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Contents lists available at ScienceDirect

Digestive and Liver Disease

jou rnal homepage: www.elsevier.com/locate/dld

Position Paper

Eosinophilic : Update in diagnosis and management.

Position paper by the Italian Society of and

Gastrointestinal (SIGE)

a,∗ b c a

Nicola de Bortoli , Roberto Penagini , Edoardo Savarino , Santino Marchi

a

Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

b

Gastroenterology Unit, Foundation IRCCS Ca’ Granda, Ospedale Maggiore, Policlinic, Department of Physiopathology and Transplantation, University of

Milan, Milan, Italy

c

Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the characterized by

Received 4 October 2016

symptoms related to esophageal dysfunction, as well as significant esophageal .

Received in revised form

The entity exists worldwide but has been most extensively studied in Western countries. However,

21 November 2016

a wide range of symptoms has been noticed such as chest pain or gastro-esophageal reflux disease-

Accepted 24 November 2016

like symptoms. Upper gastro-intestinal endoscopy and esophageal biopsies are crucial for the diagnosis.

Available online xxx

Endoscopy might be normal or reveal typical patterns such as rings, furrows, exudates, edema, and stric-

ture. Two to four biopsies should be performed both in the distal and in the proximal esophagus, and 15

Keywords:

Biopsies per high power field within the esophageal are the minimal threshold to diagnose

eosinophilic esophagitis.

Eosinophilic esophagitis

PPI-responsive eosinophilic esophagitis testing is recommended, although its impact to orient treatment remains to be demonstrated.

Proton pump inhibitors Eosinophilic esophagitis treatment includes medical treatment, diet and endoscopic dilation. Proton

Steroids pump inhibitors are the first-line therapy as up to 50% of patients respond well to proton pump inhibitors

Upper endoscopy

irrespective of objective evidence of GERD. Topical viscous or elimination diet are the

treatment of choice in case of unresponsiveness to proton pump inhibitors.

© 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction In order to assess the strength of our recommendations and

the evidence, the GRADE system was used [2]. Recommendations

Eosinophilic esophagitis (EoE) is a chronic immune-mediated were either strong (desirable effects outweigh undesirable effects)

disease of the esophagus characterized by symptoms related or conditional (trade-offs are less certain), and the quality of evi-

to esophageal dysfunction, as well as significant esophageal dence was either strong (further research is unlikely to change

eosinophilia [1]. confidence in the estimate), moderate (further research is likely

EoE represents an up and coming disease entity with some to change confidence in the estimate), low (further research is very

proven evidences and many open questions that need to be likely to change confidence in the estimate), or very low (the esti-

resolved. mate of the effect is very uncertain) [2]. Current management of

These guidelines, which mainly address EoE in adults, reflect the adult EoE is depicted in Fig. 1.

position of the Italian Society of Gastroenterology (SIGE) on this

topic; they put forward recommendations regarding fundamen-

tal clinical questions pertaining to the management of EoE. These

Statement 1. EoE is currently defined as a chronic, immune-

recommendations are summarized and highlighted in Table 1.

mediated characterized by symptoms related

to esophageal dysfunction and -predominant inflamma-

tion [3].

∗

Corresponding author at: Gastroenterology Unit, Department of Translational

Research and New Technologies in Medicine and Surgery, University of Pisa,

Cisanello Hospital, Via Paradisa 2, 56124 Pisa, Italy.

(Recommendation: strong; Evidence: moderate)

E-mail address: [email protected] (N. de Bortoli).

http://dx.doi.org/10.1016/j.dld.2016.11.012

1590-8658/© 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE). guide.medlive.cnDig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.11.012

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Table 1

Highlights in management of adult EoE.

Definition and diagnosis

Definition of eosinophilic esophagitis (EoE) and diagnostic criteria

1. EoE is a clinico-pathological disease diagnosed by taking into account symptoms, endoscopy and histopathological findings. Currently, EoE is defined by the

following criteria:

•

Symptoms related to esophageal dysfunction.

• Peak concentration ≥15 eosinophils/high-power field (EOS/HPF).

• The eosinophilic infiltrate is confined to the esophagus.

• Exclusion of other disorders associated with esophageal hypereosinofilia.

2. Esophageal biopsies are essential for EoE diagnosis. A minimum of 2–4 biopsies at the level of the proximal and distal esophagus are recommended.

3. Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is no longer considered an exclusion criterium for EoE, but as belonging to the clinical

spectrum of EoE.

4. Response to PPIs has no correlation with gastroesophageal reflux disease.

Treatments

Therapeutic endpoints in EoE

5. EoE therapy aims to improve clinical symptoms and eosinophilic infiltration in the esophagus, in order to obtain a complete regression of the disease.

6. Symptoms are an important marker of therapeutic response in EoE but need to be coupled with results of endoscopy and biopsies in order to properly

evaluate disease activity and response to therapy.

7. The first line treatment of EoE is generally represented by PPIs for at least 8 weeks.

8. Topical steroids (i.e. for an initial period of 8 weeks) are generally prescribed after failure of PPI therapy.

9. Patients without symptomatic and histological improvement after topical steroids may benefit from treatment with a higher dose, or with systemic

steroids, or with dietary elimination.

10. Dietary elimination may also be considered as an initial therapy of EoE.

11. The decision to use a specific dietary approach (elemental, empiric, or targeted elimination diet) should be tailored to individual patient needs and

available resources.

