Eosinophilic esophagitis (EoE) was first described in a child in 1983 (1). During the last 15 years, EoE has become recognized as an important clinicopathologic entity by primary care providers, gastroenterologists, and allergists. The number of publications that focused on EoE have markedly increased from 2 in 1993 to >110 in 2011. In 2007, the first consensus guidelines on the diagnosis and treatment of EoE were published and then updated in 2011 (2,3). The present guidelines define EoE as an esophageal disease characterized by clinical symptoms caused by esophageal dysfunction and histologic evidence of eosinophil-predominant inflammation (≥15 eosinophils per high-power field [hpf]) upon exclusion of other causes of esophageal eosinophilia (3).
Mounting data from animals and humans support the pathogenesis of EoE as a chronic antigen-driven immune response occurring in a genetically susceptible individual (3). The clinical manifestations of EoE in children vary by age. They may include feeding difficulties, failure to thrive, gastroesophageal reflux, nausea, vomiting, chest or epigastric pain, food impaction, and dysphagia (4–6). Atopy is frequent, with up to 60% of children with EoE having a concurrent atopic disease such as allergic rhinitis, asthma, eczema, and IgE-mediated food allergies (6–8). EoE occurs with greater frequency in non-Hispanic white males in childhood and early adulthood; however, EoE has been reported at any age, in both sexes, and in most racial and ethnic groups (3,9). The management of EoE is centered primarily on medical (corticosteroid) or dietary therapy (3). EoE poses a large burden to the health care system because of the chronic nature of the disease; requirement of endoscopy for diagnosis, monitoring of disease activity, and management of complications; and involvement of multidisciplinary services including dieticians and allergists.
Despite the growing interest and publications on EoE, few studies have evaluated the population-based incidence and prevalence of EoE. A recent systematic review of the epidemiology of EoE in adults found that the prevalence of EoE varied widely based on the study population, with estimates highest in patients with acute food bolus obstruction (48%) (10) and lowest in population-based studies (0.23/1000) (11,12). In children, the incidence and prevalence of EoE have not yet been systematically reviewed. The objectives of our study were to conduct a systematic review and meta-analysis on the incidence and prevalence of EoE in children and to evaluate the variation in incidence and prevalence across different geographic regions, time periods, and disease states. Improved knowledge of the incidence and prevalence of EoE enhances our understanding of the burden of disease.
We conducted a systematic literature search using a predetermined protocol in accordance with the quality of reporting meta-analyses of observational studies in epidemiology (13). We searched 2 computer-stored databases, MEDLINE (1950–May 2011) and Embase (Excerpta Medica Database; 1980–May 2011), for studies describing the epidemiology of EoE in children. The search strategy for MEDLINE and Embase was based on 2 themes. The first theme combined the exploded version of medical subject headings “eosinophilic esophagitis” or “esophagitis.” The second theme combined the exploded version of medical subject headings terms “incidence” or “prevalence” or “demography” or “epidemiology.” All key words were used to search titles and abstracts. The 2 themes were then combined using the Boolean operator “AND.” The search was not limited by language or human subjects to ensure the capture of all appropriate studies. The reference lists of relevant articles were also reviewed and appropriate studies were included.
Two reviewers (J.D. and I.S.) conducted an initial search of identified abstracts and titles independently. Abstracts were eliminated if they were not EoE-related, nonhuman, or did not report original data (eg, review articles). The remaining abstracts were eligible for further review. We included articles or abstracts that described their study design, defined a source population, and reported an incidence rate and/or prevalence of EoE or provided adequate information to calculate these estimates. Studies describing the incidence or prevalence of EoE only in adults (ie, age at diagnosis >18 years) were excluded as a recent systematic review on the epidemiology of EoE in adults was published (12). Disagreement between reviewers was resolved by consensus with a third-party expert (G.K.).
Patient characteristics at diagnosis including age, sex, ethnicity, and personal and family history of atopy were documented. Secondary variables extracted included study design (ie, retrospective or prospective); country of origin; publication year; time of study; source of subjects; and information on key indicators of study quality, using meta-analyses of observational studies in epidemiology (13). Two reviewers independently completed data extraction forms for each study. Prevalence and incidence rates with 95% confidence intervals (CIs) for the overall study period were collected. Incidence rates and prevalence for the different time periods were documented. The prevalent studies were categorized by population-based studies (8,14,15), all of the children undergoing an esophagogastroduodenoscopy (EGD) for any indication (7,15–18), children with histologic esophageal disease detected on EGD (7,14,17–20), and specific subgroups including children with celiac disease (21–25), children post–liver transplantation (26,27), children with ulcerative colitis (UC) (28), children with abdominal pain (29–31), and children who underwent EGD for esophageal food impaction or dysphagia (32,33).
