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Role of Reflux in the Pathogenesis of Eosinophilic Esophagitis

Comprehensive Appraisal With Off- and On PPI Impedance-pH Monitoring

Frazzoni, Marzio MD1; Penagini, Roberto MD2,3; Frazzoni, Leonardo MD4,1; de Bortoli, Nicola MD5; Mauro, Aurelio MD2,3; Tolone, Salvatore MD6; Bertani, Helga MD7; Marsico, Maria MD8; Marocchi, Margherita MD8; Marchi, Santino MD5; Conigliaro, Rita MD7; Savarino, Edoardo MD9

American Journal of Gastroenterology: October 2019 - Volume 114 - Issue 10 - p 1606–1613
doi: 10.14309/ajg.0000000000000379
ARTICLE
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OBJECTIVES: Role of reflux and mechanisms of response to proton pump inhibitor (PPI) therapy in eosinophilic esophagitis (EoE) have not yet been fully elucidated. Comprehensive assessment by impedance-pH monitoring could clarify these issues.

METHODS: Prospective multicenter study comparing EoE patients with healthy controls and gastroesophageal reflux disease cases. Patients with EoE were evaluated off- and on PPI; responsiveness was assessed by histology. Impedance-pH appraisal included chemical clearance, assessed with the postreflux swallow-induced peristaltic wave (PSPW) index, and mucosal integrity measured with mean nocturnal baseline impedance (MNBI).

RESULTS: Sixty consecutive patients with EoE were compared with 60 age- and sex-matched healthy controls and 60 subjects with gastroesophageal reflux disease. The number of total refluxes was higher, while the PSPW index was lower in patients with EoE than in healthy controls. Off PPI, a lower MNBI gradient between the mid and distal esophagus distinguished 20 patients with PPI-refractory EoE from 40 patients with PPI-responsive EoE and was a predictor of PPI failure. On PPI, a lower PSPW index was the sole reflux parameter distinguishing PPI-refractory from PPI-responsive EoE; all reflux parameters improved in PPI-responsive patients, whereas the PSPW index was not modified in PPI-refractory cases and was independently associated with PPI-responsiveness. MNBI in the distal and mid esophagus improved much more in PPI-responsive than in PPI-refractory EoE.

DISCUSSION: Reflux plays a role in the pathogenesis of EoE, more relevant in PPI-responsive cases. Low impedance gradient between the mid and distal esophagus may be useful to predict PPI refractoriness. PPIs mainly act by improving chemical clearance, i.e., by an antireflux action supporting long-term prescription in PPI-responsive EoE.

1Department of Specialized Medicine, Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy;

2Department of Pathophysiology and Transplantation, University of Milano;

3Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy;

4Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy;

5Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy;

6Department of Surgery, Mini-Invasive and Bariatric Surgery Unit, University of Campania, Napoli, Italy;

7Department of Specialized Medicine, Digestive Endoscopy Unit, Baggiovara Hospital, Modena, Italy;

8Department of Specialized Medicine, Gastroenterology Unit, Policlinico Hospital, Modena, Italy;

9Department of Surgery, Oncology and Gastroenterology, Gastroenterology Unit, University of Padova, Padova, Italy.

Correspondence: Marzio Frazzoni, MD. E-mail: marziofrazzoni@gmail.com.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/B268 and http://links.lww.com/AJG/B269

Received December 24, 2018

Accepted July 10, 2019

Online date: August 21, 2019

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INTRODUCTION

Eosinophilic esophagitis (EoE) is currently defined as a chronic, immune-mediated esophageal disease characterized by symptoms related to esophageal dysfunction and eosinophil-predominant inflammation (1,2). As a consequence of esophageal dysfunction and impaired bolus clearance, adult patients with EoE mainly complain of intermittent dysphagia and/or food impaction. Proton pump inhibitor (PPI) therapy, the mainstay of medical treatment for gastroesophageal reflux disease (GERD), induces clinical and histological remission in many patients with EoE and is currently regarded as one of the first-line therapies for EoE (1,2), but the mechanisms underlying the effectiveness of this treatment have not yet been elucidated. GERD is a common disease, and EoE may not be as rare as once believed (3), so the 2 conditions may coexist in the same patient. Indeed, the relationship between GERD and EoE can be ambivalent (4): EoE might cause GERD because of impaired esophageal clearance of physiological reflux, and GERD could cause EoE if reflux leads to a leaky epithelial barrier, through which food antigens may induce a T-helper 2–driven immune response with cytokine-mediated recruitment of eosinophils.

