HHS Public Access

Author manuscript
Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.
Author Manuscript

Published in final edited form as:

Gastrointest Endosc. 2014 April ; 79(4): 577–85.e4. doi:10.1016/j.gie.2013.10.027.

A phenotypic analysis shows eosinophilic esophagitis is a

progressive fibrostenotic disease
Evan S. Dellon, MD, MPH1,2, Hannah P. Kim, MD1, Sarah L.W. Sperry, MD1, David A.
Rybnicek, MD1, John T. Woosley, MD, PhD3, and Nicholas J. Shaheen, MD, MPH1,2
1Centerfor Esophageal Diseases and Swallowing, University of North Carolina School of
Medicine, Chapel Hill, NC
Author Manuscript

2Centerfor Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology,

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
3Department of Pathology and Laboratory Medicine, University of North Carolina School of
Medicine, Chapel Hill, NC

Abstract
Background—Phenotypes of eosinophilic esophagitis (EoE) are not well characterized.

Objective—To describe clinical features of EoE patients with predefined phenotypes, determine
predictors of these phenotypes, and make inferences about the natural history of EoE.

Design—Retrospective study.
Author Manuscript

Setting—Tertiary care center.

Patients—Incident EoE cases from 2001–2011 who met consensus diagnostic guidelines.

Interventions—n/a

Main outcome measurements—Endoscopic phenotypes, including fibrostenotic,

inflammatory, or mixed. Other groups of clinical characteristics examined included atopy, level of
esophageal eosinophilia, and age of symptom onset. Multinominal logistic regression assessed
predictors of phenotype status.

Results—Of 379 cases of EoE identified, there were no significant phenotypic differences by
atopic status or level of eosinophilia. Those with the inflammatory phenotype were more likely to
be younger than those with mixed or fibrostenotic (13 vs 29 vs 39 years, respectively; p<0.001),
Author Manuscript

and less likely to have dysphagia, food impaction, and esophageal dilation (p<0.001 for all). The
mean symptom length prior to diagnosis was shorter for inflammatory (5 vs 8 vs 8 years; p=0.02).
After multivariate analysis, age and dysphagia independently predicted phenotype. The OR for
fibrostenosis for each 10-year increase in age was 2.1 (1.7–2.7). The OR for dysphagia was 7.0
(2.6–18.6).

Limitations—Retrospective, single-center study.

Corresponding Author: Evan S. Dellon MD, CB#7080, Bioinformatics Building, 130 Mason Farm Rd., UNC-CH, Chapel Hill, NC
27599-7080, Phone: (919) 966-2513, Fax: (919) 843-2508, edellon@med.unc.edu.
 Dellon et al. Page 2

Conclusions—In this large EoE cohort, the likelihood of fibrostenosing disease increased
Author Manuscript

markedly with age. For every ten year increase in age, the odds of having a fibrostenotic EoE
phenotype more than doubled. This association suggests that the natural history of EoE is a
progression from an inflammatory to a fibrostenotic disease.

Keywords
eosinophilic esophagitis; phenotype; stricture; inflammation; natural history

Introduction
Over the past decade, eosinophilic esophagitis (EoE) has rapidly emerged as an important
cause of upper GI disease.1 EoE is defined as a clinicopathologic immune/allergen-mediated
disorder characterized by symptoms of esophageal dysfunction and a marked eosinophilic
Author Manuscript

infiltrate on esophageal biopsy.2 EoE appears to be a chronic disease, but there are few
cohorts that have been observed long-term without therapeutic interventions.3, 4 In general,
patients with EoE tend to be younger, male, white, and have associated atopic disorders.5
Dysphagia is the hallmark symptom of EoE, and EoE is the cause in more than 50% of cases
of food impaction presenting to the emergency department.2, 5, 6 Typical findings on
endoscopy include esophageal rings, linear furrows, white plaques or exudates, decreased
vascularity, strictures, and mucosal fragility.7, 8

Despite these commonalities, there can be substantial variability in EoE at the patient level.
It is well recognized that clinical and endoscopic features of children and adults with EoE
differ.2, 5, 7, 9–13 Children tend to present with heartburn, vomiting, abdominal pain, feeding
intolerance, or failure to thrive, while adults primarily present with dysphagia. While adults
often have esophageal rings and strictures requiring dilation, children tend to have more
Author Manuscript

furrows, plaques, and decreased vascularity on endoscopy. Similarly, while atopy is

common in EoE, it is by no means universal.9, 14–17 Recently, there has been a question of
whether different EoE phenotypes are responsible for divergent clinical presentations and
outcomes.2, 18, 19 However, it is unknown whether specific phenotypes accurately
characterize subgroups of patients with EoE and whether these phenotypes are the result of
disease progression. It is also unknown whether EoE is a disease consisting of one or more
discrete subtypes, or whether it is a single condition with changes in expression over time. In
the latter conception, the manifestations primarily present in children and young adults
might represent an early inflammatory phase, while the manifestations in adults would
represent chronic fibrostenotic manifestations which are sequelae of this inflammation.

