Advertisement
Mayo Clinic Proceedings Home

The Role of Environmental Exposures in the Etiology of Eosinophilic Esophagitis

A Systematic Review
  • Daniel J. Green
    Affiliations
    Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
    Search for articles by this author
  • Cary C. Cotton
    Affiliations
    Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
    Search for articles by this author
  • Evan S. Dellon
    Correspondence
    Correspondence: Address to Evan S. Dellon, MD, MPH, University of North Carolina at Chapel Hill, CB#7080, Bioinformatics Building, 130 Mason Farm Rd, Chapel Hill, NC 27599-7080.
    Affiliations
    Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
    Search for articles by this author

      Abstract

      Eosinophilic esophagitis (EoE) is an emerging clinicopathologic entity defined by abnormal esophageal eosinophilic infiltration. Management of this disease is hampered by limited understanding of etiologic and controllable risk factors. The aim of this systematic review was to determine the environmental risk factors for EoE. We searched the PubMed, Web of Science, and EMBASE databases from January 1, 1950, through June 30, 2015. To identify additional relevant studies, we hand searched bibliographies of included articles. We limited the review to articles using human subjects and consisting of case reports, case series, cross-sectional and cohort studies, and clinical trials. Nineteen articles discuss the risk of environmental exposures on EoE and indicate that environment plays a large role in the etiology of EoE. Seasonal, geographic, and climate-based differences in disease prevalence have been reported, but the exact mediators of this process, possibly aeroallergens that vary over time and from place to place, remain elusive.

      Abbreviations and Acronyms:

      aOR (adjusted odds ratio), AR (allergic rhinitis), CHOP (Children's Hospital of Philadelphia), EE (esophageal eosinophilia), EGD (esophagogastroduodenoscopy), EoE (eosinophilic esophagitis), FBOE (food bolus obstruction events), GE (gastroenterology), GERD (gastroesophageal reflux disease), HPF (high-power field), NA (not applicable), NR (not reported), OR (odds ratio), PPI (proton pump inhibitor), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), ref. (referent group), UNC (University of North Carolina)
      Article Highlights
      • This systematic review identified 19 articles pertaining to environmental risk factors for eosinophilic esophagitis (EoE).
      • Study designs included case reports, case series, case-control studies, and cohort studies. There were no experimental studies or clinical trials assessing environmental risk factors.
      • Data were strongest for climate, seasonality, low population density, and early-life exposures.
      • Data were less strong for pollen and aeroallergens.
      • The results suggest, but do not prove, that environmental exposures may contribute to EoE etiology, but additional prospective studies at more granular levels are needed.
      Eosinophilic esophagitis (EoE) is a newly recognized, immune-mediated, chronic disease defined by symptoms of esophageal dysfunction, eosinophilic infiltration of the esophagus that persists after a proton pump inhibitor trial, and exclusion of secondary causes of eosinophilia.
      • Dellon E.S.
      • Gonsalves N.
      • Hirano I.
      • Furuta G.T.
      • Liacouras C.
      • Katzka D.A.
      ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
      Although EoE was almost entirely unknown 20 years ago, it is now regularly encountered in endoscopy suites and is a leading cause of emergency department visits for food impactions in the United States.
      • Desai T.K.
      • Stecevic V.
      • Chang C.H.
      • Goldstein N.S.
      • Badizadegan K.
      • Furuta G.T.
      Association of eosinophilic inflammation with esophageal food impaction in adults.
      • Kerlin P.
      • Jones D.
      • Remedios M.
      • Campbell C.
      Prevalence of eosinophilic esophagitis in adults with food bolus obstruction of the esophagus.
      • Sperry S.L.
      • Crockett S.D.
      • Miller C.B.
      • Shaheen N.J.
      • Dellon E.S.
      Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis.
      Accordingly, it now accounts for a substantial amount of health care–related spending in the United States.
      • Jensen E.T.
      • Kappelman M.D.
      • Martin C.F.
      • Dellon E.S.
      Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.
      Eosinophilic esophagitis affects infants, children, and adults, although the disease can manifest with different symptoms and endoscopic findings at different ages.
      • Furuta 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.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      The etiology of EoE is still incompletely understood. Animal models have found that allergen exposure can recapitulate the histopathologic phenotype of EoE through the activation of TH2 immune cells, and similar mechanisms have been identified in humans.
      • Mishra A.
      • Hogan S.P.
      • Brandt E.B.
      • Rothenberg M.E.
      An etiological role for aeroallergens and eosinophils in experimental esophagitis.
      • Straumann A.
      • Bauer M.
      • Fischer B.
      • Blaser K.
      • Simon H.U.
      Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.
      • Clayton F.
      • Fang J.C.
      • Gleich G.J.
      • et al.
      Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
      • Rothenberg M.E.
      Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
      Epidemiologic studies further support the role of allergens in disease pathogenesis because patients frequently have a history of atopic disease or food allergies.
      • Furuta 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.
      Moreover, allergen-free formulas are highly effective for treating this condition and provide proof-of-principle of the importance of food allergens in EoE pathogenesis.
      • Kelly K.J.
      • Lazenby A.J.
      • Rowe P.C.
      • Yardley J.H.
      • Perman J.A.
      • Sampson H.A.
      Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
      • Markowitz J.E.
      • Spergel J.M.
      • Ruchelli E.
      • Liacouras C.A.
      Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.
      Dietary elimination therapies for EoE are supported by a broad base of literature, which suggests that dietary antigens can be crucial disease triggers.
      • Spergel J.M.
      • Andrews T.
      • Brown-Whitehorn T.F.
      • Beausoleil J.L.
      • Liacouras C.A.
      Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • Mota-Huertas T.
      • Yague-Compadre J.L.
      Tolerance of a cow's milk-based hydrolyzed formula in patients with eosinophilic esophagitis triggered by milk.
      • Lieberman J.A.
      • Morotti R.A.
      • Konstantinou G.N.
      • Yershov O.
      • Chehade M.
      Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort.
      • Rodriguez-Sanchez J.
      • Gomez Torrijos E.
      • Lopez Viedma B.
      • et al.
      Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
      • Gonsalves N.
      • Yang G.Y.
      • Doerfler B.
      • Ritz S.
      • Ditto A.M.
      • Hirano I.
      Elimination diet effectively treats eosinophilic esophagitis in adults: food reintroduction identifies causative factors.
      • Colson D.
      • Kalach N.
      • Soulaines P.
      • et al.
      The impact of dietary therapy on clinical and biologic parameters of pediatric patients with eosinophilic esophagitis.
      • Kagalwalla A.F.
      • Shah A.
      • Li B.U.
      • et al.
      Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
      • Henderson C.J.
      • Abonia J.P.
      • King E.C.
      • et al.
      Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
      • Lucendo A.J.
      • Arias A.
      • Gonzalez-Cervera J.
      • et al.
      Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
      • Kagalwalla A.F.
      • Sentongo T.A.
      • Ritz S.
      • et al.
      Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.
      • Wolf W.A.
      • Jerath M.R.
      • Sperry S.L.
      • Shaheen N.J.
      • Dellon E.S.
      Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
      • Spergel J.M.
      • Brown-Whitehorn T.F.
      • Cianferoni A.
      • et al.
      Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.