At pH-only monitoring, normal esophageal acid exposure time (EAET) has been reported in most patients with EoE, and EAET values did not predict symptomatic and histological PPI response (5). These findings and in vitro experiments in acidic environment (6) suggested direct anti-inflammatory rather than acid-suppressive mechanism of action of PPIs and a minor role, if any, of gastroesophageal reflux in EoE (4). However, the diagnostic limitations of EAET have long been recognized. Specificity and sensitivity are suboptimal, the former because pH drops below 4.0 are often due to acidic swallows (7), and the latter because normal results in up to 20% of patients with reflux esophagitis (8) and day-to-day variability (9) have been documented. Such drawbacks can be overcome by impedance-pH monitoring, which allows an accurate estimate of all reflux events, off- and on PPI therapy, as well as of esophageal chemical clearance and mucosal integrity by means of new metrics, namely the postreflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI) (10–12). There is evidence that mucosal impedance is reduced and correlates with eosinophilia in EoE (13,14), and low values have been reported in the distal as well in the mid and proximal esophagus using through-the-scope probes (15,16). However, studies addressing the relationship between EoE and GERD have been limited by lack of comprehensive testing (17); since the pathophysiology of GERD is multifactorial, its presence cannot be rejected on the basis of negative results of a single test (17,18).

In PPI-responsive EoE, long-term treatment is effective in maintaining disease remission (19) and is currently advised (1,2); however, PPIs are approved for GERD but not for EoE, and concerns about their safety could discourage prolonged use in the absence of some demonstration that reflux plays a role in EoE. Recently, on-PPI impedance-pH monitoring provided a relevant contribution to clarify the mechanisms of PPI response in patients with reflux-related heartburn, i.e., typical GERD (20). Similarly, the mechanisms of PPI response in EoE could be elucidated by on-PPI impedance-pH assessment, possibly substantiating long-term PPI usage in case of demonstrated antireflux action of PPIs.

Aim of this study was to assess the role of reflux in the pathogenesis of EoE by means of: (i) analysis of conventional and new impedance-pH metrics in patients with EoE as compared to those detected in healthy controls and subjects with GERD and (ii) assessment of reflux parameters as modified by PPI therapy in PPI-responsive and PPI-refractory patients, to clarify the mechanisms of PPI response.

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METHODS

Consecutive patients referred for intermittent solid food dysphagia or history of food impaction requiring urgent endoscopic removal, and who received a diagnosis of EoE based on the detection of esophageal eosinophilia, i.e., ≥15 eosinophils in at least 1 high-power field (HPF) (1,2), with/without endoscopic signs assessed by the Endoscopic Reference Score (EREFS) (21), entered this prospective multicenter study. The study was conducted in accordance with the Declaration of Helsinki and was approved by institutional review boards. Patients underwent clinical investigations only after providing a written informed consent.

Impedance-pH monitoring was performed before starting PPI therapy and was always preceded by conventional or high-resolution esophageal manometry for location of the lower esophageal sphincter (LES) and exclusion of major motility disorders (22). Impedance-pH monitoring was performed by means of a probe allowing detection of intraluminal impedance at 3, 5, 7, 9, 15, and 17 cm and of pH at 5 cm above the LES. Tracings were manually assessed with the aid of commercial software (Autoscan, Sandhill Scientific, CO). Liquid and liquid–gas reflux events were distinguished into acidic (nadir pH < 4.0), weakly acidic (nadir pH between 4.0 and 7.0), and weakly alkaline (nadir pH not below 7.0); meal times were excluded (23). Conventional parameters included percentage EAET and number of total, acid, weakly acidic, and weakly alkaline refluxes.

