We have read with interest the paper by Hoshikawa et al,1 addressing a very important issue in our clinical practice, that is, the so‐called proton pump inhibitor (PPI) dependence in patients with gastro‐esophageal reflux disease (GERD) symptoms. Indeed, the management of these patients is challenging since, even following a more accurate assessment with sophisticated and not widely available techniques ‐impedance‐pH monitoring and esophageal high‐resolution manometry‐, the partial PPI response and the exacerbation of symptoms following discontinuation of PPI raise diagnostic uncertainties and, consequently, high costs. The Authors have originally explored this field and, according to their findings, there is no difference in esophageal acid exposure or gastric acidity between patients with and without symptom exacerbation. Indeed, within the small number of patients enrolled, some of them were already defined as PPI refractory and only 10 patients belonged to the group without symptom relapse. Unexpectedly, symptom‐reflux association indexes were positive in the same proportion of patients with or without early exacerbation of symptoms. It would have been of interest to know impedance‐pH and symptom data before PPI therapy and the proportion of reflux hypersensitivity patients, likely accounting for the relapse.

As the author speculates in the Discussion, the visceral hypersensitivity may play a relevant role in this matter. It has been demonstrated that an impaired esophageal epithelial integrity, related to dilation of intercellular spaces diameter (DIS),2, 3 may facilitate the passage of H+ ions across the epithelium thus stimulating the nerve endings.4 We also focused on the feature of DIS2, 3 and transient receptor potential channel vanilloid member‐1 (TRPV1) expression5 in non‐erosive patients with GERD symptoms sensitive to PPIs and the same dilation and TRPV1 over expression was found in patients with or without an increased esophageal acid exposure. Finally, it has been demonstrated that an optimal PPI course leads to a complete recovery of DIS in the majority of GERD patients.6 In this scenario, the role of increased visceral hypersensitivity is intriguing, although far to be fully understood and a possible anti‐inflammatory effect of PPIs is a fascinating hypothesis.7

In our opinion, the investigation by Hoshikawa et al is very interesting and the study design is original. Hopefully, this study has contributed to paving the way for future investigations, warranted by the clinical impact of PPI response and PPI dependence in GERD.

我们感兴趣地阅读了Hoshikawa等人的论文，1解决了我们临床实践中一个非常重要的问题，即患有胃食管反流病（GERD）症状的患者的所谓质子泵抑制剂（PPI）依赖性。的确，这些患者的治疗具有挑战性，因为即使在使用复杂且尚不广泛使用的技术进行更准确的评估后，即阻抗pH监测和食管高分辨率测压，部分PPI反应以及PPI中断后症状加重会增加诊断的不确定性，从而导致高昂的成本。作者最初探讨了这一领域，根据他们的发现，有无症状加重的患者在食管酸暴露或胃酸度方面没有差异。确实，在少数患者中，其中一些已经定义为PPI难治性，只有10例患者没有症状复发。出乎意料的是，在有或没有早期症状加重的患者中，相同比例的症状反流关联指数为阳性。在进行PPI治疗之前了解阻抗pH值和症状数据以及反流超敏反应患者的比例（可能是复发的原因）可能会很有趣。

正如作者在讨论中所推测的那样，内脏超敏反应可能在此问题上发挥了相关作用。已经证实，与细胞间隙直径（DIS），2、3的扩张有关的食道上皮完整性受损可促进H +离子穿过上皮的通过，从而刺激神经末梢。4我们还专注于DIS 2、3和瞬时受体电位通道香草素1（TRPV1）表达的特征5在有或没有食管酸暴露增加的患者中，非侵蚀性GERD症状对PPIs敏感的患者均具有相同的扩张和TRPV1过表达。最后，已证明最佳的PPI疗程可导致大多数GERD患者的DIS完全康复。6在这种情况下，内脏超敏性增加的作用很有趣，尽管尚需充分了解，而且PPI可能产生的抗炎作用是一个有趣的假设。7

我们认为，Hoshikawa等人的研究非常有趣，研究设计是独创的。希望这项研究为将来的研究铺平了道路，这由GERD中PPI反应和PPI依赖的临床影响所证实。