The Predictive Factors of Responsiveness to Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis

Round 1

Reviewer 1 Report

This MS describes the Japanese experience with predictive factors of responsiveness of patients with diagnosed eosinophilic esophagitis (EoE) to proton pump inhibitor (PPI) therapy. The frequency of EoE prevalence in Japan is generally less than in Western countries, although the number of these cases is nowadays increasing. The number of patients recruited for the present study (n=78) is rather small but satisfactory enough for collection of conclusive results. Approximately 70% patients with EoE responded to PPI therapy. Authors reported that the most frequent symptom was dysphagia in about 76 percent. Only 34% of patients had elevated eosinophils counts and about 72% of patients had allergic diseases. The food allergies in some patients were developed to i.e. eggs, seafood’s, fruit, cucumber, soba and almonds. Authors conclude that this higher rate of response to PPI might be due to divergent populations and lesser severity of the disease since no cases with strictures and food impaction was recorded.

This evidence is interesting and properly managed especially after the final conclusion that the subject’s symptoms in PPI-responders were milder than those monitored in non-responders.  Few minor critical comments are addressed to Authors for data clarification and the overall paper improvement.

Critical comments:

1.       The number of cases is satisfactory but could be increased for better outcome of multivariate analysis. Authors should specify whether the gender of EoE patients was considered in this study? How the proportion between males and females were adjusted? Comments on that should made in Methods.

2.       The eosinophilic infiltration is presented in Fig. 2 (d) but other endoscopic findings are presented in Fig. 2 (a, b, and c, respectively) for PPI-responders and non-responders according to this Figure caption.  These photographic inserts for PPI-responders and non-responders should be presented separately for each group of patients,  to compare the differences between PPI responders and non-responders.

3.       The infection of Helicobacter pylori is quite high in terms of epidemiology and prevalence of this bug in Japan.  Interestingly, there was no difference between the PPI-responders and non-responders in this study on EoE. On the other hand, the PPI are standard drugs for triple Helicobacter pylori eradication therapy. How this lack of correlation between Helicobacter pylori positive EoE patients and PPI-treatment in EoE could be then explained? Authors should comment on that in Discussion.

4.       PPIs were more effective in patients with higher incidence of reflux esophagitis. Can Authors elaborate on the nature of this reflux esophagitis in their patients? Was this mainly acid reflux esophagitis, alkaline reflux esophagitis or the mixed acid-bile reflux esophagitis? Any analysis of acid secretory status of these patients might be useful but if no data available, at least comments in Discussion on this issue could enrich this paper.

Author Response

Reviewer #1: This MS describes the Japanese experience with predictive factors of responsiveness of patients with diagnosed eosinophilic esophagitis (EoE) to proton pump inhibitor (PPI) therapy. The frequency of EoE prevalence in Japan is generally less than in Western countries, although the number of these cases is nowadays increasing. The number of patients recruited for the present study (n=78) is rather small but satisfactory enough for collection of conclusive results. Approximately 70% patients with EoE responded to PPI therapy. Authors reported that the most frequent symptom was dysphagia in about 76 percent. Only 34% of patients had elevated eosinophils counts and about 72% of patients had allergic diseases. The food allergies in some patients were developed to i.e. eggs, seafood’s, fruit, cucumber, soba and almonds. Authors conclude that this higher rate of response to PPI might be due to divergent populations and lesser severity of the disease since no cases with strictures and food impaction was recorded.

This evidence is interesting and properly managed especially after the final conclusion that the subject’s symptoms in PPI-responders were milder than those monitored in non-responders.  Few minor critical comments are addressed to Authors for data clarification and the overall paper improvement.

Critical comments:

1.       The number of cases is satisfactory but could be increased for better outcome of multivariate analysis. Authors should specify whether the gender of EoE patients was considered in this study? How the proportion between males and females were adjusted? Comments on that should made in Methods.

Response:

Thank you for your comment. Although men are predominant in EoE, there were no differences between PPI responders and non-responders between men and women in univariate analysis as we showed in Table 1. (male sex: 65.9% in PPI-responders versus 66.7% in non-responders, p=1). Therefore, we did not adjust the proportion between males and females in multivariate analysis in this study.

