Pi Is 0016508520302651
Pi Is 0016508520302651
Pi Is 0016508520302651
indirect comparator. For these recommendations, risk makes it difficult to provide a precise estimate of an abso-
ratios (RRs) are presented by applying the baseline risk lute effect size and raises important concerns regarding
from the untreated control arms from steroid RCTs to the variation in the criteria for patient selection, study design, as
RR. As was reported in the technical review, use of this well as PPI duration, dosing, and formulation. Furthermore,
comparator should not be viewed the same as a direct most studies were noncomparative, single-arm, retrospec-
control group comparison, but as an approximated mea- tive studies. Based on these factors, the strength of the
sure that is permissible under Grading of Recommenda- recommendation was lowered. Nevertheless, a clinical
tions Assessment, Development, and Evaluation (GRADE) benefit to the use of PPI monotherapy may be evident for
methodology. certain patients. It is important to note that a European and
The guideline was developed utilizing a process outlined an International consensus recommendation have recently
elsewhere.3 Briefly, both the AGA and JTF process for removed the PPI trial from the diagnostic criteria of EoE.7,8
developing clinical practice guidelines incorporates GRADE After the exclusion of secondary causes of esophageal
methodology3 and best practices as outlined by the Institute eosinophilia, symptomatic esophageal eosinophilia is now
of Medicine.4 GRADE methodology was utilized to prepare viewed as synonymous with EoE. PPIs are positioned as an
the background information for the guideline and the effective, primary therapeutic option for certain patients
technical review that accompanies it.2 GRADE uses the PICO with EoE. Based on their longstanding safety profile and
format, which frames a clinical question by defining a spe- ease of administration, patients may prefer to start with this
cific population (P), intervention (I), comparator (C), and form of therapy before trials of glucocorticosteroids or
outcomes (O). The PICO questions focused on the use of elimination diets. It should be emphasized that direct com-
therapeutics in patients with EoE. Each of the selected PICO parison of the efficacy of PPI and other medical or dietary
questions was addressed in this review using the GRADE EoE therapies is limited because, up to this time, most trials
framework using evidence profiles, except for the last 2 in EoE have excluded patients with esophageal eosinophilia
PICO questions, which were addressed using a GRADE that responded to a PPI (formerly denoted as PPI-
narrative review format. All recommendations were responsive esophageal eosinophilia).
formulated using the GRADE evidence to decision frame-
work (Tables 1–3). Optimal understanding of this guideline
will be enhanced by reading applicable portions of the Question 2. Should Topical Glucocorticosteroids
technical review. A unique aspect of this guideline and the Be Used in Patients With Eosinophilic
corresponding technical review was their development Esophagitis?
through a collaboration between AGA and JTF, which is
composed of the American Academy of Allergy, Asthma and
Immunology and American College of Allergy, Asthma and
Immunology. In addition, representatives of both pediatric In patients with EoE, the AGA/JTF recommends
topical glucocorticosteroids over no treatment.
and adult medicine were included as well as a patient with (Strong recommendation, moderate quality evidence)
EoE. This collaborative guideline reflects the interdisci-
plinary nature of EoE that integrates clinical and investi-
gative efforts of multiple domains and builds on prior Eight double-blind placebo-controlled studies enrolling
consensus recommendations published in both the allergy 437 patients followed for a mean of 8 weeks compared
and gastroenterology literature.5,6 treatment with topical budesonide or topical fluticasone to
placebo.2 It is of note that most of these studies required
that patients first fail a PPI trial or excluded patients with
Recommendations known gastroesophageal reflux disease, which may not
Question 1. Should Proton Pump Inhibitors Be reflect routine clinical practice or the most current
Used in Patients With Esophageal Eosinophilia? consensus-driven recommendations. Two of the trials used
formulations of topical steroids developed specifically for
esophageal delivery (tablet or liquid), whereas the
CLINICAL PRACTICE GUIDELINES
Strength of
recommendation For the patient For the clinician
Strong Most individuals in this situation would want the Most individuals should receive the recommended course of
recommended course of action and only a action. Formal decision aids are not likely to help individuals
small proportion would not. make decisions consistent with their values and preferences.
Conditional The majority of individuals in this situation Different choices will be appropriate for different patients.
would want the suggested course of action, Decision aids may be useful in helping individuals in making
but many would not. decisions consistent with their values and preferences.
