review article: proton pump inhibitor therapy for ... · gastro-oesophageal reflux disease (gerd)...

20/06/13 www.medscape.com/viewarticle/805022_print

www.medscape.com/viewarticle/805022_print 1/12

www.medscape.com

Abstract and Introduction

Abstract

Background Recent advances in eosinophilic oesophagitis (EoE) have confirmed the existence of a new disease

phenotype, proton pump inhibitor (PPI)-responsive oesophageal eosinophilia (PPI-REE).

Aim To summarise evidence supporting the use of PPI therapy in patients with suspected EoE (oesophageal

dysfunction plus >15 eos/HPF in oesophageal biopsies).

Methods A literature search was conducted through MEDLINE, using the MeSH search terms 'eosinophilic

oesophagitis', 'proton pump inhibitors' and 'oesophageal eosinophilia'. Relevant articles and their reference lists were

identified through manual review.

Results Ten articles, including 258 patients with suspected EoE (152 children, 106 adults) undergoing clinico-

histological re-evaluation after PPI therapy, were identified. In children, clinical response ranged from 78% to 86% and

histological remission from 23% to 40%. In adults, symptom response ranged from 25% to 80% and histological

remission from 33% to 61%. Among PPI-REE patients with oesophageal pH-monitoring, 35 showed pathological and 10

normal studies. PPI-REE was significantly commoner with documented gastro-oesophageal reflux disease (GERD)

when compared to patients with negative pH monitoring (70% vs. 29%, P < 0.001). Symptom improvement/resolution

occurred in 50–85% of patients without histological remission on PPI therapy. Six PPI-REE patients demonstrated

clinico-histological relapse on PPI therapy.

Conclusions At least one third of patients with suspected EoE achieve clinico-histological remission on PPI therapy.

Response is more limited in children compared with that in adults. pH monitoring does not accurately predict response

to PPI therapy, albeit histological remission is significantly higher, up to 70%, upon documented GERD. Symptom

improvement is common with PPI therapy despite persistent eosinophilic infiltration.

Introduction

Eosinophilic oesophagitis (EoE) has dramatically emerged over the last decade as a prevalent cause of gastrointestinal

morbidity in adults and children. In fact, scientific publications have nearly doubled since the first consensus guidelines

for diagnosis of EoE were published in 2007.[1] It is currently considered the second cause of chronic oesophagitis after

gastro-oesophageal reflux disease (GERD) and the first cause of food impaction in young patients.[2] EoE is a chronic

inflammatory disorder, confined to the oesophagus, characterised clinically by oesophageal dysfunction (mainly

dysphagia and food impaction) and histologically by eosinophil-predominant inflammation (usually a minimum of 15

eosinophils per high power field (eos/HPF)).[2]

The presence of oesophageal eosinophilia, however, is not specific and may occur in a variety of disorders including

GERD, EoE, eosinophilic gastroenteritis, coeliac disease, achalasia, inflammatory bowel disease, infection,

hypereosinophilic syndrome, vasculitis, drug and/or iatrogenic-induced states such as caustic injury, multiple convulsive

therapy syndrome and immunosuppression following solid organ transplantation.[1, 3] The diagnosis of EoE, thus,

requires exclusion of other possible causes of oesophageal eosinophilia. In 2007, the first consensus guidelines

established that EoE could be distinguished from GERD by either normal oesophageal acid exposure on oesophageal

pH monitoring or persistent oesophageal eosinophilia despite high-dose acid suppressive therapy, with the assumption

that only GERD responds to proton pump inhibitor (PPI) therapy.[2] Nonetheless, the complex relationship between EoE

and GERD has become increasingly acknowledged with evolving evidence.[4]

In 2006, a case series presented two children and an adult with clinical, endoscopic and histological data suggestive of

EoE, which all completely responded to PPI therapy.[5] This study raised the question as to whether these three

patients had GERD or could EoE respond to a pharmacological effect of PPIs independent of acid suppression. Since

Review Article: Proton Pump Inhibitor Therapy for SuspectedOsinophilic OesophagitisJ. Molina-Infante, D. A. Katzka, J. P. Gisbert

Aliment Pharmacol Ther. 2013;37(12):1157-1164.

http://www.medscape.com/



then, several studies have confirmed the existence of patients with clinical symptoms of oesophageal dysfunction and

oesophageal eosinophilia responsive to PPI therapy. As such, the 2011-updated guidelines for the diagnosis of EoE

highlighted the description of a new potential disease phenotype, the PPI-responsive oesophageal eosinophilia (PPI-

REE).[2]

The aim of this review is to summarise the evidence over the last decade supporting the use of PPI therapy in patients

with an EoE profile in clinical practice, noting the impact of PPI therapy on either clinical and histological outcomes and

the role of pH monitoring to predict response to PPI therapy.

