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Feeding Disorders in Children With Autism Spectrum
Disorders Are Associated With Eosinophilic Esophagitis
y
Theresa A. Heifert,
Apryl Susi,
Elizabeth Hisle-Gorman,
z
Christine R. Erdie-Lalena,
Gregory Gorman,
z
Steve B. Min, and
Cade M. Nylund
ABSTRACT
Objectives: Eosinophilic esophagitis (EoE) can present as food selectivity
or feeding disorders in children. Children with autism spectrum disorders
(ASDs) commonly demonstrate behavioral food selectivity in type and
texture, which often leads to the diagnosis of feeding disorder. We sought
to evaluate the association of ASD with EoE.
Methods: A retrospective matched case-cohort study was performed using
the Military Health System database from October 2008 to September 2013.
We performed a 1:5 case-control match by age, sex, and enrollment
timeframe. Feeding disorders, EoE, and atopic disorders were defined
using diagnostic and procedure codes.
Results: There were 45,286 children with ASD and 226,430 matched
controls. EoE was more common in children with ASD (0.4%) compared
with controls (0.1%). Feeding disorders were associated with EoE in both
children with ASD and controls. Feeding disorders also had a higher odds
ratio for EoE compared with other atopic conditions, among both children
with ASD (7.17, 95% confidence interval [CI] 4.87–10.5) and controls
(11.5, 95% CI 7.57– 17.5). Compared with controls with a feeding disorder,
children with ASD and a feeding disorder had no difference in the rate of
diagnosed EoE (0.85, 0.95% CI 0.39–1.88).
Conclusions: Children with ASD are more likely to be diagnosed with EoE
compared with controls; however, among children with feeding disorders,
there is no difference in the odds of EoE. A diagnosis of feeding disorder was
strongly associated with EoE. Feeding disorders in children with ASD
should not be assumed to be solely behavioral and an
esophagogastroduodenoscopy should be performed to evaluate for EoE.
Key Words: absolute eosinophil count, autism, child developmental
disorders, eosinophilic esophagitis, feeding and eating disorders of childhood
(JPGN 2016;63: e69– e73)
Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-
mediated, esophageal disease characterized clinically by
symptoms related to esophageal dysfunction and histologically
by eosinophil-predominant inflammation (1). Pediatric onset EoE
can present with a variety of clinical symptoms, which vary by age;
these symptoms include feeding disorders, vomiting, abdominal
pain, dysphagia, and food impaction (2). In infants and young
children with EoE, feeding difficulties, failure to thrive, and classic
gastroesophageal reflux symptoms predominate (3). Cross-sec-
tional studies show that feeding dysfunction occurs very commonly
in children with EoE with a prevalence of 14% to 58.9% (4,5).
Autism spectrum disorders (ASD) are lifelong developmen-
tal disabilities that present early in life and are defined by diagnostic
criteria that include deficits in social communication and social
interaction and restricted, repetitive patterns of behavior, interests,
or activities (6,7). Children with ASD frequently have tactile and
oral defensiveness. This oral defensiveness can lead to food selec-
tivity in type and texture, which often leads to the diagnosis of a
behavioral feeding disorder (8). Furthermore, children with ASD
often cannot communicate symptoms of discomfort such as dys-
phagia or odynophagia.
Because the clinical symptoms of EoE are nonspecific, and
may easily be overlooked, it is possible that unrecognized EoE may
contribute to behavioral problems and feeding issues in children
with ASD (9). EoE represents a treatable condition, and such
treatment may improve feeding difficulties in children with
ASD. The association of EoE in children with ASD, particularly
in those with feeding disorders, is unknown. We sought to evaluate
the rate of EoE in children with ASD, to evaluate the association of
feeding disorders with EoE among children with and without ASD,
What Is Known
Both autism spectrum disorder and eosinophilic eso-
phagitis can present with food selectivity or feeding
disorders in children. No previous studies exploring
the prevalence of eosinophilic esophagitis in children
with autism spectrum disorder have been published.
What Is New
Children with autism are more likely to be diagnosed
with eosinophilic esophagitis. Among children with
autism spectrum disorder and controls, those with
feeding disorders have similarly increased odds of
eosinophilic esophagitis suggesting that feedings
disorders should not be assumed to be merely beha-
vioral in any child.
Received August 12, 2015; accepted May 26, 2016.
From the Department of Pediatrics, Uniformed Services University,
Bethesda, MD, the yDepartment of Pediatrics, Womack Army Medical
Center, Fort Bragg, NC, and the zDepartment of Pediatrics, Walter Reed
National Military Medical Center, Bethesda, MD.