      Arias A, Lucendo AJ, Martinez-Fernandez P, et al. Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic esophagitis [published online February 1, 2015]. Clin Exp Allergy. http://dx.doi.org/10.1111/cea.12504.

      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      Recent publications have also described variations in EoE prevalence by climate type, geography, and season, and a study of inheritance patterns in EoE suggests that environmental factors play a larger etiologic role than genetics.
      • Alexander 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.
      However, except for rare case reports,
      • Martin-Munoz M.F.
      • Lucendo A.J.
      • Navarro M.
      • et al.
      Food allergies and eosinophilic esophagitis: two case studies.
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      it is difficult to identify an inciting allergic event that triggers EoE.
      In contrast to the well-described role of limiting dietary triggers as a treatment for disease, the role of environmental exposures in the etiology of EoE is not well characterized. Therefore, the aim of this systematic review was to summarize the existing clinical literature on the etiology of EoE as it relates to environmental exposures and causation of the disease.

      Methods

      Search Strategy

      We conducted a systematic review by searching the PubMed, Web of Science, and EMBASE databases. To identify relevant articles, 2 authors (D.J.G. and C.C.C.) independently performed the search, which was developed with the assistance of a reference librarian with expertise in systematic review methods. We used the following search terms for EoE (the “*” before terms ensured that European spellings were detected): *eosinophilic esophagitis OR allergic *esophagitis OR corrugated *esophagus OR ringed *esophagus. These terms are similar to those used in a previous systematic review of EoE diagnosis.
      • Sperry S.L.
      • Shaheen N.J.
      • Dellon E.S.
      Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE.
      We limited the search to include only EoE articles on environmental, aeroallergen, or allergy-related risk factors by using the terms *environment OR pollen OR rural OR urban OR aeroallergen OR allergy OR allergic OR allergies OR allergen OR allergens OR diet OR dietary OR food. Articles relating to dietary therapy were excluded from abstraction. To limit the search to epidemiologic topics, we further limited the search to articles including the terms risk factor OR risk factors OR exposure. The complete PubMed search string was (eosinophilic *esophagitis OR allergic *esophagitis OR corrugated *esophagus OR ringed *esophagus) AND (*environment OR pollen OR rural OR urban OR aeroallergen OR allergy OR allergic OR allergies OR allergen OR allergens OR diet OR dietary OR food) AND (risk factor OR risk factors OR exposure). This search string was reformatted as necessary for the syntax of EMBASE and Web of Science searches. Both readers (D.J.G. and C.C.C.) subsequently hand searched the bibliographies of all identified articles and considered relevant articles for inclusion. We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist to ensure thorough methods.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

      Article Inclusion Criteria

      All articles published from January 1, 1950, through June 30, 2015, were eligible for inclusion. Owing to the limited literature on this topic, we accepted case reports and case series as well as cross-sectional studies, cohort studies, and clinical trials focusing on EoE written in any language. Nonhuman studies, review articles, and letters to the editor that did not present new clinical information were excluded. Articles describing dietary elimination therapy of EoE were excluded. After the search was complete, 1 of us (D.J.G.) reviewed the article titles and then abstracts to determine whether they were eligible for inclusion. This process was repeated independently by a second reviewer (C.C.C.). When there were discrepancies between the lists of articles to include, we read the full text and came to a consensus; adjudication, if needed, was performed by the senior author (E.S.D.). Both reviewers agreed on the final list of included material before analysis began.

      Data Abstraction

      Extracted data included study type; the number of patients in the study with EoE (which could be less than the total number of participants in a study); the number of patients in the comparator group; study population demographic characteristics, such as mean age, sex distribution, and allergy history; and main environmental risk–related findings, reported as crude and adjusted risk estimates (risk ratio and odds ratio [OR]). The validity of the articles was assessed by examining study design, precision of estimates, and potential for bias and measurement error. Owing to the wide range of study types and substantial heterogeneity between studies, a meta-analysis was not performed for this systematic review.

      Results

      Literature Search Results

      The combined search yielded 240 articles; 19 met the inclusion criteria and were the focus of this review (Figure). Of the initial 240 publications, we excluded 121 based on the title. These were typically review articles, based on animal models, or focused on treatment or diagnostic criteria. Of the remaining 119 articles, an additional 46 were excluded after reading the abstract. After reading the full text of the remaining 73 articles, 62 were excluded because they did not address the topic of interest. Hand searching the bibliographies of the 11 included articles and germane review articles resulted in inclusion of an additional 8 articles not found in the initial search strategy. The 19 included articles consisted of observational epidemiologic studies and case series. There were no randomized studies. One article was a case report,
      • Ramirez R.M.
      • Jacobs R.L.
      Eosinophilic esophagitis treated with immunotherapy to dust mites.
      2 were case series,
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      • Roy-Ghanta S.
      • Larosa D.F.
      • Katzka D.A.
      Atopic characteristics of adult patients with eosinophilic esophagitis.
      1 was a cross-sectional study,
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      9 were case-control studies,
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      and 6 were cohort studies.
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      All the articles were published in the past decade, with the earliest published in 2007. One study was conducted in Spain,
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      1 in Canada,

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      and another in Australia,
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      with the remaining 11 completed in the United States. Studies included adults and children.
      Figure thumbnail gr1
      FigureThe combined search yielded 240 articles; 19 met the inclusion criteria and were the focus of this review. Of the initial 240 publications, we excluded 121 based on the title. These were typically review articles, based on animal models, or focused on treatment or diagnostic criteria. Of the remaining 119 articles, an additional 46 were excluded after reading the abstract. After reading the full text of the remaining articles, more were excluded as they did not address the topic of interest. Hand searching the bibliography of the 11 included articles as well as germane review articles resulted in inclusion of an additional 8 articles not found in the initial search strategy.
      The aim, year, and environmental exposure investigated are presented in Table 1. Only 1 study was population based,
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      with the remaining drawing from clinical populations. All but 3 studies