12. Endoscopic esophageal dilation is an effective therapy in symptomatic patients with strictures that persist in spite of medical or dietary therapy.

13. Long term treatment with half dose of the effective drug is presently recommended.

Legend: EoE: eosinophilic esophagitis; EOS: eosinophils; HPF: high power filed; PPI-REE: proton pump inhibitor-responsive esophageal eosinophilia; PPI: proton pump

inhibitors.

1.1. Summary of evidences therapy, in the absence of clinical or pathophysiological features of

GERD [9,10].

Eosinophilic infiltration of the esophagus was first described in Furthermore, recent studies have shown that esophageal

the 1990s, and later it was recognized to be independent from mediators of eosinophlic inflammation, such as eotaxin-3 (a

condition from the presence of gastroesophageal reflux disease chemoattractant that plays a major role in the pathogenesis of

(GERD) [4]. EoE), have similar levels and esophageal transcriptome is within

The main characteristic of EoE is that it is a disorder trig- the same molecular spectrum in PPI-REE and EoE, but much dif-

gered by food and/or . Although the etiology remains ferent in GERD [11,12]. Thus in 2016 an international task force

unknown, the predisposition or the presence of documented aller- proposed that PPIs not be used a as a diagnostic tool, but rather as

gic condition remains the most likely possibility. In fact, several first line treatment, before diet and steroids [8].

studies have suggested a central role of food and aeroal- In the present paper PPI-REE will be considered as a clinical

lergens as possible etiologic agents [3,5–7]. EoE is defined by the entity belonging to EoE and the term PPI-REE will not be mentioned

presence of ≥15 eosinophils in at least one high-power field (HPF) any longer.

found in one or more of the esophageal mucosa biopsies [1]. Evi-

Statement 3. EoE is a condition with an apparent increase of

dences on histopathology are debated below.

incidence.

Statement 2. Proton pump inhibitor-responsive esophageal

(Recommendation: strong; Evidence: moderate)

eosinophilia (PPI-REE) should be diagnosed when patients have

esophageal symptoms and histological findings of EoE, but achieve

1.3. Summary of evidences

clinical and histological remission on PPI therapy. The latest guide-

lines suggest that PPI-REE represents a clinical entity belonging to

Currently, EoE occurs in children and adults, males and females,

the clinical spectrum of EoE and this term should no longer be used

[8]. and in individuals from a range of ethnic backgrounds with equal

probability [1]. The highest prevalence of EoE has been reported

(Recommendation: strong; Evidence: moderate) from North America, Sweden [13,14], and Australia [15], with an

incidence estimated around 5–7/100.000 inhabitants and a preva-

1.2. Summary of evidences lence estimated around 50–60/100.000 inhabitants. In Europe, the

main data come from Switzerland with an estimated prevalence of

Proton pump inhibitor-responsive eosinophilic esophagitis about 23/100.000 inhabitants [16].

(PPI-REE) comprises a distinct subgroup of patients, around 50% A recent population-based Canadian study found that an

of all patients, presenting clinical and histological findings of EoE increase in the EoE incidence from 2,1 per 100.000 to 11,0 per

but, at the same time, a clinical response and a complete regres- 100.000 persons was significantly influenced by a higher rate of

sion of the eosinophilic infiltrate of the esophagus following a PPI obtaining esophageal biopsies [17], even if, at the same time, the

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE). Digguide.medlive.cnLiver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.11.012

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Fig. 1. Current management for inducing and maintaining clinical and histological remission in adult EoE.

Legend: EoE: eosinophilic esophagitis; PEC: peak eosinophil count; HSS: histologic scoring system; PPI: proton pumps inhibitors.

proportion of patients with undergoing gastroscopy has 3 that are responsible for the recruitment of eosinophils in the

also significantly increased [18]. This increase in incidence of EoE esophagus [21]. Eotaxin-3 and thymic stromal limphoprotein

has not been seen in Asia, Latin America nor Africa, but limited data (TSLP) seem directly involved, along with some interleukins (IL-

are available. 5, IL-9, IL-13), both in maintaining the inflammatory reaction and

It is estimated that the male/female ratio is 3/1, even though in activating the fibroblasts. This inflammatory process induces an

this data does not have a pathophysiological explanation [19]. esophageal remodelling, which leads to esophageal dysfunction and

White Americans seem most affected (58%) than African Amer- bolus impaction [22,23].

ican patients (34%) and other ethnic groups (8%) [20].

Statement 5. Food and aeroallergens have been identified as fre-

Statement 4. EoE is characterised by an eosinophil infiltra- quent triggers in the genesis of EoE.

tion within the esophageal epithelium, and T-helper 2 (Th2)-type

(Recommendation: conditional; Evidence: low)

immune responses, which are typical of other atopic conditions.

The inflammatory response is restricted to the esophagus and does

1.5. Summary of evidences

not involve the stomach and the .

(Recommendation: conditional; Evidence: low) Both in experimental and in vivo models, the esophageal hyper-

eosinophilia appears to be directly inducible by allergens [5]

1.4. Summary of evidences responsible for the release of high amounts of interleukins (IL-13 e

IL-5) [24].

In EoE, the esophageal epithelium is infiltrated not only by Food and aeroallergens seem to have the same ability to support

eosinophils but also by T-cells (Th2) and mast cells [21]. These cells, the disease and in causing exacerbations [24]. Based on elimina-

directly involved in the inflammatory process of the esophageal tion diets and subsequent challenge-tests, wheat flour and cow’s

epithelium, increase the production of TNF-alpha and eotaxin- milk are the most common allergens (60% e 50% respectively) [25].