The aim of this study was to describe the clinical features of EoE patients with predefined
Author Manuscript

phenotypes, determine predictors of these phenotypes, and make inferences about the natural
history of EoE. The phenotypes examined include inflammatory, fibrostenotic, and mixed
phenotypes based on endoscopy, as well as defined clinical characteristics such as atopic
status, severity of esophageal eosinophilia, and onset of disease.

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 3

Methods
Author Manuscript

Study design, data source, and phenotype definitions

This was a retrospective study conducted at the University of North Carolina (UNC) Center
for Esophageal Diseases and Swallowing. Using the UNC EoE Clinicopathologic database
from 2001–2011, subjects with an incident diagnosis of EoE made at UNC who met
consensus diagnostic guidelines were included. Specifically, all patients had symptoms of
esophageal dysfunction, ≥15 eos/hpf (hpf area=0.24 mm2), and did not respond to a proton
pump inhibitor (PPI) trial.2, 20 Details of the development of this database and confirmation
of EoE case status have previously been described.9, 21, 22 This study was approved by the
UNC Institutional Review Board.

Data were extracted from electronic medical records, endoscopy reports, and pathology
records. Specific data included: demographics (age at diagnosis, gender, race); symptoms;
Author Manuscript

duration of symptoms prior to EoE diagnosis; co-existing atopic disease (allergic rhinitis or
sinusitis, asthma, or documented food allergy demonstrated by either symptomatic evidence
of allergy with reintroduction of a food or by testing directed by an Allergist); and
endoscopic findings (rings, strictures, esophageal narrowing, linear furrows, white plaques
or exudates, decreased vascularity, crêpe-paper mucosa, erosive esophagitis, and hiatal
hernia) and maneuvers (dilation). For histologic assessment, the maximum eosinophil count
(eos/hpf; hpf area = 0.24 mm2) had been determined for clinical purposes using a standard
protocol which has been shown to have excellent interobserver correlation for both attending
and resident pathologists.23, 24

EoE phenotypes were defined a priori as follows. Endoscopic phenotypes reflected the
degree of inflammation versus remodelling noted on esophageal examination. The
Author Manuscript

phenotypes were defined as fibrostenotic if there were esophageal rings, narrowing, or

strictures and no evidence of linear furrows or white plaques; as inflammatory if there were
furrows, plaques, or a normal esophagus and no evidence of fibrostenotic changes; and as
mixed if there were a combination of findings. Furrows were considered an inflammatory
change based on evidence that biopsies from these areas show a highly eosinophilic
infiltrate, and that furrowing is rapidly reversible with topical steroids.25–28 We also
assessed cases of EoE by other baseline disease characteristics. Atopy was defined as
subjects with allergic rhinitis, sinusitis, dermatitis, asthma, or food allergy. We stratified
esophageal eosinophilia by tertiles (15–50 eos/hpf, 51–99, eos/hpf and ≥100 eos/hpf).
Disease onset was separated into childhood disease onset (first symptoms at <18 yrs) versus
adult disease onset. Because we had data concerning symptom duration prior to diagnosis of
EoE, we estimated approximate date of disease onset by subtracting the pre-diagnosis
Author Manuscript

symptom duration from the date of diagnosis. For instance, an adult diagnosed at age 30
would be considered to have childhood disease onset if symptoms had been present for more
than 12 years.

Statistical analysis
Descriptive statistics were used to characterize clinical, endoscopic, and histologic features
of the EoE population in general, and then to characterize features of each of the EoE

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 4

phenotypes. Features were then compared between the different phenotype definitions.
Author Manuscript

Specifically, the three phenotypes were compared, the atopic/non atopic subjects were
compared, the eosinophil tertiles were compared, and the age of onset was compared. Means
were compared with t-tests and proportions were compared by chi-square. Finally,
multinominal logistic regression was performed to assess predictors of phenotype status
amongst the three phenotypes. Odds ratios (ORs) were assessed for multiple factors based
on the initial bivariate analysis including age (10 year increments), gender, race, symptoms
(dysphagia, heartburn, abdominal pain, vomiting), atopy, food allergies, and eosinophil
counts. The model was then reduced using a backwards elimination strategy that removed
factors that were not significant at the p < 0.05 level. We analyzed a separate model that
included symptom duration, as this was colinear with age.

Results
Author Manuscript

Characteristics of EoE cases

A total of 379 EoE cases were identified in the database (Table 1). The mean age was 25
years (ranging from 6 months to 82 years), 73% were male, and 81% were white. The most
common symptoms were dysphagia (66%), heartburn (39%), and food impaction (28%),
with a mean duration of symptoms prior to diagnosis of 7 years. More than one-third of
patients had some form of atopy. On endoscopy, typical findings of EoE were common, with
40% having esophageal rings and 40% having linear furrows. The average maximum
eosinophil count was 86 eos/hpf.