New impedance metrics included the PSPW index and MNBI. PSPW was defined as an antegrade 50% drop in impedance, originating in the proximal esophagus and reaching the distal lumen within 30s after a reflux event, indicating salivary swallow (10); the PSPW index was calculated dividing the number of PSPWs by the number of reflux events (10). MNBI was assessed during nighttime recumbent period in the most distal impedance channel: three 10-minute periods (around 1.00 AM, 2.00 AM, and 3.00 AM) were selected avoiding swallows, refluxes, and pH drops below 4.0, and the mean was calculated (10). For comparison with studies assessing mucosal impedance with through-the-scope probes (14–16), MNBI was measured in the 6 impedance channels.

Off-PPI impedance-pH findings in patients with EoE were compared with those found in age- and sex-matched healthy controls. We also compared EoE cases to consecutive patients with typical GERD, defined as endoscopy-negative but impedance-pH positive, i.e., reflux-related heartburn, investigated during the same period and characterized by PPI-responsive or PPI-refractory heartburn, all with off-PPI abnormal EAET and/or positive heartburn-reflux association combined with abnormal values of both the PSPW index and MNBI (20).

After EoE diagnosis and baseline off-PPI impedance-pH assessment, patients assumed double-daily dose PPI for 2 months and then underwent on-PPI impedance-pH monitoring followed by upper gastrointestinal endoscopy with 6 esophageal biopsies to evaluate the effects of therapy (1,2). According to current guidelines (1,2), the primary outcome measure of the study was PPI-responsiveness as objectively defined by histology, i.e., less than 15 eosinophils per HPF, the cutoff reportedly most accurate for assessment of positive response to treatment (24); furthermore, off- and on-therapy dysphagia was scored using a four-grade Likert-type scale. Off- and on-PPI impedance-pH parameters were compared between PPI-responsive and PPI-refractory patients.

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Statistics

Sample size of the study was calculated to obtain 80% study power. For off-PPI impedance-pH comparisons between patients with EoE, healthy controls, and GERD cases, considering the results of our previous multicenter study (10), at least 45 cases were required in each group. For on-PPI comparison of impedance-pH parameters between PPI-responsive and PPI-refractory EoE, at least 7 cases were required in each group considering the results of our previous multicenter study concerning PPI-refractory and PPI-responsive GERD (20). Since data were found to be normally distributed, they are presented as mean and SD; continuous and categorical variables were analyzed with analysis of variance and the χ2 test with Bonferroni correction for multiple comparisons; significance was set at P < 0.05 and P < 0.0167 for two- and three-group comparisons, respectively. The pretreatment predictive value of impedance-pH metrics distinguishing PPI-responsive from PPI-refractory EoE was assessed by means of receiver operating characteristic (ROC) analysis with calculation of the area under the curve. To identify mechanisms of PPI-responsiveness, univariate conditional logistic regression analyses were performed among PPI-responsive cases, matching the impedance-pH parameters off- and on PPI therapy; significant variables (P < 0.05) at univariate analysis were entered into a multivariate conditional logistic regression, to find parameters independently associated with PPI responsiveness. All the analyses were performed using STATA statistical software, release 13 (STATA, College Station, TX).

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RESULTS

Sixty consecutive patients who received EoE diagnosis at our centers and accepted to enter the study completed the scheduled evaluation between September 2016 and October 2018 (Figure 1). The mean EREFS at entrance was 1.9 ± 1.1, while the mean number of eosinophils per HPF was 32.6 ± 12.3. Off-PPI impedance-pH tracings of EoE cases were analyzed and compared with those from 60 age- and sex-matched healthy controls and from 60 consecutive GERD cases, 31 with PPI-responsive and 29 with PPI-refractory heartburn.

Figure 1

Figure 1

Demographic characteristics and off-PPI impedance-pH parameters in healthy controls, patients with EoE, and patients with GERD are reported in Table 1. Comparing EoE patients with healthy controls, mean EAET was not significantly higher in EoE; values greater than 4% and 6%, the recently proposed normative values (25), were found in 3/60 (5%) and 2/60 (3%) cases, respectively. The number of total and acid refluxes was significantly higher, while the PSPW index and MNBI were significantly lower in EoE than in healthy controls. EAET and number of total refluxes were higher in GERD than in EoE, while the PSPW index was lower and MNBI was higher.

