Li W, Sha B, etal. How to distinguish PPI-refractory from PPI-responsive patients in gastro-oesophageal reflux-induced chronic cough: post-reflux swallow induced peristaltic wave index and MNBI provide new predictive factors/ERJ OpenRes 2024;10:00299-2024

Авторы: Li W. / Sha B. / Bai H. / Zhang T. / Wang Sh. / Kumar Y.A. / Zhu Y. / Yu L.  / Xu X.

 How to distinguish PPI-refractory from PPI-responsive patients in gastro-oesophageal reflux-induced chronic cough: post-reflux swallow induced peristaltic wave index and mean nocturnal baseline impedance provide new predictive factors

¹ Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China. ² W. Li, B. Sha and H. Bai contributed equally to this article as joint first authors. ³ L. Yu and X. Xu contributed equally to this article as lead authors and supervised the work.


Cite this article as: Li W, Sha B, Bai H, et al. How to distinguish PPI-refractory from PPI-responsive patients in gastro-oesophageal reflux-induced chronic cough: post-reflux swallow induced peristaltic wave index and mean nocturnal baseline impedance provide new predictive factors. ERJ Open Res 2024; 10: 00299-2024 [DOI: 10.1183/23120541.00299-2024].

Abstract

Background The results of empirical trials with proton pump inhibitors (PPIs) for management of gastro-oesophageal reflux-induced chronic cough (GERC) have resulted in considerable controversy, and the mechanism of PPI refractoriness remains unclear. Our study aims to identify the predictors of PPI refractoriness of GERC in a retrospective clinical study.

Methods In total, 128 GERC patients were enrolled between March 2018 and October 2022. Regression analysis was utilised to create a model for predicting PPI-refractory of GERC using retrospective analysis of the general data and MII-pH indicators.

Results The post-reflux swallow induced peristaltic wave index (PSPWI) was lower in the PPI-refractory group than the PPI-responsive group (33.89±7.38 versus 39.45±9.47, respectively, p<0.001), as were the mean nocturnal baseline impedance (MNBI) and proximal MNBI (2092.11 (IQR: 652.23)] versus 2426.52 (IQR: 917.39) Ω, respectively, p=0.012; 1599.50 (IQR: 1206.63) versus 2274.50 (IQR: 1775.29) Ω, respectively, p=0.001). Multivariate logistic regression analysis identified the PSPWI (odds ratio 0.919, p=0.001) as an independent predictor of PPI-refractory GERC.

Conclusions The diagnostic value of both proximal MNBI ⩽39.90% and MNBI ⩽2233.58 Ω had moderate sensitivity (71.67%) and specificity (75.00%) to identify PPI-refractory GERC.

Background

Gastro-oesophageal reflux-induced chronic cough (GERC), one of the most common causes of chronic cough, is characterised by reflux backflow of stomach acid or other stomach contents into the oesophagus [1]. The incidence of GERC is reportedly increasing [2]. Based on the type of reflux, GERC is classified as acid or non-acid [3].

Guidelines of the European Respiratory Society (ERS) and American College of Clinical Pharmacy (ACCP) point out that a 3-month empirical trial of proton pump inhibitors (PPIs) with and without a prokinetic agent was conducted to assess the efficacy of PPIs for treatment of GERC with heartburn and regurgitation [4]. But the therapeutic effect of PPI on GERC has been controversial in several randomised clinical trials [5, 6]. Our study and other clinical studies have shown that a standard dose of PPIs for 8 weeks could relieve the symptoms of GERC in a proportion of patients [7, 8], and up to 36% of patients are resistant to the course of standard therapy but favourably respond to intensified anti-reflux treatment such as doubling the dose of PPI [9]. However, 25% of patients with refractory GERC were still unresponsive to therapy with high-dose PPIs and needed an add-on therapy [10]. In a meta-analysis of suspected GERC patients, it was found that patients with non-acid reflux do not receive a significant benefit on cough outcomes from PPI above placebo, and patients with acid reflux only marginally so [6]. Herein, PPI refractoriness remained an issue in the management of GERC. Long-lasting PPI trials and PPI refractoriness may delay other effective treatments, resulting in GERC patients lacking confidence in and compliance with next-step treatment.