Fibrotic, inflammatory, and mixed phenotypes and phenotype predictors

When the 374 patients with endoscopic data were divided into phenotypes, 134 (36%) were
inflammatory, 163 (43%) were mixed, and 77 (21%) were fibrostenotic (Table 2). Those
Author Manuscript

with an inflammatory phenotype were on average much younger than those with mixed or
fibrostenotic (13 vs 29 vs 39 years, respectively; p <0.001). Dysphagia was less likely in
inflammatory compared to mixed or fibrostenotic (36% vs 77% vs 92%; p<0.001), as were
food impaction (15% vs 37% vs 39%; p<0.001) and esophageal dilation (0% vs 24% vs
47%; p<0.001). Abdominal pain, vomiting, and failure-to-thrive were more common in the
inflammatory phenotype (p<0.001 for all), as were atopy and food allergies (p<0.05). The
mean symptom length prior to diagnosis was shorter for inflammatory compared to mixed
and fibrostenotic (5 vs 8 vs 8 years; p=0.02). The maximum eosinophil counts did not
significantly vary between the groups (84 vs 80 vs 102; p=0.12). These results were
unchanged in a supplemental analysis comparing the inflammatory EoE cases to EoE cases
with any element of fibrostenosis (ie combining the mixed and fibrostenotic groups)
(Supplemental Table 1).
Author Manuscript

After multivariate analysis, only age at diagnosis and dysphagia were independent predictors
of phenotype status. The OR for a 10 year increase in age for a mixed phenotype compared
to inflammatory was 1.64 (95% CI 1.35–1.99) and for fibrostenotic was 2.14 (1.70–2.70).
This indicates that for every decade of life, the odds of developing a fibrostenotic phenotype
more than doubles. The predicted probability of developing a fibrosteontic EoE phenotype
by age is graphed in Figure 1. The ORs for the presence of dysphagia as a predictor of

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 5

mixed or fibrostenosing phenotype were 3.07 (1.71–5.49) and 7.00 (2.63–18.64),

Author Manuscript

respectively. When symptom duration prior to EoE was assessed separately, the findings
were similar. The OR for each 1 year of symptoms prior to EoE diagnosis for a fibrostenotic
vs inflammatory phenotype was 1.05 (1.01–1.10), indicating that the odds of developing
fibrostenosis increased 5% with every year of symptoms prior to diagnosis. The OR for a 10
year symptom duration prior to EoE diagnosis was 1.60 (1.05–2.44).

Atopy, eosinophil counts and age of disease onset

There were 177 EoE cases with atopy, 128 in the highest tertile of eosinophil counts (≥100
eos/hpf), and 172 with childhood onset of disease. Those with atopy tended to be diagnosed
at an earlier age than those without atopy (22 vs 26 yrs; p=0.06), but there were no other
differences by atopic status for gender, race, symptoms, endoscopy findings, or eosinophil
counts (Supplemental Table 2).
Author Manuscript

For the eosinophilia phenotype, there were no significant differences by age, gender, race,
symptoms, atopic status, or endoscopy findings based on eosinophil counts at diagnosis
(Supplemental Table 3).

Those with childhood onset of EoE were more commonly male (81% vs 67%; p<0.001) and
non-white (25% vs 15%; p=0.02), had more abdominal pain, vomiting, and failure-to-thrive
(p<0.01 for all), and less dysphagia (p<0.001) than those with adult onset. While those with
childhood onset were more likely to have a normal endoscopic exam (28% vs 8%; p<0.001),
there was no difference in eosinophil count by age of symptom onset (Table 3). These
results were unchanged in a supplemental analysis where childhood onset was defined as
age < 12 years (see Supplemental Table 4).
Author Manuscript

Discussion
With increasing knowledge about EoE, the variability in the disease has been recognized,2
and differences in characteristics between adults and children7, 9–12 and by race or gender
have been described.29–31 This has raised the question of whether underlying EoE
phenotypes are responsible for different clinical presentations and outcomes, and whether
such phenotypes might impact on or be the result of the natural history of the condition. The
purpose of this study was to characterize clinical features of predefined EoE phenotypes,
determine predictors of these phenotypes, and make inferences about the natural history of
EoE.

We found that fibrostenotic, inflammatory, and mixed phenotypes were associated with
significant clinical differences between groups of EoE patients. In particular, those with an
Author Manuscript

inflammatory phenotype were younger, less likely to have dysphagia, food impaction, or
esophageal dilation, and more likely to have abdominal pain, vomiting, failure-to-thrive, and
atopy. Importantly, the mean symptom length prior to diagnosis was shorter for
inflammatory compared to the mixed and fibrostenotic phenotypes. This suggests that EoE
may progress from an inflammatory to fibrostenotic disease, and the multivariate analysis
demonstrates this change in risk over time. For every 10 year increase in age, the odds of
having a fibrostenotic phenotype more than doubles. The odds were similar for longer

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 6

duration of symptoms prior to diagnosis. In contrast, baseline atopic status or eosinophil

Author Manuscript

count were not associated with important differences in clinical characteristics. High
eosinophil counts were also seen in EoE patients with a fibrostenotic phenotype and a long
symptom duration prior to diagnosis, suggesting that the inflammation in this group is not
“burning out,” or becoming less severe over time.