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

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Despite these evidences and the presence of elevated plasma levels (Recommendation: strong; Evidence: moderate)

of IgE, skin-prick tests are only able to predict 13% of the cases with

clinical response to elimination diet.

1.8. Summary of evidences

Statement 6. Patients with EoE may present a wide range of

symptoms, including dysphagia, bolus impaction, and

Since esophageal hypereosinophilia distribution may be patchy,

chest pain. The clinical presentation may be very different accord-

it is essential to perform multiple biopsies in different parts of the

ing to the age of onset.

esophagus in order to maximize the diagnostic yield of EoE. Recent

studies recommend taking at least 2–4 biopsies in the distal esoph-

(Recommendation: strong; Evidence: moderate)

agus, and 2–4 biopsies in the proximal esophagus, to confirm EoE

diagnosis in 97% of patients [36].

1.6. Summary of evidences

In the histological diagnosis of EoE we must consider some

potential risks of misdiagnosis. In the first place, the eosinophils

In adults, intermittent dysphagia for solids is the most typical

are recruited from the deeper layers of the esophageal wall and,

symptom of EoE (ranging from 25 to 100%) [10,26] with long-lasting

consequently, it is possible to find low-density areas of eosinophils

food-impaction representing the most frequent and severe pre-

in the upper layers. Therefore, superficial mucosal biopsies may

sentation of dysphagia [27,28]. It is not uncommon that patients

be negative. Secondly, the esophageal eosinophilia is not an exclu-

modify their chewing habits (i.e., eating food more slowly and

sive feature of EoE. For a correct diagnosis of EoE, it is necessary

washing down solid food with liquids), thereby making the clinical

to rule out other diseases such as GERD, Crohn’s disease, some

manifestations of EoE less evident and leading to delayed diagno-

connective tissue diseases, infectious esophagitis, celiac disease,

sis [29]. In children with EoE, the symptomatic presentation can be

graft-versus-host disease, eosinophilic , and hyper-

rather non-specific and usually includes dyspepsia, heartburn or

eosinophilic syndrome. These conditions cannot be distinguished

abdominal pain (ranging from 5 to 82%) [30].

from the biopsy alone but it is essential to perform a proper clinical

In children younger than 2 years of age, feeding disorders

appraisal [1].

(refusal to eat, chewing problems, choking after liquids or solids

ingestion) and failure to thrive are dominant symptoms [3].

Statement 9. Endoscopy with biopsy should be performed in

Given the variability of the type and severity of symptoms in

order to assess the effectiveness (eosinophils <15/HPF) of PPIs,

EoE patients, it is increasingly necessary to have clinical scores for

dietary and/or steroid therapy. In addition, endoscopy should be

evaluating disease activity.

repeated in case of reintroduction of foods after dietary elimination

In this regard, there are two validated instruments available to

to identify triggers of esophageal inflammation and symptoms.

measure EoE symptom severity in adult patients: the Eosinophilic

Esophagitis Activity Index; EEsAI-PRO instrument [31] and the Dys-

(Recommendation: conditional; Evidence: low)

phagia Symptom Questionnaire (DSQ) [32]. Both instruments were

developed following the patient-reported outcome (PRO) guide-

lines. 1.9. Summary of evidences

Statement 7. Upper endoscopy with multiple esophageal biopsies

In patients with EoE, endoscopic and histological remission can

must be the first step in the diagnostic approach to patients with

be identified with a very low level of precision considering the sole

suspected EoE, as well as in patients with dysphagia.

parameter of symptom improvement.

(Recommendation: strong; Evidence: moderate) Symptom resolution cannot be considered a sufficiently reliable

parameter to define the remission of the disease. This finding has

1.7. Summary of evidences been recently confirmed in a prospective series of 269 consecu-

tive patients diagnosed with EoE (multicenter study) that showed

A considerable number of endoscopic findings might be a significant discrepancy between the presence of symptoms and

observed in patients with suspected EoE. They include normal endoscopic or histological response to drug therapy [37].

endoscopy, signs of active inflammation such as mucosal edema Therefore, an endoscopic and histological follow-up is always

(pallor due to decreased vascular markings), presence of exu- recommended and a decrease in eosinophils <15/HPF necessary in

dates (whitish plaques), furrows or signs of chronic inflammation order to consider remission. However, the 15 eosinophils/HPF cut-

with tissue remodeling such as rings (trachealization), stricture or off is to some extent arbitrary and clinical judgement is required

“crêpe-paper” (fragility of the mucosa) [33,34]. to interpret the significance of borderline counts. Recently, an EoE-

Sometimes, these different patterns may coexist in the same specific histology score has been proposed by Collins et al. [38]. It

patient. Sixteen to twenty-four percent of patients with dysphagia acknowledges the patchy histologic nature of the disease and the

can have completely normal endoscopy [33]. In the same study, limitations of relying solely on eosinophil peak count. Besides peak

it was shown that approximately 10% of patients with positive eosinophil count, this score includes different histologic features

endoscopic signs did not show histological features of EoE [33]. (i.e., basal zone hyperplasia, eosinophil microabscess formation,

Recently, Hirano et al. have proposed an endoscopic classifica- eosinophil surface layering, dilated intercellular spaces, surface

tion of EoE, which incorporated the grading of major esophageal epithelial alteration dyskeratosis, and lamina propria fibrosis) each

features (rings, furrows, exudates, edema), and the presence of one with a grade (severity) and stage (extent) along a 4-point scale.

additional features of feline esophagus (or transient esophageal A composite histology score was more strongly associated with

rings), strictures and “crêpe paper” esophagus [35]. treatment status than eosinophil peak count alone. However, appli-

In adults biopsies in the stomach or duodenum should only be cability and usefulness of this new score in clinical practice still

taken in presence of symptoms suggestive of gastric or intestinal needs to be evaluated.

involvement of eosinophilic inflammation.