Summary of Data
The incidence of EoE in children was summarized using incidence rates, defined as the number of cases per 100,000 children per year. When incidence rates were adjusted for confounding factors, these estimates were reported. Prevalence of EoE in children was defined as the number of prevalent cases in a defined region per 100,000 children.
In studies that reported at least 4 time points, we conducted time–trend analyses using joinpoint regression analysis whereby a series of permutations were used to assess whether the addition of joinpoints resulted in statistically significant linear changes in the direction of magnitude of the rates in comparison with the linear line (34). Two joinpoints at most were considered. The parameter estimate used to summarize the trend during the fixed interval was the average annual percentage change according to a generalized log-linear model that assumed a Poisson distribution.
A meta-analysis of incidence and prevalence of EoE of all of the studies was not conducted because of the diversity in population subgroups and limited number of studies. We limited our meta-analyses to subgroups with ≥5 studies that reported the prevalence of EoE. These subgroups for children who had an esophageal biopsy included all children undergoing an EGD for any indication (7,15–18) and children with histologic esophageal disease detected on EGD (7,14,17–20). A sensitivity analysis was performed in subgroups with ≥5 full-text studies to minimize heterogeneity. Only studies that reported diagnostic criteria of EoE were included in any meta-analysis; studies that did not report EoE diagnostic criteria were still described in the systematic review but not included in any meta-analysis. Heterogeneity was assessed with the Q statistic (5% level). Random effects models were used because of heterogeneity between studies. The possibility of publication bias was assessed using the Begg tests.
The search strategy retrieved 384 unique citations: 157 from MEDLINE and 365 from Embase. Of these, 304 citations were excluded after the first screening based on titles and abstracts, leaving 80 articles for possible inclusion (Fig. 1). For the first review of titles and abstracts, the observed agreement between reviewers was 96%, corresponding to a κ statistic of 0.87. The second review of 80 full-text articles and abstracts excluded 56 studies (reasons listed in Fig. 1), leaving 24 studies. One additional study was found from reference review of relevant articles. Hence, a total of 25 studies (16 full-text studies and 9 abstracts from conference proceedings) were included in the systematic review. The first study appeared in 2003 (33). The agreement between reviewers for eligibility of articles was 100%, corresponding to a κ of 1. Characteristics of the 25 included studies are shown in Table 1.
The annual incidence rates varied by geographic region, with an incidence rate of 1.6 in Denmark (35), 8.0 in United Kingdom (16), and ranging from 0.7 to 10/100,000 children in the United States (8,19,36,37). Heterogeneity across studies was observed (Q statistic 165; P < 0.001). Two studies reported temporal trends of incidence rates, with both demonstrating a significant increase during the study period (Fig. 2) (8,19). The average annual percentage increase in incidence of EoE was 17% (95% CI 9.7–25) in a retrospective study that reexamined esophageal biopsy specimens obtained between 1983 and 1992 (19). Similarly, an average annual percentage increase in incidence of EoE of 12% (95% CI 0–25) was shown in a retrospective population-based cohort study identifying cases of EoE from a pathology database between 2000 and 2003 (Table 1) (8).
The population-based prevalence also varied by geographic region, with most present reported rates ranging between 0.2 in United Kingdom (15), 8.9 in Australia (14) and 43/100,000 children in the United States (8). Two studies reported temporal trends of prevalence of EoE (Fig. 3). One study demonstrated a significant increase in prevalence between 2000 and 2003, with an average annual percentage increase of 56% (95% CI 25–96) (8).
For children who underwent an EGD for any indication, the prevalence of EoE ranged from 2.3% to 6.8%, with a pooled prevalence of 3.7% (95% CI 2.4–5.1; Fig. 4) (5,7,15–18). There was significant heterogeneity across studies (Q statistic 33; P < 0.001). The prevalence rates of EoE among EGDs with histological esophageal disease ranged from 18% to 32%, with a pooled prevalence of 24% (95% CI 19–28; Fig. 5) (5,7,14,17–20). Heterogeneity across studies was observed (Q statistic 31; P < 0.001). A sensitivity analysis including only full-text studies resulted in a similar pooled prevalence of 24% (95% CI 18–29). The prevalence of EoE among children with EGD done for esophageal food impaction was 63% (32), and among children with dysphagia and/or food impaction, the prevalence of EoE was 88% (33).