Our findings support a trend of new thinking about EoE. In recent years there has been much
discussion about possible phenotypes of EoE, though there are few published data on this
topic.2, 18, 32, 33 It has been well described that symptoms differ between adults and children
and appear to progress, with failure to thrive and feeding intolerance in the youngest
children, then abdominal pain, vomiting/regurgitation, and heartburn in older children, then
dysphagia and food impaction in adolescents and adults.9–12 Similarly, endoscopic findings
have been reported to vary by age as well, with a normal appearing esophagus, linear
furrows, and white plaques more common in children, and esophageal rings, strictures, and
Author Manuscript

narrowing more common in adults.7, 9, 13 In natural history studies, while there are few
children who have been observed for many years without treatment,3, 14, 15, 34, 35
progression from inflammatory to fibrostenotic phenotypes has been noted anecdotally.

In our study, there was highly active eosinophilic inflammation in all patients, regardless of
phenotype. One could postulate that with longer exposure to inflammation, there is a higher
risk of fibrosis. Indeed, eosinophilic inflammation resulting in esophageal fibrosis has been
well described in studies of the pathogenesis of EoE. Aceves and colleagues first reported
sub-epithelial fibrosis in children with EoE,36 and this has been confirmed in both children
and adults.37–39 Fibrosis appears to be mediated by active eosinophilic and mastocytotic
inflammation in the esophageal mucosa,36, 40–42 and may involve deeper layers of the
esophagus wall, as suggested by endoscopic ultrasound imaging.43–45 Kwiatek, Hirano, and
Author Manuscript

colleagues have used a novel functional lumen imaging probe to characterize decreased
esophageal compliance in patients with EoE, a result of ongoing esophageal remodelling and
fibrosis.46 They have also shown that esophageal compliance correlates with
endoscopically-defined phenotypes of EoE,26, 47 similar to the phenotypes used in this
study. Our findings are also consistent with recent data presented by Schoepfer, Straumann,
and colleagues showing that the duration of untreated inflammation is strongly associated
with stricture development.48 Specially, they found that 17% of subjects with 0–2 years of
symptom duration had a stricture, compared to 38% with 9–11 years and 67% with more
than 20 years. Taken in the context of these data, our results support the hypothesis that
fibrostenotic complications are likely the result of chronic inflammation leading to disease
progression in EoE.
Author Manuscript

In addition to improving our understanding of the pathogenesis of EoE, recognition of

phenotypes of EoE may also have implications for treatment decisions and outcome
assessment. For example, if EoE is progressive, there may be an impetus to aggressively
treat eosinophilic inflammation in subjects who have not yet developed fibrostenotic
complications in order to prevent esophageal stricture development. Data suggest that
children who are treated may not have the severe phenotypes that are seen in adults who are
diagnosed after prolonged symptoms,34, 49, 50 and that long-term topical corticosteroid
treatment might alter the natural history of EoE.51 EoE phenotype might also dictate specific

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 7

treatments. Patients with fibrostenosis might require dilation as a primary treatment,

Author Manuscript

particularly since symptoms and levels of esophageal inflammation correlate poorly or not at
all.19, 33, 52, 53 Additionally, for drug development, patients with a predominantly
inflammatory phenotype, as opposed to those with established fibrostenosis, may be a
desirable target population for new medications with a strong anti-eosinophil/anti-
inflammatory effect.

In interpreting the results from this study, there are potential limitations. First, this is a
retrospective study from a single center, so the generalizability of the results is unclear.
However, the characteristics of this EoE population are quite similar to EoE patients
reported from other centers and practice settings. Because it relies on endoscopically-
defined phenotypes, the reproducibility of these findings may be questioned (for example,
the definition of “narrowing” is not standardized). However, recent work suggests there is
fair to good agreement among gastroenterologists for endoscopic findings of EoE.8, 54
Author Manuscript

Additionally, the data presented here are cross-sectional in nature, but are being used to
make inferences about disease progression. While the ideal study design to accomplish this
would be a long-term prospective cohort study, it is neither practical nor ethical to observe a
population of EoE cases for a decade or more to determine the true rate of fibrostenotic
complications. Furthermore, increasing risk for fibrostenotic progression was found to be
not only associated with age (a cross-sectional measure), but also with symptom duration
prior to diagnosis, a factor that capitulates retrospectively what a prospective cohort study
would measure. However, we acknowledge that confounding factors (for example,
concomitant use by atopic patients of intranasal or inhaled corticosteroids) could impact the
course of the disease, and therefore the observed EoE phenotype. Finally, this paper is
limited to clinicopathologic phenotypes. Future studies might determine whether
genetically-defined phenotypes of EoE exist and might be used for diagnosis, prognosis, or
Author Manuscript

to guide therapy.

