroe C. Woodruff S.A. Depetris G. et al.A novel histological scoring system to evaluate mucosal biopsies from patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2009; 7 (749–755.e11)Google Scholar Radiographic and endoscopic studies have identified many features of EE, including strictures, mucosal rings, ulcerations, whitish papules, and polyps23Liacouras C.A. Spergel J.M. Ruchelli E. et al.Eosinophilic esophagitis: a 10-year experience in 381 children.Clin Gastroenterol Hepatol. 2005; 3: 1198-1206Google Scholar, 68Fox V.L. Nurko S. Teitelbaum J.E. et al.High-resolution EUS in children with eosinophilic “allergic” esophagitis.Gastrointest Endosc. 2003; 57: 30-36Google Scholar; however, nearly 30% of patients with EE have normal endoscopy results,69Dahshan A. Rabah R. Correlation of endoscopy and histology in the gastroesophageal mucosa in children: are routine biopsies justified?.J Clin Gastroenterol. 2000; 31: 213-216Google Scholar indicating the importance of endoscopic biopsies in diagnosis of this disease.Disease PathogenesisThe pathogenesis of EE is associated with atopy, based on studies of disease co-occurrence, studies in animal models, and the reported success of allergen avoidance (primarily diet control). The majority of patients have evidence of food and aeroallergen hypersensitivity50Fox V.L. Nurko S. Furuta G.T. Eosinophilic esophagitis: it's not just kid's stuff.Gastrointest Endosc. 2002; 56: 260-270Google Scholar and a concurrent history of respiratory allergies (see Figure 1).24Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Google Scholar Unlike food anaphylaxis, which occurs in ∼15% of patients with EE,33Assa'ad A.H. Putnam P.E. Collins M.H. et al.Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.J Allergy Clin Immunol. 2007; 119: 731-738Google Scholar polysensitization to a variety of foods (based on skin prick testing) occurs in most patients with EE.70Spergel J.M. Andrews T. Brown-Whitehorn T.F. 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: 336-343Google Scholar, 71Spergel J.M. Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients.Curr Opin Allergy Clin Immunol. 2007; 7: 274-278Google Scholar The key role of food antigen sensitization has been demonstrated by the success of reducing specific food exposures (based on results of skin and patch tests), avoiding the most common 6 food types, or using an amino acid–based formula; all of these approaches induce disease remission.72Kagalwalla A.F. Sentongo T.A. Ritz S. et al.Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2006; 4: 1097-1102Google ScholarMouse models of EE have been developed through exposure of animals to allergens and overexpression of cytokines produced by Th2 cells.73Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Google Scholar, 74Mishra A. Hogan S.P. Brandt E.B. et al.Interleukin-5 promotes eosinophil trafficking to the esophagus.J Immunol. 2002; 168: 2464-2469Google Scholar Repeated intranasal exposure to the aeroallergen Aspergillus fumigatus induces simultaneous eosinophilic airway and esophageal inflammation (without inducing lower gastrointestinal eosinophilia).73Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Google Scholar Intratracheal delivery of human or mouse IL-13 induces experimental EE in a dose-dependent manner75Mishra A. Rothenberg M.E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.Gastroente
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