Table 1

Table 1

On PPI, histological response was detected in 40/60 (67%) patients with EoE. The mean EREFS was 0.1 ± 0.2 and 1.3 ± 1.0 in PPI-responsive and PPI-refractory cases (P < 0.001), while the mean number of eosinophils per HPF was 3.5 ± 3.6 and 31.1 ± 13.0, respectively (P < 0.001). In PPI-responsive cases, EREFS decreased from 2.0 ± 1.1 to 0.1 ± 0.2 (P < 0.001), and the mean number of eosinophils per HPF decreased from 31.6 ± 9.7 to 3.5 ± 3.6 (P < 0.0001). Mean dysphagia score decreased from 2.2 ± 0.4 to 0.0 ± 0.2 and from 2.0 ± 0.6 to 0.7 ± 0.8 in PPI-responsive and PPI-refractory cases, respectively (P < 0.0001), and on-therapy values were significantly higher in the latter group (P < 0.0001).

Off-PPI MNBI values as measured along the esophagus in PPI-responsive and PPI-refractory EoE are reported in Table 2. Higher values were detected in PPI-responsive EoE in the mid (9 cm above the LES) and proximal esophagus (15 and 17 cm above the LES). Progressive increase from the distal to the proximal esophagus was observed in patients with PPI-responsive EoE, while no significant increase was detected in PPI-refractory cases. For comparison of MNBI values in EoE and GERD, since proximal MNBI (15 and 17 cm above the LES) could not be measured in several GERD cases owing to large hiatal hernias, we decided to focus on distal MNBI (3 cm above the LES) and mid MNBI (9 cm above the LES) (Table 3). Overall, distal and mid MNBI were lower in the EoE group, but no significant difference was found comparing PPI-responsive EoE and PPI-responsive GERD, while lower mid MNBI values distinguished PPI-refractory EoE from PPI-refractory GERD cases. At ROC analysis, the area under the curve of the gradient between mid and distal MNBI ([INCREMENT]MNBI 9–3 cm), 15 cm—MNBI and distal MNBI ([INCREMENT]MNBI 15–3 cm), and 17 cm—MNBI and distal MNBI ([INCREMENT]MNBI 17–3 cm) was 0.78 (95% confidence interval [CI] 0.65–0.90), 0.67 (95% CI 0.53–0.81), and 0.75 (95% CI 0.62–0.87), respectively (see Figure, Supplemental Digital Content 1, http://links.lww.com/AJG/B268, showing ROC curves); the [INCREMENT]MNBI 9–3 cm that maximized sensitivity (72%) and specificity (80%) was 242 Ohms.

Table 2

Table 2

Table 3

Table 3

Off PPI, EAET, number of total refluxes, PSPW index, and distal MNBI did not differ between patients with PPI-responsive and PPI-refractory EoE (Table 4); on therapy, the PSPW index was the sole reflux parameter distinguishing PPI-responsive from PPI-refractory EoE cases, and the latter group was also characterized by persisting impairment of mucosal integrity as shown by lower distal and mid MNBI.

Table 4

Table 4

Impedance-pH parameters as modified by PPI therapy in EoE are reported in Table 5. As expected, PPIs transformed nearly all acid refluxes into weakly acidic refluxes. The PSPW index and number of total refluxes were not modified by therapy in PPI refractory EoE but significantly improved in PPI-responsive EoE; only the PSPW index was independently associated with PPI-responsiveness (odds ratio 1.143, 95% CI 1.049–1.247, P = 0.002) (see Table, Supplemental Digital Content 2, http://links.lww.com/AJG/B269). Figure 2 shows the mean PSPW index as modified by therapy in patients with PPI-responsive and PPI-refractory EoE as compared to GERD cases. Figure 3 shows mean distal and mid MNBI as modified by therapy in PPI-responsive and PPI-refractory EoE.