Address correspondence and reprint requests to Theresa A. Heifert, MD,
Department of Pediatrics, Womack Army Medical Center, 2817 Riley
Rd, Fort Bragg, NC 28310 (e-mail: theresa.a.heifert.mil@mail.mil).
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are
provided in the HTML text of this article on the journal’s Web site
(www.jpgn.org).
The study was conducted with support from the Congressional Directed
Medical Research Programs, Autism Research Award W81XWH-12-2-
0066.
The views expressed in this article are those of the authors and do not reflect
the official policy or position of the Uniformed Services University of the
Health Sciences, United States Army, United States Navy, United States
Air Force, Department of Defense, or the U.S. Government.
The authors report no conflicts of interest.
Copyright #2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001282
ORIGINAL ARTICLE:GASTROENTEROLOGY
JPGN Volume 63, Number 4, October 2016 e69
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
and to identify additional associated conditions that may help risk
stratify the need for endoscopic evaluation for EoE.
METHODS
We performed a retrospective case-cohort study in children
with and without ASD using billing records from the TRICARE
Management Activity Military Health System (MHS) database.
This database includes records from all eligible United States
uniformed services members and their dependents cared for in
military and civilian healthcare facilities. Cases of ASD were
defined using a previously validated method (10,11). Cases
included children ages 2 up to age 18 with International Classifi-
cation of Diseases, Ninth Revision, Clinical Modification (ICD-9-
CM) diagnostic codes for an ASD diagnosis at 2 separate clinical
encounters from October 1, 2000 to September 30, 2013 (Supple-
mental Digital Content, Table, http://links.lww.com/MPG/A709).
Exclusion criteria included ICD-9-CM diagnostic codes for child-
hood disintegrative or degenerative disorders (330.8, 299.10, and
299.11). In addition, cases were enrolled in the MHS database at
least 6 months before their first ASD diagnosis and for at least
6 months after receiving this ASD diagnosis. Cases were matched
with 5 controls without replacement by age, sex, and enrollment
timeframe. Enrollment timeframe for the controls must have been as
long as or longer than the case. After matching was completed all
enrollment timeframes for controls were cropped to match the case.
This resulted in all case-control matches having the same sex, same
age (within a few days), and being followed for the same length
of time.
Records for cases and controls were then reviewed for
feeding disorders based on ICD-9-CM codes (Supplemental Digital
Content, Table, http://links.lww.com/MPG/A709). EoE was defined
by ICD-9-CM diagnostic code for EoE and a preceding esophago-
gastroduodenoscopy (EGD) defined by either an ICD-9-CM pro-
cedure code or current procedural terminology code (Supplemental
Digital Content, Table, http://links.lww.com/MPG/A709). We also
evaluated both cases and controls for some conditions known to be
associated with a diagnosis of EoE, including allergic rhinitis,
atopic dermatitis, food allergies, and asthma, which were also
identified using ICD-9-CM codes (12). The diagnosis of food
allergy was included in the model only if the diagnosis was made
before the diagnosis of EoE. Cases and controls were evaluated for
atopic conditions and EoE only during the timeframe of October 1,
2008 to September 31, 2013 as the ICD-9-CM diagnostic code for
EoE was implemented in fiscal year 2009. There was a subsample of
subjects who had a complete blood count drawn in a military
treatment facility laboratory and whose values were available for
review. Using these values, the subgroup was evaluated for an
abnormal blood eosinophil count, categorically defined as any level
above 500 cells/mcL.
To evaluate the association of ASD with feeding disorders
and the diagnosis of EoE, conditional logistic regression was
performed with EoE as the dependent variable, and 1 of 4 categories
as the independent variable: ASD with feeding disorder, ASD
without feeding disorder, no ASD with feeding disorder, and no
ASD without feeding disorder. In addition, categorical independent
variables such as food allergy, asthma, allergic rhinitis, and atopic
dermatitis also were included in the multivariable model yielding
odds ratios (ORs) with 95% confidence intervals. A conditional
logistic regression model, which included a categorical variable for
abnormal absolute eosinophil count as a covariate was also per-
formed for the subgroup that had available laboratory data. Stra-
tified conditional logistic regression models were also prepared to
compare the association of atopic conditions with EoE between
children with and without ASD. An alpha level of 0.05 was used to
determine statistical significance. Analyses were conducted using
SAS 9.3 (SAS Institute, Cary, NC). The study was reviewed and
approved by the responsible institutional review boards.