Statement 10. Some additional tests may be useful to complete

Statement 8. The presence of ≥15 eosinophils in at least one high-

and confirm the diagnosis of EoE.

power field (HPF) found in one or more of the esophageal mucosa

biopsies is required for the histological diagnosis of EoE. (Recommendation: conditional; Evidence: low)

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

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1.10. Summary of evidences The elemental diet includes total elimination of all food aller-

gens with elemental or amino-acid-based formula (aminoacids,

A recent consensus conference on EoE recommends an evalu- carbohydrates and medium chain triglycerides). This approach has

ation by an allergologist or immunologist to assess the presence shown excellent results in children [49,50]. A single experience has

of concomitant disorders such as , , eczema or food been reported in adults with limited benefits (only 50% of the sub-

allergies. This advice is given because of the high rates (about 65%) jects reported an improvement) [51]. In fact, this diet is not very

of concurrent allergic diseases found in patients with EoE [10]. palatable and may impact the quality of a patient’s life.

Serum IgE and skin-prick testing are recommended to detect The approach with empiric diet is a targeted elimination diet

the presence of food-induced allergic diseases. The consensus rec- guided by allergy testing. In general, the success of this nutritional

ommends performing both serum IgE and skin-prick testing for approach is good and oscillates between 55% and 75% in children

aeroallergens because of probable allergic comorbidity or the pos- [19].

sibility of sensitization [10]. In adults, the use of a targeted diet has yet to be confirmed by

Esophageal 24-h pH (or pH-impedance) monitoring should clinical studies. The major limitation of this diet is linked to the

be prescribed in order to evaluate concomitant presence of difficulty of detecting with certainty which foods contain specific

GERD, although it does not predict the response of esophageal allergens.

eosinophilia to PPI therapy [9]. Ultimately, to overcome the limitations of the empiric targeted

Barium swallow, according to a standardized protocol [39], diet and to increase the acceptability of dietary therapy, an empiric

provides data on regions of decreased compliance (i.e., smaller six-food elimination diet has been proposed, which eliminates the

diameter) in the esophageal body and it may guide decision to pro- six most common known food groups that are triggers of EoE

ceed to endoscopic dilation in patients not responding clinically to (milk, egg, wheat, seafood, nuts, and soy). This diet has been pro-

pharmacologic or diet therapy. It is relevant to underline that it posed both in children and adults [25,52]. In 2012, a study showed

represents the best method to detect the presence of esophageal that 64% of adult patients showed histological and 94% of them

narrowing [39]. symptomatic improvement after a 6-week nutritional therapy [25].

Esophageal manometry has been proposed to evaluate Systematic food reintroduction identified milk and wheat as the

esophageal function in patients with EoE. Using high resolution most common triggers. The identification of food to be reintroduced

manometry, it has been shown that motility abnormalities com- can be very complex. Endoscopy with biopsies is recommended to

monly reported in GERD patients are also frequent in EoE patients re-evaluate the effect of each group of reintroduced foods. Some-

responsive to PPI. However, a typical pattern useful to identify EoE times, several food groups may be involved.

has not been found, thus limiting the diagnostic role of manom- In conclusion, dietary therapy is a valid option to achieve con-

etry in EoE [40,41]. Interestingly, the presence of pan-esophageal trol of symptoms and to reduce the eosinophilic infiltrate both in

pressurization was more frequently observed in EoE than in GERD children and adults. This approach is considered as an effective

and healthy controls. This pattern might be a hallmark of reduced alternative to steroids. At present, there are no comparative data

esophageal compliance in EoE [40]. on clinical trials with enough numbers between dietary therapy

and topical steroids. Patient motivation and constant dietary mon-

Statement 11. The first line treatment of EoE is represented by

itoring are crucial to obtain the best results from the nutritional

PPIs; in case of no response, the treatment continues with topical

therapeutic strategy.

steroids and dietary elimination.

Statement 13. Endoscopic esophageal dilation may be used as

(Recommendation: strong; Evidence: moderate)

an effective therapy in symptomatic patients with strictures that

persist in spite of medical or dietary therapy and in patients with

1.11. Summary of evidences

severe esophageal stenosis, endoscopically documented at onset of

symptoms.

Considering their favorable safety profile, ease of administra-

tion, and high response rates [42], PPIs must be considered as first (Recommendation: strong; Evidence: moderate)

line therapy in patients with EoE. From a practical point of view, a

double dose is usually prescribed for at least 8 weeks to assess the 1.13. Summary of evidences

response to PPIs [10].