Clinicians should expect to spend more time with patients
when working toward a decision.
was downgraded for inconsistency due to heterogeneity of significance of this difference, however, is unclear, given
the studies. In short-term studies of 3 months, there was that symptomatic improvement was similar in both groups
no increased risk of adverse events in patients treated with with 72% response rates in the prednisone arm vs 65% in
steroids compared with placebo (RR, 1; 95% CI, 0.85–1.19), the fluticasone arm. Relapse rates were also similar at 45%
although local viral and fungal infections and very limited in both groups at week 24. Systemic complications were
description of adrenal suppression have been described in increased at 40% in the prednisone group, including weight
certain populations. Longer-term studies prospectively gain and cushingoid appearance, compared with a 15% rate
assessing the safety of topical glucocorticosteroid use, of oral candidiasis in the fluticasone group. Based on the
including adrenal function and growth suppression in chil- similar effectiveness and well-characterized side effects of
dren, are ongoing. It is relevant to consider that the same systemic glucocorticosteroids, topical glucocorticosteroids
inhaled steroid agents are considered very safe for use in are preferred over prednisone for treatment of children
children and adults with asthma and are routinely used in with EoE. Similarities in disease pathogenesis and clinical
the primary management of this disease. While no medica- manifestations in children and adults with EoE support the
tions have been yet approved for treatment of EoE by the extension of the recommendation to adult populations. The
Food and Drug Administration, the European Medicines potential benefits of systemic glucocorticosteroids in EoE
Agency approved a budesonide tablet formulation for EoE patients that are refractory to topical glucocorticosteroids
in 2018. are currently unknown.
vs systemic glucocorticosteroids in 80 children with EoE.2 The relevant data on efficacy of elemental diets (amino
Prednisone was given at a dose of 1 mg/kg twice a day, acid–based formulas) for treatment of EoE are derived from
while fluticasone was given at a dose of 2 puffs 4 times a 6 single-arm, observational studies without control group
day (110 mg/puff for those aged < 10 years and 220 mg/puff comparators, which indicate that very few (6.4%) of these
for those aged 11–18 years) for 4 weeks, followed by subjects on elemental diet failed to achieve histologic
tapered dosing over 8 weeks. The primary end point was remission (defined as <15 eos/hpf).2 This contrasts with
the histologic response, which was based on a score failure to achieve histologic remission in 86.7% of a his-
consisting of the percentage of basal cell hyperplasia and torical placebo comparison group from glucocorticosteroid
eosinophil density (eos/hpf). Both groups had similar his- trials, resulting in an estimated RR of 0.07 (95% CI, 0.05–
tologic improvement, defined as a 1-point drop in this score. 0.12).2 Adult studies had a lower proportion of participants
However, this score showed statistically greater improve- achieving histologic remission than pediatric studies.2
ment in the prednisone-treated group compared to the Difficulty adhering to elemental diets for reasons such as
fluticasone-treated group at 4 weeks. The clinical taste, nutritional concerns, practical implementation within
May 2020 AGA and JTF Clinical Guidelines for the Management of EoE 1779
Quality Definition
High We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate We are moderately confident in the effect estimate. The true effect is likely to be close
to the estimate of the effect, but there is a possibility that it is substantially
different.
Low Our confidence in the effect estimate is limited. The true effect may be substantially
different from the estimate of the effect.
Very low We have very little confidence in the effect estimate. The true effect is likely to be
substantially different from the estimate of effect
the context of overall dietary alternatives, breadth of all were single-arm, observational studies.2 The RR for
avoidance in this style of diet, and cost are of concern. failure to achieve histologic remission relative to placebo
Harms include interference with development of oral motor based on historical controls was 0.38 (95% CI, 0.32–0.43).2
skills in children, social isolation created by dining re- While uniformly beneficial from these observational studies,
strictions, the potential need for gastrostomy tube, costs of certainty in the effect estimate was rated down, as none of
elemental formula, and burden of repeated endoscopies the studies were controlled trials. Although these studies
during gradual food re-introduction. From a food allergy were reported as “6-food” elimination diets, the inclusion of
perspective, there may be some risk of developing de novo both tree nuts and peanuts as well as finned fish and
IgE-mediated food allergy in previously tolerant patients on shellfish could be considered as 8 separate food groups.
elimination diets for EoE, as has been noted in isolated case Furthermore, this approach entails a higher number of
reports in EoE as well as in atopic dermatitis.9,10 There is actual foods because of the multiple different types of tree
insufficient literature beyond a handful of case reports nuts, finned fish, and shellfish. In addition, 2 studies elimi-
describing such events to determine whether such risk ex- nated foods to which patients had abnormal skin testing and
ists, and further studies are needed to evaluate this concern. 1 also eliminated corn, rice, and legumes.