Among children who underwent EGD for abdominal pain, the prevalence of EoE ranged from 2.1% to 4.9% (29–31), whereas the prevalence of EoE among children with celiac disease ranged from 1.1% to 5.1% (21–25). The prevalence of EoE among children post–liver transplantation were 2.4% and 3.0% (26,27). The only study evaluating the prevalence of EoE among children with UC reported a prevalence of 8.0% (28).
All population-based studies reported a male predominance (range 54%–83%) (8,14,16,19,35–37). The mean/median ages at diagnosis ranged from 6.0 to 10.5 years for population-based studies (8,16). In contrast, the mean age at diagnosis from a single study evaluating the prevalence of EoE among children with esophageal food impaction was 10.1 years (33). Personal history of atopy was found in 14% to 100% (8,16,20,25–27,32,33,35–37) and family history of atopy was present in 7% to 38% of children (8,20,32,35). No publication bias was observed among all subgroups using the Begg test: P = 0.19 (EGD for any indication) and P = 0.88 (EGD with histologic esophageal disease).
We present the first systematic review and meta-analysis of the incidence and prevalence of EoE in children. The population-based incidence rates of EoE in children varied by geographic region, ranging from 1.6 in Denmark (35) to 10 per 100,000 children per year in the United States (8). Likewise, the population-based prevalence varied by geographic region, with the most present reported rates ranging between 0.2 in United Kingdom (15), 8.9 in Australia (14) and 43 per 100,000 children in the United States (8). Similar to our findings, a recent systematic review of the epidemiology of EoE in adults demonstrated a wide variation in population-based prevalence ranging from 20 to 700/100,000 with a pooled prevalence of 30/100,000 individuals (11,12,38). In our systematic review, given that both studies in Australia and the United States were conducted in sole referral centers for the region from which the denominator population was determined, referral bias is less likely to contribute to variations in population-based prevalence; however, the variations may be because of differing distributions of ethnicity, sex, age groups, diagnostic criteria for EoE, and threshold to perform endoscopy and biopsy between study centers. In particular, because EoE is diagnosed endoscopically, detection of disease is largely driven by accessibility to endoscopy services, which may vary widely between regions depending on the presence and number of pediatric gastroenterologists along with wait times to assessment by gastroenterologists and to endoscopy. In addition, detection of EoE is affected by physician awareness and/or willingness to perform an EGD in a patient who presents with symptoms suggestive of EoE and whether a physician routinely obtains esophageal biopsies at the time of EGD regardless of macroscopic appearance of the esophagus.
During the last few decades, both incidence and prevalence increased significantly, with average annual percentage increases of 12% to 17% and 56%, respectively (8,19). The increased incidence of EoE over time in children may be because of a genuine increase in incidence, greater recognition of EoE, or higher use of diagnostic EGDs in children, with the wide variety of symptoms suggestive of EoE. In the study by DeBrosse et al (19), the authors reexamined esophageal biopsy specimens obtained between 1982 and 1999 and found that the proportion of biopsy specimens with ≥15 eosinophils/hpf remained stable in spite of a 40-fold increase in the number of biopsy specimens collected, suggesting that the rise in incidence of EoE is because of enhanced disease recognition rather than higher detection from increased EGD use.
Although EoE accounts for only a minority of children who underwent EGD for any indication (pooled prevalence 3.7%) (7,15–18), the prevalence of EoE among EGDs performed in children with esophageal food impaction and/or dysphagia was high (63%–88%) (32,33). Similarly, the prevalence of EoE in unselected adults undergoing an EGD ranged from 1.0% to 6.5% (39,40). In comparison to children, adults with food bolus impaction or dysphagia had lower prevalence of EoE (12%–48%) (10,41,42). The lower prevalence of EoE in adults with food bolus impaction or dysphagia compared with children may be accounted for by the wider differential diagnosis for food bolus impaction or dysphagia in adults such as esophageal malignancy, peptic stricture, and connective tissue disorders. Because the highest diagnostic yield of endoscopy for EoE occurred among children with dysphagia or food impaction, children with such presenting complaints should be identified at triage and undergo rapid and timely evaluation with EGD to facilitate the diagnosis of EoE. Limited studies have investigated the prevalence of EoE among specific immune-mediated conditions. The pooled prevalence of EoE was 2.3% for children with celiac disease (21–25). Detection bias from frequent biopsy sampling is unlikely to fully explain the elevated prevalence of EoE in celiac disease. A gluten-free diet in patients with celiac disease reduced esophageal eosinophilia in some studies (43,44), whereas others demonstrated persistent esophageal eosinophilia (24,25). Although EoE is thought to be a TH2-mediated atopic disease and celiac disease is a TH1-mediated autoimmune disease, an association between these 2 diseases may be biologically plausible because recent studies suggest the coexistence of TH1- and TH2-mediated diseases is the result of generalized immune dysregulation (22,43,44).