The strengths of this study should also be acknowledged. This is large sample of well-
characterized EoE cases that provides sufficient power to subdivide the population in
multiple phenotypes. We selected phenotypes a priori that match the evolving
understanding of EoE. In addition, the predictive analysis using multinomial regression can
provide patients with quantifiable data as to what to expect for disease progression.

In conclusion, in this large cohort of subjects with EoE, the likelihood of fibrostenosing
disease increased with age. For every ten year increase in age, the odds of having a
fibrostenotic EoE phenotype more than doubled. The association of fibrostenosis with age
suggests that the natural history of EoE is a progression from an inflammatory to a
Author Manuscript

fibrostenotic disease. Further work should confirm these findings, and assess whether these
phenotypes predict response to various therapies or prognosis.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 8

Acknowledgments
Author Manuscript

Grant support: This work was supported, in part, by NIH Award K23 DK090073.

References
1. Katzka DA. Eosinophilic Esophagitis: From Rookie of the Year to Household Name. Clin
Gastroenterol Hepatol. 2009; 7:370–371. [PubMed: 19049833]
2. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: Updated consensus
recommendations for children and adults. J Allergy Clin Immunol. 2011; 128:3–20. e6. [PubMed:
21477849]
3. Straumann A, Spichtin HP, Grize L, et al. Natural history of primary eosinophilic esophagitis: a
follow-up of 30 adult patients for up to 11. 5 years. Gastroenterology. 2003; 125:1660–9. [PubMed:
14724818]
4. Straumann A. The natural history and complications of eosinophilic esophagitis. Thorac Surg Clin.
2011; 21:575–87. [PubMed: 22040638]
Author Manuscript

5. Dellon ES. Diagnosis and management of eosinophilic esophagitis. Clin Gastroenterol Hepatol.
2012; 10:1066–78. [PubMed: 22728382]
6. Desai TK, Stecevic V, Chang CH, et al. Association of eosinophilic inflammation with esophageal
food impaction in adults. Gastrointest Endosc. 2005; 61:795–801. [PubMed: 15933677]
7. Kim HP, Vance RB, Shaheen NJ, et al. The Prevalence and Diagnostic Utility of Endoscopic
Features of Eosinophilic Esophagitis: A Meta-Analysis. Clin Gastroenterol Hepatol. 2012; 10:988–
996. e5. [PubMed: 22610003]
8. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal features of
eosinophilic oesophagitis: validation of a novel classification and grading system. Gut. 2013;
62:489–95. [PubMed: 22619364]
9. Dellon ES, Gibbs WB, Fritchie KJ, et al. Clinical, endoscopic, and histologic findings distinguish
eosinophilic esophagitis from gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2009;
7:1305–1313. [PubMed: 19733260]
10. Straumann A, Aceves SS, Blanchard C, et al. Pediatric and adult eosinophilic esophagitis:
Author Manuscript

similarities and differences. Allergy. 2012; 67:477–90. [PubMed: 22313241]

11. Lucendo AJ, Sanchez-Cazalilla M. Adult versus pediatric eosinophilic esophagitis: important
differences and similarities for the clinician to understand. Expert Rev Clin Immunol. 2012;
8:733–45. [PubMed: 23167685]
12. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004; 351:940–1.
[PubMed: 15329438]
13. Vashi RA, Kagalwalla AF, Amsden K, et al. Systematic, endoscopic assessment demonstrates
increased fibrostenotic and decreased inflammatory esophageal features in adults compared with
children with eosinophilic esophagitis. Gastroenterology. 2013; 144 (Suppl 1):S494, Su1862.
14. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic esophagitis:
clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009; 48:30–6. [PubMed: 19172120]
15. Assa’ad AH, Putnam PE, Collins MH, et al. Pediatric patients with eosinophilic esophagitis: an 8-
year follow-up. J Allergy Clin Immunol. 2007; 119:731–8. [PubMed: 17258309]
16. Penfield JD, Lang DM, Goldblum JR, et al. The Role of Allergy Evaluation in Adults With
Eosinophilic Esophagitis. J Clin Gastroenterol. 2010; 44:22–7. [PubMed: 19564792]
Author Manuscript

17. Roy-Ghanta S, Larosa DF, Katzka DA. Atopic Characteristics of Adult Patients With Eosinophilic
Esophagitis. Clin Gastroenterol Hepatol. 2008; 6:531–5. [PubMed: 18304887]
18. Prieto R, Richter JE. Eosinophilic esophagitis in adults: an update on medical management. Curr
Gastroenterol Rep. 2013; 15:324. [PubMed: 23703154]
19. Hirano I. Therapeutic End Points in Eosinophilic Esophagitis: Is Elimination of Esophageal
Eosinophils Enough? Clin Gastroenterol Hepatol. 2012; 10:750–2. [PubMed: 22366179]

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 9

20. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a
systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology.
Author Manuscript

2007; 133:1342–63. [PubMed: 17919504]