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      reported positive findings (Table 2). Most studies, excluding 4 studies based in national pathology databases, were limited by a relatively small number of cases. Assessments of bias, precision, and measurement error are presented in Table 3. The following are the main categories of environmental risk factors determined from the literature search.
      Table 1Aim, Design, and Exposure of Interest for Studies Included for Analysis
      Reference, yearAimDesignEnvironmental exposure of Interest
      Lee et al,
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      2015
      To compare demographic and clinical characteristics of urban vs rural patients with EoE with a PPI trial.Cohort, retrospectivePopulation density (urban vs rural)
      Castro Jiménez et al,
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      2013
      To describe the demographic and clinical characteristics and allergy sensitization of patients with EoE in a Spanish region.Cross sectionalAeroallergens
      Wolf et al,
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      2013
      To offer initial human evidence of the EoE etiology mechanism proved in mouse models.Case seriesAeroallergens
      Ramirez and Jacobs,
      • Ramirez R.M.
      • Jacobs R.L.
      Eosinophilic esophagitis treated with immunotherapy to dust mites.
      2013
      To describe a case of dust mite hypersensitivity and EoE with clinical and pathologic improvement after desensitization.Single caseAeroallergens
      Hurrell et al,
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      2012
      To examine the relationship between EE (not EoE) and climate.Case-controlClimate
      Jensen et al,
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.
      2013
      To explore early-life exposures as risk factors for EoE.Case-controlChildhood antibiotics, cesarean delivery
      Radano et al,
      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      2014
      To investigate associations between EoE and dietary, environmental, and medical exposures during infancy.Case-controlChildhood antibiotics, cesarean delivery
      Slae et al,

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      2015
      To determine whether smoking and other exposures linked with the development of atopic disease are also associated with EoE.Case-controlChildhood antibiotics, cesarean delivery, breast-feeding, smoking
      Franciosi et al,
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      2009
      To determine demographic, socioeconomic, and geographic characteristics of CHOP's EoE cohort for pediatric patients.Case-controlPopulation density (urban vs rural)
      Roy-Ghanta et al,
      • Roy-Ghanta S.
      • Larosa D.F.
      • Katzka D.A.
      Atopic characteristics of adult patients with eosinophilic esophagitis.
      2008
      To identify the specific environmental and food allergy profile of adults with EoE.Case seriesMultiple
      Jensen et al,
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      2014
      To assess the relationship between EoE prevalence and population density.Case-controlPopulation density (urban vs rural)
      Philpott et al,
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      2015
      To determine whether a seasonal and geographic pattern exists in patients with EoE with recurrent FBOEs.Case-controlSeason
      Moawad et al,
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      2010
      To determine whether there is seasonal variation and whether it correlates with seasonal pollen count.Cohort, retrospectiveAeroallergens, season
      Almansa et al,
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      2009
      To determine whether there is a seasonal pattern in the diagnosis of EoE in adults.Cohort, retrospectiveSeason
      Elias et al,
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      2015
      To confirm in a larger group of patients a seasonal pattern of EoE diagnosis.Cohort, retrospectiveSeason
      Jensen et al,
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      2015
      To determine whether there is seasonal variation in the detection and diagnosis of EE and EoE.Case-controlSeason
      Prasad et al,
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      2009
      To assess the epidemiology and outcomes of EE in Olmsted County, MN, over the past 3 decades.Cohort, retrospectiveSeason
      Wang et al,
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      2007
      To examine the seasonal distribution of newly diagnosed EoE in children.Cohort, retrospectiveSeason
      Burk et al,

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      2015
      To test whether sensitization to galactose-α-1,3-galactose is a risk factor for EoE.Case-controlInsect
      CHOP = Children's Hospital of Philadelphia; EoE = eosinophilic esophagitis; FBOE = food bolus obstruction event; PPI = proton pump inhibitor.
      Table 2Study and Comparator Populations, Demographics, and Main Findings
      Reference, yearStudy populationCases (No.)Comparator populationSex (M:F ratio)Mean age (y [range])White race (%)History of atopic disease (%)Main findings
      Lee et al,
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      2015
      University of Iowa GE clinic patients with EGD and biopsy for esophageal indications57NA2:126.7 (NR)911.8 seasonal allergy, 12.3 asthmaEoE was equally common, dysphagia significantly more common in urban than rural setting
      Castro Jiménez et al,
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      2013
      2006-2011 EoE patients at GE clinic of Ciudad Real University General Hospital43NA3:133.6 (6-63)NR83.7Patients with EoE have diverse sensitizations to specific IgE, skin prick testing, and patch testing
      Wolf et al,
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      2013
      3 Patients with EoE after specific large-volume aeroallergen exposures3NAAll male23.7 (20-29)NRNRDescription of history of exposure before diagnosis
      Ramirez and Jacobs,
      • Ramirez R.M.
      • Jacobs R.L.
      Eosinophilic esophagitis treated with immunotherapy to dust mites.
      2013
      1 Case of EoE in a young child1NAMale4NRFood allergiesEoE remission after dust mite desensitization
      Hurrell et al,
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      2012
      US national pathology database of 233,649 patients999571,948 noncases from 2008-20102:1 cases; 1:2 controlsCases: 44.4 (NR); controls: 53.7 (NR)NRNRTropical aOR, 0.87 (95% CI, 0.71-1.08), arid aOR, 1.27 (95% CI, 1.19-1.36), temperate (ref.), cold aOR, 1.39 (95% CI, 1.34-1.47)
      Jensen et al,
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.
      2013
      Pediatric EoE patients, 2004-2010, and population of 26 cleft lip/palate patients from UNC3126 from plastic surgery clinic; 26 from GERD patientsNRCases: 11 (NR); GERD controls: 12 (NR); plastics controls: 8 (NR)73-85Cases: 74 GERD, 54 plastics, 35 allergyOR, 6.0 for antibiotics
      Radano et al,
      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      2014
      EoE cases from clinic visits between March 2011 and May 2012 and endoscopies between January 2008 and May 20122574 recruited from well-child, follow-up clinics4:1 cases; 2:1 controlsCases: median, 3.4; controls: 4.3Cases: 68; controls: 68Cases: 75 eczema, 67 food allergyEoE more often cesarean delivery (60% vs 34%; P=.03) and antibiotic use in first year of life (67% vs 33%; P=.004)
      Slae et al,

