Eosinophilic esophagitis (EoE) is an emerging disease that appears to be increasing in prevalence, affecting approximately 1/1000 people in the U.S.(1) It has recently been reported that individuals with EoE have an increased prevalence of Autism Spectrum Disorder (ASD) and developmental delay.(2) ASD and other developmental disorders (DD) are common in children, affecting 0.5–3% and 17.8% of U.S. children, respectively.(3) Like EoE, these disorders are more common in males and are hypothesized to be related to immune system dysregulation.(4) In this study, we sought to determine the prevalence of ASD and DD in our pediatric EoE population and examine whether children with co-morbid ASD/DD have unique clinical characteristics compared to those with solely EoE.
A cross-sectional study of pediatric (≤18 years old) EoE patients seen at the University of Virginia (UVA) from October 2015 to August 2019 was performed. Individuals with EoE were identified from the UVA Electronic Health Record (EPIC) using ICD-10 (K20.0) codes. A retrospective chart review was then performed to confirm the diagnosis of EoE according to consensus guidelines.(5) The diagnoses of ASD and DD were defined per physician diagnosis, also using ICD-10 codes, as defined in the Online Repository. Information on demographics, prematurity, presenting symptoms, comorbid atopic conditions (allergic rhinitis, asthma, eczema, self-reported food allergy, total IgE, allergic sensitization), and EoE measures (peak serum absolute eosinophil count, peak eosinophils/hpf on biopsy, and peak EREFs) were extracted from the medical record. As a standard definition does not yet exist for “disordered eating,” this was defined as the presence of learned maladaptive behaviors, immature diet selection, or oral aversion. For comparison, the prevalence of ASD/DD among children with allergic rhinitis, asthma, atopic dermatitis, and type 1 diabetes were also assessed using ICD-10 codes. Differences in categorical variables were compared using chi-squared tests and differences in means were compared using Mann Whitney U tests (Stata 14.2, College Station, Texas). Use of the data was approved by the UVA Institutional Review Board.
A total of 266 children with a diagnosis of EoE were identified, of which 229 were confirmed to have EoE upon chart review (median age at diagnosis 6.5 y; IQR 2–11 y). In the final study population, 29 children had a diagnosis of ASD (12.7%), and 70 children had a diagnosis of DD (30.6%), as shown in Table 1. Children with ASD were more likely to be male (26 [90%] vs 139 [70%]; p=0.02) and to present with disordered eating (13 [46%] vs 38 [19%]; p=0.001) than those with EoE alone. Similarly, children with DD were more likely to be male (59 [84%] vs 106 [67%]; p=0.006), and to present with disordered eating (25 [36%] vs 26 [16%]; p=0.001) than those with EoE alone. Children with DD also presented with EoE earlier than those without DD (5.3 years vs 7.5 years; p=0.001). There was no difference in race, other presenting symptoms, allergic conditions, or EoE clinical characteristics between those with and without ASD/DD (Table 2). The prevalence of ASD/DD in children with other IgE-mediated atopic disorders and in type 1 diabetes mellitus were lower than in children with EoE (Table 1).
Table 1.
Prevalence of ASD and DD in children with EoE and other disorders
| Total | With ASD | With DD | |
|---|---|---|---|
| EoE | 229 | 29 (13%) | 70 (31%) |
| Allergic Rhinitis | 15772 | 549 (3%) | 2810 (18%) |
| Asthma | 13829 | 450 (3%) | 2492 (18%) |
| Atopic Dermatitis | 6336 | 122 (2%) | 945 (15%) |
| Type 1 Diabetes | 613 | 25 (4%) | 70 (11%) |
Values are depicted as n (%)
Table 2.
Differences in characteristics among children +ASD/DD and −ASD/DD and EoE
| ASD n=29 (12.7) | No ASD n=200 (87.3) | P value | DD n=70 (30.6) | No DD n=159 (69.4) | p value | |
|---|---|---|---|---|---|---|
| Age at presentation (y)* | 5 (3–8) | 7 (2–11) | 0.28 | 4 (2–8) | 8 (3–11) | 0.003 |
| Male Sex | 26 (90) | 139 (70) | 0.02 | 59 (84) | 106 (67) | 0.006 |
| Race/Ethnicity | 0.85 | 0.66 | ||||
| Non-Hispanic White | 23 (79) | 166 (83) | 60 (86) | 129 (81) | ||
| Non-Hispanic Black | 3 (10) | 15 (8) | 5 (7) | 13 (8) | ||
| Other | 3 (10) | 19 (10) | 5 (7 | 17 (11) | ||
| Atopic Conditions | ||||||
| Asthma | 16 (55) | 96 (48) | 0.47 | 33 (47) | 79 (50) | 0.72 |
| Allergic Rhinitis | 21 (72) | 130 (65) | 0.43 | 49 (70) | 102 (64) | 0.39 |
| Eczema | 10 (36) | 89 (45) | 0.38 | 29 (42) | 70 (44) | 0.78 |
| Food Allergy | 7 (26) | 58 (29) | 0.91 | 14 (21) | 51 (32) | 0.10 |
| Presenting Symptoms | ||||||
| Dysphagia | 11 (39) | 83 (42) | 0.82 | 23 (33) | 71 (45) | 0.11 |
| Food Impaction | 2 (7) | 33(17) | 0.20 | 7 (10) | 28 (18) | 0.15 |
| Abdominal Pain | 15 (54) | 91 (46) | 0.42 | 27 (39) | 79 (50) | 0.14 |
| Vomiting | 12 (43) | 100 (50) | 0.48 | 36 (52) | 76 (48) | 0.54 |
| Poor weight gain/FTT | 4 (14) | 33(17) | 0.77 | 13 (19) | 24 (15) | 0.48 |
| Disordered eating | 13 (46) | 38 (19) | 0.001 | 25 (36) | 26 (16) | 0.001 |
| EoE Measurements | ||||||
| EREFS Score* | 2.5 (2–3) | 3 (2–3) | 0.73 | 3 (2–3) | 3 (2–4) | 0.99 |
| Eos/hpf* | 40 (30–50) | 37.5 (25–50) | 0.14 | 35 (25–45) | 40 (25–50) | 0.37 |
| Serum AEC* | 325 (245–605) | 505 (300–782) | 0.04 | 420 (270–690) | 500 (300–780) | 0.17 |
| Total IgE† | 224 (132–379) | 152 (113–204) | 0.43 | 122 (73–205) | 177 (129–244) | 0.15 |
Values are depicted as n (%) unless otherwise stated.
