Eosinophilic Esophagitis: Review Article

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Review Article

Julie R. Ingelfinger, M.D., Editor

Eosinophilic Esophagitis
Glenn T. Furuta, M.D., and David A. Katzka, M.D.​​

O
From the Department of Pediatrics, Sec- nce considered a rare condition, eosinophilic esophagitis is
tion of Gastroenterology, Hepatology, and now one of the most common conditions diagnosed during the assess-
Nutrition, University of Colorado School
of Medicine, and the Gastrointestinal Eo- ment of feeding problems in children and during the evaluation of dyspha-
sinophilic Diseases Program, Mucosal In- gia and food impaction in adults.1 The entity exists worldwide but has been most
flammation Program, Digestive Health extensively studied in Western countries, where its prevalence has been estimated
Institute, Children’s Hospital Colorado,
Aurora (G.T.F.); and the Division of Gastro- to be 0.4% among all children and adults.2 Whether eosinophilic esophagitis is
enterology and Hepatology, Mayo Clinic, truly a new disease or simply a recently recognized one is uncertain.3 In this re-
Rochester, MN (D.A.K.). Address reprint view, we consider the diagnostic criteria, pathophysiological and clinical features,
requests to Dr. Katzka at the Division of
Gastroenterology and Hepatology, Mayo and treatment of this increasingly prevalent disease.
Clinic, 200 First Ave. SW, Rochester, MN
55905, or at ­katzka​.­david@​­mayo​.­edu.
Defini t ion a nd Differ en t i a l Di agnosis
N Engl J Med 2015;373:1640-8.
DOI: 10.1056/NEJMra1502863 Esophageal eosinophilia was initially considered solely a manifestation of gastro-
Copyright © 2015 Massachusetts Medical Society.
esophageal reflux disease (GERD). However, in the mid-1990s, experienced clini-
cians identified esophageal eosinophilia in both adults and children who had other
symptoms. Neither the clinical symptoms nor the histologic changes in these pa-
tients responded to acid suppression and antireflux surgery, which suggested that
the condition was distinct from GERD. Two studies of case series4,5 and evidence
of the resolution of esophageal eosinophilia in response to therapy with an elemental-
formula diet6 suggested that eosinophilic esophagitis was a unique entity. How-
ever, clear diagnostic criteria were lacking.
More recently, evaluation and treatment recommendations have been developed
on the basis of clinical experiences from different medical subspecialties and the
increasing body of knowledge derived from clinical and basic research.7,8 Eosino-
philic esophagitis is currently defined as a chronic, immune-mediated or antigen-
mediated esophageal disease characterized by symptoms related to esophageal dys-
function and eosinophil-predominant inflammation. The dominant antigens that
mediate this disease appear to be food-based. Clinically, eosinophilic esophagitis
is defined by several components. First, symptoms include — but are not limited
to — feeding problems, vomiting, and abdominal pain in children and dysphagia
and food impaction in adolescents and adults. Second, esophageal mucosal eo-
sinophilia of at least 15 eosinophils per high-power field is present. Other causes
of these findings, particularly GERD, must be ruled out.7,8 However, GERD may be
difficult to rule out, because neither the response to proton-pump inhibitors nor
the duration of exposure to esophageal acid, measured by means of ambulatory pH
monitoring, definitively distinguishes GERD from eosinophilic esophagitis.9 Other
causes of esophageal eosinophilia (e.g., parasitic infection, allergic vasculitis, esoph-
ageal leiomyomatosis, and Crohn’s disease of the esophagus) are rare.