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      2015
      EoE cases and controls from pediatric clinic and endoscopy visits, recruitment period not specified1021674:1 cases; 1:1 controlsCases: 10.8 (NR); controls: 10.0 (NR)NRCases: 57 eczema, 47 asthma, 62 AR, 10 FoodSmoking, breast-feeding, cesarean delivery, childhood antibiotics not found to be associated with EoE
      Franciosi et al,
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      2009
      CHOP EoE patients, using 20 eosinophils per HPF as a cutoff value335Pediatric GE and pediatric allergy clinics3:1NR83.6NRaOR, 2.08 (95% CI, 1.22-3.54) for suburban living (vs urban) in EoE group vs allergy patients
      Roy-Ghanta et al,
      • Roy-Ghanta S.
      • Larosa D.F.
      • Katzka D.A.
      Atopic characteristics of adult patients with eosinophilic esophagitis.
      2008
      Adult patients with EoE by consensus guidelines seen in University allergy clinic23NA1.6:135.2 (18-57)NR78Patients sensitized to danders, grass pollen, mite allergen, ragweed, and tree pollen
      Jensen et al,
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      2014
      Patients with >15 eosinophils per HPF and dysphagia from national pathology database14,381292,621 noncases2:1 cases; 1:2 controlsCases: 45 (NR); controls: 54 (NR)86NRaOR, 1.59 (95% CI, 1.45-1.76) odds of EoE bottom to top quintile of population density
      Philpott et al,
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      2015
      Patients with recurrent FBOEs at 5 tertiary hospitals619 noncase recurrent FBOEs4:1 cases; 3:1 controlsCases: 39.1 (NR); controls: 62.0 (NR)NRNR67% to 5% EoE vs noncase, October 1 to January 1, P=.005
      Moawad et al,
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      2010
      Adult EGD population 2006-2008, symptoms and histology of EoE at Army Medical Center127NA6:1NR (19-92)8233 AREoE diagnosis was significantly more common in spring and less in winter, not seen with trees or weeds
      Almansa et al,
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      2009
      37 EoE cases, 41 validations at Mayo Clinics, consensus diagnosis between August 2006 and July 200779EGD case volume during that period3:251.5 (16.1)94.951 Clinical history of allergiesMore diagnoses in spring and summer months than in fall and winter, P<.019, despite constant EGD rate
      Elias et al,
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      2015
      Adult patients from center's disease registry372NA3:141.9 (14.7)NR72 AR, 46 asthmaNo significant seasonal trend, more cases in opposite seasons reported elsewhere
      Jensen et al,
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      2015
      Patients with >15 eosinophils per HPF from national pathology database14,52490,459 controls2:145.0 (16.2)NRNRSmall but consistent seasonal variation in diagnosis, with cases more frequent during summer months
      Prasad et al,
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      2009
      Residents of Olmstead County, MN, from 1976-2005 with EoE, consensus diagnosis78NA1:1 adults; 2:1 childrenAdults: 37 (NR); children: 10 (NR)NRAdults: 50 allergy; children: 53.8More EoE diagnosis in late summer and early fall
      Wang et al,
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      2007
      234 EoE patients, Pediatric Hospital, 1998-2004234NA2:17.0 (0.2-19.5)NR32 Any atopyWinter had fewer EoE diagnoses than the other seasons and less severe inflammation than summer and fall
      Burk et al,

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      2015
      Prospective collection of 50 cases and 50 controls among UNC EGD patients50EGD noncases3:238.1 (10.6)8635 Asthma, 9 eczema, 65 AR, 32 foodGalactose-α-1,3-galactose sensitization not significantly greater in cases than in controls
      aOR = adjusted odds ratio; AR = allergic rhinitis; CHOP = Children's Hospital of Philadelphia; EE = esophageal eosinophilia; EGD = esophagogastroduodenoscopy; EoE = eosinophilic esophagitis; FBOE = food bolus obstruction event; GE = gastroenterology; GERD = gastroesophageal reflux disease; HPF = high-power field; NA = not applicable; NR = not reported; OR = odds ratio; ref. = referent group; UNC = University of North Carolina.
      Table 3Potential for Bias, Imprecision, and Measurement Error in Each Study
      Reference, yBiasDirection of biasPrecisionMeasurement error
      Lee et al,
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      2015
      Not population based, nonrandomizedIndefinite, possibly dependent on local referral patternsSufficient to detect large, consistent effectsConsensus diagnostic criteria, valid geocoding
      Castro Jiménez et al,
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      2013
      Not population based, nonrandomized, does not temporally place sensitization ahead of EoE diagnosisLikely toward larger effect due to selective referral of patients with suspected atopyAppropriate for inferenceUse of valid diagnostic criteria and tests hypersensitivity in multiple pathways
      Wolf et al,
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      2013
      Study describes cases but does not report numeric estimatesNANAConsensus definition of cases, exposure history soon after event minimizes recall bias
      Ramirez and Jacobs,
      • Ramirez R.M.
      • Jacobs R.L.
      Eosinophilic esophagitis treated with immunotherapy to dust mites.
      2013
      Study describes cases but does not report numeric estimatesNANAConsensus definition of case, prick and patch testing
      Hurrell et al,
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      2012
      Large national pathology registry, not population based, general to endoscopy populationToward exaggerated effect, socioeconomic or ethnic patternsAppropriate for inferenceNonconsensus diagnostic criteria, indefinite PPI trial
      Jensen et al,
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.
      2013
      Multiple control groups, not population based, potential for recall biasLikely toward larger effect due to recall biasAppropriate for inferenceUse of valid diagnostic criteria and standardized collection instruments
      Radano et al,
      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      2014
      Not population based, nonrandomized, single center, appropriate adjustment proceduresIndefinite, possibly dependent on local referral patternsAppropriate for inferenceConsensus diagnostic criteria, standardized data collection instruments
      Slae et al,