Methods

A literature search was conducted through PubMed (from February 2003 to February 2013) examining all published

articles linked to the MeSH search terms 'eosinophilic oesophagitis' and 'oesophageal eosinophilia' or 'proton pump

inhibitors responsive oesophageal eosinophilia' from journals in English language. Relevant articles (case series with at

least four patients) were identified through manual review. Furthermore, the reference lists of these articles were reviewed

to include further appropriate articles. Randomised controlled studies that compared PPI therapy against standard

therapy (topical steroids) were also used. As our intention was to perform a narrative review and not a systematic review

with a meta-analysis component, we did not include abstracts from international meetings in the search strategy.

As EoE is well characterised as a clinicopathological entity,[1, 2] we mainly focused on studies in which clinical and

histological follow-up on PPI therapy had been assessed. Complete histological response was defined as <5 eos/HPF in

oesophageal biopsies after PPI therapy and partial histological response when PPI therapy led to a maximum eosinophil

count >5 eos/HPF but <15 eos/HPF. Studies addressing only clinical response on PPI therapy were also considered,

albeit this analysis may be hampered by heterogeneity due to lack of an objective specific tool to assess symptom

response in EoE.

Results

Patient Characteristics

We identified 10 relevant publications,[6–15] comprising 258 patients with suspected EoE (152 children, 106 adults) who

were clinically and histologically reassessed after PPI therapy (). The articles included two randomised controlled trials,

one randomised noncontrolled trial, two prospective series (all in adults) and five retrospective series (four in children and

one in adults).

Table 1. Studies evaluating clinical and histological response after PPI therapy in patients with oesophageal symptoms

and >15 eos/HPF in oesophageal biopsies

First

author,

year,

country

Design n SubjectsPatients

profile

PPI therapy

(drug, dose,

duration)

Clinical

response on

PPI therapy

(definition)

Histological

remission on

PPI therapy

(definition)

pH

monitoring

in PPI

responders

Dranove

2009, US6 R 43 Children

- >15 eos/HPF

- Oesophageal

symptoms

Not available

37/43 (86%)

(symptom

improvement)

17/43 (40%)

(<5 eos/HPF)

Pathological

(n = 7)

Normal (n =

5)

Sayej


- >15 eos/HPF

- Oesophageal

symptoms

High-dose

therapy, ≥12

week

28/36 (78%)

(any clinical

response)

14/36 (38%)

(<5 eos/HPF)

Not

performed

Peterson

2010, US8 RCT 15 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction/chest

pain

Esomeprazole

40 mg/day 8

week

3/12 (25%)

(symptom

improvement)

4/12 (33%)

(<5 eos/HPF)

Performed,

not specified



Molina-

Infante

2011,

Spain9

P 35 Adults

- >15 eos/HPF

- Upper GI

symptoms

- >15 eos/HPF

-

Dysphagia/food

impaction

- Typical

endoscopic

findings

Rabeprazole

20 mg bid 8

week

28/35 (80%)

(clinical

remission)

26/35 (75%)

(< 5 eos/HPF)

9/15 (60%)

(<5 eos/HPF)

Pathological

(n = 7)

Normal (n =

2)

Abe 2011,

Japan10 R 12 Adults

- >15 eos/HPF

- oesophageal

symptoms

Drug and

dose not

specified,

4–8 week

5/6 (83%)

(almost

complete

remission)

3/7 (42%)

(<5 eo/sHPF)

Not

performed

Francis

2012,

US11P 18 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Esomeprazole

40 mg bid 6

week

11/18 (61%)

(MDQ 2 levels

lower than

baseline)

11/18 (61%)

(<5 eos/HPF)

18 (100%

pathological)

Levine

2012,

US13R 38 Children

- >15 eos/HPF

- Upper GI

symptoms

Lansoprazole

Omeprazole

1.2 ± 0.6

mg/kg/day

Maintenance

therapy

26/38 (68%)

(complete

clinical

remission)

10/38 (26%)

(<15 eos/HPF)

Not

performed

Fujiwara

2012,

Japan12P 5 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Rabeprazole

10 mg/day 8

week

3/5 (60%)

(symptom

improvement)

3/5 (60%)

(<15 eos/HPF)

Not

performed

Moawad

2013,

US14RCT 21 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Esomeprazole

40 mg/day 8

week

MDQ before

(19 ± 21)

and after

therapy (1.4 ±

4.5)

7/21 (33%)

(<7 eos/HPF)

Performed,

not specified

Schroeder

2013,

US15R 35 Children - >15 eos/HPF

Drug not

specified

1–2

mg/Kg/day

≥8 week

Not

dissociated

from

histological

response

8/35 (23%)

(<15 eos/HPF)

Not

performed



Eos/HPF, eosinophils per high power field; MDQ, Mayo Dysphagia Questionnaire; P, prospective; PPI, proton pump

inhibitors; R, retrospective; RCT, randomised controlled trial.