RESULTS
A total of 45,286 children with ASD and 226,430 matched
controls were identified from the MHS database during the 5-year
study period, representing a total of 1,211,039 person-years. All cases
were matched successfully to a control by sex, and most subjects
(99.8%) were matched on the exact date of birth. When not matched
on date of birth the mean difference was 2.1 days with a maximum
difference of 35 days. 36,197 (80 %) of the children with autism were
boys. The median (interquartile range [IQR]) age at diagnosisof ASD
was 6.4 years (3.8– 10.1). A higher proportion of children with ASD
had an EGD performed than controls (2.9% vs 1.1%).
Feeding disorders were diagnosed in 2584 (5.7%) of children
with ASD and 1333 (0.6%) of controls (P<0.001). There was no
difference in median age at first diagnosis for feeding disorders,
4.3 years (IQR 2.9–7.2) and 4.6 years (IQR 2.8–8.0) in ASD and
controls, respectively (P¼0.18; Table 1). There were a total of
496 (0.18 %) cases of EoE in the combined study population. EoE
was more common in children with ASD, 183 (0.4%), compared
with controls, 313 (0.14%; P<0.001). Median age at diagnosis of
EoE was 7.6 years (IQR 4.6 –11.3) in children with ASD and
9.6 years (IQR 6.2–12.7) in controls (P¼0.004). The proportion
of boys who were diagnosed with both EoE and feeding disorders
by ASD status are presented in Table 1.
The rate and ORs of EoE by ASD and feeding disorder are
presented in Table 2. Both groups of children—those with and
without ASD—who had feeding disorders, had an increased risk of
EoE when compared with those without feeding disorders. There
was no significant difference in rates of EoE between the children
who had ASD and feeding disorders and those without ASD and
feeding disorders (OR 0.85; 95% confidence interval, 0.39– 1.88).
Table 3 lists predictors of a diagnosis of EoE stratified by
ASD status. Feeding disorders were the strongest predictor of EoE
compared with all other associated variables among both children
with ASD and controls. Table 4 presents the results of conditional
logistic regression analysis for the subgroup of 110,068 subjects
whose laboratory data were available. Elevated blood eosinophil
counts were associated with a diagnosis of EoE even after adjusting
for the effect of other atopic diagnoses.
TABLE 1. Age at first diagnosis and sex by autism status
Age at first diagnosis median (interquartile range) Male number (%)
ASD No ASD PASD No ASD P
Eosinophilic esophagitis 7.6 (4.6– 11.3) 9.6 (6.2– 12.7) 0.004 160 (87.43%) 283 (90.42%) 0.30
Feeding disorders 4.3 (2.9– 7.2) 4.6 (2.8– 8.0) 0.18 1994 (77.17%) 1117 (83.67%) <0.001
ASD ¼autism spectrum disorder.
Heifert et al JPGN Volume 63, Number 4, October 2016
e70 www.jpgn.org
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
DISCUSSION
Only 1 previous case report has evaluated EoE in a child with
ASD and a feeding disorder (13). Our study demonstrates that
children with ASD are more likely to be diagnosed not only with
feeding disorders but also with EoE. Children with ASD and
feeding disorders are just as likely as controls with feeding disorders
to be diagnosed with EoE. All of the atopic disorders evaluated,
including asthma, allergic rhinitis, and eczema were associated with
EoE, but feeding disorders were the conditions most highly associ-
ated with EoE. In a subgroup analysis, an elevated blood absolute
eosinophil count also was associated with a diagnosis of EoE.
ASDs affect as many as 1 in 68 children in the United
States with the prevalence in boys (1/42) being higher than that
in girls (1/189) (6). Children with ASD are frequently seen by
pediatric gastroenterologists for a variety of gastrointestinal com-
plaints including feeding disorders (14). A previous meta-analysis
showed that children with ASD can have up to a 5-fold elevated risk
of developing a feeding disorder compared with their peers (15).
These feeding disorders are commonly attributed to food refusal,
extreme food neophobia, restricted dietary variety, and food selec-
tivity due to texture, and they may not raise appropriate clinical
attention as growth parameters may be normal (16,17). If further
evaluation, including endoscopy, is omitted, pathological causes of
feeding disorders such as EoE can be overlooked or inappropriately
categorized as behavioral in origin.