Elimination diets of any type should be used with discretion Several practical concerns limit the utilization of empiric
and for as short a period as is suitable to treat the under- elimination diets in EoE. Heterogeneity in response rates could
lying EoE. Consultation with a board-certified allergist who reflect selection bias and potential for exclusion of patients with
is skilled in the management of IgE-mediated food allergy limited adherence to the diet. Incomplete or inconsistent diet
should be a strong consideration. reintroduction may reflect the challenges in adherence and
Therefore, although the evidence for efficacy of activity assessment defining disease relapse (symptoms vs
elemental diets is of moderate quality due to possible large pathology) during the reintroduction process. As is common to
effects, we suggest a conditional recommendation for any form of elimination diet, the time, risk, and financial burden
elemental diet. Clinicians should consider patient age and of repeated endoscopies are also potential implementation
preferences for alternative medical and dietary manage- barriers, as is long-term adherence after the identification of
ment therapeutic options when considering elemental diets. specific food trigger(s) in the re-introduction process, and the
possible development of de novo IgE-mediated food allergy
upon re-introduction.11
Question 5. Should an Empiric Food Elimination Several trials were reviewed utilizing empiric elimina-
Diet Be Used in Patients With Eosinophilic tion diets that limited the number of avoided foods to 1, 2,
Esophagitis? or 4, given data by Kagalwalla et al suggestive that peanut/
tree nut and finfish/shellfish reintroduction after 6-food
elimination diet was associated with low rates of disease
In patient with EoE the AGA/JTF suggests using an recurrence, and that not all major allergens needed to be
CLINICAL PRACTICE GUIDELINES
empiric six-food elimination diet over no treatment. removed initially.2 Although this approach potentially
(Conditional recommendation, low quality evidence) reduces the burden of repeated endoscopies during the
Comment: Patients who put a higher value on avoiding reintroduction process and can improve lifestyle and
the challenges of adherence to diet involving elimination adherence, the effectiveness appears to be lower.2 Never-
of multiple common food staples and the prolonged theless, the emerging data on less-restrictive diets may
process of dietary reintroduction may reasonably decline
this treatment option. increase both provider and patient preference for an
empiric elimination diet in EoE. Furthermore, less-invasive
procedures, such as transnasal endoscopy (which does not
Ten studies reported the effectiveness of an empiric, require sedation), as well as nonendoscopic, office-based
6-food elimination diet with an overall, unweighted histo- methods to assess disease activity through assessment of
logic response rate of 68%, although these also suffered surrogate markers, are under development and could
from the same limitations of elemental diet studies in that obviate the need for repeated biopsy sampling during the
1780 Hirano et al Gastroenterology Vol. 158, No. 6
Table 3.American Gastroenterological Institute and Joint Task Force on Allergy-Immunology Practice Parameters Guideline
Recommendations on the Management of Eosinophilic Esophagitis
Strength of
Recommendation recommendation Quality of evidence
11. Recommendation: In patients with EoE, the AGA/JTF suggests Conditional Very low quality
against the use of anti-IgE therapy for EoE.
12–15. Recommendation: In patients with EoE the AGA/JTF suggest No recommendation Knowledge gap
using montelukast, cromolyn sodium, immunomodulators, and
anti-TNF for EoE only in the context of a clinical trial.
May 2020 AGA and JTF Clinical Guidelines for the Management of EoE 1781
reintroduction process, thereby increasing the practical significant difference between studies that used patch
application of elimination diet for EoE.12 testing and those that did not; however, a sensitivity anal-
ysis excluding studies using serum-specific IgE was not
performed. There may be a potential role for aeroallergen
Question 6. Should Allergy-Based Testing Be testing and treatment in EoE, which is presently being
Used for the Purpose of Identifying Food Triggers evaluated. Similar to potential risks for other dietary elim-
in Patients With Eosinophilic Esophagitis? ination strategies, there may be challenges with long-term
adherence to dietary elimination and a potential risk of de
novo IgE-mediated food allergy upon re-introduction.
