Title: Epidemiology and Natural History of Eosinophilic Esophagitis
Abstract: Eosinophilic esophagitis (EoE) has emerged over the past 2 decades as a major cause of upper gastrointestinal morbidity. Over this time, the epidemiology of EoE has also rapidly evolved. EoE has transformed from a rare case-reportable condition to disease that is commonly encountered in the gastroenterology clinic, hospital emergency room, and endoscopy suite. The incidence and prevalence are increasing at rates that outpace increased disease recognition. Current incidence estimates range from 5 to 10 cases per 100,000, and current prevalence estimates range from 0.5 to 1 case per 1000. We review the data and potential reasons behind this increase, examine risk factors, and identify important areas for research into disease etiology. The article also discusses the progression of EoE from an inflammatory to fibrostenotic phenotype. An accurate view of the natural history of EoE is central to discussions with patients regarding disease prognosis and decisions about long-term use of medical, endoscopic, and diet therapies. Progressive remodelling appears to be gradual, but not universal, and the duration of untreated disease is the best predictor of stricture risk. Ultimately, prospective, long-term outcome studies focusing on multiple aspects of disease activity are needed to fully understand the natural history of EoE. Eosinophilic esophagitis (EoE) has emerged over the past 2 decades as a major cause of upper gastrointestinal morbidity. Over this time, the epidemiology of EoE has also rapidly evolved. EoE has transformed from a rare case-reportable condition to disease that is commonly encountered in the gastroenterology clinic, hospital emergency room, and endoscopy suite. The incidence and prevalence are increasing at rates that outpace increased disease recognition. Current incidence estimates range from 5 to 10 cases per 100,000, and current prevalence estimates range from 0.5 to 1 case per 1000. We review the data and potential reasons behind this increase, examine risk factors, and identify important areas for research into disease etiology. The article also discusses the progression of EoE from an inflammatory to fibrostenotic phenotype. An accurate view of the natural history of EoE is central to discussions with patients regarding disease prognosis and decisions about long-term use of medical, endoscopic, and diet therapies. Progressive remodelling appears to be gradual, but not universal, and the duration of untreated disease is the best predictor of stricture risk. Ultimately, prospective, long-term outcome studies focusing on multiple aspects of disease activity are needed to fully understand the natural history of EoE. Ikuo HiranoView Large Image Figure ViewerDownload Hi-res image Download (PPT) Eosinophilic esophagitis (EoE) is an allergen/immune-mediated disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa in the absence of secondary causes of eosinophilia.1Liacouras C.A. Furuta G.T. Hirano I. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128: 3-20.e6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Dellon E.S. Gonsalves N. Hirano I. et al.ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis.Am J Gastroenterol. 2013; 108: 679-692Crossref PubMed Scopus (0) Google Scholar The first cases of EoE were reported in the late 1970s,3Dobbins J.W. Sheahan D.G. Behar J. Eosinophilic gastroenteritis with esophageal involvement.Gastroenterology. 1977; 72: 1312-1316Abstract Full Text PDF PubMed Google Scholar, 4Landres R.T. Kuster G.G. Strum W.B. Eosinophilic esophagitis in a patient with vigorous achalasia.Gastroenterology. 1978; 74: 1298-1301Abstract Full Text PDF PubMed Google Scholar but the disease as it is recognized today was described in 3 case series in the early and mid-1990s.5Attwood S.E. Smyrk T.C. Demeester T.R. et al.Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome.Dig Dis Sci. 1993; 38: 109-116Crossref PubMed Scopus (452) Google Scholar, 6Straumann A. Spichtin H.P. Bernoulli R. et al.[Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings].Schweiz Med Wochenschr. 1994; 124 ([Article in German]): 1419-1429PubMed Google Scholar, 7Kelly K.J. Lazenby A.J. Rowe P.C. et al.Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (673) Google Scholar Since then, EoE has transformed from a rare case-reportable condition to a disease that is commonly encountered in the clinic and endoscopy suite,8Dellon E.S. Liacouras C.A. Advances in clinical management of eosinophilic esophagitis.Gastroenterology. 