Neuromodulators and some adjuvant treatments are potential selective and optimal treatment options for GERC. Baclofen, an inhibitor of transient lower oesophageal sphincter (LES) relaxation [11], has been shown to reduce acid reflux [12]. When patients present with objective, proven reflux and cough and GERC is suspected, the respiratory physician at the cough centre may use baclofen cautiously at a low dose. The process requires attention to risks such as central depression and discontinuation of the drug [13]. A prior study reported that baclofen effectively relieved refractory GERC in 57% of patients [7]. Gabapentin was also shown to attenuate GERC in 75% of patients by inhibition of the sensitised cough centre [14]. As an adjunct anti-reflux treatment, flupentixol combined with melitracen was reported to alleviate symptoms of GERC [15]. While these neuromodulators or anti-psychotic agents have comparable therapeutic efficacy by permeating the blood–brain barrier, they can cause neurological side-effects such as sedation. Given this limitation, most GERC patients in clinics had undergone 8 to 12 weeks of anti-reflux therapy before commencing these adjuvant therapies.

Considering the prevalence of PPI refractoriness in GERC treatment, it is important to identify potential predictive factors for GERC patients with PPI refractoriness, which can timely dispense with the unnecessary stage of anti-reflux and add these adjuvant therapies directly to improve treatment efficiency and precision. On the other hand, finding potential predictive factors for GERC patients with PPI refractoriness builds on our knowledge of the PPI-refractory mechanism and opens up new avenues for treating patients with GERCs.

The purpose of this study was to identify potential predictive factors for PPI refractoriness in GERC patients to establish a standardised approach to managing GERC.

Methods

Study approval and patient consent
The study protocol was approved by the Ethics Committee of Tongji Hospital (approval no. K-2020-025) and conducted in accordance with the ethical principles for medical research involving human subjects described in the Declaration of Helsinki. Prior to inclusion in this study, written informed consent was obtained from all subjects.

Patient groups
In total, 128 patients with suspected GERC were enrolled from Tongji Hospital from March 2018 to October 2022. Patients with other common causes of chronic cough, such as upper airway cough syndrome, cough variant asthma, eosinophilic bronchitis, atopic cough and other psychogenic factors, were excluded using an established step-by-step algorithm [16], the findings of laboratory studies and a favourable response to subsequent therapeutic trials.

The criteria for a diagnosis of GERC were: 1) cough symptoms lasting at least 8 weeks with or without typical gastrointestinal indications; 2) patients revealed acid reflux positive by acid exposure time (AET) ⩾6.0% and/or an acid reflux symptom association probability (SAP) ⩾95% and/or an acid reflux symptom index (SI) ⩾50% and/or acidic reflux episodes in 24 h >80; or patients with non-acid reflux positive by AET <6%, non-acid reflux SAP ⩾95% and/or non-acid SI ⩾50% and/or non-acidic reflux episodes in 24 h >80; and/or total number of reflux episodes in 24 h >80 and/or SAP ⩾95% and/or SI ⩾95%; and 3) symptom improvement by >50% in response to anti-reflux therapy (standard or high dose of PPIs) with or without add-on therapies (ranitidine, histamine H2 receptor antagonist or baclofen), or anti-reflux surgery.

The exclusion criteria were: 1) pregnancy and lactation; 2) smoking within 2 years; 3) reading and writing disabilities; 4) other causes of chronic cough, such as upper airway cough syndrome, cough variant asthma, eosinophilic bronchitis, atopic cough, COPD, use of angiotensin-converting enzyme inhibitors and other psychogenic factors; 5) improved symptoms after treatment for other concomitant causes; 6) rale and obvious abnormalities by lung physical examination, chest radiograph or chest computed tomography; and 7) inability to tolerate the multichannel intraluminal impedance pH monitoring (MII-pH) examination.