AEC: Absolute eosinophil count
Median values (IQR)
Geometric mean (95% CI)
In this retrospective study of 229 children with EoE at an academic institution, we found that there was a high prevalence of both ASD and DD compared to the national prevalence (0.5–3% and 17.8%).(3) This was unique to EoE, as the prevalence of ASD/DD in children with other atopic disorders and type 1 diabetes mellitus were similar to national estimates. We further found that children with ASD/DD and EoE were more likely to be male, to present with EoE at an earlier age, and to endorse the symptoms of disordered eating. However, there was no difference in underlying allergic disease or clinical characteristics of EoE.
Our finding that children with EoE have a high prevalence of ASD/DD is consistent with data from other academic centers,(2) but to our knowledge, this is the first study to demonstrate that this is uniquely true with EoE, compared to other allergic and non-allergic disorders. Previous studies have similarly found that children with ASD/DD have a high prevalence of EoE,(6) and other self-reported allergic conditions.(7) While it is possible that this high prevalence of EoE is due to increased access to healthcare in medically-complex children, it is also possible that there are shared immunologic pathways that promote the development of these conditions. Evidence for this hypothesis includes the observation that, compared to matched controls, unstimulated peripheral blood mononuclear cells from children with ASD produced higher levels of the Th2-associated cytokines IL-4, IL-5 and IL-13, which are known to be associated with EoE.(8) Furthermore, a murine model of IL-4 deficiency demonstrated increased social interactions compared to wild-type mice, which suggests an interaction between social behavior and adaptive immunity.(9) The shared role of type 2 allergic inflammation in the pathogenesis of both disorders supports the possibility of a link between them and warrants further study.
In this study, children with both ASD/DD and EoE were more likely to present with disordered eating than children without ASD/DD. Feeding disorders are common in children with ASD, affecting up to 75% of this population. It is thus possible that the increase we found in disordered eating is due to common behaviors in patients with ASD, such as food refusal and texture avoidance. It is also possible that the increase in disordered eating among the patients with DD is due to the fact that they were diagnosed with EoE at an earlier age than those without DD, when symptoms of feeding dysfunction predominate. However, our findings also support those of Heifert et al that providers should have an increased suspicion of EoE in children with ASD/DD who present with disordered eating.(6) Identifying and treating an underlying medical disorder that could contribute to these symptoms could ultimately enhance the efforts to treat feeding disorders in children with these conditions. This analysis is limited by the retrospective study design and reliance on provider documentation and ICD-10 codes. This was addressed by performing an in-depth chart review to confirm the diagnoses of EoE and ASD/DD, but further misclassification could have occurred with other included variables. We were also unable to assess the prevalence of ASD/DD in other non-IgE mediated gastrointestinal conditions due to limitations of using these ICD-10 codes and the small number of cases in our study population. As these conditions may be more appropriate comparison groups, it would be worthwhile to assess this in future, larger studies. This study is further limited by the potential for selection bias, as children with ASD/DD may have increased access to healthcare resources and endoscopic evaluation for EoE when presenting with disordered eating. This may have resulted in an overestimate of the prevalence of ASD and DD in this EoE population. We also acknowledge that this study was performed in a single, tertiary referral center and may not represent what is seen in community settings.
Despite these limitations, this is the first study to provide a comprehensive analysis of patients presenting with ASD/DD and EoE in the pediatric population. We found that the prevalence of ASD and DD in the pediatric EoE population is high, and whether this is due to shared immunologic and/or genetic pathways, or increased recognition of these disorders, is unknown and warrants further study.
Clinical Implications:
Children with EoE have a high prevalence of Autism Spectrum Disorder and other developmental disorders, which is unique to EoE and only seen in the pediatric population, suggesting this may be due to shared immunologic pathways or over-diagnosis.
Funding:
This work was funded by the NIH through the following grants: K23AI123596 and R21AI151497
Footnotes
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Disclosure of Potential Conflicts of Interest: J. Sohn, B. Barnes, A. Al-Hazaymeh, and B. Sauer have no potential conflicts of interest. E. McGowan has received grants from the National Institutes of Health (NIH), the American Academy of Allergy, Asthma and Immunology (AAAAI), and Food Allergy Research and Education (FARE) and consulting fees from Shire.
Contributor Information
Julia K. Sohn, University of Virginia School of Medicine, Division of Allergy and Immunology, Charlottesville, VA.
Barrett H. Barnes, University of Virginia School of Medicine, Division of Pediatric Gastroenterology/Nutrition, Charlottesville, VA.
Amani Al-Hazaymeh, University of Virginia School of Medicine, Division of Allergy and Immunology, Charlottesville, VA.
Bryan Sauer, University of Virginia School of Medicine, Division of Gastroenterology and Hepatology, Charlottesville, VA.
Emily C. McGowan, University of Virginia School of Medicine, Division of Allergy and Immunology, Charlottesville, VA.
Johns Hopkins, University School of Medicine, Division of Allergy and Clinical Immunology, Baltimore, MD.
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