In patients with EoE, the AGA/JTF suggests allergy
testing-based elimination diet over no treatment. Question 7. Should Maintenance Therapy Be
(Conditional recommendation, very low quality
evidence) Recommended in Patients With Eosinophilic
Comment: Due to the potential limited accuracy of Esophagitis?
currently available, allergy-based testing for the
identification of specific food triggers, patients may
prefer alternative medical or dietary therapies to an
exclusively testing-based elimination diet. In patient with EoE in remission after short-term use of
topical glucocorticosteroids, the AGA/JTF suggests
continuation of topical glucocorticosteroids over
Like elemental and empiric elimination diets, the discontinuation of treatment. (Conditional
evidence-base for using allergy-based testing to identify recommendation, very low quality evidence)
Comments: Patients who put a high value on the
food triggers in patients with EoE is limited to single-arm, avoidance of long-term topical steroid use and its
observational studies that have noncomparative study possible associated adverse effects, and/or place a
designs. Testing-based diets involve the scientific rationale lower value on the prevention of potential long-term
of identifying a potential immune-mediated mechanism of undesirable outcomes (eg, recurrent dysphagia, food
food allergy involving either food-specific IgE or cell- impaction, and esophageal stricture), could reasonably
mediated pathways, as opposed to empiric diets, which prefer cessation of treatment after initial remission is
achieved, provided clinical follow-up is maintained.
CLINICAL PRACTICE GUIDELINES
from inflammation to esophageal strictures in a proportion eosinophilia with dilation, and dilation is considered a point
of EoE patients with untreated disease.1 of care option for the endoscopist.
At this time, there are a paucity of studies and, therefore, Despite the initial case reports of increased complica-
very limited evidence, to define what constitutes effective tions from dilation in EoE, large series using a more con-
maintenance therapy in EoE.2 Only 1 very small trial ran- servative dilation approach in experienced centers found
domized patients to a year of low-dose budesonide (0.25 mg that major complications were not increased over rates
twice a day) or placebo. While a significant reduction in expected from dilation of non-EoE, benign esophageal
eosinophil density was noted with active drug compared to strictures.2 The technical review identified no mortality
placebo, only 36% of patients maintained an eosinophil associated with dilation. The pooled rate of perforation was
density <5 eos/hpf at 1 year, and no dose-finding study 0.4%, hospitalization was 1.2%, and significant gastroin-
supported the choice of the 0.25 mg twice a day as appro- testinal hemorrhage was 0.1% after dilation. Most of the
priate or sufficient vs other amounts. The use of a low perforations were before 2009, with subsequent improve-
maintenance dose of budesonide compared to the induction ment in perforation rate after this time period, which was
dose of 1 mg twice a day likely reduced the efficacy, speculated to be the result of the adoption of a more
although development of steroid-tolerance or selection of conservative dilation approach. The most common adverse
steroid-refractory patients is plausible. Additional single- event reported was chest discomfort or pain. Of note, a
arm observational studies of topical steroids also reported patient questionnaire reported chest pain in 74% of patients
a high proportion of patients with histologic recurrence, but after dilation, while retrospective chart review identified
most also utilized dosing lower than administered during chest pain in only 7%, consistent with under-reporting of
induction. In contrast, 3, single-arm observational studies of this dilation-associated outcome.14
PPIs noted sustained histologic response in the majority of For individual patients that place a higher value on the
adults, despite dose reduction. Very limited data are avail- avoidance of the uncommon complications of dilation, it
able on the long-term effectiveness of elimination diets. may be reasonable to use medical or dietary therapy before
Until more data are available, the continued use of PPIs, using dilation. Although strictures may be present in many
topical glucocorticosteroids, or elimination diets are EoE patients, it has not been demonstrated that these pa-
reasonable options, and this is a very preference-sensitive tients will necessarily respond better to dilation as opposed
area of management. As there was limited evidence on PPI to alternative therapies. Esophageal strictures in EoE may
or diet therapies, the guideline recommendation was writ- be related to both inflammation and fibrosis, with the
ten to include topical glucocorticosteroids only. The limited former being amenable to medical or diet therapy.15,16
data, as well as uncertainties in the natural history of EoE, Retrospective case series have identified lower utilization
provide very low confidence in the estimated benefits of of esophageal dilation among patients treated effectively
long-term therapy for EoE, but must also be balanced with with medical therapy. Esophageal dilation alone as a treat-
the risks of potential disease recurrence in individual pa- ment modality for patients with EoE and daily dysphagia
tients when treatment is discontinued. has only been reported in a small retrospective series and
required maintenance dilation on average every 2 years.17
The limited available data support the use of medical/diet
Question 8. Should Esophageal Dilation Be Used therapy in combination with periodic dilation as necessary
in Patients With Eosinophilic Esophagitis? for adults with EoE and esophageal stricture.
In adult patients with dysphagia from a stricture Question 9. Should Anti–Interleukin-5 Therapy Be
associated with eosinophilic esophagitis, the AGA/ Used in Patients With Eosinophilic Esophagitis?