Research procedure
All patients initially received standard anti-reflux therapy with omeprazole at 20 mg two times per day plus mosapride at 10 mg three times per day. If cough remission was not achieved, the PPI dose was doubled (omeprazole at 40 mg two times per day) and continued for 8 weeks. For patients who responded to the doubled dose, the regimen was continued until cough resolution. For patients who did not achieve cough resolution, baclofen at 10–20 mg three times per day was added for 4 weeks and mosapride was discontinued [17]. For patients not responsive to medicinal therapy, anti-reflux surgery was recommended. None of the enrolled patients with GERC in this study were taking any antitussive medications.

For analysis, the PPI-responsive group included patients who responded to standard or high-dose PPIs, while the PPI-refractory group included those who did not respond to PPI treatment.

Laboratory examination
The severity of reflux was assessed using the gastro-oesophageal reflux questionnaire (GerdQ) [18] and the severity of cough severity was measured using the cough symptom score described by HSU et al. [19]. The scale of cough symptom score was divided into two parts, daytime and night-time. According to the time of occurrence of cough, the frequency and intensity of cough, and the degree of impact on sleep and daily activities, the daytime and night-time score were classified as grade 0–5 with 0 being no cough and 5 being the most severe cough. In addition to this, we used the Visual Analogue Scale as an adjunct and complementary method to assess cough symptoms in the enrolled patients with GERC [20]. According to the self-perceived severity of cough, patients mark the corresponding position on the line, and then measure the distance from the beginning of the line to the mark as the score value. The cough sensitivity index was determined using a modified capsaicin sensitivity test based on the guidelines of the European Respiratory Society [4] and described by Fujimura et al. [21]. The lowest inhalation capsaicin solutions that induced ⩾2 or ⩾5 coughs were defined as C2 and C5, respectively. The pulmonary function test and histamine bronchial excitation test were performed in accordance with the guidelines established by the American College of Chest Physicians [22] and the Chinese Medical Association [23].

Oesophageal manometry was used to localise the LES. An MII-pH catheter (diameter 2.1 mm) with six impedance channel sensors (K6011-E10632; Unisensor AG, Attikon, Switzerland) and an antimony pH electrode (819100; Medical Measurement System BV, Enschede, The Netherlands) were inserted transnasally into the patient’s oesophagus, with the impedance channel sensors located 3, 5, 7, 9, 15 and 17 cm above the LES and the pH electrode located 5 cm above the proximal LES. A portable data logger (Ohmega; Medical Measurement System BV) was used to record all data from the seven channels. The patient was required to record the time points of coughing, meal periods and changes in position on a diary card during the monitoring period. The data were analysed automatically with specific software (MMS database, v8.7), and reflux events were reviewed manually.

Reflux events were classified as gas, liquid or mixed according to the impedance curve and were further classified as acid reflux events (pH<4.0), weak acid reflux events (pH 4.0–7.0) or weak base reflux events (pH>7.0). >80 reflux episodes over a period of 24 h was considered abnormal. Other pH-impedance parameters are described below.

AET was defined as the percentage of total monitoring time with pH values below 4 divided by the total monitoring time. In accordance with the Lyon Consensus, an AET of <4% was considered normal (physiological), while an AET >6% was considered abnormal. Values between these limits were considered inconclusive. The DeMeester score is a measure of the overall oesophageal acid exposure level and includes six parameters: 1) total number of reflux episodes; 2) % AET; 3) % upright time with oesophageal pH <4; 4) supine time with oesophageal pH <4; 5) number of reflux episodes ⩾5 min duration; and 6) longest reflux episode (minutes). The SAP was employed to depict the relationship over time between coughs documented daily by the study participants and the reflux that occurred in the prior 2-min interval. The SI was defined as the total number of symptom episodes (specifically cough) related to reflux divided by the overall number of symptom episodes. The mean nocturnal baseline impedance (MNBI) was assessed from the most distal impedance channel during the night-time recumbent period. Three 10-min time periods (1:00, 2:00 and 3:00 h) were selected and the mean was calculated, with avoidance of time periods of swallows, reflux events and decreased pH values. The distal-MNBI was calculated as the mean MNBI value from the channels located at 3, 5, 7 and 9 cm above the LES. The proximal MNBI was calculated as the mean MNBI value from the channels located at 15 and 17 cm above the LES. The post-reflux swallow induced peristaltic wave index (PSPWI) was defined as decreased antegrade impedance of 50% from the proximal oesophagus to the distal section in <30 s following reflux and calculated as the number of post-reflux swallow induced peristaltic waves (PSPWs) divided by the total number of reflux events.