All patients had oesophageal eosinophilic infiltration ≥15 eos/HPF and oesophageal symptoms. As for children with PPI-

REE, there was a male predominance (69%). The presenting symptoms most commonly found were vomiting (54%),

abdominal/epigastric pain (51%) and dysphagia (28%). No allergic history was detailed in any of these studies.

Regarding adult patients, there was a male predominance as well (78%) and almost all patients (90%) suffered from

dysphagia, food impaction or chest pain. Most adult patients were atopic (62%), aeroallergen sensitisation was frequent

(32%) and seasonal asthma or rhinoconjunctivitis were the most common atopic diseases.[9, 14]

Clinical and Histological Response on PPI Therapy

After PPI therapy, clinical response was reported in a mean of 69% ± 22 patients (adults 58% ± 29, children 82% ± 5),

whereas histological remission was achieved in a mean of 44% ± 14 patients (adults 45% ± 13, children 33% ± 9). In

children, clinical response ranged from 86% to 78% and histological remission from 23% to 40%. In adults, clinical

response varied from 25% to 80% and histological remission from 33% to 61%. An in-depth analysis of all identified

studies, including country of origin, design, patients' characteristics, type of PPI therapy, definition and rates of clinical

and histological outcomes and pH monitoring results, is displayed in . No clinical, endoscopic or histological features

showed capacity to differentiate who responded to PPI therapy neither in children[6, 7, 15] nor in adult studies.[8, 9, 14]

Table 1. Studies evaluating clinical and histological response after PPI therapy in patients with oesophageal symptoms

and >15 eos/HPF in oesophageal biopsies

First

author,

year,

country

Design n SubjectsPatients

profile

PPI therapy

(drug, dose,

duration)

Clinical

response on

PPI therapy

(definition)

Histological

remission on

PPI therapy

(definition)

pH

monitoring

in PPI

responders

Dranove


- >15 eos/HPF

- Oesophageal

symptoms

Not available

37/43 (86%)

(symptom

improvement)

17/43 (40%)

(<5 eos/HPF)

Pathological

(n = 7)

Normal (n =

5)

Sayej


- >15 eos/HPF

- Oesophageal

symptoms

High-dose

therapy, ≥12

week

28/36 (78%)

(any clinical

response)

14/36 (38%)

(<5 eos/HPF)

Not

performed

Peterson

2010, US8 RCT 15 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction/chest

pain

Esomeprazole

40 mg/day 8

week

3/12 (25%)

(symptom

improvement)

4/12 (33%)

(<5 eos/HPF)

Performed,

not specified

Molina-

Infante

2011,

Spain9

P 35 Adults

- >15 eos/HPF

- Upper GI

symptoms

- >15 eos/HPF

-

Dysphagia/food

impaction

- Typical

endoscopic

findings

Rabeprazole

20 mg bid 8

week

28/35 (80%)

(clinical

remission)

26/35 (75%)

(< 5 eos/HPF)

9/15 (60%)

(<5 eos/HPF)

Pathological

(n = 7)

Normal (n =

2)



Abe 2011,

Japan10 R 12 Adults

- >15 eos/HPF

- oesophageal

symptoms

Drug and

dose not

specified,

4–8 week

5/6 (83%)

(almost

complete

remission)

3/7 (42%)

(<5 eo/sHPF)

Not

performed

Francis

2012,

US11P 18 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Esomeprazole

40 mg bid 6

week

11/18 (61%)

(MDQ 2 levels

lower than

baseline)

11/18 (61%)

(<5 eos/HPF)

18 (100%

pathological)

Levine

2012,

US13R 38 Children

- >15 eos/HPF

- Upper GI

symptoms

Lansoprazole

Omeprazole

1.2 ± 0.6

mg/kg/day

Maintenance

therapy

26/38 (68%)

(complete

clinical

remission)

10/38 (26%)

(<15 eos/HPF)

Not

performed

Fujiwara

2012,

Japan12P 5 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Rabeprazole

10 mg/day 8

week

3/5 (60%)

