Ribolsi M, De Bortoli N, Frazzoni M, Marchetti L, Savarino E, etal. Proximal esophageal impedance baseline increases the yield of impedance-pH and is associated with response to PPIs in chronic cough patients. Neurogastroenterology&Motility.2024;36:e14775

Авторы: Ribolsi M. / de Bortoli N. / Frazzoni M. / Marchetti L.  / Savarino E.V. / Cicala M.

Proximal esophageal impedance baseline increases the yield of impedance-pH and is associated with response to PPIs in chronic cough patients

¹ Department of Digestive Diseases, Campus Bio Medico University of Rome, Roma, Italy
² Department of New Technologies and Translational Research in Medicine and Surgery, University of Pisa, Pisa, Italy
³ Digestive Pathophysiology Unit, Azienda Ospedaliero-Universitaria di Modena Ospedale Civile di Baggiovara, Modena, Italy
⁴ Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine and Surgery, Padova, Italy

Correspondence: Mentore Ribolsi, Dipartimento di Malattie dell'Apparato Digerente, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 200—00128, Rome, Italy. Email: m.ribolsi@unicampus.it

Abstract

Background: Chronic cough significantly impairs the quality of life. Although various studies focused on MNBI as assessed in the distal esophagus, scarce data are available on the clinical value of proximal measurements.

Aim: To investigate the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response.

Methods: Demographic, clinical, endoscopy findings, impedance-pH and HRM tracings from consecutive cough patients were evaluated. MNBI was calculated at proximal and distal esophagus.

Results: One hundred and sixty four patients were included. In addition to traditional variables, when considering also the PSPW index or MNBI at 3 cm or 15 cm, the proportion of patients with pathological impedance-pH monitoring significantly increased. 70/164 patients were responders, while 94 (57.3%) were non-responder to double PPI dose (p < 0.05). Patients with pathologic MNBI at 3 cm and/or 15 cm as well as those with pathologic PSPW index were characterized by a significantly higher proportion of responders than that observed among patients with normal impedance-pH variables (p < 0.001). The proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). At multivariable model, pathological MNBI at both 3 cm and 15 cm as well as PSPW index were associated with PPI responsiveness. The strongest association with PPI response was observed for MNBI at 15 cm.

Conclusions: The assessment of MNBI at proximal esophagus increases the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough.

KEYWORDS: GERD, impedance-pH, MNBI, PPI, PSPW

Key points Among extra-esophageal symptoms, chronic cough significantly impairs the quality of life. No studies have yet investigated the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response. Our results show that the assessment of MNBI at proximal esophagus increases the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough.

1 | INTRODUCTION

Gastro-esophageal reflux disease (GERD) is defined by the presence of esophageal and extra-esophageal symptoms due to a pathological reflux and represents a common disease, with an increasing worldwide prevalence.[1,2] Among extra-esophageal symptoms, chronic cough significantly impairs the quality of life.[3 ]

Nowadays, the clinical management of patients with suspected GERD-related chronic cough is challenging and their response to acid suppressive therapy is often unsatisfactory.[4] In this scenario, a rigorous patients selection is crucial, aimed to better defining whether cough is due to GERD and, therefore, patients may respond to proton pump inhibitors (PPIs).

Ambulatory multichannel intraluminal impedance-pH monitoring has improved the diagnosis of GERD in patients with unexplained chronic cough, displaying a positive association between cough and weakly acidic reflux episodes.[5–7] On the other hand, data concerning the association between the conventional impedance-pH variables, acid exposure time (AET) and symptom-association probability (SAP), and PPI response in suspected GERD-related chronic cough patients are controversial.[4 ]

In the last few years, new variables, namely post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI) values measured at distal esophagus, have been implemented in the impedance-pH testing, being able to increase the diagnostic yield of impedance-pH monitoring.[8,9] Several investigations have highlighted that both pathological MNBI and pathological PSPW index values are associated with PPI responsiveness in patients with GERD symptoms.[10–16 ]

Although various studies focused on MNBI as assessed in the distal esophagus, scarce data are available on the clinical value of proximal measurements. Very recently, in patients with typical GERD symptoms we have demonstrated that proximal MNBI increases the diagnostic yield of impedance-pH monitoring and is associated with PPI responsiveness even better than distal MNBI.[17] Nevertheless, no studies have yet investigated the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response, and clarifying these issues represents the aim of the present study.

2 | MATERIALS AND METHODS

2.1 | Patients

Demographic, clinical, and upper endoscopy findings together with ambulatory 24-h impedance-pH data from consecutive adult patients (age >18 years), prospectively assessed in four centers in Italy between January 2019 and December 2022 for suspected GERD-related cough as main symptom persisting for >8 weeks, were retrospectively evaluated.