Outcome measure and follow-up
Overall cough resolution was the primary end-point [3]. Cough was considered as controlled upon complete resolution, improved when the cough symptom score decreased by ⩾50%, and failed when cough worsened or was not alleviated to any noticeable degree [24].

Review of clinical information
A retrospective study was conducted to compare general characteristics, parameters of MII-pH monitoring and other evaluations between the PPI-refractory and PPI-responsive groups. Subsequently, stepwise logistic regression was performed to identify markers of PPI refractoriness of GERC patients during the initial evaluations.

Statistical analysis
Normally distributed data were compared using the t-test and are presented as the mean±SD, while non-normally distributed data were compared using the chi-square test and nonparametric tests, and are presented as the median and interquartile range (IQR). Univariate and multivariate logistic regression analyses were used to identify independent predictors of PPI-refractory GERC. The results of multivariate (backward stepwise) logistic regression analysis were used to construct the final prediction model. Hosmer–Lemeshow chi-square statistics were used to evaluate calibration, and a p-value of >0.05 supported the goodness of calibration [25].

The ratio of PPI-responsive patients to PPI-refractory patients was set at 1.39, as described in a previous study [5]. Based on this ratio, the estimated numbers of PPI-responsive patients and PPI-refractory patients were calculated with a statistical power of 80% (PASS 15.0 sample size software). The numbers of PPI-responsive patients and PPI-refractory patients were 20 and 28, respectively, to achieve a statistical power of 92% with an expected dropout rate of 10%.

Receiver operating characteristic (ROC) curves were constructed to identify independent predictors of the therapeutic efficacy of PPIs. The area under the ROC curve (AUC) was used to assess the discrimination power, with an AUC of 0.70–0.79 indicating acceptable discrimination [26]. The Delong test was used to compare the ROC curves.

Results

General clinical information
Among 675 patients with chronic cough, 201 had suspected GERC. Of these, 128 individuals satisfied the inclusion criteria and were ultimately diagnosed with GERC after receiving stepwise targeted treatment and MII-pH assessment, while 54 were excluded after failure of additional therapies or anti-reflux surgery and diagnosis of other chronic cough-related diseases. The 54 excluded patients comprised 18 with cough variant asthma, 18 with upper airway cough syndrome, eight with eosinophilic bronchitis, eight with atopic cough and two with a psychogenic condition. 19 cases dropped out of the study midway during the course of treatment, with five dropping out because they could not tolerate the nausea and flatulence caused by the PPIs, and 14 dropping out due to lack of PPI efficacy. Of the 128 individuals diagnosed with GERC, cough was controlled in 51, improved in 17 and treatment failed in 60. The overall treatment success rate was 53.125% (68 out of 128). The remaining 60 patients (46.87%) were not responsive to PPI therapy. Of 95 patients with acid GERC, 53 patients responded to PPIs, and the remaining 42 did not and received baclofen therapy. 15 of 33 patients with non-acid GERC responded to PPIs, and 18 require baclofen for improvement.

The demographic and clinical characteristics of the PPI-responsive and PPI-refractory groups are described in table 1. Overall, 34 of 68 PPI-responsive patients and 28 of 60 PPI-refractory patients had typical symptoms of heartburn, regurgitation and belching. None of the patients had received prior foregut or fundoplication surgery.

