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Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
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.
Division of Gastroenterology and Hepatology, Center for Esophageal Diseases and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, NC
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.
This systematic review identified 19 articles pertaining to environmental risk factors for eosinophilic esophagitis (EoE).
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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.
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Data were strongest for climate, seasonality, low population density, and early-life exposures.
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Data were less strong for pollen and aeroallergens.
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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.
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.
Eosinophilic esophagitis affects infants, children, and adults, although the disease can manifest with different symptoms and endoscopic findings at different ages.
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.
Epidemiologic studies further support the role of allergens in disease pathogenesis because patients frequently have a history of atopic disease or food allergies.
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.
Dietary elimination therapies for EoE are supported by a broad base of literature, which suggests that dietary antigens can be crucial disease triggers.
Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
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.
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.
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.
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.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
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,
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.
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.
with the remaining 11 completed in the United States. Studies included adults and children.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
This was a rare example demonstrating an environmental trigger as causing EoE, with a mechanism that mirrors how some experimental animal models are induced.
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.
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.
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.
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.
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.
The first study used a retrospective cohort design to compare rates of EoE diagnosis across seasons and adjusted for seasonal esophagogastroduodenoscopy case volume.
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.
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.
A study of 234 children with EoE assessed rate of diagnosis between months and inflammation severity based on histopathologic characteristics of biopsy tissue.
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.
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.
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.
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.
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.
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.
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.
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.
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,
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.
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.
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.
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.
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,
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,
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.
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.
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Katzka D.A.
ACG clinical guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE).
Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet.
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.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
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.
Grant Support: This work was funded in part by grants T32 DK 007634 (C.C.C.), K23 DK090073 (E.S.D.), and R01 DK101856 (E.S.D.) from the National Institutes of Health .
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