Currently, topical steroids and dietary therapy are considered The fibrostenotic complications in EoE include focal esophageal

the next step for the treatment of EoE [43], although this latter stenosis and narrow-caliber esophagus [10,53,54]. Esophageal dila-

approach is not universally accepted [44]. In fact, endoscopy with tion is an effective treatment, and was one of the first therapeutic

biopsies is needed to re-evaluate the effect of each group of rein- approaches used for adult patients with EoE [10]. In several large

troduced foods. Sometimes, several food groups may be involved series, esophageal dilation relieved dysphagia in most patients

and, thus, multiple endoscopic examinations are required. [55–58], with a mean duration of response, which was more than a

Several biologic agents have been evaluated in EoE, but at year [57]. In some post-dilation surveys, there was also a very high

present there are no promising results both in children and adults degree of patient acceptance with all patients willing to undergo

[45–48]. repeated dilation as needed [57]. In general, it is preferable to

reserve endoscopic dilation after an ineffective medical and/or

Statement 12. The decision to use a specific dietary approach (ele-

nutritional therapy (add-on approach or post-failure) [10].

mental, empiric, or targeted elimination diet) should be tailored to

The risk of perforation as a result of the esophageal dilation is

individual patient needs and available resources.

very low, and certainly lower than that reported from case stud-

(Recommendation: strong; Evidence: low) ies in 1990 to 2000. Today, it is considered an effective and safe

procedure [59].

1.12. Summary of evidences However, if a critical stricture is encountered on an initial

endoscopy, or food impaction has occurred, then dilation can be

Since food allergens are implicated in the pathogenesis of EoE, performed as first-line therapeutic approach. The role of dilation as

different strategies for dietary therapy have evolved: elemental a primary monotherapy of EoE is still controversial and controlled

diet, empiric elimination diet, and targeted 6-food elimination diet. clinical studies are not available.

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

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Statement 14. Long-term treatments halving the dosage both for References

PPI and steroids have been suggested. The long terms outcome data

[1] Dellon ES, Gonsalves N, Hirano I, et al. ACG clinical guideline: evidenced

are lacking.

based approach to the diagnosis and management of esophageal eosinophilia

and eosinophilic esophagitis (EoE). The American Journal of Gastroenterology

(Recommendation: conditional; Evidence: very low)

2013;108:679–92, quiz 93.

[2] Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. rating the

quality of evidence. Journal of Clinical Epidemiology 2011;64:401–6.

1.14. Summary of evidences

[3] 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 2007;133:1342–63.

In adults patients responding to PPIs recent results showed

[4] Attwood SE, Smyrk TC, Demeester TR, et al. Esophageal eosinophilia with dys-

that low-dose maintenance PPI therapy for at least a year leads

phagia: a distinct clinicopathologic syndrome. Digestive Diseases and Sciences

to a sustained histological response in the large majority (73%) 1993;38:109–16.

[5] Mishra A, Hogan SP, Brandt EB, et al. An etiological role for aeroallergens and

[60]. Although the remaining patients lost histological response to

eosinophils in experimental esophagitis. The Journal of Clinical Investigation

maintenance low-dose PPI therapy, an 8-week PPI therapy inten-

2001;107:83–90.

sification trial led to regaining histological remission in a majority [6] di Pietro M, Fitzgerald RC. Research advances in esophageal diseases: bench to

of patients, all of whom had recurrence of esophageal eosinophilia bedside. F1000prime Reports 2013;5:44.

[7] Chehade M, Aceves SS. and eosinophilic esophagitis. Current Opin-

limited to the distal esophagus [60].

ion in Allergy and Clinical Immunology 2010;10:231–7.

In EoE patients treated with steroids the commonly used

[8] Molina-Infante J, Bredenoord AJ, Cheng E, et al. Proton pump inhibitor-

maintenance regimen is half of the induction dose, which is a responsive oesophageal eosinophilia: an entity challenging current diagnostic

criteria for eosinophilic oesophagitis. Gut 2016;65:524–31.

total of 880 mcg of fluticasone or 1 mg of budesonide daily [61].

[9] Molina-Infante J, Ferrando-Lamana L, Ripoll C, et al. Esophageal eosinophilic

Recently, Straumann et al. showed that low-dose budesonide is

infiltration responds to proton pump inhibition in most adults. Clinical Gas-

more effective than placebo in maintaining EoE in histologic and troenterology and 2011;9:110–7.

[10] Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated con-

clinical remission [62]. Further studies are needed to determine

sensus recommendations for children and adults. The Journal of Allergy and

the appropriate dose needed to keep EoE patients in remission and

Clinical Immunology 2011;128:3–20, e6; quiz 1–2.

delay or prevent development of fibrostenotic features [63]. Long- [11] Wen T, Dellon ES, Moawad FJ, et al. Transcriptome analysis of proton

pump inhibitor-responsive esophageal eosinophilia reveals proton pump

term administration of topical corticosteroids was well tolerated

inhibitor-reversible allergic inflammation. The Journal of Allergy and Clinical

without induction of epithelial atrophy. Topical steroids are safe

Immunology 2015;135:187–97.

medications, although may occur following [12] Moawad FJ, Wells JM, Johnson RL, et al. Comparison of eotaxin-3 biomarker

in patients with eosinophilic oesophagitis, proton pump inhibitor-responsive

treatment [1].

oesophageal eosinophilia and gastro-oesophageal reflux disease. Alimentary

Recent series have also shown that patients responsive to diet or

Pharmacology & Therapeutics 2015;42:231–8.

topical steroids may achieve remission also with PPIs and viceversa [13] Ronkainen J, Talley NJ, Aro P, et al. Prevalence of oesophageal eosinophils and

[64,65], thus the anti-inflammatory treatment can be changed over eosinophilic oesophagitis in adults: the population-based Kalixanda study. Gut

2007;56:615–20.

time depending on side effects (i.e., for topical steroids) or practical

[14] Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in

issues (i.e., for diets).

the United States. Clinical Gastroenterology and Hepatology 2014;12:589–96,

e1.