Differences in MII-pH examination parameters between groups
Among the general variables, the median duration of cough was significantly longer in the PPI-refractory group than PPI-responsive group (13.5 (IQR: 42) versus 6 (IQR: 20) months, respectively, p=0.0119). With regard to the MII-pH examination parameters, such as AET, DeMeester score and reflux episodes, there were no differences between the PPI-refractory and PPI-responsive groups. However, the PSPWI was lower in the PPI-refractory group than the PPI-responsive group (33.89±7.38 versus 39.45±9.47, respectively, p<0.001). Similarly, the median MNBI and proximal MNBI were lower in the PPI-refractory group than the PPI-responsive group (2092.11 (IQR: 652.23) versus 2426.52 (IQR: 917.39) Ω, respectively, p=0.012; 1599.50 (IQR: 1206.63) versus 2274.50 (IQR: 1775.29) Ω, respectively, p=0.001) (table 2).

Factors associated with refractoriness to PPI therapy
The variables with statistically significant differences between the PPI-refractory and PPI-responsive groups identified by univariate logistic analysis included duration of cough, PSPWI, MNBI and proximal MNBI, which were negatively correlated with refractoriness to PPI therapy (table 3). Furthermore, multivariate logistic regression demonstrated that the PSPWI (odds ratio (OR) 0.919, p=0.001) was an independent predictor of refractoriness to PPI therapy (table 4). In addition, by multivariate logistic regression, the MNBI (OR=0.99, p=0.001) was a less reliable predictor than the proximal MNBI for PPI-refractory patients, given the small sample.

By stepwise logistic regression, the equation of PPI-refractory GERC was logit p=4.345 – 0.084X1 – 0.001X2, where X1 is the PSPWI and X2 is the proximal MNBI. The equation explained 23.6% of the variation in PPI-refractory GERC (Nageire R²), demonstrating that 64.06% of patients were correctly diagnosed. The Hosmer–Lemeshow test (χ² (2)=7.833, p=0.455) verified good calibration.

When p⩾0.394 was used as a cut-off value, the logistic regression equation had good ability to discriminate refractory patients from responders, with a sensitivity of 85.00% and a specificity of 54.40%, as indicated by ROC analysis (figure 1).

FIGURE 1. The internal accuracy of the logistic regression model is evaluated by ROC analysis. The AUC was 0.740 (95% CI: 0.655–0.814, p<0.001), which indicates that for 64.04% of the paired participants (one PPI-refractory patient, one PPI-responsive patient), the PPI-refractory patient scored higher. These results suggest that the logistic regression model used in this study had a good ability to discriminate between PPI-refractory and PP- responsive participants. AUC: area under the curve; CI: confidence interval; ROC: receiver operating characteristic.


Comparison of the PSPWI and proximal MNBI to predict PPI-refractory GERC
The PSPWI and proximal MNBI showed moderate ability to predict PPI-refractory GERC (figure 2). The optimal cut-off values for the PSPWI and proximal MNBI were ⩽39.90% and ⩽2233.58 Ω, respectively. The powers of proximal MNBI ⩽2233.58 Ω and PSPWI ⩽39.90% to predict PPI-refractory GERC were equal, because there was no significant difference in the AUC values (Z=0.0410, p=0.9673), even though the Youden index and kappa value were a little higher for MNBI ⩽2233.58 Ω than PSPWI ⩽39.90%. The diagnostic value of PSPWI ⩽39.90% combined with proximal MNBI ⩽2233.58 Ω was superior to either criterion alone, with moderate sensitivity of 71.67% and specificity of 75.00%. Notably, PSPWI ⩽39.90% or MNBI ⩽2233.58 Ω had the highest sensitivity of 95.00% to predict PPI-refractory GERC (table 5, figure 3).
 