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Eosinophilic Esophagitis

Patho gene sis aggrin22 in vitro. Altered epithelial permeability23


can lead to a permissive environment that en-
Environmental Factors Conferring a hances antigen presentation, which in turn leads
Predisposition to Eosinophilic Esophagitis
to recruitment of eosinophils.
The increasing prevalence of eosinophilic esoph-
agitis has focused attention on environmental ex- Enhanced Th2 Activity and Allergic
posures. Birth by cesarean section, premature de- Susceptibility
livery, antibiotic exposure during infancy, food Several lines of evidence support the concept that
allergy, lack of breast-feeding, and living in an area eosinophilic esophagitis is an entity mediated by
of lower population density have all been associ- type 2 helper T (Th2) cell activity and induced
ated with eosinophilic esophagitis,10,11 which may primarily by food antigens. Studies of case series
imply that altered stimulation of the immune have repeatedly reported that patients with eosino-
system at an early age confers a predisposition to philic esophagitis have environmental and food
this disease. Studies have also suggested that a hypersensitivity, have a response to dietary elim-
lack of early exposure to microbes11 and an altered ination of food antigens, and have a relapse with
microbiome may play a role, as has been suggested reintroduction of similar food antigens.6,24 Where-
for other atopic diseases, such as asthma and as food antigens are primarily identified as the
atopic dermatitis.12 There is speculation that these allergic triggers, inhaled aeroallergens have also
exposures early in life create an epigenetic sig- been implicated in some patients; this finding may
nature that increases the probability of develop- represent a manifestation of cross-sensitization to
ing eosinophilic esophagitis. food allergens.25 Indeed, murine models of eosino-
philic esophagitis can be induced by sensitizing
Genetic Predisposition and challenging mice with aeroallergens and ov-
The male predominance of eosinophilic esopha- albumin26,27 or by overexpressing the cytokines
gitis, as well as studies of family history and twin seen in human eosinophilic esophagitis in the
concordance and genomewide association stud- animals.28 Several lines of evidence suggest that
ies, suggest that there is a genetic component to interleukin-5 and interleukin-13 may play a role
eosinophilic esophagitis. In almost every study, in the pathogenesis of eosinophilic esophagitis.
male sex has a 3:1 preponderance.13 A family his- Interleukin-5–null mice develop less esophageal
tory of eosinophilic esophagitis is frequently re- eosinophilia in allergen-induced models, as com-
ported, with the heritability risk estimated to be pared with wild-type mice. Interleukin-13 is over-
2% on the basis of results from a nuclear family– expressed in biopsy specimens from patients with
based cohort of 914 probands with eosinophilic eosinophilic esophagitis and has been found to
esophagitis and 63 twin probands.14 Genomewide regulate a number of related cytokines in in vitro
association studies have reported three genes with studies22 and in studies of mice. In addition, sepa-
proposed functional sequelae (the genes encod- rate prospective trials have shown that treatment
ing thymic stromal lymphopoietin,15 eotaxin-3 with anti–interleukin-5 or anti–interleukin-13 anti-
[also called chemokine C-C motif ligand 26],16 and bodies reduces numbers of esophageal eosinophils
calpain-1417,18) as being altered in eosinophilic in children and adults.29,30 There are also cytokine-
esophagitis. directed and thymic stromal lymphopoietin–
directed proliferation and recruitment of eosino-
Impaired Barrier Function phils, IgE-bearing mast cells,31 Th2 lymphocytes,32
Assessment of esophageal tissues from patients basophils33 and natural killer cells34 in patients
with eosinophilic esophagitis has revealed a strik- with eosinophilic esophagitis.
ing pattern of dilated interepithelial spaces,19 al- The predominant mechanism of food allergy
tered epithelial barrier function,20 and down-regu- in eosinophilic esophagitis appears to be a non–
lation of proteins associated with barrier function IgE-mediated process, because omalizumab, an
(filaggrin and zonulin-119) and adhesion molecules anti-IgE biologic treatment, is not effective in hu-
(desmoglein-121) (Fig. 1). Interleukin-13 has been mans,35 esophageal eosinophilia can develop in
shown to down-regulate desmoglein-121 and fil- IgE-null and B-cell–null mice,36 and IgE-based

n engl j med 373;17 nejm.org October 22, 2015 1641


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The n e w e ng l a n d j o u r na l of m e dic i n e

Genetic abnormalities Food antigens Aeroallergens Environmental factors?