Statement 15. The natural history of EoE is poorly defined, even if [15] Cherian S, Smith NM, Forbes DA. Rapidly increasing prevalence of eosinophilic

oesophagitis in Western Australia. Archives of Disease in Childhood

it seems characterized by symptom recurrence after discontinuing

2006;91:1000–4.

treatment due to the chronic nature of this condition.

[16] Straumann A, Simon HU. Eosinophilic esophagitis: escalating epidemiology?

The Journal of Allergy and Clinical Immunology 2005;115:418–9.

(Recommendation: conditional; Evidence: very low)

[17] Syed AA, Andrews CN, Shaffer E, et al. The rising incidence of eosinophilic

oesophagitis is associated with increasing biopsy rates: a population-based

study. Alimentary Pharmacology & Therapeutics 2012;36:950–8.

1.15. Summary of evidences [18] Kerlin P, Jones D, Remedios M, et al. Prevalence of eosinophilic esophagitis in

adults with food bolus obstruction of the esophagus. Journal of Clinical Gas-

troenterology 2007;41:356–61.

Since the first publication in 2003 by Straumann et al. [66] the

[19] Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-

natural history of EoE in adults remains largely undefined. Avail-

year experience in 381 children. Clinical Gastroenterology and Hepatology

able information can be gleaned from multiple sources, including a 2005;3:1198–206.

[20] Weiler T, Mikhail I, Singal A, et al. Racial differences in the clinical presenta-

prospective cohort [54], placebo arms of randomized clinical treat-

tion of pediatric eosinophilic esophagitis. The Journal of Allergy and Clinical

ment trials [23,47,67–70], and multiple retrospective case series

Immunology In Practice 2014;2:320–5.

[19,30,71–75]. EoE is a chronic disease [10,66], and in many cases, [21] Straumann A, Bauer M, Fischer B, et al. Idiopathic eosinophilic esophagitis is

associated with a T(H)2-type allergic inflammatory response. The Journal of

especially in adults, there can be a decade or more of symptoms

Allergy and Clinical Immunology 2001;108:954–61.

prior to diagnosis [57]. Cross-sectional symptom and endoscopy

[22] Aceves SS, Newbury RO, Chen D, et al. Resolution of remodeling in eosinophilic

data suggest that a sub-group of patients with EoE may progress esophagitis correlates with epithelial response to topical corticosteroids.

Allergy 2010;65:109–16.

from an inflammatory to a fibrotic process, and this could explain

[23] Straumann A, Conus S, Degen L, et al. Budesonide is effective in adoles-

differences in presentation and findings between children and

cent and adult patients with active eosinophilic esophagitis. Gastroenterology

adults [30,72,76,77]. 2010;139:1526–37, 37 e1.

[24] Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagi-

Recently, a long-term study with a follow-up of 13 years

tis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology

enrolled patients with naïve-EoE. In this small sized study,

2003;125:1419–27.

fibrostenotic EoE appeared to be a chronic, persistent disease that [25] Gonsalves N, Yang GY, Doerfler B, et al. Elimination diet effectively treats

was symptomatically amenable to treatment with a combination of eosinophilic esophagitis in adults; food reintroduction identifies causative fac-

tors. Gastroenterology 2012;142:1451–9, e1; quiz e14–5.

dilation and acid inhibition. This therapy achieved long-term symp-

[26] Straumann A. Clinical evaluation of the adult who has eosinophilic esophagitis.

tom control with patient satisfaction with no adverse events when

Immunology and Allergy Clinics of North America 2009;29:11–8, vii.

patients complied with the recommended follow-up. Mucosal [27] Desai TK, Stecevic V, Chang CH, et al. Association of eosinophilic inflamma-

tion with esophageal food impaction in adults. Gastrointestinal Endoscopy

eosinophils remained confined to the esophagus without spread

2005;61:795–801.

to other areas of the [78].

[28] Sgouros SN, Bergele C, Mantides A. Eosinophilic esophagitis in adults:

a systematic review. European Journal of Gastroenterology & Hepatology

2006;18:211–7.

Conflict of interest

None declared.

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE). Digguide.medlive.cnLiver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.11.012

G Model

YDLD-3300; No. of Pages 7 ARTICLE IN PRESS

N. de Bortoli et al. / Digestive and Liver Disease xxx (2016) xxx–xxx 7

[29] Katzka DA. Demographic data and symptoms of eosinophilic esophagitis in [54] Straumann A. The natural history and complications of eosinophilic esophagi-

adults. Gastrointestinal Endoscopy Clinics of North America 2008;18:25–32, tis. Gastrointestinal Endoscopy Clinics of North America 2008;18:99–118, ix.

viii. [55] Jung KW, Gundersen N, Kopacova J, et al. Occurrence of and risk factors for

[30] Dellon ES, Gibbs WB, Fritchie KJ, et al. Clinical, endoscopic, and histologic find- complications after endoscopic dilation in eosinophilic esophagitis. Gastroin-

ings distinguish eosinophilic esophagitis from gastroesophageal reflux disease. testinal Endoscopy 2011;73:15–21.