FIGURE 2. ROC analysis of PSPWI, MNBI and proximal MNBI for predicting PPI-refractory of GERC. a) When PSPWI was used to predict the PPI-refractory of GERC, the AUC was 0.669 (95% CI: 0.576–0.762, p<0.001), with a moderately good predictive ability. When 39.90% was adopted as a cut-off point, the Youden index was highest (0.293). b) When MNBI was used to be a predictor, the AUC was 0.629 (95% CI: 0.532–0.726, p=0.009), with a moderately good predictive ability. When 2227.16 Ω was adopted as a cut-off point, the Youden index was highest (0.280). c) When proximal MNBI was used to be a predictor, the AUC was 0.672 (95% CI: 0.578–0.765, p<0.001), with a moderately good predictive ability. When 2233.58 Ω was adopted as a cut-off point, the Youden index was highest (0.329). AUC: area under the curve; CI: confidence interval; ROC: receiver operating characteristic; PSPWI: post-reflux swallow induced peristaltic wave index; MNBI: mean nocturnal baseline impedance; PPI: proton pump inhibitor; GERC: gastro-oesophageal reflux-induced chronic cough.




FIGURE 3. The predicting value of 1) PSPWI<39.90%; 2) proximal MNBI<2233.58Ω. PSPWI: post-reflux swallow induced peristaltic wave index; MNBI: mean nocturnal baseline impedance.

Discussion

Micro-aspiration of refluxate into the airways (reflux theory) and oesophageal–tracheobronchial reflexes mediated by the afferent neurons in the distal oesophagus (reflex theory) are the two basic processes driving GERC [27, 28]. Both of these theories are associated with airway inflammation and hypersensitivity. Neurogenic inflammation of the oesophageal efferent nerves caused by low regurgitation and pharyngeal airway inflammation can stimulate long-term proximal reflux, resulting in damage to the airway epithelium and subsequent exposure of cough receptors [29, 30]. Such exposure results in both remodelling and increased numbers of cough receptors, with subsequent increased airway sensitivity, which may directly contribute to the occurrence of cough. With PPI therapy, cough can be resolved by eliminating the acidity and volume of refluxate [31]. Complete acid suppression with high doses of PPIs may cause considerable blockade of acid signal transduction and reduce the amount of neurogenic inflammation factors in the oesophageal bronchial reflex, followed by cessation of coughing [32]. However, during impedance pH monitoring, PPIs transform the majority of acid reflux events to weakly acidic [33], which can continue to elicit cough through micro-aspiration or an oesophageal–tracheobronchial reflex. That is one of the mechanisms underlying PPI-refractory GERC [28]. Additionally, the use of PPIs cannot modify transient lower oesophageal sphincter relaxation and oesophageal motility, which are more frequently involved in PPI-refractory GERC [34]. Therefore, PPI refractoriness is common in GERC.

As new MII-pH parameters to assess oesophageal chemical clearance and mucosal integrity, the PSPWI and MNBI have recently been proposed for gastro-oesophageal reflux disease (GERD). The PSPWI and MNBI are diagnostically useful for MII-pH monitoring, particularly to distinguish individuals with erosive reflux disease, non-erosive reflux disease (NERD) and functional heartburn [35]. However, some studies have reported that the PSPWI and MNBI are better predictors of the effectiveness of PPI therapy than AET [35]. According to Frazzoni et al. [36], the PSPWI can effectively differentiate PPI-refractory erosive reflux disease from functional heartburn. Similarly, another study confirmed that the MNBI was linked to a higher likelihood of GERD patients to respond to PPI therapy [37]. The MNBI is typically lower for refractory reflux oesophagitis than responsive reflux oesophagitis and NERD, reflecting the severity of oesophageal mucosal damage in relation to acidic and weakly acidic reflux events [38, 39].