2.       The eosinophilic infiltration is presented in Fig. 2 (d) but other endoscopic findings are presented in Fig. 2 (a, b, and c, respectively) for PPI-responders and non-responders according to this Figure caption.  These photographic inserts for PPI-responders and non-responders should be presented separately for each group of patients, to compare the differences between PPI responders and non-responders.

Response:

Both PPI responders and non-responders are included in EoE. Their characteristic endoscopic findings such as furrows, rings and white plaques are same, so we showed typical endoscopic and histological pictures.

3.       The infection of Helicobacter pylori is quite high in terms of epidemiology and prevalence of this bug in Japan.  Interestingly, there was no difference between the PPI-responders and non-responders in this study on EoE. On the other hand, the PPI are standard drugs for triple Helicobacter pylori eradication therapy. How this lack of correlation between Helicobacter pyloripositive EoE patients and PPI-treatment in EoE could be then explained? Authors should comment on that in Discussion.

Response:

The clinical data were collected before PPI treatment in patients with EoE and Helicobacter pylori eradication therapy were not performed during this study. We think it is difficult to discuss about association between Helicobacter pylori positive EoE patients and PPI-treatment in EoE in this study.

4.       PPIs were more effective in patients with higher incidence of reflux esophagitis. Can Authors elaborate on the nature of this reflux esophagitis in their patients? Was this mainly acid reflux esophagitis, alkaline reflux esophagitis or the mixed acid-bile reflux esophagitis? Any analysis of acid secretory status of these patients might be useful but if no data available, at least comments in Discussion on this issue could enrich this paper.

Response:

We did not perform esophageal impedance pH monitoring as we mentioned in the Discussion section, so the nature of this reflux esophagitis was unknown.

We added the following text to the Discussion section (page 6, line 186 – line 188):

“The nature of this reflux esophagitis such as acid reflux esophagitis, alkaline reflux esophagitis and the mixed acid-bile reflux esophagitis were unknown in this study.”.

Reviewer 2 Report

 The author has described that endoscopic findings of either "ring" negative or "reflux esophagitis" positive is an indicator of PPI-responder. However, the author has not described on "ring" negative and "reflux esophagitis" positive cases, "ring" positive and "reflux esophagitis" negative cases, "ring" positive and "reflux esophagitis" positive cases, and "ring" negative and "reflux esophagitis" negative cases in PPI-responder and non-responder respectively. I hope to know the number of these cases in the present study.

Furthermore, if combination the findings of "ring" and "reflux esophagitis", will the determination of PPI-responder or non-responder be more certain?

Author Response

Reviewer #2: The author has described that endoscopic findings of either "ring" negative or "reflux esophagitis" positive is an indicator of PPI-responder. However, the author has not described on "ring" negative and "reflux esophagitis" positive cases, "ring" positive and "reflux esophagitis" negative cases, "ring" positive and "reflux esophagitis" positive cases, and "ring" negative and "reflux esophagitis" negative cases in PPI-responder and non-responder respectively. I hope to know the number of these cases in the present study.

Furthermore, if combination the findings of "ring" and "reflux esophagitis", will the determination of PPI-responder or non-responder be more certain?

Response:

Thank you for your comment. In PPI responders, 11 cases are "ring" negative and "reflux esophagitis" positive, 6 cases are "ring" positive and "reflux esophagitis" negative, 6 cases are "ring" positive and "reflux esophagitis" positive, and 18 cases are "ring" negative and "reflux esophagitis" negative. In non-responders, no cases are "ring" negative and "reflux esophagitis" positive, 10 cases are "ring" positive and "reflux esophagitis" negative, 1 case is "ring" positive and "reflux esophagitis" positive, and 7 cases are "ring" negative and "reflux esophagitis" negative. The rate of "ring" negative and "reflux esophagitis" positive in PPI-responders was significantly higher than in non-responders (p=0.013), and the rate of "ring" positive and "reflux esophagitis" negative in PPI-responders was significantly lower than in non-responders (p=0.003). Although it is important to consider about combination the findings, we think that it is more important that "ring" negative and "reflux esophagitis" positive are independent predictive factors in multivariate analysis respectively in this study.