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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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 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

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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 (Table 1). 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, countryDesign n SubjectsPatients profilePPI therapy (drug, dose, duration)Clinical response on PPI therapy (definition)Histological remission on PPI therapy (definition)pH monitoring in PPI responders
  1. Eos/HPF, eosinophils per high power field; MDQ, Mayo Dysphagia Questionnaire; P, prospective; PPI, proton pump inhibitors; R, retrospective; RCT, randomised controlled trial.

Dranove 2009, US[6]R43Children

- >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 2009, US[7]R36Children

- >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, US[8]RCT15Adults

- >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, Spain[9]P35Adults

- >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, Japan[10]R12Adults

- >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, US[11]P18Adults

- >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, US[13]R38Children

- >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, Japan[12]P5Adults

- >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, US[14]RCT21Adults

- >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, US[15]R35Children- >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

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 Table 1. 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]

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 (Table 2). 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 (Table 2) 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 (%)
  1. EoE, eosinophilic oesophagitis; GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor.

Dranove 2009, US[6]7/17 (41)5/11 (45)
Molina-Infante, 2011, Spain[9]24/29 (82)2/6 (33)
Francis, 2012,US[11]11/18 (61)
Moawad, 2013, US[14]4/4 (100)3/17 (18)

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

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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 (Table 3). 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)
  1. EoE, eosinophilic oesophagitis; PPI, proton pump inhibitors; PPI-REE, proton pump inhibitor-responsive oesophageal eosinophilia.

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

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.

image

Figure 1. Potential theories to explain proton pump inhibitor-responsive oesophageal eosinophilia. GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor therapy.

Download figure to PowerPoint

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 Table 3, should be a matter of further research.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

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 supervised the article. All authors approved the final version of the manuscript.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Commentary
  7. Authorship
  8. Acknowledgement
  9. 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: 134263.
  • 2
    Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 310.
  • 3
    Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology 2009; 137: 123849.
  • 4
    Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am J Gastroenterol 2007; 102: 13016.
  • 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: 166670.
    Direct Link:
  • 6
    Dranove JE, Horn DS, Davis MA, et al. Predictors of response to proton pump inhibitor therapy among children with significant esophageal eosinophilia. J Pediatr 2009; 154: 96100.
  • 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: 17.
  • 8
    Peterson KA, Thomas KL, Hilden K, et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci 2010; 55: 13139.
  • 9
    Molina-Infante J, Ferrando-Lamana A, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol 2011; 9: 1107.
  • 10
    Abe Y, Iijima K, Ohara S, et al. A Japanese case series of 12 patients with esophageal eosinophilia. J Gastroenterol 2011; 46: 2530.
  • 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. Aliment Pharmacol Ther 2012; 35: 3007.
  • 12
    Fujiwara Y, Sugawa T, Tanaka F, et al. A multicenter study on the prevalence of eosinophilic esophagitis and PPI-responsive esophageal eosinophilic infiltration. Intern Med 2012; 51: 32359.
  • 13
    Levine J, Lai J, Edelman M, Schuval SJ. Conservative long-term treatment of children with eosinophilic esophagitis. Ann Allergy Asthma Immunol 2012; 108: 3636.
  • 14
    Moawad FJ, Veerappan GR, Dias JA, et al. Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia. Am J Gastroenterol 2013; 108: 36672.
  • 15
    Schroeder S, Capocelli KE, Masterson JC, et al. Effect of proton pump inhibitor on esophageal eosinophilia. J Pediatr Gastroenterol Nutr 2013; 56: 16672.
  • 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: 14139.
  • 17
    Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc 2004; 59: 35561.
  • 18
    Desai TK, Stecevic V, Chang CH, et al. Association of eosinophilic inflammation with esophageal food impaction in adults. Gastrointest Endosc 2005; 61: 795801.
  • 19
    Tomomatsu Y, Yoshino J, Inui K, et al. Clinical features of eosinophilic esophagitis: ten Japanese cases. Dig Endosc 2013; 25: 11724.
  • 20
    Morrow JB, Vargo JJ, Goldblum JR, et al. The ringed esophagus: histological features of GERD. Am J Gastroenterol 2001; 96: 9849.
    Direct Link:
  • 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: 37785.
  • 22
    Dellon ES. Diagnosis and management of eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012; 10: 106678.
  • 23
    Peery AF, Shaheen NJ, Dellon ES. Practice patterns for the evaluation and treatment of eosinophilic esophagitis. Aliment Pharmacol Ther 2010; 32: 137382.
  • 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 Pediatr Gastroenterol Nutr 2011; 52: 3006.
  • 25
    Lack G. Clinical practice food allergy. N Engl J Med 2008; 359: 125260.
  • 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: 1322.
  • 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: 5438.
  • 28
    Shouza RF, Huo X, Vittal M, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 2009; 137: 177684.
  • 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: 23127.
  • 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: 60710.
  • 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: 3735.
  • 34
    Krarup AL, Villadsen GE, Mejlgaard E, et al. Acid hypersensitivity in patients with eosinophilic esophagitis. Scand J Gastroenterol 2010; 45: 27381.
  • 35
    Sifrim D, Zebib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut 2012; 61: 134054.
  • 36
    Straumann A, Conus S, Degen L, et al. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 2010; 139: 152637.
  • 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: 4009.