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      2015
      Not population based, nonrandomized, single center, controls represent EGD populationIndefinite, possibly dependent on local referral patternsAppropriate for inferenceConsensus diagnostic criteria, standardized data collection instruments
      Franciosi et al,
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      2009
      Not population based, nonrandomized, single centerIndefinite, possibly dependent on local referral patternsAppropriate for inferenceConsensus diagnostic criteria, valid geocoding
      Roy-Ghanta et al,
      • Roy-Ghanta S.
      • Larosa D.F.
      • Katzka D.A.
      Atopic characteristics of adult patients with eosinophilic esophagitis.
      2008
      Not population based, nonrandomized, does not temporally place sensitization ahead of EoE diagnosisLikely toward a larger prevalence of sensitivity due to selective referral of patients with suspected atopyAppropriate for inferenceUse of valid diagnostic criteria but specific IgE testing only
      Jensen et al,
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      2014
      Large national pathology registry, not population based, general to endoscopy populationToward exaggerated effect, socioeconomic or ethnic patternsAppropriate for inferenceNonconsensus diagnostic criteria, indefinite PPI trial, sensitivity analyses
      Philpott et al,
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      2015
      Not population based but likely adequate approximation of catchment area given acuity of eventIndefinite, socioeconomic or ethnic differences from controls, case definitionSufficient to detect large, consistent effectsNonconsensus diagnostic criteria, indefinite PPI trial
      Moawad et al,
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      2010
      Findings internally valid but limited to a single center, influence of scheduling practices is difficult to quantifyPossibly toward null due to case definitionSufficient to detect large, consistent effectsNonconsensus diagnostic criteria, indefinite PPI trial
      Almansa et al,
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      2009
      Findings internally valid but limited to a single center, influence of scheduling practices is difficult to quantifyLikely toward overestimating seasonal trendSufficient to detect large, consistent effectsSeason of incidence from timing of diagnosis limited by long subclinical phase
      Elias et al,
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      2015
      Findings internally valid but limited to a single center, influence of scheduling practices is difficult to quantifyLikely toward overestimating seasonal trendAppropriate for inferenceLimits of retrospective collection, long subclinical phase
      Jensen et al,
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      2015
      Large national pathology registry, not population based, general to endoscopy populationPossibly toward null due to case definition, strongest control of confoundingAppropriate for inferenceNonconsensus diagnostic criteria, indefinite PPI trial, sensitivity analyses
      Prasad et al,
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      2009
      Population-based study of incident diagnoses, case definition lacks PPI trialPossibly toward null due to case definitionAppropriate for inferenceNonconsensus diagnostic criteria, indefinite PPI trial
      Wang et al,
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      2007
      Findings internally valid but limited to a single center, influence of scheduling practices is difficult to quantifyIndefinite, possibly dependent on local referral patternsAppropriate for inference63% With negative 24-h pH impedance, no PPI trial
      Burk et al,

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      2015
      Not population based, nonrandomizedCohort, prospectiveAppropriate for inferenceSensitization to galactose-α-1,3-galactose proxy for exposure to lone star tick
      EGD = esophagogastroduodenoscopy; EoE = eosinophilic esophagitis; NA = not applicable; PPI = proton pump inhibitor.

      Pollen and Aeroallergens

      An initial case report documented the correlation between the number of eosinophils seen on biopsy, clinical symptom severity, and pollen counts over 4 years, demonstrating proof-of-principle that aeroallergens can affect disease activity in EoE.
      • Fogg M.I.
      • Ruchelli E.
      • Spergel J.M.
      Pollen and eosinophilic esophagitis.
      Although another report did not confirm this relationship,
      • Schlegel C.R.
      • Quintanilla N.M.
      • Olive A.P.
      • Minard C.G.
      • Davis C.M.
      Relationship of pediatric eosinophilic esophagitis diagnosis to pollen and mold counts.
      a retrospective cohort study of 127 adults found that the rate of EoE diagnosis throughout the year was correlated with fluctuations in daily average pollen counts in the Washington, DC, area.
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      Specifically, there were approximately twice as many cases of EoE in the spring than in the winter, and there was a strong statistical correlation between case volume and grass pollen. A cross-sectional study of 43 patients in Spain investigated the allergy sensitization profile of patients with EoE.
      • Castro Jiménez A.
      • Gomez Torrijos E.
      • Garcia Rodriguez R.
      • et al.
      Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
      Patients had positive skin prick test results for a variety of aeroallergens, including grasses and olive pollens, Planatus, and animal dander. Finally, a case series documented 3 patients who had new-onset EoE after a large-volume allergen exposure.
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      This was a rare example demonstrating an environmental trigger as causing EoE, with a mechanism that mirrors how some experimental animal models are induced.
      • Mishra A.
      • Hogan S.P.
      • Brandt E.B.
      • Rothenberg M.E.
      An etiological role for aeroallergens and eosinophils in experimental esophagitis.

      Insects

      A prospective case-control study found that sensitization to galactose-α-1,3-galactose, an allergic reaction to mammalian meat induced by a lone star tick bite, was not a risk factor for EoE.

      Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

      One case report described a young child with EoE and food allergies who entered remission after high-dose immunotherapy to Dermatophagoides farinae and Dermatophagoides pteronyssinus.
      • Ramirez R.M.
      • Jacobs R.L.
      Eosinophilic esophagitis treated with immunotherapy to dust mites.

      Climate

      We identified 1 case-control study that examined the risk of EoE by climate type.
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      Using a large national pathology database, the prevalence of EoE was compared among tropical, arid, cold, and temperate climate zones in the United States using the Köppen-Geiger climate class system. For the 9995 EoE cases and 71,948 controls included, there was a statistically significant increase in the odds of EoE in arid (adjusted OR [aOR], 1.27; 95% CI, 1.19-1.36) and cold (aOR, 1.39; 95% CI, 1.34-1.47) climates. No other publications to date have investigated a similar question.

      Urban vs Rural Populations

      There were 3 studies that examined urban vs rural environments as a risk factor for EoE. The first study used a case-control design to compare 335 pediatric patients with EoE with clinic-based controls and with 2000 US census data.
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      After adjusting for race and other confounders, the aOR for EoE in suburban vs urban census blocks was 2.08 (95% CI, 1.22-3.54) compared with allergy clinic controls, but there was not a significant difference in risk of EoE comparing cases with gastroenterology clinic controls. The second study was a retrospective cohort that compared clinical features of EoE in urban and rural regions based on 2010 US census data using a population density cutoff point of 1000 people per square mile.
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      There was no statistically significant difference in prevalence between urban and rural areas, but there were some differences in clinical features. Urban patients, for example, were more likely to present with dysphagia, and rural patients were more likely to experience heartburn and reflux. The third study used a large pathology database to assess population density as a risk factor for EoE.
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      A total of 14,381 EoE cases were compared with almost 90,000 controls from throughout the United States, and the odds of EoE increased with decreasing population density. For example, comparing the least to most dense quintile of population density, the aOR was 1.59 (95% CI, 1.45-1.76).