Table 5

Table 5

Figure 2

Figure 2

Figure 3

Figure 3

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DISCUSSION

In the present prospective multicenter study, for the first time, a comprehensive and prospective analysis of impedance-pH tracings was performed, including parameters assessing reflux and parameters evaluating mucosal integrity, in patients with PPI-responsive and PPI-refractory EoE, evaluated off and on therapy. Off PPI, the number of total refluxes was higher, and the PSPW index was lower in patients with EoE as compared to healthy controls. Off therapy, low values of MNBI extended to the mid and proximal esophagus distinguished PPI-refractory from PPI-responsive EoE. On therapy, the PSPW index improved in patients with PPI-responsive EoE but not in patients with PPI-refractory EoE, and MNBI improved less in the latter group.

Reflux episodes are followed by secondary peristaltic waves removing the greatest part of refluxed bolus (volume clearance) (25). However, for complete removal of refluxate, additional chemical clearance due to a vagal esophagosalivary reflex eliciting primary peristalsis is most often required (25), consisting of salivary swallow with delivery of bicarbonate and epidermal growth factor, in turn increasing pH and hastening mucosal reparative processes. The PSPW index is a measure of reaction to reflux, i.e., of the efficiency of chemical clearance as a defense mechanism. Low values indicate prolonged contact time of the esophageal mucosa with acidic/weakly acidic refluxes, being consistent with reflux-related heartburn (10–12,26–28) and predicting GERD response to PPI therapy (29,30) and to antireflux surgery (12). In other terms, impaired chemical clearance is a major determinant of reflux burden, according to the higher diagnostic yield of the PSPW index in comparison with number of total refluxes and EAET in GERD (10,11), In this study, the PSPW index and number of total refluxes were not modified by therapy in PPI-refractory EoE, whereas significant improvement was detected in PPI-responsive cases. The PSPW index was the sole on-therapy reflux parameter distinguishing PPI-refractory from PPI-responsive EoE, however, and was independently associated with PPI-responsiveness. Interestingly, PPI-induced variations of the PSPW index in PPI-responsive and PPI-refractory EoE and GERD were quite similar. Overall, these results show that reflux events act as a trigger, but it is chemical clearance the major determinant of reflux burden and of different responses to PPIs in EoE and in GERD, suggesting common mechanisms of PPI action in both diseases.

Low baseline impedance reflects impairment of mucosal integrity, representing a consequence of GERD (18) as well as of EoE (13–17). MNBI allows for reliable (10) assessment of nocturnal baseline impedance, and low values are predictive of response to PPI therapy in GERD (29–31). In previous studies using through-the-scope probes, patients with EoE who failed PPI therapy were investigated, and low impedance values along the esophagus were detected (14–16). In our series, more than half of patients with EoE were PPI-responsive and were characterized by progressive increase of MNBI values in the mid and proximal esophagus. Conversely, similar low MNBI values along the esophagus were found in PPI-refractory EoE cases; interestingly, we found that a low off-PPI impedance gradient between the mid and distal esophagus may represent a clinically useful predictor of PPI refractoriness. In patients with GERD, we found lower MNBI values in the distal than in the mid esophagus both in PPI-responsive and in PPI-refractory cases, confirming that reflux mainly damage the distal esophagus; notably, distal and mid MNBI did not differ between PPI-responsive EoE and GERD, further suggesting a relevant role of reflux in PPI-responsive EoE. Remarkably, improvement of distal and mid MNBI was consistent in patients with PPI-responsive EoE but modest only in patients with PPI-refractory EoE, indicating persistent increased mucosal permeability in the latter group, in turn allowing for ongoing penetration of food antigens and determining persistent esophageal eosinophilia with attendant persistent dysphagia.