21. Dellon ES, Chen X, Miller CR, et al. Tryptase staining of mast cells may differentiate eosinophilic
esophagitis from gastroesophageal reflux disease. Am J Gastroenterol. 2011; 106:264–71.
[PubMed: 20978486]
22. Dellon ES, Chen X, Miller CR, et al. Diagnostic utility of major basic protein, eotaxin-3, and
leukotriene enzyme staining in eosinophilic esophagitis. Am J Gastroenterol. 2012; 107:1503–11.
[PubMed: 22777338]
23. Dellon ES, Fritchie KJ, Rubinas TC, et al. Inter- and intraobserver reliability and validation of a
new method for determination of eosinophil counts in patients with esophageal eosinophilia. Dig
Dis Sci. 2010; 55:1940–9. [PubMed: 19830560]
24. Speck O, Woodward K, Covey S, et al. A training curriculum for pathologists yields highly
reproducible esophageal eosinophil counts. Gastroenterology. 2013; 144 (Suppl 1):S499, Su 1881.
25. Gupta SK, Fitzgerald JF, Chong SK, et al. Vertical lines in distal esophageal mucosa (VLEM): a
true endoscopic manifestation of esophagitis in children? Gastrointest Endosc. 1997; 45:485–9.
Author Manuscript

[PubMed: 9199905]
26. Lin Z, Nicodeme F, Chen J, et al. Esophageal compliance parameters assessed with the Functional
Luminal Imaging Probe (FLIP) among eosinophilic esophagitis (EoE) phenotypes.
Gastroenterology. 2013; 144 (Suppl 1):S487.
27. Saffari H, Peterson KA, Fang JC, et al. Patchy eosinophil distributions in an esophagectomy
specimen from a patient with eosinophilic esophagitis: Implications for endoscopic biopsy. J
Allergy Clin Immunol. 2012; 130:798–800. [PubMed: 22502795]
28. Straumann A, Conus S, Degen L, et al. Budesonide is effective in adolescent and adult patients
with active eosinophilic esophagitis. Gastroenterology. 2010; 139:1526–37. 1537 e1. [PubMed:
20682320]
29. Sperry SLW, Woosley JT, Shaheen NJ, et al. Influence of race and gender on the presentation of
eosinophilic esophagitis. Am J Gastroenterol. 2012; 107:215–21. [PubMed: 21971538]
30. Bohm M, Malik Z, Sebastiano C, et al. Mucosal Eosinophilia: Prevalence and Racial/Ethnic
Differences in Symptoms and Endoscopic Findings in Adults Over 10 Years in an Urban Hospital.
J Clin Gastroenterol. 2012; 46:567–574. [PubMed: 22186744]
Author Manuscript

31. Moawad FJ, Veerappan GR, Dias JA, et al. Race may play a role in the clinical presentation of
eosinophilic esophagitis. Am J Gastroenterol. 2012; 107:1263. [PubMed: 22859003]
32. Lin Z, Kahrilas PJ, Xiao Y, et al. Functional luminal imaging probe topography: an improved
method for characterizing esophageal distensibility in eosinophilic esophagitis. Therap Adv
Gastroenterol. 2013; 6:97–107.
33. Bohm ME, Richter JE. Review article: oesophageal dilation in adults with eosinophilic
oesophagitis. Aliment Pharmacol Ther. 2011; 33:748–57. [PubMed: 21320137]
34. Menard-Katcher P, Marks KL, Liacouras CA, et al. The natural history of eosinophilic
oesophagitis in the transition from childhood to adulthood. Aliment Pharmacol Ther. 2013;
37:114–21. [PubMed: 23121227]
35. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381
children. Clin Gastroenterol Hepatol. 2005; 3:1198–206. [PubMed: 16361045]
36. Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodeling in pediatric eosinophilic
esophagitis. J Allergy Clin Immunol. 2007; 119:206–12. [PubMed: 17208603]
Author Manuscript

37. Chehade M, Sampson HA, Morotti RA, et al. Esophageal subepithelial fibrosis in children with
eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2007; 45:319–28. [PubMed: 17873744]
38. Lucendo AJ, Arias A, De Rezende LC, et al. Subepithelial collagen deposition, profibrogenic
cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult
eosinophilic esophagitis: a prospective study. J Allergy Clin Immunol. 2011; 128:1037–46.
[PubMed: 21880354]
39. Aceves SS. Tissue remodeling in patients with eosinophilic esophagitis: what lies beneath the
surface? J Allergy Clin Immunol. 2011; 128:1047–9. [PubMed: 22036097]

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 10

40. Aceves SS, Chen D, Newbury RO, et al. Mast cells infiltrate the esophageal smooth muscle in
patients with eosinophilic esophagitis, express TGF-beta1, and increase esophageal smooth muscle
Author Manuscript

contraction. J Allergy Clin Immunol. 2010; 126:1198–204. e4. [PubMed: 21047675]