Eosinophilic esophagitis is a chronic, inflammatory, and
relapsing disease of the esophagus and is characterized histologi-
cally by dense esophageal eosinophilia and significant squamous
epithelial hyperplasia. It is accompanied by a variety of clinical
findings such as dysphagia, vomiting, abdominal pain, weight loss,
and feeding aversion in children and is diagnosed more frequently
in boys than in girls (18). Our findings suggest that children with
feeding disorders should undergo endoscopic evaluation to evaluate
for EoE as a possible contributor to feeding difficulties. EoE is a
treatable condition with several treatment options that may be used
alone or in combination. These treatments include dietary changes
(targeted or empiric food elimination, amino acid–based formula)
or ingested topical corticosteroids (19). For many children with
ASD the feeding disorder may be multifactorial with a combination
of both organic and behavioral components that may arise from
longstanding odynophagia or other discomfort associated with
eating. Eliminating the discomfort associated with eating by iden-
tifying and treating a potential diagnosis of EoE could enhance
ongoing treatment efforts focused on the behavioral aspects of any
feeding disorder in children with ASD.
We demonstrate an association of allergic rhinitis, eczema,
and asthma with EoE. EoE has a high rate of atopy in children
with approximately 50% to 80% of children with EoE having
coexisting atopic disorders (12,20–22). The association with aller-
gic rhinitis and asthma may be directly linked to sensitization of
ingested aeroallergens (23,24). We demonstrated that having an
atopic condition is associated with EoE among children with and
without ASD. The one exception was that food allergies were not
significant, which in the overall model but in the models stratified
by ASD status was significant only in children without ASD. Food
allergies are known to be associated with EoE and removal of
allergic foods is a treatment option for EoE. In our study we limited
the definition of food allergies to a diagnosis before the diagnosis of
EoE. Many subjects may not undergo allergy testing until EoE is
identified, which could explain the lack of association found in
our results.
Among all variables we evaluated, having a diagnosis of a
feeding disorder was most highly associated with EoE. This further
supports our assertion that any child with a feeding disorder—
whether or not he or she has ASD—should have endoscopic evalu-
ation. For the subgroup that had laboratory values available, having
an elevated absolute eosinophil count was also associated with EoE
TABLE 2. Incidence, unadjusted, and adjusted odds ratios for diagnosis of eosinophilic esophagitis
Total
number
Number with
eosinophilic
esophagitis
Unadjusted model
odds ratios
(95% confidence interval)
Multivariable model
odds ratios
(95% confidence interval)
ASD and Feeding Disorder Status
ASD with feeding disorder 2584 79 19.37 (11.97, 31.35) 17.44 (10.15, 29.98)
ASD without feeding disorder 42,702 104 2.06 (1.64, 2.59) 2.04 (1.60, 2.61)
No ASD with feeding disorder 1333 40 22.77 (11.74, 44.17) 17.49 (8.46, 36.14)
No ASD without feeding disorder 225,097 273 Reference Reference
Atopic disorders
Allergic rhinitis 14,696 119 6.06 (4.56, 8.06) 4.25 (3.02, 6.00)
Eczema 56,848 227 3.17 (2.57, 3.90) 2.26 (1.77, 2.90)
Asthma 5775 35 2.98 (1.94, 4.57) 1.90 (1.12, 3.23)
Food allergy 8650 82 5.56 (4.01, 7.70) 2.68 (1.79, 3.99)
The multivariable model includes all variables listed in the table.
ASD ¼autism spectrum disorders.
TABLE 3. Predictors of a diagnosis of eosinophilic esophagitis stratified
by autism spectrum disorder status
ASD model
odds ratios
(95% confidence
interval)
No ASD model
(95% confidence
interval)
Feeding disorders 10.63 (7.85, 14.41) 17.48 (12.32, 24.81)
Asthma 1.82 (0.99, 3.35) 1.80 (1.15, 2.81)
Allergic rhinitis 2.89 (1.99, 4.20) 3.53 (2.66, 4.69)
Eczema 2.26 (1.66, 3.06) 1.92 (1.51, 2.44)
Food allergy 1.31 (0.84, 2.06) 3.12 (2.26, 4.32)
Sex (male vs female) 1.93 (1.24, 3.00) 2.23 (1.53, 3.25)
The 2 models were multivariable and included all variables listed in the
table.
ASD ¼autism spectrum disorders.