PPIs are approved for GERD but not for EoE. More than half of our patients with EoE were PPI-responsive, a result in agreement with a recent meta-analysis (32). PPIs require an acidic environment such as the parietal cell canaliculus to be activated. In vitro studies have shown direct anti-inflammatory properties of acid-activated omeprazole by means of eotaxin-3 secretion blockage in EoE and GERD mucosa (6). Eosinophils can release protons from their exocytic granules and lysosomes into the microenvironment with resultant acidification, thus possibly allowing for a direct anti-inflammatory action of PPIs (4), at present demonstrated by in vitro studies only (17). Microenvironment acidification, possibly allowing activation of PPIs and then direct anti-inflammatory activity, could also be favored by acid reflux. In our series, at off-PPI evaluation, EAET was normal in nearly all EoE cases, and only the number of acid refluxes was higher in EoE than in healthy controls. Notably, on PPI therapy, EAET and acid refluxes were almost undetectable, and esophageal eosinophilia was nearly abolished in PPI-responsive cases: hence, esophageal acidification may no longer persist during ongoing treatment in PPI-responsive EoE and may not explain persisting PPI efficacy during maintenance treatment.

In GERD, reflux promotes a proinflammatory response characterized by innate immunity with overexpression of cytokines, such as interleukin (IL)-8 (33) with active recruitment of neutrophils and lymphocytes. In EoE, genetically determined aberrant Th2 response involves IL-4, IL-5, and IL-13 with local production of eotaxin-3, a chemokine that attracts eosinophils (4). We speculate that abnormal reflux burden, as represented by augmented number of reflux events and impaired chemical clearance, increases the permeability of epithelial barrier to food antigens, thus determining in genetically susceptible individuals the cascade leading to esophageal eosinophilia. By reducing the acidity of gastric refluxate, PPIs can exert an anti-inflammatory action in the distal esophagus which could induce partial restoration of the afferent limb of the vagal esophagosalivary reflex, in turn inducing improvement of chemical clearance with reduction of reflux burden in PPI-responsive EoE. In PPI-refractory EoE, more proximal extension of esophageal mucosal damage may be scarcely affected by PPI-induced suppression of the acidic component of refluxate, with persistent impairment of the esophagosalivary reflex and lack of improvement of chemical clearance and hence of reflux burden.

In conclusion, our study shows that EoE is characterized by abnormal reflux burden. Low impedance gradient between the mid and distal esophagus may predict PPI refractoriness, in turn characterized by lack of on-therapy improvement of impaired chemical clearance and marginal recovery of mucosal integrity. Conversely, in PPI-responsive EoE, less-extensive mucosal damage is associated with on-therapy improvement of chemical clearance and foremost recovery of mucosal integrity. Our findings indicate that reflux plays a role in the pathogenesis of EoE, more relevant in PPI-responsive cases, and that PPIs mainly act by antireflux mechanisms, supporting long-term prescription in PPI-responsive EoE.

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CONFLICTS OF INTEREST

Guarantor of the article: Marzio Frazzoni, MD.

Specific author contributions: M.F.: study concept and design; collection, analysis, and interpretation of data; and drafting of the manuscript. R.P., L.F., N.D.B., A.M., S.T., H.B., M.M., M.M., S.M., R.C., and E.S.: collection, analysis and interpretation of data; critical revision of the manuscript.

Financial support: None.

Potential competing interests: None.

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Study Highlights

WHAT IS KNOWN

  • ✓ Most patients with EoE show normal esophageal acid exposure at pH monitoring.
  • ✓ Many patients with EoE respond to PPI therapy, but esophageal acid exposure does not predict response, and the mechanism of action of PPIs is uncertain.
  • ✓ Long-term PPI therapy is required for most PPI-responsive EoE cases, but is currently approved only for patients with GERD.
  • ✓ Esophageal mucosa impedance is low in EoE, reflecting impaired mucosal integrity.
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WHAT IS NEW HERE

  • ✓ At off-PPI impedance-pH monitoring, higher reflux burden and impaired chemical clearance distinguish patients with EoE from healthy controls.
  • ✓ Off PPI, less severe impairment of mucosal integrity in the mid and proximal esophagus characterizes PPI-responsive EoE as compared to PPI-refractory EoE.
  • ✓ On PPI, chemical clearance and reflux burden improve in PPI-responsive but not in PPI-refractory EoE.
  • ✓ Accordingly, minor only improvement of mucosal impedance is detected in PPI-refractory EoE on therapy, reflecting persistent impairment of mucosal integrity.
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