(symptom

improvement)

3/5 (60%)

(<15 eos/HPF)

Not

performed

Moawad

2013,

US14RCT 21 Adults

- >15 eos/HPF

-

Dysphagia/food

impaction

Esomeprazole

40 mg/day 8

week

MDQ before

(19 ± 21)

and after

therapy (1.4 ±

4.5)

7/21 (33%)

(<7 eos/HPF)

Performed,

not specified

Schroeder

2013,

US15R 35 Children - >15 eos/HPF

Drug not

specified

1–2

mg/Kg/day

≥8 week

Not

dissociated

from

histological

response

8/35 (23%)

(<15 eos/HPF)

Not

performed

Eos/HPF, eosinophils per high power field; MDQ, Mayo Dysphagia Questionnaire; P, prospective; PPI, proton pump

inhibitors; R, retrospective; RCT, randomised controlled trial.

At the present time, two randomised controlled trials in adults have compared topical steroids and PPI therapy.[8, 14] In

both trials, esomeprazole 40 mg daily was compared to swallowed fluticasone 440 μg bid for 8 weeks. Histological

remission was documented in 33% of patients under PPI therapy in both trials. Of note, histological remission (<5

eos/HPF) was more frequent under PPIs compared to aerosolised fluticasone in both studies (33% vs. 15% and 33% vs.

19%).

Dissociation Between Clinical and Histological Response After PPI Therapy

After PPI therapy in patients with suspected EoE, clinical and histological response were not always concordant, neither

in children[7, 12] nor in adults.[8–11] Specifically, in patients who had complete histological response to PPI, there was

commonly but not always uniform clinical response (45–100%). Conversely, in patients without histological remission on

PPI therapy, a clinical response, ranging from improvement to complete symptom elimination, has been reported in

nearly two thirds of patients (50–85%).[7, 9–12]



Partial Histological PPI Responders

Of note, the study by Peterson et al.[8] revealed that histological remission rate after PPI therapy increased from 33% to

50% after changing the diagnostic histological threshold from <5 eos/HPF to <15 eos/HPF. No additional studies have

addressed the clinical and histological course of these 'partial responder' patients after long-term PPI therapy.

Role of Oesophageal pH Monitoring to Predict Response to PPI Therapy

A paucity of studies in children[6] and adults[9, 11, 14] have evaluated the role of pH monitoring to predict response to PPI

therapy in patients with an EoE phenotype (). An interesting study in this respect is the study by Francis et al.[11] The

authors performed a prospective trial in which patients with an EoE profile were assigned to high-dose PPI therapy for

abnormal results on pH monitoring (n = 18) or topical steroids if the pH study was normal (n = 28). Histological response

on PPI therapy (pathological pH monitoring) was 61% and 57% on oral budesonide (normal pH monitoring). At present,

three studies up have evaluated the rate of histological remission of oesophageal eosinophilia after PPI therapy, either

with or without documented GERD. Dranove et al.[7] showed in a retrospective fashion that response to PPI treatment in

children occurred in 41% of patients with abnormal pH monitoring study and in 45% in those with normal pH monitoring

study. Molina-Infante et al.[9] and Moawad et al.[14] recently demonstrated a 33% and 18% of PPI response in adult

patients with a normal pH study and 82% and 100% with a pathological pH monitoring respectively. Overall, histological

response to PPI therapy () was significantly higher in the presence of documented GERD [70% (35/50) vs. 29.4%

(10/34), P < 0.001]. This difference was more evident when only considering prospective studies in adults [84.8% (28/33)

vs. 21.7% (5/23), P < 0.001].

Table 2. Studies evaluating response to PPI therapy in patients with an EoE phenotype, depending on the existence of

documented GERD

Histological remission

Pathological pH monitoring or erosive oesophagitis

(%)

Normal pH monitoring

(%)

Dranove 2009, US6 7/17 (41) 5/11 (45)

Molina-Infante, 2011,

Spain9 24/29 (82) 2/6 (33)

Francis, 2012,US11 11/18 (61) –

Moawad, 2013, US14 4/4 (100) 3/17 (18)

EoE, eosinophilic oesophagitis; GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor.

Table 2. Studies evaluating response to PPI therapy in patients with an EoE phenotype, depending on the existence of

documented GERD

Histological remission

Pathological pH monitoring or erosive oesophagitis

(%)

Normal pH monitoring

(%)

Dranove 2009, US6 7/17 (41) 5/11 (45)

Molina-Infante, 2011,

Spain9 24/29 (82) 2/6 (33)

Francis, 2012,US11 11/18 (61) –

Moawad, 2013, US14 4/4 (100) 3/17 (18)

EoE, eosinophilic oesophagitis; GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor.