The MNBI refers to the mean impedance derived from MII-pH monitoring during three consistent 10-min intervals at around 1:00, 2:00 and 3:00 h [40]. Exposing the oesophageal epithelium to acid for long periods can gradually increase permeability, resulting in decreased transepithelial resistance, increased paracellular permeability and dilation of intercellular spaces [39], thus decreasing baseline impedance. Exposure of the distal oesophagus to acid reflux can lead to changes to the exposed mucosa and the non-exposed tissue of the upper oesophagus [41]. According to Caviglia et al. [42], dilated intercellular spaces found in NERD may appear both around the gastro-oesophageal junction and the upper oesophagus. The extension of dilated intercellular spaces from the lower to upper oesophagus could potentially be linked to the release of histamine from mast cells, activation of sensory neurons that respond to capsaicin and discharge of neuropeptides. These neuropeptides either induce neurogenic inflammation or indirectly activate neuropeptide receptors on the surface of mast cells, which stimulate cough receptors, resulting in cough. Low values of the MNBI and proximal MNBI might be a consequence of reflux-induced impairment of mucosal integrity even in the absence of macroscopic damage, and the values were inversely related to acidic and weakly acidic reflux [43], demonstrating that the MNBI is a potential diagnostic marker of the efficacy of PPI therapy for reflux disease.

During MII-pH monitoring, PSPW is defined as a reduction in impedance of 50% compared to the baseline value before swallowing, moving forward from the closest impedance site to all distal impedance sites, followed by a return to at least 50% of the baseline level in all distal impedance locations [44]. After a reflux episode, a key defence mechanism of the oesophageal mucosa is represented by swallowed saliva, which increases the pH levels in the oesophagus and accelerates the repair process by providing bicarbonate and epidermal growth factor [45]. A low PSPWI reflects impaired chemical clearance and implies prolonged contact of the mucosa with reflux, which further damages the oesophageal mucosa and causes micro-aspiration of refluxate despite adequate acid suppression [38, 45], which can aggravate vagal reflexes and cough hypersensitivity. Hence, patients with NERD and a low PSPWI would respond less favourably to PPI therapy. Besides, low PSPWI, i.e., fewer number of PSPW coupled with refluxes, may be associated with the frequency or strength of peristalsis influenced by prokinetic agent [46]. PSPWI is also potentially valuable for evaluating the efficacy of prokinetic agents. Well-designed clinical trials should be conducted to further explore the potential value of PSPWI in assessing the efficacy of prokinetic drugs in patients with GERC, especially in combination with oesophageal motility disorders.

In this study, a large group of GERC patients was used to elucidate the roles of general variables and MII-pH parameters, including the novel parameters PSPWI and MNBI, to predict PPI-refractory GERC. Of the 128 patients, 60 reported unsatisfactory responses to PPIs, which is in agreement with the findings of a recent meta-analysis [6]. There was no significant difference in the demographic characteristics between the PPI-refractory and PPI-responsive groups. Overall, the PSPWI, MNBI and proximal MNBI were significantly lower, while the duration of cough was significantly longer, in the PPI-refractory group than the PPI-responsive group. Multivariate logistic regression analysis revealed an OR of 0.919 for PSPWI and 0.999 for proximal MNBI in PPI-refractory prediction, which are both close to 1. We further found that when PSPWI changes by every 5 units, the OR value is 0.656 with a p-value of 0.001; when proximal MNBI changes by every 200 units, the OR value is 0.858 with a p-value of 0.001. Considering the changes of PSPWI and proximal MNBI in data, we concluded the two metrics were independent protective factors of PPI-refractory GERC.

A low MNBI reflects impaired integrity of the oesophageal mucosa, as a consequence of reflux and putative mechanism of reflux perception [47]. A previous study conducted in our department demonstrated that proximal reflux is often weakly acidic [48]. Both the repaired MNBI and dilated intercellular spaces can manifest in both the upper oesophagus and around the gastro-oesophageal junction in patients with NERD. In this study, the proximal MNBI was significantly lower in the PPI-refractory group than the PPI-responsive group, indicating more severe ongoing impairment of mucosal integrity and oesophageal hypersensitivity induced by weakly acidic reflux in PPI-refractory GERC despite augmented PPI therapy. Besides, we speculate that more frequent swallowing of mucus by patients with GERC could damage the proximal oesophageal mucosa, resulting in oesophageal bronchial reflex and PPI refractoriness.