JTF suggests endoscopic dilation over no dilation,
(Conditional recommendation, very low-quality
evidence)
Comment: Esophageal dilation does not address the In patients with EoE the AGA/JTF recommends using
esophageal inflammation associated with EoE. anti–interleukin-5 therapy only in the context of a
CLINICAL PRACTICE GUIDELINES
difference in ages of enrollees of these trials and similar IL-4 receptor-a inhibiting the signaling of both IL-13 and IL-
mechanisms of action of these therapies, although formal 4, demonstrated symptom, histologic, and endoscopic effi-
noninferiority between the drugs has not been studied. cacy compared to placebo in 47 adults with EoE.19 While
While a reduction in tissue eosinophilia was observed, very these newer preliminary results appear favorable, the use of
few participants achieved prespecified histologic remission anti–IL-13 therapy in EoE is not recommended for clinical
with <15 eos/hpf. More than 90% of patients in treatment use outside of a clinical trial at this time.
groups failed to achieve histologic remission (RR, 0.92; 95%
CI, 0.84–1.00). Symptomatic improvement was evaluated
differently in each study and not grouped for GRADE anal- Question 11. Should Anti-IgE Therapy Be Used in
ysis; however, a significant improvement in symptoms Patients With Eosinophilic Esophagitis?
compared with placebo was not observed. No significant
safety issues occurred in any of the trials.
Anti–IL-5 therapies are currently approved for use in In patients with EoE the AGA/JTF suggests against the
moderate to severe persistent eosinophilic asthma. Initial use of anti-IgE therapy for EoE. (Conditional
studies in asthmatics demonstrated a reduction in tissue recommendation; very low-quality evidence)
eosinophilia, but lack of clinical improvement. Follow-up In patients with EoE, the AGA/JTF recommends
studies that focused treatment on a more-specific patient topical steroids over no treatment (strong
recommendation, moderate quality evidence).
population with steroid-resistant refractory eosinophilic
asthma were needed to better understand potential clinical
benefit. In a similar fashion, additional studies in patients IgE is involved in anti-helminthic responses and medi-
with EoE are needed before use in clinical practice can be ates type 1 hypersensitivity reactions. However, IgE is not
recommended. known to be directly involved in the development or
recruitment of eosinophils. Anti-IgE therapy is currently
approved for use in patients with moderate to severe
Question 10. Should Anti–Interleukin-13 Therapy persistent atopic asthma and in patients with chronic urti-
Be Used in Patients With Eosinophilic caria who are refractory to first-line therapy.
Esophagitis? There has been 1 RCT involving 30 adult participants
evaluating use of anti-IgE therapy in EoE.2 This study did
not demonstrate any change in esophageal eosinophilia or
reduction in symptoms. Based on limited evidence and lack
In patients with EoE, the AGA/JTF recommends using
anti–IL-13 or anti–IL-4 receptor-a therapy for EoE only of a biologically plausible mechanism, use of anti-IgE ther-
in the context of a clinical trial. (No recommendation; apy in EoE is not recommended for clinical use. A condi-
knowledge gap) tional recommendation against use was made for anti-IgE
therapy because of the quality of the RCT and the inclusion
of the primary end point evaluated in this guideline (<15
The IL-4 and IL-13 pathway is known to be involved in Th2 eos/hpf). Other interventions, such as montelukast (did not
inflammatory conditions by directing eosinophil production, include eos/hpf) and cromolyn sodium (very low sample
prolonged survival, and trafficking into tissues. Anti–IL-4 and size), had very major limitations and therefore insufficient
anti–IL-13 therapy has shown benefit in Th2-associated con- evidence to recommend against and, therefore, no recom-
ditions, such as atopic dermatitis and asthma, and there is a mendation was made about their use.
biologically plausible pathway for use in EoE. IL-13 is overex-
pressed in the esophageal mucosa and induces a gene expres-
sion profile that closely resembles the EoE transcriptome. Questions 12–15. Should Montelukast,
Three clinical trials have evaluated the efficacy of bio- Cromolyn, Immunomodulators, or Anti-TNF
logic therapy directed at the IL-13 pathway in EoE. One RCT Therapy Be Used in Patients With Eosinophilic
involving 25 adult participants evaluated the use of anti–IL- Esophagitis?