2014; 147: 1238-1254Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and a major cause of upper gastrointestinal morbidity and increasing health care costs.9Jensen E.T. Kappelman M.D. Martin C.F. et al.Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.Am J Gastroenterol. 2015; 110: 626-632Crossref PubMed Google Scholar Over this time, our understanding of the epidemiology of EoE has also rapidly evolved. The incidence and prevalence are increasing at rates that outpace increased recognition,10Dellon E.S. Gibbs W.B. Fritchie K.J. et al.Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.Clin Gastroenterol Hepatol. 2009; 7: 1305-1313Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 11Dellon E.S. Erichsen R. Baron J.A. et al.The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.Aliment Pharmacol Ther. 2015; 41: 662-670Crossref PubMed Scopus (0) Google Scholar, 12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar indicating the importance of environmental rather than genetic changes.13Jensen E.T. Dellon E.S. Environmental and infectious factors in eosinophilic esophagitis.Best Pract Res Clin Gastroenterol. 2015; 29: 721-729Crossref PubMed Google Scholar, 14Alexander E.S. Martin L.J. Collins M.H. et al.Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.J Allergy Clin Immunol. 2014; 134: 1084-1092 e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Descriptive epidemiology research in EoE has also matured, and there is now a focus on identifying etiologic factors. Although we know much about the pathogenesis of EoE,15Rothenberg M.E. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.Gastroenterology. 2015; 148: 1143-1157Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar we do not fully understand why EoE develops in an individual patient.16Wolf W.A. Jerath M.R. Dellon E.S. De-novo onset of eosinophilic esophagitis after large volume allergen exposures.J Gastrointestin Liver Dis. 2013; 22: 205-208PubMed Google Scholar We review the incidence and prevalence of EoE, present potential reasons for the increase in EoE, examine possible risk factors, and discuss the natural history and possible progression of this chronic condition. The incidence of EoE has been investigated in several population-based studies, conducted primarily in North America and Europe.11Dellon E.S. Erichsen R. Baron J.A. et al.The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.Aliment Pharmacol Ther. 2015; 41: 662-670Crossref PubMed Scopus (0) Google Scholar, 12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar, 17Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (558) Google Scholar, 18Straumann A. Simon H.U. Eosinophilic esophagitis: escalating epidemiology?.J Allergy Clin Immunol. 2005; 115: 418-419Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 19Hruz P. Straumann A. Bussmann C. et al.Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County.Switzerland. J Allergy Clin Immunol. 2011; 128: 1349-1350 e5Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 20Prasad G.A. Alexander J.A. Schleck C.D. et al.Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.Clin Gastroenterol Hepatol. 2009; 7: 1055-1061Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 21Dalby K. Nielsen R.G. Kruse-Andersen S. et al.Eosinophilic oesophagitis in infants and children in the region of Southern Denmark: a prospective study of prevalence and clinical presentation.J Pediatr Gastroenterol Nutr. 2010; 51: 280-282Crossref PubMed Scopus (47) Google Scholar, 22van Rhijn B.D. Verheij J. Smout A.J. et al.Rapidly increasing incidence of eosinophilic esophagitis in a large cohort.Neurogastroenterol Motil. 2013; 25: 47-52 e5Crossref PubMed Scopus (76) Google Scholar, 23Syed A.A. Andrews C.N. Shaffer E. et al.The rising incidence of eosinophilic oesophagitis is associated with increasing biopsy rates: a population-based study.Aliment Pharmacol Ther. 2012; 36: 950-958Crossref PubMed Scopus (0) Google Scholar, 24Arias A. Lucendo A.J. Prevalence of eosinophilic oesophagitis in adult patients in a central region of Spain.Eur J Gastroenterol Hepatol. 2013; 25: 208-212Crossref PubMed Scopus (0) Google Scholar, 25Homan M. Blagus R. Jeverica A.K. et al.Pediatric eosinophilic esophagitis in Slovenia: data from a retrospective 2005-2012 epidemiological study.J Pediatr Gastroenterol Nutr. 2015; 61: 313-318Crossref PubMed Scopus (0) Google Scholar Using the most recent time point from these studies, incidence rates range from a low of 2.1/100,000/year in the Netherlands22van Rhijn B.D. Verheij J. Smout A.J. et al.Rapidly increasing incidence of eosinophilic esophagitis in a large cohort.Neurogastroenterol Motil. 