A reduced PSPWI indicates deficient chemical elimination, resulting in extended periods of exposure of the oesophageal lining to acidic and mildly acidic reflux [37]. Previous studies reported that the PSPWI was unaffected by acid suppression [28], while the results of the present study found that the PSPWI was significantly lower in the PPI-refractory group as compared to the PPI-responsive group. Insufficient enhancement of the PSPWI seems to be a significant factor influencing PPI refractoriness of GERC. Overall, these data showed that timely PSPWs are a major defence mechanism against reflux.

The combination of the criteria PSPWI ⩽39.90% and MNBI ⩽2233.58 Ω had moderately good ability to predict PPI refractoriness with moderate sensitivity (71.67%) and specificity (75.00%). In clinical practice, these criteria are predictive of PPI-refractory GERC, which can be treated with neuromodulators and other add-on treatments directly to avoid unnecessary anti-reflux treatment and achieve high therapeutic success. For those GERC patients who fail to satisfy the above criteria, appropriate courses of anti-reflux treatments are suggested. The present study was an initial evaluation of the potential of MII-pH variables, such as the new indicators MNBI and PSPWI, for effective screening of PPI-refractory GERC and should prove useful for the standardisation of management strategies. Besides, the PSPWI and proximal MNBI could help to develop new treatment options for patients unresponsive to PPI therapy.

There are certain limitations associated with the study that must be acknowledged. A small sample size and recruitment from only one centre are some of these limitations. It is important to enrol more cases in a prospective study to validate the findings of this report. Second, during MII-pH monitoring, it was unclear whether the PSPWI and proximal MNBI had significantly changed because MII-pH monitoring was not performed again after treatment. The MII-pH monitoring parameters must be further verified to predict PPI-refractory cases before considering add-on/alternative medical therapy or anti-reflux surgery. Thirdly, an analysis of outcomes in patients with GERC and typical reflux symptoms versus non-GERC is needed. Future data from large samples need to be included to explore the relationship between typical reflux symptoms and the outcome of PPI response in patients with GERC. Lastly, due to the number of other missed diagnoses as a result of omitting cough events or mislabelling cough time, establishing an accurate difference between the refractory and responsive groups in terms of SAP analysis is limited. In future studies, by combining continuous intra-oesophageal manometry and a cough frequency recorder we may improve the positivity rate of SAP and identify the differences in SAP between the two groups.

In conclusion, the PSPWI and proximal MNBI were useful to predict PPI-refractory GERC. A diagnosis of PPI-refractory GERC should be considered when PSPWI ⩽39.90% and proximal MNBI ⩽2233.58 Ω are reached at the same time. Nonetheless, further prospective studies are needed to confirm the predictive accuracy of these parameters.

Provenance: Submitted article, peer reviewed.

Ethics statement: The study was based on the Declaration of Helsinki (as revised in 2013) and approved by the hospital’s Ethics Committee (K-2020-025). All the patients have provided signed, informed consent. Written informed consent for publication was obtained from all individuals before study enrolment.

Author contributions: X. Xu and L. Yu were involved in the conception of study and grant application; W. Li and B. Sha collected and analysed data; H. Bai and T. Zhang reviewed the chart and interpreted data; S. Wang and Y.A. Kumar were involved in statistical analysis; W. Li and Y. Zhu prepared the paper; X. Xu and L. Yu revised the manuscript. All the authors approved the final version of the manuscript.

Conflict of interest: The authors have no conflicts of interest to declare.

Support statement: This study was supported by the National Natural Science Foundation of China (grants 82070102 and 82270114), the Project of Science and Technology Commission of Shanghai Municipality (22Y11901300, 21Y11901400 and 20ZR1451500), the Program of Shanghai Academic Research Leader (22XD1422700), the Fund of Shanghai Youth Talent Support Program, and the Fund of Shanghai Municipal Health Commission for Excellent Young Scholars (No. 2018YQ01). Funding information for this article has been deposited with the Crossref Funder Registry.

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