JPGN Volume 63, Number 4, October 2016 Eosinophilic Esophagitis in Children With Autism Spectrum Disorders
www.jpgn.org e71
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
even after adjusting for other atopic disorders. This suggests that
having an elevated absolute eosinophil count may be a specific
marker of EoE among children with other forms of atopy. Schlaget al
(25) demonstrated the potential of absolute eosinophil count as a
biomarker for EoE. In their randomized, controlled, double-blind
trial of budesonide the investigators found that absolute eosinophil
count correlated with esophageal tissue eosinophil count. Although
further prospective studies are warranted, absolute eosinophil count
may prove to be a clinically helpful biomarker for EoE. Pending
further validation studies, however, having a normal absolute eosi-
nophil count should not deter full evaluation with an EGD in children
with feeding disorders. Our study demonstrates that children with
ASD and a feeding disorder have a higher rate of EoE than controls
without a feeding disorder. This finding may be due to ascertainment
bias as children with ASD are more likely to have endoscopy
compared with the general population due to higher rates of feeding
disorders. The association between ASD and EoE could, however,
certainly be valid as well, especially considering that a biological
plausibility for an association does exist. Children with autism have
been found to have increased gastrointestinal symptoms and gastro-
intestinal inflammatory diseases such as celiac disease and inflam-
matory bowel disease (26– 31). The common link between
inflammatory diseases of the gut may be increased bowel per-
meability which has also been found to be increased in inflammatory
bowel disease, celiac disease, EoE, and some children with autism
(32– 35). It is possible that luminal antigens cross the gut mucosa and
triggers an immunological response that promotes intestinal inflam-
mation. It has also been suggested that immune dysregulation may
play some role in the etiology of autism (36–38). Another suggested
hypothesis is that both atopic disease and ASD may have a shared
mechanism in the hygiene hypothesis (39). Furthermore, Chen et al
(40) found that early childhood atopic disease is associated with an
increased risk of subsequent development of ASD. Magalha
˜es et al
(41) found that children with Asperger syndrome had higher rates of
atopy, higher incidences of positive skin prick allergy testing, and
serum levels of IgE. Cross-sectional data from the National Survey of
Children’s Health demonstrated that children with atopic dermatitis
had 3 times the odds of having a diagnosis of autism (42). Further
studies will be needed to evaluate the identified association between
ASD and EoE.
Strengths of our study are the use of the TRICARE Manage-
ment Activity MHS database which includes a large, representa-
tive, demographically, and geographically diverse population of
children cared for both in military and civilian facilities. Potential
bias due to access to care was minimized in our study as TRICARE
beneficiaries have universal access to care. An additional strength
of our study is the 1:5 case-control match which controlled for age,
sex, and the timeframe in which they were enrolled in TRICARE.
One weakness in our study was that it relied on ICD-9-CM
diagnostic codes, which may be prone to misclassification bias.
We attempted to minimize misclassification bias by using pre-
viously validated codes for ASD. The diagnostic codes for EoE
have been evaluated for validity and have a high specificity but a
low sensitivity (43). Feeding disorders have not been previously
validated. To minimize misclassification bias for feeding disorder
we elected to include only 2 codes and avoided symptom-based
codes such as dysphagia. As mentioned previously, ascertainment
bias also is a weakness of our study as children with ASD are more
likely to have feeding disorders and, therefore, more likely to have
endoscopy performed.
CONCLUSION
Children with ASD are more likely to be diagnosed with
EoE. We found that in children, with and without ASD, a diagnosis
of feeding disorder was most highly associated with EoE among
other risk factors evaluated in the study. Feeding disorder in
children with ASD should not be assumed to be purely behavioral
and should be further evaluated with EGD for evaluation of EoE.
The absolute eosinophil count, along with additional atopic diag-
noses, may be predictive of EoE and may prove to be helpful in
stratifying the need for endoscopy.
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TABLE 4. The incidence, unadjusted, and adjusted odds ratios for the diagnosis of eosinophilic esophagitis for the subgroup with available
absolute eosinophil count
Total
number
Number with
eosinophilic
esophagitis
Unadjusted model odds ratios
(95% confidence interval)
Multivariable model odds ratios
(95% confidence interval)
ASD 21,248 106 2.71 (2.12, 3.46) 1.48 (1.12, 1.96)
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ASD ¼autism spectrum disorders.
Heifert et al JPGN Volume 63, Number 4, October 2016
e72 www.jpgn.org
Copyright © ESPGHAL and NASPGHAN. All rights reserved.
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JPGN Volume 63, Number 4, October 2016 Eosinophilic Esophagitis in Children With Autism Spectrum Disorders
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