CLINICAL PRACTICE GUIDELINES
13 therapy with QAX576 in EoE.2 This study did not meet its
primary end point of a >75% decrease in peak eosinophil
counts 12 weeks after starting therapy. Mean esophageal
eosinophil counts decreased compared with placebo, but no In patients with EoE, the AGA/JTF suggest using
significant difference was observed in symptoms. Two montelukast, cromolyn sodium, immunomodulators,
and anti-TNF only in the context of a clinical trial.
additional RCTs that utilized monoclonal antibodies target- (No recommendation; knowledge gap)
ing the IL-13 pathway were not included, as the full articles
were not available at the time of this systematic review,
both of which showed promise. The first was a phase 2 Given the few studies and low quality of evidence, use of
study using RPC4046, a monoclonal antibody against IL-13 montelukast, cromolyn, immunomodulators, and anti-TNF
that demonstrated histologic and endoscopic efficacy therapies are not recommended for clinical use.2 These
compared to placebo in 99 adults with EoE.18 The second therapeutic agents have been grouped together for the
study using dupilumab, a monoclonal antibody against the purposes of this guideline based on limited evidence for a
1784 Hirano et al Gastroenterology Vol. 158, No. 6
mechanistic role of their biologic markers in the develop- manifestations.2,21 Dissociation between biologic activity
ment of EoE and limited studies surrounding each therapy. and symptoms in adults is further compounded by the
Montelukast is a leukotriene receptor antagonist presence of strictures related to fibrostenosis that do not
approved for use in the treatment of persistent asthma and reflect mucosal inflammatory activity. This concept is
exercise-induced bronchospasm. There is 1 RCT with adult evident in the symptom relief provided by esophageal
participants (n ¼ 41) comparing montelukast with placebo dilation in the absence of improvement in esophageal
for maintenance therapy after histologic remission was inflammation.
already achieved and did not show any difference in The importance of the documentation of adequate
symptoms. A histologic outcome was not included in the suppression of mucosal inflammation after therapeutic
study design. intervention is indirectly supported by several retrospective
Cromolyn is a mast cell stabilizer that can prevent the studies that have associated prolonged, untreated disease
release of inflammatory mediators in patients with allergic with the increased prevalence of esophageal strictures.1 In
rhinitis and asthma. Mast cell and mast cell mediators have addition, retrospective case series have reported a reduction
been implicated in EoE pathogenesis. There has been 1 RCT in frequency of esophageal dilation as well as food impac-
of cromolyn compared to placebo (n ¼ 16), which demon- tions, with improvement in pathology with topical gluco-
strated that only 1 patient treated with cromolyn achieved corticosteroids. Nevertheless, the supposition that reduction
histologic remission. in esophageal eosinophilia will prevent progressive disease
Two immunomodulators (azathioprine and 6-mercap- remodeling consequences requires confirmation in pro-
topurine) have been retrospectively reported in a total of 4 spective, long-term studies. Similarly, although the use of
patients with EoE but without any use of control subjects. endoscopic outcomes in gastroesophageal reflux disease
All patients had EoE refractory to other therapies and and inflammatory bowel disease serve as precedents, their
multiple confounders that make it difficult to discern the application to EoE needs further study to demonstrate their
impact of immunomodulatory therapy.2 relevance to long-term disease outcomes.
TNF-related apoptosis-inducing ligand has been shown While not a formal recommendation of this guideline, the
to promote inflammation in EoE. One observational case use of repeat EGD with biopsy to assess disease activity
series described open-label use of anti-TNF in a clinical trial after a change in therapy is reasonable. The criteria for
in 3 adult patients with EoE, all of whom had inadequate histologic and endoscopic improvement after therapy are
response to prior therapy.2 The 3 case reports all reported being actively investigated to identify core outcome metrics
different outcomes, including symptom scores, esophageal for both clinical trials and clinical practice.2 Until such
eosinophilia, and endoscopic changes. While interval metrics are established, a threshold of <15 eos/hpf to
improvement was observed, the differences in patient pre- define an adequate therapeutic response serves as a
sentation, outcome measures, and lack of control subjects response criterion until a better measure is established.3,22
limit extrapolation of these findings. The recommended frequency for EGD with biopsy during
clinical follow-up is identified as a knowledge gap and may
vary, depending on the severity of initial clinical
Question 16. Should Repeat presentation.
Esophagogastroduodenoscopy Be Used to
Assess Patients With Eosinophilic Esophagitis
After a Change in Treatment? Question 17. What Is the Management of
Numerous randomized, placebo-controlled trials of Patients Who Become Asymptomatic After Initial
medical therapies for EoE included in this guideline and Proton Pump Inhibitor Treatment?