Transient PPI-REE

Up to now, eosinophilic inflammation has been reported to recur in six paediatric PPI-REE patients, despite continuous

PPI therapy, at similar or even higher doses than used at the first PPI trial.[15, 16] This phenomenon has been coined as

'transient' PPI-REE. No long-term follow-up series for PPI-REE patients have been reported yet, so the prevalence and



the mechanisms underlying this subphenotype remain to be elucidated.

Symptomatic Response After a PPI Trial

We identified three articles in which symptomatic but not histological response to PPI therapy had been addressed for

patients with suspected EoE. Clinical response was mostly defined in these studies by improvement in symptoms.

Response rates were 3/12 (25%),[17] 8/17 (47%)[18] and 2/6 (35%).[19] In addition, two studies reported the clinical

usefulness of PPI monotherapy along with dilation for patients with eosinophilic infiltration and oesophageal ring of

narrowing,[20, 21] notwithstanding the fact of persistent eosinophilic inflammation.[21]

Commentary

The present review is the first one gathering evolving evidence on patients with PPI-REE. This phenotype has emerged

over the last 5 years as a clinically prevalent group of patients (at least one third of patients with suspected EoE are PPI

responders, with a trend to higher response rates in adults) rather than anecdotal case reports. The importance of this

group is underscored by its important position in the updated 2011 consensus guidelines on EoE.[2] The recognition of

PPI-REE implies that a PPI trial is mandatory not only to confirm the presence of EoE, but to evaluate for PPI

responsiveness in patients with oesophageal eosinophilia and a phenotype of EoE.[22] Nonetheless, PPI-REE still

remains underappreciated in clinical practice. Two recent surveys conducted in US identified that only one third of

physicians thought it is necessary to initiate a PPI trial before diagnosing EoE in both paediatric and adult patients.[23,24]

As part of the dynamic and rapidly changing spectrum of EoE, there are several unresolved issues regarding PPI-REE ().

It remains uncertain as to whether these patients have an atypical presentation of GERD, a variant of EoE that responds

to PPI therapy, or a completely different entity. At the present time, no clinical, endoscopic, histological features nor pH

testing have demonstrated capacity to predict response to PPI therapy. Therefore, further research is warranted to

develop new and more accurate diagnostic approaches (e.g. molecular biomarkers, genetic testing) to distinguish EoE

and PPI-REE and better understand their unique and/or common pathophysiological origins.

Table 3. Unresolved issues regarding diagnosis and treatment in proton pump inhibitor-responsive oesophageal

eosinophilia (PPI-REE)

Dose and duration required for initial PPI trial

Influence of PPI metabolism phenotype (CYP2C19 rapid/medium/slow metabolisers) in short- and long-term PPI

response

Pathogenesis of PPI-REE

Molecular biomarkers/genetic testing distinguishing PPI-REE from EoE

Optimal PPI dosing as maintenance therapy

Rate of sustained remission on PPI therapy

Long-term outcome of partial PPI responders (5–15 eos/HPF)

Need and frequency of endoscopy in follow-up

Impact of allergenic exposure in maintained PPI response

EoE, eosinophilic oesophagitis; PPI, proton pump inhibitors; PPI-REE, proton pump inhibitor-responsive oesophageal

eosinophilia.

There are a number of possible explanations for PPI-REE[4] (Figure 1). The most prevailing hypothesis is that coexisting

GERD might be the primary event, contributing to the development of an allergic oesophagitis by allowing the potential

entry of food derived allergenic molecules through acid-induced epithelial damage. The normal oesophageal epithelium is

highly impermeable to food allergens, which size ranges normally between 3 and 90 kD.[25] Nonetheless, oesophagus

has been shown to become permeable to molecules as big as 20 kD after acid and pepsin exposure, by means of

dilated intercellular spaces due to GERD.[26] Allergens entry may trigger a Th2 immune response that stimulates local

eotaxin-3 production, cytokine secretion and the gross histological changes of EoE. Reversal of epithelial barrier

dysfunction through PPI treatment would explain symptomatic and histological response in PPI-REE. This review shows

a higher rate of PPI-REE upon documented GERD (erosive oesophagitis or pathological pH monitoring), highlighting the



relative importance of acid reflux in this entity. Nonetheless, both endoscopic and pH testing criteria may have technical

limitations for ruling out GERD, on account of a substantial false negative rate. In this regard, dilated intercellular

spaces, which have lately gained interest as a marker of non-erosive GERD reflecting an increase in paracellular

permeability, have been reported either with pathological or physiological oesophageal acid exposure time.[27] This

finding would support the existence of PPI-REE upon GERD, either with normal or abnormal acid exposure time, as we

have shown in this review.