The prevalence of EoE ranged from 2.4% to 3.0% for children post–liver transplantation (26,27). In liver transplant recipients, de novo development of food allergy and gastrointestinal eosinophilic inflammation may be attributed to the potential effect of tacrolimus suppression of TH1 response and promotion of TH2 signal pathways (26,45–47). The prevalence of EoE was 8% among children with UC (28). Like EoE, UC is thought to be TH2 mediated (48).
In our systematic review, EoE primarily was more commonly diagnosed among male children of white ethnicity who had a personal and/or family history of atopy. The male predominance was also seen in adults (12). The median age at diagnosis reported in the studies ranged from 5.4 to 9.6 years. The presenting symptoms of EoE vary by age. Younger children are more likely to present with a wider variety of symptoms compared with older children, who often present with dysphagia or food bolus impaction (6). The predominant symptom of EoE in young adults is dysphagia, similar to that of older children (12). Therefore, the index of suspicion for EoE and rapidity of evaluation with EGD should be guided by the clinical presentation.
In the meta-analyses performed for population-based incidence, children who underwent EGD, and children with histologic esophageal disease, significant heterogeneity was found. Heterogeneity may be explained by differences in geographic region, study period, and intrinsic biases associated with observational studies. Given the small number of studies, stratified or sensitivity analyses were not possible to explore reasons for heterogeneity. To account for heterogeneity, a random effects model was used in all of the meta-analyses. Using the Begg test, we did not find any evidence of publication bias in these subgroups.
The limitations of our systematic review should be considered. First, the quality of the studies was not always optimal. An ideal quality study would be a prospective population-based study with well-described methods of case ascertainment and diagnostic criteria. For optimal accuracy of estimates, this ideal study would take place in a region with a well-defined source population, readily available endoscopy services, and appropriate physician awareness and willingness to conduct EGD and collect esophageal biopsies in patients presenting with symptoms suggestive of EoE. Our systematic review yielded variable methods of case ascertainment and minimal prospective studies. We limited the meta-analyses to subgroups containing ≥5 studies, and studies in which the diagnostic criteria were not reported were excluded from the meta-analyses. Quality characteristics of each study (study design, source of population, and diagnostic criteria for EoE) are shown in Table 1. Second, in the studies identified through the systematic review, the case definition of EoE focused primarily on histologic findings, whereas the present definition of EoE encompasses both clinical and histologic manifestations. Also, the histologic criteria of EoE varied between studies, ranging from 15 to 24 eosinophils/hpf. Acknowledging that the 2011 consensus guidelines recommend a minimum threshold of 15 eosinophils/hpf for the diagnosis of EoE, the incidence and prevalence of EoE in previous studies were likely underestimated (2,3). Third, our search strategy revealed only a small number of studies, all from developed countries. Thus, we cannot comment on the incidence and prevalence of EoE in developing countries. Despite these limitations, we used a comprehensive search strategy and included studies published in all languages and in both abstract and full-article format. Therefore, this review provides a comprehensive summary of the present literature on the epidemiology of EoE in children.
EoE is a chronic disease that has major implications for the consequential burden of disease. Children with EoE will use health care resources in procedures such as EGD, hospital admissions, and clinic visits for diagnosis, monitoring response to therapy, and management of complications (3). In addition, children with EoE often require multidisciplinary services including gastroenterologist, allergist, and dietician.
In conclusion, the incidence rates and prevalence of EoE in children vary by geographic regions in developed countries, with significant increases in these rates with time. Although the prevalence of EoE is low among children who undergo EGD or children with abdominal pain, the prevalence of EoE is high among children who present with food impaction or dysphagia. In younger children with chronic unexplained upper gastrointestinal symptoms unresponsive to present management strategies, the diagnosis of EoE should be considered. To improve our understanding of the worldwide epidemiology of EoE in children, future studies using recently accepted diagnostic criteria for EoE in defined geographic regions should be conducted, especially in developing countries.
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Keywords:© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
eosinophilic esophagitis; epidemiology; pediatrics