Clinical Gastroenterology and Hepatology 2009;7:1305–13, quiz 261. [56] Dellon ES, Gibbs WB, Rubinas TC, et al. Esophageal dilation in eosinophilic

[31] Schoepfer AM, Straumann A, Panczak R, et al. Development and validation esophagitis: safety and predictors of clinical response and complications. Gas-

of a symptom-based activity index for adults with eosinophilic esophagitis. trointestinal Endoscopy 2010;71:706–12.

Gastroenterology 2014;147:1255–66, e21. [57] Schoepfer AM, Gonsalves N, Bussmann C, et al. Esophageal dilation in

[32] Dellon ES, Irani AM, Hill MR, et al. Development and field testing of a novel eosinophilic esophagitis: effectiveness, safety, and impact on the underlying

patient-reported outcome measure of dysphagia in patients with eosinophilic inflammation. The American Journal of Gastroenterology 2010;105:1062–70.

esophagitis. Alimentary Pharmacology & Therapeutics 2013;38:634–42. [58] Bohm M, Richter JE, Kelsen S, et al. Esophageal dilation: simple and effective

[33] Mackenzie SH, Go M, Chadwick B, et al. Eosinophilic oesophagitis in patients treatment for adults with eosinophilic esophagitis and esophageal rings and

presenting with dysphagia—a prospective analysis. Alimentary Pharmacology narrowing. Diseases of the Esophagus 2010;23:377–85.

& Therapeutics 2008;28:1140–6. [59] Sodikoff J, Hirano I. Therapeutic strategies in eosinophilic esophagitis: induc-

[34] Prasad GA, Talley NJ, Romero Y, et al. Prevalence and predictive factors of tion, maintenance and refractory disease. Best Practice & Research Clinical

eosinophilic esophagitis in patients presenting with dysphagia: a prospective Gastroenterology 2015;29:829–39.

study. The American Journal of Gastroenterology 2007;102:2627–32. [60] Molina-Infante J, Rodriguez-Sanchez J, Martinek J, et al. Long-term loss of

[35] Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal response in proton pump inhibitor-responsive esophageal eosinophilia is

features of eosinophilic oesophagitis: validation of a novel classification and uncommon and influenced by CYP2C19 genotype and rhinoconjunctivitis. The

grading system. Gut 2013;62:489–95. American Journal of Gastroenterology 2015;110:1567–75.

[36] Nielsen JA, Lager DJ, Lewin M, et al. The optimal number of biopsy fragments [61] Moawad FJ, Cheng E, Schoepfer A, et al. Eosinophilic esophagitis: current per-

to establish a morphologic diagnosis of eosinophilic esophagitis. The American spectives from diagnosis to management. Annals of the New York Academy of

Journal of Gastroenterology 2014;109:515–20. Sciences 2016;1380(September (1)):204–17.

[37] Safroneeva E, Straumann A, Coslovsky M, et al. Symptoms have modest [62] Straumann A, Conus S, Degen L, et al. Long-term budesonide maintenance treat-

accuracy in detecting endoscopic and histologic remission in adults with ment is partially effective for patients with eosinophilic esophagitis. Clinical

eosinophilic esophagitis. Gastroenterology 2016;150:581–90, e4. Gastroenterology and Hepatology 2011;9:400–9, e1.

[38] Collins MH, Martin LJ, Alexander ES, et al. Newly developed and validated [63] Singla MB, Chehade M, Brizuela D, et al. Early comparison of inflammatory vs.

eosinophilic esophagitis histology scoring system and evidence that it outper- fibrostenotic phenotype in eosinophilic esophagitis in a multicenter longitudi-

forms peak eosinophil count for disease diagnosis and monitoring. Diseases of nal study. Clinical and Translational Gastroenterology 2015;6:e132.

the Esophagus 2016 [Epub ahead of print]. [64] Sodikoff J, Hirano I. Proton pump inhibitor-responsive esophageal eosinophilia

[39] Gentile N, Katzka D, Ravi K, et al. Oesophageal narrowing is common and does not preclude food-responsive eosinophilic esophagitis. The Journal of

frequently under-appreciated at endoscopy in patients with oesophageal Allergy and Clinical Immunology 2016;137:631–3.

eosinophilia. Alimentary Pharmacology & Therapeutics 2014;40:1333–40. [65] Lucendo AJ, Arias A, Gonzalez-Cervera J, et al. Dual response to dietary/topical

[40] Roman S, Savarino E, Savarino V, et al. Eosinophilic oesophagitis: from phys- steroid and proton pump inhibitor therapy in adult patients with eosinophilic

iopathology to treatment. Digestive and Liver Disease 2013;45:871–8. esophagitis. The Journal of Allergy and Clinical Immunology 2016;137:931–4,

[41] Savarino EV, Tolone S, Bartolo O, et al. The GerdQ questionnaire and high resolu- e2.

tion manometry support the hypothesis that proton pump inhibitor-responsive [66] Straumann A, Spichtin HP, Grize L, et al. Natural history of primary eosinophilic

oesophageal eosinophilia is a GERD-related phenomenon. Alimentary Pharma- esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterol-

cology & Therapeutics 2016;44(September (5)):522–30. ogy 2003;125:1660–9.