Figure 1.

Potential theories to explain proton pump inhibitor-responsive oesophageal eosinophilia. GERD, gastro-oesophageal

reflux disease; PPI, proton pump inhibitor therapy.

Recently, experimental GERD has been shown to cause oesophageal inflammation through a cytokine-mediated

mechanism rather than direct epithelial caustic injury.[28] In this study, the authors observed that the first inflammatory

sign detected was a lymphocytic infiltration of the submucosa after surgical induction of reflux, which progressed to the

mucosal surface. Interestingly, mucosal erosions did not appear until post-operative week 4. These findings suggest that

reflux oesophagitis develops primarily as an immune-related injury rather than solely as a caustic chemical injury. As

such, one can speculate that PPI-REE might be attenuating a GERD-induced aberrant inflammatory Th2 response in

some specific predisposed atopic patients, mimicking EoE, but responsive to PPI treatment. More data are needed to



fully assess this pathway.

Improvement of oesophageal symptoms with PPI therapy has been considered prima facie evidence of GERD. However,

PPIs have been found to have antioxidant properties and direct effects on eosinophils, neutrophils, monocytes,

endothelial and epithelial cells that might prevent inflammation,[29] independent of their acid-suppressing properties. In

fact, emerging translational research in experimental asthma and EoE[30–32] is highlighting that PPIs might exert

eosinophil-reducing effects. Eotaxin-3 is a potent eosinophil chemoattractant that plays a key role in trafficking

eosinophils to the oesophagus in EoE. The expression of eotaxin-3 is stimulated by Th2 cytokines, such as IL-4 and IL-

13 (normally overproduced in allergic diseases), whose effects are mediated by the signal transducer and activator of the

transcription (STAT) 6 signalling pathway.

In 2009, novel anti-inflammatory effects of PPIs were reported in murine asthma.[23] PPIs (including omeprazole,

lansoprazole and esomeprazole) inhibited in vitro IL-4 and IL-13 signalling STAT6, reducing significantly the presence of

inflammatory cells in bronchoalveolar lavage fluid and lung sections, including eosinophils.[30] Of note, a recent article

has demonstrated that both EoE and GERD primary cells express similar levels of eotaxin-3 after IL-4 and IL-13

stimulation and, interestingly, omeprazole blocked this expression in oesophageal squamous cell cultures from both

GERD and EoE patients.[31] More recently, omeprazole and lansoprazole have been shown to inhibit IL-4 and IL-13

stimulated eotaxin-3 expression in EoE oesophageal cells through blocking STAT6.[32] As these are in vitro cultured

cells, the observed PPI effects must be independent of their effects on gastric acid production. Overall, these findings

suggest that PPIs can have anti-inflammatory actions in patients with oesophageal eosinophilia independent of their

effects on acid-secretion and cast doubt on the assumption that a positive response to PPI therapy necessarily

establishes a diagnosis of GERD.[33] Indeed, these observations provide a rationale for PPI use in EoE and support the

role of molecular in vitro and cytokine-mediated mechanisms to explain PPIr-OEE. However, further studies are

warranted to confirm whether these PPI effects are applicable to patients in clinical practice.

A remarkable finding is the high rate of clinical response to PPI therapy reported in EoE patients who do not achieve

histological remission on PPI therapy. EoE patients have been recently shown to have symptomatic acid

hypersensitivity, as they had significantly lower thresholds for onset of symptoms and pain after oesophageal acid

infusions when compared to healthy volunteers.[34] Of note, EoE patients without proven GERD showed an earlier

burning sensation than EoE patients with concomitant GERD or healthy volunteers. To a lesser extent, histological

remission on PPIs without symptom improvement has been reported. Apart from non-GERD related causes, such as

superimposed motility disorders, underlying GERD is likely to be the main cause of persistent symptoms. Several

mechanisms such as persistent acid or weakly acidic reflux, oesophageal hypersensitivity or coexisting functional

digestive disorders may influence the clinical response to PPI therapy.[35] Moreover, the reported course of symptoms

after PPI therapy in patients with oesophageal eosinophilia has shown marked variation perhaps due to the absence of

an objective specific tool to assess symptom response in EoE, such as symptom disappearance or clinical

improvement,[6, 7, 9, 10] the Reflux Disease Questionnaire[8] or, lately, the Mayo Dysphagia Questionnaire.[11, 14]