      Season

      Multiple studies have observed that there can be seasonal variation of EoE diagnosis.
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      The first study used a retrospective cohort design to compare rates of EoE diagnosis across seasons and adjusted for seasonal esophagogastroduodenoscopy case volume.
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      They found that EoE diagnosis was more common in spring and summer, or the outdoor months, than in winter and fall, or the indoor months. A similar study found that 33% of patients were diagnosed in the spring and only 16% were diagnosed in the winter, and the temporal correlation with grass pollen counts was compelling.
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      A study in Olmstead County, Minnesota, examined all patients with EoE from 1976 through 2005 and found that significantly more patients were diagnosed in late summer and early fall.
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      A study of 234 children with EoE assessed rate of diagnosis between months and inflammation severity based on histopathologic characteristics of biopsy tissue.
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      This study found not only that winter had significantly fewer newly diagnosed cases of EoE than did other seasons but also that winter cases had less severe inflammation than did summer and fall cases. A further study set in a large, national pathology database replicated these findings.
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      This study found the highest odds of diagnosis in July at an aOR of 1.13 (95% CI, 1.03-1.24), and the relationship persisted through several sensitivity analyses. However, an adequately powered, single-center registry study did not identify a seasonal trend and found a pattern contrary to that reported in other studies.
      • Elias M.K.
      • Kopacova J.
      • Arora A.S.
      • et al.
      The diagnosis of esophageal eosinophilia is not increased in the summer months.
      A predominance of cases during the winter was significant in another study that examined the proportion of recurrent food bolus obstruction events attributed to EoE and found winter predominance.
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      These studies of the seasonality of EoE diagnosis are generally limited in that they assess the timing of diagnosis rather than actual onset of disease.

      Early-Life Exposures

      We identified 3 studies that examined the risk of EoE due to selected early-life exposures in pediatric patients.
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      The first used a case-control design to assess exposures of interest, including cesarean delivery, preterm birth, antibiotic drug use in infancy, group B streptococcal infection, nonexclusive breast-feeding, and others.
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.
      Although antibiotic drug use during infancy was the only exposure that resulted in a statistically significant increase in odds, with an OR of 6.0 (95% CI, 1.7-20.8), there were trends toward increased risk with other exposures, particular cesarean delivery. A subsequent and larger case-control study replicated these findings with respect to antibiotic drug exposure and found a statistically significant effect of cesarean delivery.
      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      A further case-control study did not replicate the effects of childhood antibiotic agents and cesarean delivery and found no effect of smoking or breast-feeding duration.

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      Discussion

      Eosinophilic esophagitis is defined as an allergen/immune-mediated condition.
      • Dellon E.S.
      • Gonsalves N.
      • Hirano I.
      • Furuta G.T.
      • Liacouras C.
      • Katzka D.A.
      ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
      • Furuta 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.
      Although the current model of EoE pathogenesis holds that an allergic exposure triggers a TH2-mediated response that results in eosinophils infiltrating the esophageal mucosa,
      • Rothenberg M.E.
      Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
      identifying the exact inciting event in a given patient is typically not possible.
      • Wolf W.A.
      • Jerath M.R.
      • Dellon E.S.
      De-novo onset of eosinophilic esophagitis after large volume allergen exposures.
      For many patients, elimination of dietary allergens can induce remission,
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      and this observation has supported a central role for food allergy in the etiology of EoE.
      • Dellon E.S.
      • Liacouras C.A.
      Advances in clinical management of eosinophilic esophagitis.
      • Rothenberg M.E.
      Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
      However, emerging data suggest that the role of environmental factors may also be important.
      • Dellon E.S.
      Epidemiology of eosinophilic esophagitis.
      This systematic review, which assessed the impact of environmental exposures on disease development, has a variety of interesting results. First, there are relatively limited data addressing the question of environmental risk factors in EoE. We found only 19 pertinent articles after a comprehensive search. Second, there were a variety of potential risk factors for EoE, and evidence was strongest for an effect of climate or season, low population density, and early-life exposures, but the evidence for an effect of pollen or aeroallergens was lower. Finally, there were no studies that conclusively found an etiologic environmental risk factor in a large population that was prospectively assessed.
      Data on climate and seasonality, although mixed, suggest that trends related to climate zone, seasonality, or aeroallergens may affect EoE diagnosis.
      • Mishra A.
      • Hogan S.P.
      • Brandt E.B.
      • Rothenberg M.E.
      An etiological role for aeroallergens and eosinophils in experimental esophagitis.
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      • Hurrell J.M.
      • Genta R.M.
      • Dellon E.S.
      Prevalence of esophageal eosinophilia varies by climate zone in the United States.
      • Jensen E.T.
      • Shah N.D.
      • Hoffman K.
      • Sonnenberg A.
      • Genta R.M.
      • Dellon E.S.
      Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
      • Philpott H.
      • Nandurkar S.
      • Thien F.
      • et al.
      Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
      • Almansa C.
      • Krishna M.
      • Buchner A.M.
      • et al.
      Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
      • Moawad F.J.
      • Veerappan G.R.
      • Lake J.M.
      • et al.
      Correlation between eosinophilic oesophagitis and aeroallergens.
      • Prasad G.A.
      • Alexander J.A.
      • Schleck C.D.
      • et al.
      Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota.
      • Wang F.Y.
      • Gupta S.K.
      • Fitzgerald J.F.
      Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
      • Fogg M.I.
      • Ruchelli E.
      • Spergel J.M.
      Pollen and eosinophilic esophagitis.
      • Schlegel C.R.
      • Quintanilla N.M.
      • Olive A.P.
      • Minard C.G.
      • Davis C.M.
      Relationship of pediatric eosinophilic esophagitis diagnosis to pollen and mold counts.
      However, these studies are still at a general level, and it remains to be seen whether trends in seasonality or climate will be able to be linked to a discrete environmental factor that could affect an individual patient. A similar statement could be made for EoE being more common in areas with low population density.
      • Franciosi J.P.
      • Tam V.
      • Liacouras C.A.
      • Spergel J.M.
      A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
      • Jensen E.T.
      • Hoffman K.
      • Shaheen N.J.
      • Genta R.M.
      • Dellon E.S.
      Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
      • Lee Y.J.
      • Redd M.
      • Bayman L.
      • Frederickson N.
      • Valestin J.
      • Schey R.
      Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
      This broad finding currently lacks a definitive explanation, and although multiple hypotheses are possible, further research is needed to explicate the underlying reasons for this trend. The studies on early-life exposures, although intriguing and more granular, are still preliminary.
      • Jensen E.T.
      • Kappelman M.D.
      • Kim H.P.
      • Ringel-Kulka T.
      • Dellon E.S.
      Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.

      Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

      • Radano M.C.
      • Yuan Q.
      • Katz A.
      • et al.
      Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
      Recall bias is a particular concern with these studies, and prospective cohort studies are needed to confirm these findings. The impact of aeroallergens in individual patients has been reported,
      • Fogg M.I.
      • Ruchelli E.
      • Spergel J.M.
      Pollen and eosinophilic esophagitis.
      but why these might be important in some patients with EoE and not in others remains to be determined. Interestingly, emerging data with component-resolved diagnostics find that there can be cross reaction between certain environmental and food allergens,
      • van Rhijn B.D.
      • van Ree R.
      • Versteeg S.A.
      • et al.
      Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis.
      and this could provide a link between an environmental and a dietary etiology of EoE. Finally, it is important to note that the quality of the studies included in this systematic review varied, ranging from case reports to retrospective cohorts to prospective case-control designs. Overall, the findings summarized herein do not yet prove causality of any particular exposure.
      When interpreting the results of this study, there are several limitations to acknowledge. Because we were concerned with nondietary environmental risk factors, articles relating to dietary therapy were excluded from this systematic review. We also excluded studies that evaluated the efficacy of treatments for EoE, limiting the search to articles that aimed to provide clinical evidence of the pathogenesis or etiology of EoE. Therefore, these findings should be taken in the context of the broader EoE literature that supports the efficacy of dietary elimination treatments for some patients with EoE.
      • Arias A.
      • Gonzalez-Cervera J.
      • Tenias J.M.
      • Lucendo A.J.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      In reality, the causal pathway from environmental exposure to clinical presentation with EoE is likely complex, and the temporal association of particular exposure can be inherently limited if the subclinical phase of pathogenesis is long or if it varies greatly in duration. Although it is possible that we may have missed some studies, the study design assessing multiple literature sources with 2 independent data abstractors was comprehensive.

      Conclusion

      We identified 19 articles assessing environmental risk factors for EoE, and several trends were identified. Studies that directly supported the specific role of pollen and aeroallergens in EoE were not as strong in their findings as studies that indirectly supported a different environmental cause. Indirect evidence for an environmental exposure causing EoE depends on reports highlighting increased diagnosis of EoE in spring or summer seasons, increased risk of EoE in arid or cold climate zones, higher rates of disease in rural areas with low population density, and selected early-life exposures, such as antibiotic drug use. These findings all suggest, but do not prove, that an environmental exposure contributes to EoE etiology. Whether this increased risk relates to differing environmental allergens, exposures from agricultural activity, or ecologic differences in social or economic factors should be an area of future investigation. Finally, possible early-life factors that could increase the risk of EoE are intriguing and, if confirmed, could raise the possibility of disease prevention or modification.

      References

        • Dellon E.S.
        • Gonsalves N.
        • Hirano I.
        • Furuta G.T.
        • Liacouras C.
        • Katzka D.A.
        ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
        Am J Gastroenterol. 2013; 108: 679-692
        • Desai T.K.
        • Stecevic V.
        • Chang C.H.
        • Goldstein N.S.
        • Badizadegan K.
        • Furuta G.T.
        Association of eosinophilic inflammation with esophageal food impaction in adults.
        Gastrointest Endosc. 2005; 61: 795-801
        • Kerlin P.
        • Jones D.
        • Remedios M.
        • Campbell C.
        Prevalence of eosinophilic esophagitis in adults with food bolus obstruction of the esophagus.
        J Clin Gastroenterol. 2007; 41: 356-361
        • Sperry S.L.
        • Crockett S.D.
        • Miller C.B.
        • Shaheen N.J.
        • Dellon E.S.
        Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis.
        Gastrointest Endosc. 2011; 74: 985-991
        • Jensen E.T.
        • Kappelman M.D.
        • Martin C.F.
        • Dellon E.S.
        Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States.
        Am J Gastroenterol. 2015; 110: 626-632
        • Furuta 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: 1342-1363
        • Dellon E.S.
        • Liacouras C.A.
        Advances in clinical management of eosinophilic esophagitis.
        Gastroenterology. 2014; 147: 1238-1254
        • Mishra A.
        • Hogan S.P.
        • Brandt E.B.
        • Rothenberg M.E.
        An etiological role for aeroallergens and eosinophils in experimental esophagitis.
        J Clin Invest. 2001; 107: 83-90
        • Straumann A.
        • Bauer M.
        • Fischer B.
        • Blaser K.
        • Simon H.U.
        Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.
        J Allergy Clin Immunol. 2001; 108: 954-961
        • Clayton F.
        • Fang J.C.
        • Gleich G.J.
        • et al.
        Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
        Gastroenterology. 2014; 147: 602-609
        • Rothenberg M.E.
        Molecular, genetic, and cellular bases for treating eosinophilic esophagitis.
        Gastroenterology. 2015; 148: 1143-1157
        • Kelly K.J.
        • Lazenby A.J.
        • Rowe P.C.
        • Yardley J.H.
        • Perman J.A.
        • Sampson H.A.
        Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.
        Gastroenterology. 1995; 109: 1503-1512
        • Markowitz J.E.
        • Spergel J.M.
        • Ruchelli E.
        • Liacouras C.A.
        Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.
        Am J Gastroenterol. 2003; 98: 777-782
        • Spergel J.M.
        • Andrews T.
        • Brown-Whitehorn T.F.
        • Beausoleil J.L.
        • Liacouras C.A.
        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
        • Lucendo A.J.
        • Arias A.
        • Gonzalez-Cervera J.
        • Mota-Huertas T.
        • Yague-Compadre J.L.
        Tolerance of a cow's milk-based hydrolyzed formula in patients with eosinophilic esophagitis triggered by milk.
        Allergy. 2013; 68: 1065-1072
        • Lieberman J.A.
        • Morotti R.A.
        • Konstantinou G.N.
        • Yershov O.
        • Chehade M.
        Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort.
        Allergy. 2012; 67: 1299-1307
        • Rodriguez-Sanchez J.
        • Gomez Torrijos E.
        • Lopez Viedma B.
        • et al.
        Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis.
        Allergy. 2014; 69: 936-942
        • Gonsalves N.
        • Yang G.Y.
        • Doerfler B.
        • Ritz S.
        • Ditto A.M.
        • Hirano I.
        Elimination diet effectively treats eosinophilic esophagitis in adults: food reintroduction identifies causative factors.
        Gastroenterology. 2012; 142: 1451-1459
        • Colson D.
        • Kalach N.
        • Soulaines P.
        • et al.
        The impact of dietary therapy on clinical and biologic parameters of pediatric patients with eosinophilic esophagitis.
        J Allergy Clin Immunol Pract. 2014; 2: 587-593
        • Kagalwalla A.F.
        • Shah A.
        • Li B.U.
        • et al.
        Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
        J Pediatr Gastroenterol Nutr. 2011; 53: 145-149
        • Henderson C.J.
        • Abonia J.P.
        • King E.C.
        • et al.
        Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.
        J Allergy Clin Immunol. 2012; 129: 1570-1578
        • Lucendo A.J.
        • Arias A.
        • Gonzalez-Cervera J.
        • et al.
        Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease.
        J Allergy Clin Immunol. 2013; 131: 797-804
        • Kagalwalla 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: 1097-1102
        • Wolf W.A.
        • Jerath M.R.
        • Sperry S.L.
        • Shaheen N.J.
        • Dellon E.S.
        Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2014; 12: 1272-1279
        • Spergel J.M.
        • Brown-Whitehorn T.F.
        • Cianferoni A.
        • et al.
        Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.
        J Allergy Clin Immunol. 2012; 130: 461-467
      1. Arias A, Lucendo AJ, Martinez-Fernandez P, et al. Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic esophagitis [published online February 1, 2015]. Clin Exp Allergy. http://dx.doi.org/10.1111/cea.12504.