accompanying technical review have demonstrated signifi- The recently published European and International
cant improvement in symptom, endoscopic, and histologic consensus statements have removed the PPI trial from the
end points using validated instruments.2 Generally, the diagnostic criteria for EoE.7,8 Based on this revised defini-
improvement in objective parameters of endoscopy and tion of EoE, the use of repeat EGD with biopsy after PPI
pathology have been more robust and consistent than the therapy would follow the same rationale as
CLINICAL PRACTICE GUIDELINES
While swallowed, topical glucocorticosteroids were the 11. Wang R, Hirano I, Doerfler B, et al. Assessing adherence
only therapy to receive a strong recommendation, the evi- and barriers to long-term elimination diet therapy in
dence supported conditional recommendations for PPI and adults with eosinophilic esophagitis. Dig Dis Sci 2018;
diet therapy as well as esophageal dilation. The use of novel, 63:1756–1762.
targeted biologic therapies for EoE are being actively eval- 12. Hiremath G, Gupta SK. Promising modalities to identify
uated. A common theme apparent in both the guideline and and monitor eosinophilic esophagitis. Clin Gastroenterol
the accompanying technical review includes the need for Hepatol 2017;15:1655–1664.
uniform end points in clinical trials to facilitate meaningful 13. Moole H, Jacob K, Duvvuri A, et al. Role of endoscopic
comparisons between therapies. Furthermore, a deeper esophageal dilation in managing eosinophilic esophagi-
understanding of the natural history of EoE in both children tis: a systematic review and meta-analysis. Medicine
and adults is needed to inform clinical decisions regarding (Baltimore) 2017;96(14):e5877.
the optimal use of disease monitoring and long-term, 14. Schoepfer AM, Gonsalves N, Bussmann C, et al.
maintenance therapy. In the dawn of this new disease, Esophageal dilation in eosinophilic esophagitis: effec-
much light has been shed and the future is bright. tiveness, safety, and impact on the underlying inflam-
mation. Am J Gastroenterol 2010;105:1062–1070.
15. Carlson DA, Hirano I, Zalewski A, et al. Improvement in
esophageal distensibility in response to medical and diet
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Correspondence
9. Chang A, Robison R, Cai M, et al. Natural history of food- Address correspondence to: Chair, Clinical Guidelines Committee, American
triggered atopic dermatitis and development of immedi- Gastroenterological Association, National Office, 4930 Del Ray Avenue,
Bethesda, Maryland 20814. e-mail: clinicalpractice@gastro.org; Joint Task
ate reactions in children. J Allergy Clin Immunol Pract Force on Allergy-Immunology Practice Parameters, 555 E Wells Street, Suite
2016;4:229–236 e221. 1100, Milwaukee, Wisconsin 53212. e-mail: drdanawallace@gmail.com.
10. Ho HE, Chehade M. Development of IgE-mediated Acknowledgments
immediate hypersensitivity to a previously tolerated Collaborators—The AGA Clinical Guidelines Committee: Karen A. Chachu
food following its avoidance for eosinophilic gastroin- (Department of Medicine, Duke University School of Medicine, Durham, North
Carolina); Lukejohn Day (Department of Medicine, University of California, San
testinal diseases. J Allergy Clin Immunol Pract 2018; Francisco, California); Benjamin Lebwohl (Mailman School of Public Health,
6:649–650. Columbia University, New York, New York); Thiruvengadam Muniraj (Division
1786 Hirano et al Gastroenterology Vol. 158, No. 6
of Digestive Diseases, Pancreatitis, and Internal Medicine, Yale University, New Anticipated update:
Haven, Connecticut); Amit Patel (Department of Medicine, Duke University, 3 years from publication (2023).