Another novel phenomenon is the so-called 'transient PPI-REE', which has been described in a small number of patients

so far. Potential explanations might include false negative readings on initial post treatment pathology due to the patchy

nature of this disease, a variable contribution of extraoesophageal allergen exposure which primes oesophageal

eosinophilia, or that PPI-REE represents a forme fruste of EoE as a similar cytokine-mediated disease. Until more of

these patients are carefully under follow-up for longer periods of time, continued PPI therapy is warranted in these

cases. The appropriate maintenance PPI dosage for these patients remains unknown. One concern is that, similar to

symptoms in GERD, oesophageal eosinophilia might relapse during a 'step-down' process. The concept that treatment

and maintenance doses for EoE might remain the same is further supported by findings that high-dose oral budesonide

(1 mg bid) was highly effective to induce clinico-histological remission in EoE patients,[36] but results were less robust

on low-dose long-term maintenance therapy (budesonide 0.25 mg bid).[37]

In conclusion, PPI-REE occurs in at least one third of patients with suspected EoE, with response rates lower in

children and as high as 70% in adult patients with coexisting GERD. Until further studies better define the pathogenesis

of PPI-REE and identify tools to distinguish between PPI-REE and EoE, a trial of PPI therapy remains an important

prerequisite to the diagnosis of EoE. Multiple diagnostic and therapeutic dilemmas surrounding PPI-REE, as shown in ,

should be a matter of further research.

Table 3. Unresolved issues regarding diagnosis and treatment in proton pump inhibitor-responsive oesophageal

eosinophilia (PPI-REE)



Dose and duration required for initial PPI trial

Influence of PPI metabolism phenotype (CYP2C19 rapid/medium/slow metabolisers) in short- and long-term PPI

response

Pathogenesis of PPI-REE

Molecular biomarkers/genetic testing distinguishing PPI-REE from EoE

Optimal PPI dosing as maintenance therapy

Rate of sustained remission on PPI therapy

Long-term outcome of partial PPI responders (5–15 eos/HPF)

Need and frequency of endoscopy in follow-up

Impact of allergenic exposure in maintained PPI response

EoE, eosinophilic oesophagitis; PPI, proton pump inhibitors; PPI-REE, proton pump inhibitor-responsive oesophageal

eosinophilia.

References

1. 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.

2. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for

children and adults. J Allergy ClinImmunol 2011; 128: 3–10.

3. Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology 2009; 137: 1238–49.

4. Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between gastroesophageal reflux

disease and eosinophilic esophagitis. Am JGastroenterol 2007; 102: 1301–6.

5. Ngo P, Furuta GT, Antonioli DA, et al. Eosinophils in the esophagus: peptic or allergic eosinophilic esophagitis?

Case series of three patients with esophageal eosinophilia. Am J Gastroenterol 2006; 101: 1666–70.

6. Dranove JE, Horn DS, Davis MA, et al. Predictors of response to proton pump inhibitor therapy among children

with significant esophageal eosinophilia. JPediatr 2009; 154: 96–100.

7. Sayej WN, Patel RA, Baker RD, et al. Treatment with high-dose proton pump inhibitors helps distinguish

eosinophilic esophagitis from noneosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2009; 49: 1–7.

8. Peterson KA, Thomas KL, Hilden K, et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for

eosinophilic esophagitis. Dig Dis Sci 2010; 55: 1313–9.

9. Molina-Infante J, Ferrando-Lamana A, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump

inhibition in most adults. ClinGastroenterol Hepatol 2011; 9: 110–7.

10. Abe Y, Iijima K, Ohara S, et al. A Japanese case series of 12 patients with esophageal eosinophilia. J

Gastroenterol 2011; 46: 25–30.

11. Francis DL, Foxx-Orenstein A, Arora AS, et al. Results of ambulatory pH monitoring do not reliably predict

response to therapy in patients with eosinophilic esophagitis. AlimentPharmacol Ther 2012; 35: 300–7.

12. Fujiwara Y, Sugawa T, Tanaka F, et al. A multicenter study on the prevalence of eosinophilic esophagitis and

PPIresponsive esophageal eosinophilic infiltration. Intern Med 2012; 51: 3235–9.

13. Levine J, Lai J, Edelman M, Schuval SJ. Conservative long-term treatment of children with eosinophilic

esophagitis. Ann Allergy Asthma Immunol 2012; 108: 363–6.