CCL26 (eotaxin-3), 5q22 Shared epitope Altered microbiome,
(TSLP), calpain-14, sensitization decreased Th1, increased
TGF-β1, filaggrin, Th2, increased small-
desmoglein-1 bowel permeability

↓ Barrier function
Dilated intercellular
spaces ESO PHAGUS

Dilatation
Antigen
recognition
Small-caliber
DENDR ITIC esophagus
C ELL
TH2 White exudate
LYMPHOC YTE
Longitudinal
shearing
Cell recruitment and proliferation (crepe-paper
Eotaxin-3, interleukin-5, 9, and 13 esophagus)
Isolated stricture
LYMPHOC YTE

BAS OPHIL
MAS T
C ELL Inflammation Fibrosis–dysmotility
Furrows, exudates, Strictures, small-caliber
concentric rings esophagus

Acute allergic Chronic inflammation


EOS INOPHIL inflammation
TGF-β1, periostin,
Interleukin-4, 5, 13, epithelial–mesenchymal
TSLP, eotaxin-3, transition, fibroblast
prostaglandin D2 growth factor-9,
receptor, IgE, IgG4, phospholamban
eosinophil-derived
granule proteins,
bone morphogenetic
protein

Figure 1. Pathophysiological Mechanisms of Eosinophilic Esophagitis.


Eosinophilic esophagitis is an allergen-mediated disease in which eosinophils are recruited to the esophagus. The
functional consequences of this inflammation include stricture formation with proximal dilatation and longitudinal
shearing. CCL26 denotes chemokine C–C motif ligand 26, TGF transforming growth factor, Th1 type 1 helper T cell,
Th2 type 2 helper T cell, and TSLP thymic stromal lymphopoietin.

skin testing does not consistently identify food- suring wall compliance may be useful even when
antigen triggers.37 Food-specific IgG4 was recentlystricturing and fibrosis are not detectable endo-
shown to be present in the esophageal epitheli- scopically.39 Early studies with that device showed
um and to be reactive to the four most common that patients with a specific distensibility plateau
food-antigen triggers in patients with eosinophilicwere less likely to have a history of food impac-
esophagitis38 tion or to have food impaction during follow-up
evaluation. Contrast esophagography in patients
Esophageal Dysfunction and Fibrotic with abnormal esophageal-wall compliance often
Potential reveals that the esophageal caliber is decreased
An intraluminal balloon device that is used to as- and the esophagus is diffusely less distensible.40
sess esophageal stricturing and fibrosis by mea- In vitro exposure of esophageal fibroblasts and

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Eosinophilic Esophagitis

smooth-muscle cells to transforming growth fac- or whether adult patients truly have late onset of
tor β (TGF-β) leads to smooth-muscle contraction the disease or a different pathogenesis or pheno-
and fibrosis.41-43 type of the disease. In support of the hypothesis
that unrecognized childhood subclinical disease
Cl inic a l Fe at ur e s or silent chronic inflammation precedes presen-
tation in adults are results from a natural his-
Epidemiology tory study in which it was observed that 85% of
Since the establishment of diagnostic guidelines adults who had untreated symptoms for 20 years
and a diagnostic code (International Classification of presented with esophageal strictures.51
Diseases, Ninth Revision, code 530.13; International
Classification of Diseases, Tenth Revision, code K20.0), Imaging in Eosinophilic Esophagitis
some studies have estimated the prevalence of Endoscopy and contrast radiography provide com-
eosinophilic esophagitis as between 1 and 5 per plementary tools for the assessment of the esoph-
10,000 persons in the United States and Europe, agus in eosinophilic esophagitis (Fig. S1 in the
with an increasing prevalence in Asia.44-47 Certain Supplementary Appendix, available with the full
subpopulations, such as patients who are under- text of this article at NEJM.org). The most com-
going endoscopy for a history of food impaction, mon endoscopic findings are white specks (rep-
have a markedly higher prevalence, of up to 54%.48 resentative of eosinophilic exudates), mucosal
Eosinophilic esophagitis has been described in edema, linear furrows, esophageal rings, and
all age groups, but it predominantly affects white strictures.52,53 Chronic remodeling is represented
men, with an onset from school age to midlife.46 by strictures; a so-called “crepe-paper esophagus,”
A personal or family history of atopic disorders, in which linear tears occur in response to mini-
such as asthma, eczema, rhinitis, and anaphylac- mal trauma, such as passage of the endoscope50;
tic food allergy, is common, and these conditions and the “tug sign,” a firm feeling sensed by the
require treatment.49 endoscopist when performing an esophageal bi-
opsy.54 A validated endoscopic scoring system was
Clinical Presentation recently developed to standardize the assessment
Children may have a wide variety of nonspecific of eosinophilic esophagitis signs that scores the
symptoms, including feeding difficulty, nausea presence of edema, rings, exudates, furrows, and
and vomiting, heartburn, and failure to thrive. strictures (EREFS).52
In contrast, teenagers and adults are more likely The recognition of eosinophilic esophagitis as
to present with dysphagia and episodes of food a diagnostic entity has led to increased use of
impaction. Nevertheless, patients of different age barium esophagography to evaluate the esopha-
groups may have symptoms in common — for geal lumen in patients with dysphagia. In con-
example, chronic reflux symptoms. Symptoms trast to the focal distal esophageal strictures found
may be underestimated as a result of long-stand- in patients with GERD, strictures in patients with
ing and subtle accommodation, such as eating eosinophilic esophagitis may be lengthy and ta-
slowly, chewing carefully, cutting food into small pered and commonly escape detection during en-
pieces, lubricating foods with sauces, drinking doscopy but are evident in contrast esophagrams.
liquids to dilute foods, and avoiding pills and Two recent studies reported that 71% of adults
foods likely to cause dysphagia, such as meats and and 55% of children with eosinophilic esophagi-
breads. Patients may be afraid to eat in public tis did not have esophageal narrowing recognized
places, worrying that they will have difficulty eat- at the time of endoscopy but did have evidence
ing. In rare cases, eosinophilic esophagitis may of narrowing at the time of esophagography.55,56
manifest with spontaneous rupture of the esoph-
agus from forceful retching (Boerhaave’s syn- Histologic Characteristics of Eosinophilic
drome) after a food impaction. Heartburn, espe- Esophagitis
cially with the ingestion of alcohol, occurs in 30% An increased number of eosinophils in the esoph-
of adult patients.13,50 It is unclear whether years ageal epithelium, which is a mucosa that is typi-
of unrecognized childhood subclinical disease or cally devoid of eosinophils, is the histologic hall-
“silent” chronic inflammation precede presenta- mark of eosinophilic esophagitis (Fig. 2). A cutoff
tion in adults who have eosinophilic esophagitis value of at least 15 eosinophils per high-power