Raleigh, North Carolina); Anne F. Peery (Division of Gastroenterology and
Hepatology, University of North Carolina, Chapel Hill, North Carolina); Raj Conflicts of interest
Shah (Department of Medicine, Case Western Reserve University, Cleveland, These authors disclose the following: Dr Hirano is supported by National
OH); Harminder Singh (Department of Medicine and Internal Medicine, Institutes of Health grants U54AI117804 and 1P01DK117824 and has
University of Manitoba, Winnipeg, Manitoba Canada); Siddharth Singh received consulting fees and research support from Adare, Allakos, Celgene,
(Department of Clinical Medicine, University of California, San Diego, Regeneron, Shire Pharmaceuticals. Dr Chan is a member of the committee
California); Stuart J. Spechler (Baylor Scott & White Center for Esophageal for the American Gastroenterological Association and American Academy of
Diseases, Baylor University, Dallas, Texas); Shahnaz Sultan (Division of Allergy, Asthma and Immunology/American College of Allergy, Asthma and
Gastroenterology and Hepatology and Nutrition, University of Minnesota, Immunology Joint Task Force guidelines on the management of eosinophilic
Minneapolis, Minnesota); Grace L. Su (Department of Medicine, University of esophagitis. Outside of this paper, Dr Chan has received research support
Michigan, Ann Arbor, Michigan); Aaron P. Thrift (Department of Medicine, from DBV Technologies, has been a member of advisory boards for Pfizer,
Division of Gastroenterology, Baylor College of Medicine, Houston, Texas); Pediapharm, Leo Pharma, and Kaleo, is a member of the health care
Jennifer M. Weiss (Department of Medicine and Public Health, University of advisory board for Food Allergy Canada, and was an expert panel
Wisconsin, Madison, Wisconsin); Adam V. Weizman (Division of and coordinating committee member of the National Institute of Allergy and
Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON). Infectious Disease–sponsored Guidelines for Peanut Allergy Prevention, and
Collaborators—the Joint Task Force on Allergy-Immunology Practice is co-lead of the Canadian Society of Allergy and Clinical Immunology oral
Parameters: Jonathan A. Bernstein (Department of Internal Medicine, immunotherapy guidelines. Dr Sharaf receives salary support from National
University of Cincinnati College of Medicine, Cincinnati, Ohio); Chitra Dinakar Cancer Institute 1K07CA216326-01A1, NCI 5 R01 CA211723 02, and a
(Division of Pulmonary, Allergy and Critical Medicine, Stanford University Patient-Centered Outcomes Research Institute’s Improving Health Systems
School of Medicine, Stanford, California); David B. K. Golden (Department of Award. He is a paid consultant for the nonprofit Institute for Clinical and
Medicine, Johns Hopkins University, Baltimore, Maryland); David A. Khan Economic Review. Dr Stukus received consulting fees from Aimmune
(Division of Allergy and Immunology, Department of Medicine, University of Therapeutics, Inc and Before Brands to deliver unbranded educational
Texas Southwestern Medical Center, Dallas, Texas); Jay Lieberman (Division symposia. Dr Wang served on the advisory board for Ironwood
of Allergy and Immunology, The University of Tennessee Health Science Pharmaceuticals. Dr Greenhawt is supported by grant #5K08HS024599-02
Center, LeBonheur Children’s Hospital, Memphis, Tennessee); John from the Agency for Healthcare Quality and Research, is an expert panel and
Oppenheimer (Department of Internal Medicine, New Jersey Medical School, coordinating committee member of the National Institute of Allergy and
Morristown, New Jersey); Marcus Shaker (Section of Allergy and Immunology, Infectious Diseases–sponsored Guidelines for Peanut Allergy Prevention; has
Dartmouth-Hitchcock Medical Center and Dartmouth Geisel School of served as a consultant for the Canadian Transportation Agency, Thermo
Medicine, Lebanon and Hanover, New Hampshire); Dana V. Wallace Fisher, Intrommune, and Aimmune Therapeutics; is a member of physician/
(Department of Medicine, Nova Southeastern University, Davie, Florida); and medical advisory boards for Aimmune Therapeutics, DBV Technologies,
Julie Wang (Division of Allergy and Immunology, Department of Pediatrics, Sanofi/Genzyme, Genentech, Nutricia, Kaleo Pharmaceutical, Nestle,
The Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Aquestive, Allergy Therapeutics, and Monsanto; is a member of the scientific
Mount Sinai, Kravis Children’s Hospital, New York, New York). advisory council for the National Peanut Board; has received honorarium for
Guideline Panel included: Ikuo Hirano (chair), Yngve T. Falck-Ytter (co-chair, lectures from Thermo Fisher, Aimmune, DBV, Before Brands, multiple state
GRADE methodologist), Matthew A. Rank (co-chair, GRADE methodologist), allergy societies, the American College of Allergy, Asthma and Immunology,
Neil H. Stollman (member), Kenneth Wang (member), David R. Stukus the European Academy of Allergy and Clinical Immunology; is an associate
(member), Matthew Greenhawt (member), Rajiv N. Sharaf (member), and editor for the Annals of Allergy, Asthma, and Immunology; and is a member
Edmond S. Chan (member). Technical Review Panel included: Glenn Furuta of the Joint Taskforce on Allergy Practice Parameters. These relationships
(content expert), Evan Dellon (content expert), Jonathan Spergel (content are unrelated to the work on this guideline and pose no conflict of interest.
expert), Seema Aceves (content expert), Matthew Greenhawt (content The recommendations involving medications undergoing clinical trials were
expert), Yngve Falck-Ytter (GRADE methodologist), Matthew A. Rank written by members of the guideline committee without conflict of interest.
(GRADE methodologist), and Rajiv Sharaf (trainee GRADE methodologist). The remaining authors disclose no conflicts.
CLINICAL PRACTICE GUIDELINES