14. Moawad FJ, Veerappan GR, Dias JA, et al. Randomized controlled trial comparing aerosolized swallowed

fluticasone to esomeprazole for esophageal eosinophilia. Am JGastroenterol 2013; 108: 366–72.



15. Schroeder S, Capocelli KE, Masterson JC, et al. Effect of proton pump inhibitor on esophageal eosinophilia. J

Pediatr Gastroenterol Nutr 2013; 56: 166–72.

16. Dohil R, Newbury RO, Aceves S. Transient PPI responsive esophageal eosinophilia may be a clinical sub-

phenotype of pediatric eosinophilic esophagitis. Dig Dis Sci 2012; 57: 1413–9.

17. Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique

esophageal features. Gastrointest Endosc 2004; 59: 355–61.

18. Desai TK, Stecevic V, Chang CH, et al. Association of eosinophilic inflammation with esophageal food impaction

in adults. Gastrointest Endosc 2005; 61: 795–801.

19. Tomomatsu Y, Yoshino J, Inui K, et al. Clinical features of eosinophilic esophagitis: ten Japanese cases.

DigEndosc 2013; 25: 117–24.

20. Morrow JB, Vargo JJ, Goldblum JR, et al. The ringed esophagus: histological features of GERD. Am J

Gastroenterol 2001; 96: 984–9.

21. Bohm M, Richter JE, Kelsen S, et al. Esophageal dilation: simple and effective treatment for adults with

eosinophilic esophagitis and esophageal rings and narrowing. Dis Esophagus 2010; 23: 377–85.

22. Dellon ES. Diagnosis and management of eosinophilic esophagitis. ClinGastroenterol Hepatol 2012; 10: 1066–78.

23. Peery AF, Shaheen NJ, Dellon ES. Practice patterns for the evaluation and treatment of eosinophilic esophagitis.

Aliment Pharmacol Ther 2010; 32: 1373–82.

24. Spergel JM, Book WM, Mays E, et al. Variation in prevalence, diagnostic criteria, and initial management options

for eosinophilic gastrointestinal diseases in the United States. J PediatrGastroenterol Nutr 2011; 52: 300–6.

25. Lack G. Clinical practice food allergy. NEngl J Med 2008; 359: 1252–60.

26. Tobey NA, Hosseini SS, Argote CM, et al. Dilated intercellular spaces and shunt permeability in nonerosive acid-

damaged esophageal epithelium. Am J Gastroenterol 2004; 99: 13–22.

27. Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux

disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005; 100: 543–8.

28. Shouza RF, Huo X, Vittal M, et al. Gastroesophageal reflux might cause esophagitis through a cytokinemediated

mechanism rather than caustic acid injury. Gastroenterology 2009; 137: 1776–84.

29. Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and

discussion of the clinical implications. Dig Dis Sci 2009; 54: 2312–7.

30. Cortes JR, Rivas MD, Molina-Infante J, et al. Omeprazole inhibits IL-4 and IL-13 signaling signal transducer and

activator of transcription 6 activation and reduces lung inflammation in murine asthma. J Allergy Clin Immunol

2009; 124: 607–10.

31. Cheng E, Zhang X, Huo X, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from

patients with eosinophilic oesophagitis and GORD. Gut 2012; 7: e50037.

32. Zhang X, Cheng E, Huo X, et al. Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic

esophagitis cells. PLoS ONE 2012; 7: e50037.

33. Hirano I. Editorial: should patients with suspected eosinophilic esophagitis undergo a therapeutic trial of proton

pump inhibition? Am J Gastroenterol 2013; 108: 373–5.

34. Krarup AL, Villadsen GE, Mejlgaard E, et al. Acid hypersensitivity in patients with eosinophilic esophagitis.

Scand JGastroenterol 2010; 45: 273–81.

35. Sifrim D, Zebib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump



Guarantor of the article

Javier P. Gisbert.

Author contributions

Javier Molina-Infante devised, wrote and edited the article. David A. Katzka and Javier P. Gisbert edited and supervisedthe article. All authors approved the final version of the manuscript.

Aliment Pharmacol Ther. 2013;37(12):1157-1164. © 2013 Blackwell Publishing

inhibitors. Gut 2012; 61: 1340–54.

36. Straumann A, Conus S, Degen L, et al. Budesonide is effective in adolescent and adult patients with active

eosinophilic esophagitis. Gastroenterology 2010; 139: 1526–37.

37. Straumann A, Conus S, Degen L, et al. Long-term budesonide maintenance treatment is partially effective for

patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2011; 9: 400–9.

review article: proton pump inhibitor therapy for ... · gastro-oesophageal reflux disease (gerd)...

Documents