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The n e w e ng l a n d j o u r na l of m e dic i n e

and restoration of function. Three approaches


can be used to reach these goals: diet, drugs, and
dilation.65 When possible, therapy should be pro-
vided with a team approach that includes a gas-
troenterologist, an allergist, and a nutritionist.

Diet
In 1995, a study described the favorable effects of
an exclusive amino acid–based formula diet (i.e.,
one devoid of food antigens) in the treatment of
Figure 2. Histologic Characteristics of Eosinophilic 10 children with eosinophilic esophagitis.6 Both
Esophagitis. the symptoms and the histologic abnormalities
Routine staining with hematoxylin and eosin reveals improved, but they recurred after resumption of
numerous eosinophils (thin arrows), dilated intercellu- a normal diet. This small study was followed by
lar spaces (thick arrow), basal zone hyperplasia (circle), much larger studies66 and by a similar study in-
and papillary elongation (bracket).
volving adults67; in these studies, the patients had
a near complete response to therapy, and the
stage was set for the routine use of diet therapy
field is thought to approach a sensitivity of 100% in the treatment of eosinophilic esophagitis. The
and specificity of 96% for establishing the histo- expense and lack of patient interest in an ele-
logic diagnosis of eosinophilic esophagitis,57 al- mental diet led to the development of two other
though patients with lower levels of eosinophilia diet strategies (Table 1). The use of skin-prick,
and phenotypic features of eosinophilic esopha- atopy-patch, or specific serum IgE testing per-
gitis have been described.58 Characteristic, but not formed by an allergist to determine targeted di-
pathognomonic, features include aggregates of ets has been shown to have a high degree of
eosinophils or microabscess and eosinophil lay- success in children; however, more recent work
ering along the luminal surface. Other associat- indicates that this approach may not be as effec-
ed patterns of injury include dilated intercellular tive as initially thought, with only 45% of pa-
spaces, rete-peg elongation, and basal-cell hyper- tients having a sustained response.68 Neverthe-
plasia.59 Numbers of inflammatory cells, includ- less, elimination diets and the avoidance of food
ing lymphocytes, mast cells, and basophils, are anaphylaxis as directed by an allergist are rea-
also increased in the affected epithelial space.33,60 sonable treatment options. An alternative diet
treatment does not rely on food-allergy testing
Associated Complications and Conditions but rather eliminates the six most commonly
Complications that may occur in association with identified types of allergenic food (wheat, milk,
eosinophilic esophagitis include esophageal stric- soy, nuts, eggs, and seafood). This so-called six-
ture, food impaction, perforation, and malnutri- food elimination diet was found to improve symp-
tion but not cancer. A number of coexisting con- toms and histologic abnormalities in up to 26 of
ditions have been associated with patients with 35 children69 and 32 of 50 adults37 within 6 weeks.
esophageal eosinophilia, including connective- Follow-up studies are evaluating a less stringent
tissue diseases,61 celiac disease,62 and Crohn’s approach in which fewer foods are initially elimi-
disease.63 nated.70
Diet therapy can be highly effective and can
directly address the underlying allergic mecha-
T r e atmen t
nism. It may also achieve the goal of identifying
Identification of Validated Treatment End a limited number of food antigens that trigger the
Points inflammatory response. For example, because en-
Patients with eosinophilic esophagitis may have doscopy with biopsy is currently the only reliable
a mismatch between symptoms and histopatho- method for the assessment of histologic response,
logic features, which creates the need for mul- individual patients may undergo multiple endo-
tiple assessments of disease activity.64 As a result, scopic examinations in an attempt to identify the
the short-term treatment goals include the alle- foods that trigger esophageal eosinophilia.71 Less-
viation of symptoms, control of inflammation, invasive testing with a swallowed sponge admin-