        • Arias A.
        • Gonzalez-Cervera J.
        • Tenias J.M.
        • Lucendo A.J.
        Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
        Gastroenterology. 2014; 146: 1639-1648
        • Alexander 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
        • Martin-Munoz M.F.
        • Lucendo A.J.
        • Navarro M.
        • et al.
        Food allergies and eosinophilic esophagitis: two case studies.
        Digestion. 2006; 74: 49-54
        • Wolf 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: 205-208
        • Sperry S.L.
        • Shaheen N.J.
        • Dellon E.S.
        Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE.
        Am J Gastroenterol. 2011; 106 (quiz 833): 824-832
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        J Clin Epidemiol. 2009; 62: e1-e34
        • Ramirez R.M.
        • Jacobs R.L.
        Eosinophilic esophagitis treated with immunotherapy to dust mites.
        J Allergy Clin Immunol. 2013; 132: 503-504
        • Roy-Ghanta S.
        • Larosa D.F.
        • Katzka D.A.
        Atopic characteristics of adult patients with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2008; 6: 531-535
        • Castro Jiménez A.
        • Gomez Torrijos E.
        • Garcia Rodriguez R.
        • et al.
        Demographic, clinical and allergological characteristics of eosinophilic esophagitis in a Spanish central region.
        Allergol Immunopathol (Madr). 2013; 42: 407-414
        • Franciosi J.P.
        • Tam V.
        • Liacouras C.A.
        • Spergel J.M.
        A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis.
        Clin Gastroenterol Hepatol. 2009; 7: 415-419
        • Jensen E.T.
        • Hoffman K.
        • Shaheen N.J.
        • Genta R.M.
        • Dellon E.S.
        Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database.
        Am J Gastroenterol. 2014; 109: 668-675
        • Hurrell J.M.
        • Genta R.M.
        • Dellon E.S.
        Prevalence of esophageal eosinophilia varies by climate zone in the United States.
        Am J Gastroenterol. 2012; 107: 698-706
        • Jensen E.T.
        • Kappelman M.D.
        • Kim H.P.
        • Ringel-Kulka T.
        • Dellon E.S.
        Early life exposures as risk factors for pediatric eosinophilic esophagitis: a pilot and feasibility study.
        J Pediatr Gastroenterol Nutr. 2013; 57: 67-71
      2. Slae M, Persad R, Leung AJ, Gabr R, Brocks D, Huynh HQ. Role of environmental factors in the development of pediatric eosinophilic esophagitis [published online June 11, 2015]. Dig Dis Sci. doi:10.1007/s10620-015-3740-7.

        • Jensen E.T.
        • Shah N.D.
        • Hoffman K.
        • Sonnenberg A.
        • Genta R.M.
        • Dellon E.S.
        Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2015; 42: 461-469
        • Philpott H.
        • Nandurkar S.
        • Thien F.
        • et al.
        Seasonal recurrence of food bolus obstruction in eosinophilic esophagitis.
        Intern Med J. 2015; ([published online April 14, 2015])https://doi.org/10.1111/imj.12790
        • Radano M.C.
        • Yuan Q.
        • Katz A.
        • et al.
        Cesarean section and antibiotic use found to be associated with eosinophilic esophagitis.
        J Allergy Clin Immunol Pract. 2014; 2: 475-477
      3. Burk CM, Beitia R, Lund PK, Dellon ES. High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy [published online March 23, 2015]. Dis Esophagus. http://dx.doi.org/10.1111/dote.12356.

        • Almansa C.
        • Krishna M.
        • Buchner A.M.
        • et al.
        Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.
        Am J Gastroenterol. 2009; 104: 828-833
        • Lee Y.J.
        • Redd M.
        • Bayman L.
        • Frederickson N.
        • Valestin J.
        • Schey R.
        Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.
        Dis Esophagus. 2015; 28: 19-24
        • Moawad F.J.
        • Veerappan G.R.
        • Lake J.M.
        • et al.
        Correlation between eosinophilic oesophagitis and aeroallergens.
        Aliment Pharmacol Ther. 2010; 31: 509-515
        • Prasad 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: 1055-1061
        • Wang F.Y.
        • Gupta S.K.
        • Fitzgerald J.F.
        Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children?.
        J Clin Gastroenterol. 2007; 41: 451-453
        • Elias M.K.
        • Kopacova J.
        • Arora A.S.
        • et al.
        The diagnosis of esophageal eosinophilia is not increased in the summer months.
        Dysphagia. 2015; 30: 67-73
        • Fogg M.I.
        • Ruchelli E.
        • Spergel J.M.
        Pollen and eosinophilic esophagitis.
        J Allergy Clin Immunol. 2003; 112: 796-797
        • Schlegel C.R.
        • Quintanilla N.M.
        • Olive A.P.
        • Minard C.G.
        • Davis C.M.
        Relationship of pediatric eosinophilic esophagitis diagnosis to pollen and mold counts.
        Ann Allergy Asthma Immunol. 2014; 113: 321-322
        • Dellon E.S.
        Epidemiology of eosinophilic esophagitis.
        Gastroenterol Clin North Am. 2014; 43: 201-218
        • van Rhijn B.D.
        • van Ree R.
        • Versteeg S.A.
        • et al.
        Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis.
        Allergy. 2013; 68: 1475-1481