2013; 25: 47-52 e5Crossref PubMed Scopus (76) Google Scholar, 26Warners M. de Rooij W.E. Van Rhijn B.D. et al.Large increase in incidence of eosinophilc esophagitis over the last 20 years in the Netherlands: results from a nationwide pathology database.Gastroenterology. 2017; 152 (Tu1104): S862-S863Abstract Full Text PDF Google Scholar to a high of 12.8/100,000/year in Ohio in the United States17Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (558) Google Scholar (Supplementary Table 1). A meta-analysis calculated an overall pooled incident rate of 3.7/100,000/year (95% confidence interval [CI], 1.7–6.5), though there was substantial heterogeneity.27Arias A. Perez-Martinez I. Tenias J.M. et al.Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies.Aliment Pharmacol Ther. 2016; 43: 3-15Crossref PubMed Scopus (29) Google Scholar In this study, the incidence rate was higher in adults (7.0/100,000/year) than in children (5.1/100,000/year). When interpreting the published incidence data, it is important to recognize differences among studies performed at different centers and during different time periods. For example, proton pump inhibitor (PPI)-responsive esophageal eosinophilia may not have been excluded in some studies (there is controversy over this topic)28Molina-Infante J. Bredenoord A.J. Cheng E. et al.Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis.Gut. 2016; 65: 524-531Crossref PubMed Scopus (0) Google Scholar and varying case-finding approaches might have been used. All studies that have examined incidence rates of EoE over time have concluded that the incidence of EoE is increasing rapidly (Figure 1A; Supplementary Table 1). In the first report investigating this issue, incidence increased 40% over a 4-year period (2000–2003).17Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (558) Google Scholar In similar analyses, incidence increased approximately 27-fold20Prasad G.A. Alexander J.A. Schleck C.D. et al.Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.Clin Gastroenterol Hepatol. 2009; 7: 1055-1061Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar and 5-fold at 2 other North American centers.23Syed A.A. Andrews C.N. Shaffer E. et al.The rising incidence of eosinophilic oesophagitis is associated with increasing biopsy rates: a population-based study.Aliment Pharmacol Ther. 2012; 36: 950-958Crossref PubMed Scopus (0) Google Scholar In European studies, rates of increase ranged from 6-fold to more than 100-fold.11Dellon E.S. Erichsen R. Baron J.A. et al.The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.Aliment Pharmacol Ther. 2015; 41: 662-670Crossref PubMed Scopus (0) Google Scholar, 12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar, 18Straumann A. Simon H.U. Eosinophilic esophagitis: escalating epidemiology?.J Allergy Clin Immunol. 2005; 115: 418-419Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 19Hruz P. Straumann A. Bussmann C. et al.Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County.Switzerland. J Allergy Clin Immunol. 2011; 128: 1349-1350 e5Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 22van Rhijn B.D. Verheij J. Smout A.J. et al.Rapidly increasing incidence of eosinophilic esophagitis in a large cohort.Neurogastroenterol Motil. 2013; 25: 47-52 e5Crossref PubMed Scopus (76) Google Scholar, 24Arias A. Lucendo A.J. Prevalence of eosinophilic oesophagitis in adult patients in a central region of Spain.Eur J Gastroenterol Hepatol. 2013; 25: 208-212Crossref PubMed Scopus (0) Google Scholar, 25Homan M. Blagus R. Jeverica A.K. et al.Pediatric eosinophilic esophagitis in Slovenia: data from a retrospective 2005-2012 epidemiological study.J Pediatr Gastroenterol Nutr. 2015; 61: 313-318Crossref PubMed Scopus (0) Google Scholar Although it is tempting to attribute this rapid change to an associated increase in recognition of and knowledge about EoE, this is not the only explanation. Several studies have examined changes in rates of endoscopy with biopsy over the same time period as the change in rates of EoE, and have found that the increase in EoE incidence outpaces the relatively modest increase in rates of biopsy.10Dellon E.S. Gibbs W.B. Fritchie K.J. et al.Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.Clin Gastroenterol Hepatol. 2009; 7: 1305-1313Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 11Dellon E.S. Erichsen R. Baron J.A. et al.The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.Aliment Pharmacol Ther. 2015; 41: 662-670Crossref PubMed Scopus (0) Google Scholar, 12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar, 20Prasad G.A. Alexander J.A. Schleck C.D. et al.Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.Clin Gastroenterol Hepatol. 2009; 7: 1055-1061Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 29Kidambi T. Toto E. Ho N. et al.Temporal trends in the relative prevalence of dysphagia etiologies from 1999-2009.World J Gastroenterol. 2012; 18: 4335-4341Crossref PubMed Scopus (0) Google Scholar In addition, other studies have retrospectively reviewed archived esophageal biopsy blocks to determine if cases of EoE were previously present but missed.30DeBrosse C.W. Collins M.H. Buckmeier Butz B.K. et al.Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999.J Allergy Clin Immunol. 2010; 126: 112-119Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 31Whitney-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: 788-792Crossref PubMed Scopus (0) Google Scholar Although cases of EoE were found, they were identified at rates that are far below what are currently observed. Therefore, it appears that the incidence of EoE is truly increasing, and is just not an artifact of increasing surveillance and detection. This information has major implications for understanding the etiology of EoE. The prevalence of EoE has been investigated worldwide, but most population-based studies have been conducted in North America and Europe,11Dellon E.S. Erichsen R. Baron J.A. et al.The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.Aliment Pharmacol Ther. 2015; 41: 662-670Crossref PubMed Scopus (0) Google Scholar, 12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar, 17Noel R.J. Putnam P.E. Rothenberg M.E. 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Kruse-Andersen S. et al.Eosinophilic oesophagitis in infants and children in the region of Southern Denmark: a prospective study of prevalence and clinical presentation.J Pediatr Gastroenterol Nutr. 2010; 51: 280-282Crossref PubMed Scopus (47) Google Scholar to as high as 90.7/100,000 in Ohio (Supplementary Table 2).17Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (558) Google Scholar A meta-analysis estimated an overall pooled EoE prevalence of 22.7/100,000 (95% CI, 12.4–36.0), with a higher rate in adults (43.4/100,000; 95% CI, 22.5–71.2) than in children (29.5/100,000; 95% CI, 17.5–44.7), though there was substantial heterogeneity in these estimates.27Arias A. Perez-Martinez I. Tenias J.M. et al.Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies.Aliment Pharmacol Ther. 2016; 43: 3-15Crossref PubMed Scopus (29) Google Scholar EoE is a chronic disease, so prevalence rates have increased steadily at all sites that have examined changes over time (Figure 1B). EoE prevalence estimates vary with location (Figure 2). Prevalence tends to be on the same order of magnitude in Western Europe, North America, and Australia,12Giriens B. Yan P. Safroneeva E. et al.Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study.Allergy. 2015; 70: 1633-1639Crossref PubMed Scopus (23) Google Scholar, 17Noel R.J. Putnam P.E. Rothenberg M.E. Eosinophilic esophagitis.N Engl J Med. 2004; 351: 940-941Crossref PubMed Scopus (558) Google Scholar, 19Hruz P. Straumann A. 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Mays E. et al.Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States.J Pediatr Gastroenterol Nutr. 2011; 52: 300-306Crossref PubMed Scopus (0) Google Scholar, 37Dellon E.S. Jensen E.T. Martin C.F. et al.Prevalence of eosinophilic esophagitis in the United States.Clin Gastroenterol Hepatol. 2014; 12: 589-596.e1Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 38Maradey-Romero C. Prakash R. Lewis S. et al.The 2011-2014 prevalence of eosinophilic oesophagitis in the elderly amongst 10 million patients in the United States.Aliment Pharmacol Ther. 2015; 41: 1016-1022Crossref PubMed Scopus (0) Google Scholar, 39Kim S. Sheikh J. Prevalence of eosinophilic esophagitis in a population-based cohort from Southern California.J Allergy Clin Immunol Pract. 2015; 3: 978-979Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 40Mansoor E. Cooper G.S. 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