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Eosinophilic Esophagitis

istered bedside without anesthesia is currently be- Table 1. Medical Treatment of Active Eosinophilic Esophagitis.
ing studied.72 The increased cost of food, poor
adherence, and nutritional deficiencies due to the Method Specific Recommendation or Dosage
elimination of foods are concerns with diet Elemental diet therapy —
therapy. Elimination diet therapy
Six-food elimination Elimination of milk, wheat, eggs, soy,
Drugs seafood, and nuts
Proton-Pump Inhibitors
Four-food elimination Elimination of milk, wheat, eggs, and soy
Proton-pump inhibitors may play a role in the
Allergy testing–based Elimination of foods on the basis of results of
diagnostic evaluation of patients with suspected radioallergosorbent testing, skin-prick test-
eosinophilic esophagitis and in the care of those ing, or atopy-patch testing*
with the disease. First, a lack of response to proton- Omeprazole (proton-pump Children with body weight 10 to 20 kg: 10 mg
pump inhibitors is currently the only criterion inhibitor)† twice a day
available to rule out GERD as a cause of esopha- Children with body weight >20 kg: 20 mg
twice a day
geal eosinophilia. Second, patients with well- Adults: 40 mg once or twice a day
established eosinophilic esophagitis can also have Glucocorticoids
symptomatic GERD that is responsive to proton-
Fluticasone Children: 220 to 440 μg twice a day
pump inhibitor treatment and contributes to the Adults: 440 to 880 μg twice a day
development of eosinophilic esophagitis. Third, Budesonide Children: 0.25 to 0.5 mg twice a day
in vitro studies show that proton-pump inhibitors Adults: 1 to 2 mg twice a day
decrease cytokine secretion from the esophageal
epithelium independently of their effect on acid * Approximately 45% of patients have a sustained response to this type of diet
therapy.68
secretion, which leads to the hypothesis that pro- † An equivalent proton-pump inhibitor can be administered.
ton-pump inhibitors may provide an antiinflam-
matory benefit.73 These in vitro studies have fur-
ther defined a subgroup of patients with an not been approved by the Food and Drug Admin-
eosinophilic esophagitis phenotype in which the istration, fluticasone administered orally as a
esophageal eosinophilia responded to proton- spray from a metered-dose inhaler or a viscous
pump inhibitors, a phenomenon termed proton- preparation of liquid budesonide are the main-
pump inhibitor–responsive esophageal eosinophil- stays of pharmacologic therapy for eosinophilic
ia. Further study of patients with proton-pump esophagitis.79-84 The efficacy of these topical medi-
inhibitor–responsive esophageal eosinophilia has cations in improving symptoms and histologic
shown that they have clinical, histologic, and abnormalities after 2 to 12 weeks of use ranges
genetic characteristics similar to those of patients from 53%81 to 95%.64,82 Topical glucocorticoids
with eosinophilic esophagitis, which supports the may also reduce the frequency of subsequent food
possibility that the condition is a subtype of eo- impactions.83 One study has supported the ob-
sinophilic esophagitis.60,74-76 Nevertheless, the re- servation that oral viscous budesonide has more
sponse to proton-pump inhibitors, in contrast to prolonged contact with esophageal mucosa and
being completely driven by food allergies, may coats a greater length of the esophagus than does
differentiate proton-pump inhibitor–responsive nebulized budesonide.84 Recent genomic analyses
esophageal eosinophilia from eosinophilic esoph- may help identify whether patients will be more
agitis. or less likely to have a response to glucocorticoid
treatment.79 The potential side effects include lo-
Topical Glucocorticoids cal candida infection, adrenal axis suppression,
Glucocorticoids target key mechanisms in eosin- bone demineralization, and diminished growth.
ophilic esophagitis. For example, glucocorticoids Because swallowed topical glucocorticoids under-
decrease fibrosis through the reduction of inflam- go first-pass metabolism, such effects appear to
matory cells.77 Furthermore, increased levels of be uncommon.85 Nevertheless, the use of systemic
interleukin-13 (a central regulator of allergic dis- glucocorticoids to treat eosinophilic esophagitis
eases) messenger RNA and the eosinophilic esoph- leads to similar therapeutic results but incurs a
agitis transcriptome are largely reversible with greater risk of side effects than does the use of
glucocorticoid treatment in vivo.78 Although it has topical glucocorticoids.80