[42] Lucendo AJ, Arias A, Molina-Infante J. Efficacy of proton pump inhibitor drugs [67] Alexander JA, Jung KW, Arora AS, et al. Swallowed fluticasone improves his-

for inducing clinical and histologic remission in patients with symptomatic tologic but not symptomatic response of adults with eosinophilic esophagitis.

esophageal eosinophilia: a systematic review and meta-analysis. Clinical Gas- Clinical Gastroenterology and Hepatology 2012;10:742–9, e1.

troenterology and Hepatology 2016;14:13–22, e1. [68] Dohil R, Newbury R, Fox L, et al. Oral viscous budesonide is effective in chil-

[43] Carr S, Watson W. Eosinophilic esophagitis. Allergy Asthma and Clinical dren with eosinophilic esophagitis in a randomized, placebo-controlled trial.

Immunology 2011;7(Suppl. 1):S8. Gastroenterology 2010;139:418–29.

[44] Chuang MY, Chinnaratha MA, Hancock DG, et al. Topical steroid therapy for the [69] Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double-blind, placebo-

treatment of eosinophilic esophagitis (EoE): a systematic review and meta- controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.

analysis. Clinical and Translational Gastroenterology 2015;6:e82. Gastroenterology 2006;131:1381–91.

[45] Mishra A, Hogan SP, Brandt EB, et al. IL-5 promotes eosinophil trafficking to the [70] Rocha R, Vitor AB, Trindade E, et al. Omalizumab in the treatment of eosinophilic

esophagus. Journal of Immunology 2002;168:2464–9. esophagitis and food allergy. European Journal of Pediatrics 2011;170:1471–4.

[46] Mavi P, Rajavelu P, Rayapudi M, et al. Esophageal functional impairments in [71] Spergel JM, Brown-Whitehorn TF, Beausoleil JL, et al. 14 years of eosinophilic

experimental eosinophilic esophagitis. American Journal of Physiology Gas- esophagitis: clinical features and prognosis. Journal of Pediatric Gastroenterol-

trointestinal and Liver Physiology 2012;302:G1347–55. ogy and Nutrition 2009;48:30–6.

[47] Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and [72] Noel RJ, Putnam PE, Collins MH, et al. Clinical and immunopathologic effects of

adolescents with eosinophilic esophagitis: results of a double-blind, random- swallowed fluticasone for eosinophilic esophagitis. Clinical Gastroenterology

ized, placebo-controlled trial. The Journal of Allergy and Clinical Immunology and Hepatology 2004;2:568–75.

2012;129:456–63, 63 e1–3. [73] Assa’ad AH, Putnam PE, Collins MH, et al. Pediatric patients with eosinophilic

[48] Rothenberg ME, Wen T, Greenberg A, et al. Intravenous anti-IL-13 mAb QAX576 esophagitis: an 8-year follow-up. The Journal of Allergy and Clinical Immunol-

for the treatment of eosinophilic esophagitis. The Journal of Allergy and Clinical ogy 2007;119:731–8.

Immunology 2015;135:500–7. [74] DeBrosse CW, Franciosi JP, King EC, et al. Long-term outcomes in pediatric-

[49] Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to onset esophageal eosinophilia. The Journal of Allergy and Clinical Immunology

gastroesophageal reflux: improvement with an amino acid-based formula. Gas- 2011;128:132–8.

troenterology 1995;109:1503–12. [75] Menard-Katcher P, Marks KL, Liacouras CA, et al. The natural history of

[50] Markowitz JE, Spergel JM, Ruchelli E, et al. Elemental diet is an effective treat- eosinophilic oesophagitis in the transition from childhood to adulthood. Ali-

ment for eosinophilic esophagitis in children and adolescents. The American mentary Pharmacology & Therapeutics 2013;37:114–21.

Journal of Gastroenterology 2003;98:777–82. [76] Kim HP, Vance RB, Shaheen NJ, et al. The prevalence and diagnostic utility

[51] Peterson K, Clayton F, Vinson LA. Utility of elemental diet in adult eosinophilice- of endoscopic features of eosinophilic esophagitis: a meta-analysis. Clinical

sophagitis. Gastroenterology 2001;140:A1080. Gastroenterology and Hepatology 2012;10:988–96, e5.

[52] Kagalwalla AF, Shah A, Li BU, et al. Identification of specific foods responsi- [77] Straumann A. The natural history and complications of eosinophilic esophagi-

ble for inflammation in children with eosinophilic esophagitis successfully tis. Thoracic Surgery Clinics 2011;21:575–87.

treated with empiric elimination diet. Journal of Pediatric Gastroenterology [78] Lipka S, Keshishian J, Boyce HW, et al. The natural history of steroid-naive

and Nutrition 2011;53:145–9. eosinophilic esophagitis in adults treated with endoscopic dilation and proton

[53] Lee J, Huprich J, Kujath C, et al. Esophageal diameter is decreased in some pump inhibitor therapy over a mean duration of nearly 14 years. Gastrointesti-

patients with eosinophilic esophagitis and might increase with topical cor- nal Endoscopy 2014;80:592–8.

ticosteroid therapy. Clinical Gastroenterology and Hepatology 2012;10:481–6.

Please cite this article in press as: de Bortoli N, et al. Eosinophilic esophagitis: Update in diagnosis and management.

Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE). guide.medlive.cnDig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.11.012