41. Cheng E, Souza RF, Spechler SJ. Tissue remodeling in eosinophilic esophagitis. Am J Physiol
Gastrointest Liver Physiol. 2012; 303:G1175–87. [PubMed: 23019192]
42. Keshishian J, Vrcel V, Estores D, et al. Mast cells in eosinophilic esophagitis: Trends in
inflammatory and fibrostenotic phenotypes. Gastroenterology. 2013; 144 (Suppl 1):S495, Su1865.
43. Stevoff C, Rao S, Parsons W, et al. EUS and histopathologic correlates in eosinophilic esophagitis.
Gastrointest Endosc. 2001; 54:373–7. [PubMed: 11522985]
44. Fox VL, Nurko S, Teitelbaum JE, et al. High-resolution EUS in children with eosinophilic
“allergic” esophagitis. Gastrointest Endosc. 2003; 57:30–6. [PubMed: 12518127]
45. Straumann A, Conus S, Degen L, et al. Long-term budesonide maintenance treatment is partially
effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2011; 9:400–9. e1.
[PubMed: 21277394]
46. Kwiatek MA, Hirano I, Kahrilas PJ, et al. Mechanical properties of the esophagus in eosinophilic
esophagitis. Gastroenterology. 2011; 140:82–90. [PubMed: 20858491]
Author Manuscript

47. Nicodeme F, Hirano I, Chen J, et al. Esophageal Distensibility as a Measure of Disease Severity in
Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2013
48. Schoepfer A, Safroneeva E, Bussmann C, et al. Duration of untreated inflammation represents the
main risk factor for stricture development in eosinophilic esophagitis. Gastroenterology. 2013; 144
(Suppl 1):S485, Su1832.
49. Jacobs JW, Bohm M, Gupta A, et al. Most children with eosinophilic esophagitis (EoE) have a
favorable outcome as young adults. Gastroenterology. 2013; 144 (Suppl 1):S487, Su1837.
50. DeBrosse CW, Franciosi JP, King EC, et al. Long-term outcomes in pediatric-onset esophageal
eosinophilia. J Allergy Clin Immunol. 2011; 128:132–8. [PubMed: 21636117]
51. Schoepfer A, Portmann S, Safroneeva E, et al. Influence of long-term treatment with topical
corticosteroids on natural course of eosinophilic esophagitis and correlation between symptoms
and endoscopy, histology, and blood eosinophils. Gastroenterology. 2013; 144 (Suppl 1):S154,
878.
52. Bohm M, Richter JE, Kelsen S, et al. Esophageal dilation: simple and effective treatment for adults
Author Manuscript

with eosinophilic esophagitis and esophageal rings and narrowing. Dis Esophagus. 2010; 23:377–
85. [PubMed: 20353444]
53. Morrow JB, Vargo JJ, Goldblum JR, et al. The ringed esophagus: histological features of GERD.
Am J Gastroenterol. 2001; 96:984–9. [PubMed: 11316216]
54. Peery AF, Cao H, Dominik R, et al. Variable reliability of endoscopic findings with white-light
and narrow-band imaging for patients with suspected eosinophilic esophagitis. Clin Gastroenterol
Hepatol. 2011; 9:475–80. [PubMed: 21377547]
Author Manuscript

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 11
Author Manuscript
Author Manuscript

Figure 1.
Predicted probability of developing a fibrostenosing phenotype of EoE based on age.
Author Manuscript
Author Manuscript

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 12

Table 1

Characteristics of patients with EoE (n = 379)

Author Manuscript

Characteristic N (%) or mean ± SD

Age at diagnosis (mean years ± SD, range) 25.3 ± 18.7 (0.6–82)
Adults ≥ 18 years 199 (53)
Males (n, %) 278 (73)
Whites (n, %) 305 (81)
Symptoms (n, %)
Dysphagia 244 (66)
Food impaction 100 (28)
Heartburn 139 (39)
Chest pain 33 (9)
Abdominal pain 83 (23)
Author Manuscript

Nausea 38 (11)
Vomiting 91 (26)
Failure to thrive 49 (14)
Symptom length prior to diagnosis (mean years ± SD) 7.1 ± 8.8

Atopic diseases (n, %)*

Allergic rhinitis/sinusitis/dermatitis 125 (38)
Asthma 89 (27)
Food allergy 62 (19)

Endoscopic findings (n, %)†

Normal 63 (17)
Rings 148 (40)
Stricture 66 (18)
Author Manuscript

Narrowing 44 (12)
Linear furrows 150 (40)
White plaques 81 (22)
Decreased vascularity 58 (16)
Crêpe-paper mucosa 23 (6)
Erosive esophagitis 89 (24)
Hiatal hernia 35 (9)
Dilation performed 76 (20)
Maximum eosinophil count (mean eos/hpf ± SD; range) 85.7 ± 81.1 (15–609)

*
Data were available on atopic status for 332 subjects
†
Data were available on EGD findings for 374 subjects
Author Manuscript