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The n e w e ng l a n d j o u r na l of m e dic i n e

Dilation such as strictures may develop.51 Few studies have


Esophageal dilation to alleviate esophageal nar- examined the long-term benefit of diet or topical
rowing is a commonly accepted therapy for eosino- glucocorticoid therapy in eosinophilic esophagi-
philic esophagitis, particularly in older teenag- tis, although both have been proposed as options
ers and adults. Whereas earlier reports suggested for maintaining remission.89 The expert consen-
a high rate of complications related to dilation sus opinion is that evidence of chronic remodel-
in patients with eosinophilic esophagitis, a review ing, as in patients with long strictures or a small-
of several large series has shown perforation caliber esophagus, a history of food impactions
rates of less than 1% (3 of 992 dilations).86 In or severe symptoms, or rapid recurrence of ill-
patients with eosinophilic esophagitis, dilation ness while not receiving therapy, indicates the
should be performed gradually over multiple ses- need for maintenance therapy.7,8
sions, with an expectation that 75% of patients
will have chest pain after the procedure (a course C onclusions
that differs from that in patients with GERD).
Dilation successfully addresses the luminal nar- Since the initial description of eosinophilic esoph-
rowing that can complicate eosinophilic esopha- agitis in case series more than 20 years ago,
gitis but does not treat the underlying inflam- interest in it has burgeoned, and there is now a
matory process. greater awareness of the clinical features, basic
mechanisms, and effective therapeutic options.
Long-Term Complications, Quality of Life, The advent of molecular characterizations and
and Maintenance Therapy diagnostics will lead to the determination of new
One of the controversial questions in the man- therapeutic strategies.90 Progress in the treatment
agement of eosinophilic esophagitis is the role of eosinophilic esophagitis will require a better
of long-term maintenance therapy. The evidence understanding of the implications of this chronic
to date indicates that eosinophilic esophagitis is and probably lifelong disease, the development
a not premalignant disease and does not dimin- of new therapeutic approaches, and the docu-
ish life span. Furthermore, periods of prolonged mentation of the safety and efficacy of long-term
spontaneous or dilation-induced symptomatic re- therapies.
mission may occur without the need for dietary
changes or medical therapy.87 However, in most Dr. Furuta reports receiving consulting fees from Genentech
and grant support from Morphotek and Nutricia, and is co-founder
patients, eosinophilic esophagitis is a chronic of EnteroTrack. Dr. Katzka reports that his laboratory has pro-
disease, and if treatment is stopped, inflamma- vided funding to Capnostics to develop an esophageal sponge.
tion ensues and symptoms recur; quality of life, No other potential conflict of interest relevant to this article was
reported.
including vitality and general health scores, is Disclosure forms provided by the authors are available with
subsequently diminished,88 and complications the full text of this article at NEJM.org.

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Eosinophilic Esophagitis

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