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 13

Table 2

Comparison of inflammatory, mixed, and fibrostenotic phenotypes of EoE

Author Manuscript

Inflammatory (n = 134; Mixed (n = 163; 43%) Fibrostenotic (n = 77; p*

36%) 21%)
Age (mean years ± SD) 13.3 ± 14.4 29.1 ± 16.9 39.2 ± 16.3 < 0.001
Adults ≥ 18 years 26 (19) 111 (68) 62 (81) < 0.001
Males (n, %) 99 (74) 120 (74) 54 (70) 0.82
Whites (n, %) 92 (69) 142 (88) 68 (88) < 0.001
Symptoms (n, %)
Dysphagia 47 (36) 123 (77) 70 (92) < 0.001
Food impaction 15 (12) 56 (37) 27 (39) <0.001
Heartburn 63 (49) 57 (37) 18 (27) 0.008
Chest pain 8 (6) 18 (12) 7 (10) 0.25
Abdominal pain 51 (39) 24 (16) 8 (12) < 0.001
Author Manuscript

Nausea 20 (15) 6 (4) 10 (15) 0.003

Vomiting 54 (41) 22 (15) 11 (16) < 0.001
Failure to thrive 33 (26) 13 (9) 1 (1) < 0.001
Symptom length prior to dx (mean years ± 5.3 ± 7.6 8.3 ± 9.4 8.4 ± 9.2 0.02
SD)
Atopic diseases (n, %)
Allergic rhinitis, sinusitis, dermatitis 50 (39) 59 (39) 13 (20) 0.01
Asthma 35 (27) 41 (27) 13 (20) 0.47
Food allergy 32 (27) 20 (15) 9 (18) 0.05
Endoscopic findings (n, %)
Normal 63 (47) 0 0 -
Rings 0 87 (53) 61 (79) -
Author Manuscript

Stricture 0 31 (19) 35 (45) -

Narrowing 0 31 (19) 13 (17) -
Linear furrows 56 (42) 94 (58) 0 -
White plaques 39 (29) 42 (26) 0 -
Decreased vascularity 25 (19) 24 (15) 9 (12) 0.38
Crêpe-paper 7 (5) 12 (7) 4 (5) 0.69
Erosive esophagitis 14 (10) 48 (29) 27 (35) < 0.001
Hiatal hernia 2 (1) 23 (14) 10 (13) < 0.001
Dilation performed 0 39 (24) 37 (47) -
Max eosinophil count (mean eos/hpf ± SD) 84.2 ± 75.9 79.3 ± 78.4 102.3 ± 95.4 0.12

*
p values calculated using a one-way ANOVA for continuous variables and chi-square for categorical variables; p values were not compared for
the endoscopic findings used to construct the phenotype groups.
Author Manuscript

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.

 Dellon et al. Page 14

Table 3

Comparison of EoE characteristics by pediatric versus adult onset of disease

Author Manuscript

Peds. onset (n = 172; 45%) Adult onset (n = 207; 55%) p*

Age (mean years ± SD) 12.7 ± 11.3 35.7 ± 17.1 --
Adults ≥ 18 years -- -- --
Males (n, %) 140 (81) 138 (67) 0.001
Whites (n, %) 129 (75) 176 (85) 0.02
Symptoms (n, %)
Dysphagia 75 (44) 169 (83) < 0.001
Food impaction 35 (21) 65 (35) 0.003
Heartburn 73 (43) 66 (35) 0.12
Chest pain 8 (5) 25 (13) 0.005
Abdominal pain 51 (30) 32 (17) 0.004
Author Manuscript

Nausea 17 (10) 21 (11) 0.72

Vomiting 62 (37) 29 (16) < 0.001
Failure to thrive 40 (24) 9 (5) < 0.001
Symptom length prior to dx (mean years ± SD) 6.4 ± 8.2 8.2 ± 9.7 0.10
Atopic diseases (n, %)
Allergic rhinitis, sinusitis, dermatitis 36 (39) 61 (33) 0.28
Asthma 51 (31) 38 (20) 0.03
Food allergy 36 (24) 26 (17) 0.11
Endoscopic findings (n, %)
Normal 47 (28) 16 (8) < 0.001
Rings 33 (19) 115 (56) < 0.001
Stricture 14 (8) 52 (25) < 0.001
Author Manuscript

Narrowing 13 (8) 31 (15) 0.02

Linear furrows 60 (35) 90 (44) 0.08
White plaques 42 (25) 39 (19) 0.19
Decreased vascularity 38 (22) 20 (10) 0.001
Crêpe-paper 16 (9) 7 (3) 0.02
Erosive esophagitis 42 (25) 47 (23) 0.71
Hiatal hernia 6 (4) 29 (14) < 0.001
Dilation performed 13 (8) 63 (31) < 0.001
Max eosinophil count (mean eos/hpf ± SD) 81.8 ± 69.7 88.9 ± 89.4 0.40

*
p values calculated using a t-test for continuous variables and chi-square for categorical variables.
Author Manuscript

Gastrointest Endosc. Author manuscript; available in PMC 2015 October 09.