Only nonsmoker patients, presenting with a normal chest X-ray, were included. Patients using angiotensin-converting enzyme inhibitors, antitussive drugs and/or presenting with significant or recent respiratory tract infections were excluded. Before endoscopy and impedance-pH monitoring, patients were evaluated with an ear, nose, and throat (ENT) evaluation including fibrolaryngoscopy, spirometry, and methacoline test; those with a diagnosis of asthma and postnasal drip syndrome were excluded. Moreover, individuals with inadequate impedance-pH evaluation (equipment malfunction or poor study quality), evidence of achalasia, and/or esophago-gastric junction (EGJ) outflow obstruction at high-resolution manometry (HRM),[18] Barrett esophagus, eosinophilic esophagitis, connective tissue disease, psychiatric disease, history of neoplasia and prior foregut surgery were excluded.

The impact of chronic cough was assessed using the Fisman Cough Severity/Frequency Scores,[19] a validated scale, administered in presence of a senior investigator, that scores the severity of cough from 0 to 4 (0 = no cough at all; 1 = occasional hems; 2 = mild, isolated cough, without additional symptoms; 3 = moderate, paroxysmal cough, without additional symptoms; 4 = severe, strenuous cough, accompanied by chest discomfort) and cough frequency on visual analogue scale, scored from 1 to 10, where 1= “I never cough,” and 10= “I cough all day long”.[16 ]

Presence of concomitant typical esophageal symptoms (heartburn, regurgitation, and noncardiac chest pain)[20] was assessed with a validated structured questionnaire based on a four-grade Likert-type scale (0 = none; 1 = mild/occasional; 2 = moderate/frequent; 3 = severe/constant).[21] Typical symptoms were considered as troublesome if a score ≥2 was recorded.

Patients with an upper endoscopy performed within 3 months before ambulatory impedance-pH monitoring were included, with all the endoscopic procedures performed after at least 2-weeks of pharmacological washout.[22] Impedance-pH studies were always preceded by esophageal HRM for accurate location of the lower esophageal sphincter (LES) and exclusion of all motility disorders.[23] Grade B, C, and D erosive esophagitis, according to Los Angeles classification, were considered as diagnostic of erosive GERD.[24,25]

Following the impedance-pH study, all patients were treated with at least 8 weeks double-dose PPI [Esomeprazole 40 mg twice daily (bid), Pantoprazole 40 mg bid or Omeprazole 20 mg bid]. At the end of PPI treatment, patients were reassessed and a significant cough improvement was considered as achieved if patients reported a Fisman severity score ≤1.[15]

The study was carried out in accordance with the declaration of Helsinki; since patients were investigated for clinical reasons and, according to standardized routine clinical assessment, were not exposed to any additional intervention, a formal medical ethical approval was not required. Signed informed consent was always required before any clinical investigation.

2.2 | Twenty four hour impedance-pH monitoring

Intraluminal impedance-pH was monitored using a 2.3 mm diameter polyvinyl catheter assembly containing a series of impedance electrodes and a distal antimony pH electrode (Diversatek, Highlands Ranch, CO, USA). The pH electrodes were calibrated using pH 4.0 and pH 7.0 buffer solutions before impedance-pH monitoring. Following HRM, the catheter was passed through the anesthetized nostril, and positioned with the pH electrode 5 cm and impedance electrodes at 3, 5, 7, 9, 15, and 17 cm proximally to the manometrically defined upper LES border. Reflux testing was carried out off-PPI therapy (suspended at least 14 days prior to monitoring). During this time, patients were allowed to take alginate-based compounds as rescue therapies.[26 ]

Event markers, supported by paper diaries, were used to record symptoms, meal times, and supine periods. Tracings were manually assessed with the aid of commercial software. Liquid and liquid–gas reflux events were distinguished into acid (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. AET was defined as pathological if the time pH <4 exceeded 6% of the total recording time.[24] Reflux-symptom association was assessed using symptom index (SI) and symptom association probability (SAP) for all reflux episodes using previously described methodology.[27,28] MNBI was calculated by measuring baseline impedance values at 15 cm (proximal MNBI) and at 3 cm (distal MNBI) above the LES, across stable nocturnal 10-min periods (at or around 1:00 a.m., 2:00 a.m., and 3:00 a.m.), avoiding swallows and pH drops; the values from the three time periods for both levels were averaged to obtain the proximal and distal MNBI, respectively.[17] MNBI values <2000 and <2665 Ohms (Ω), at distal and proximal esophagus, respectively, defined abnormal studies.[17] The choice of these cutoffs was based on previous studies on large cohort of Italian patients, since there are significant regional differences in AET and number of reflux episodes, partially related to differences in diet, meal time, and composition. Furthermore, it is also possible that genetic mechanisms might be responsible for microscopic ultrastructure alterations of esophageal epithelium, thus affecting the MNBI values. PSPWs were defined as antegrade 50% drops in impedance, originating in the proximal esophagus within 30s after reflux events and reaching the distal lumen; the PSPW index was calculated dividing the number of PSPWs by the number of reflux events.[10–15] PSPW index values <50% were defined as abnormal, according to previously published standards.[29] All impedance-pH tracings were assessed by one expert observer (MR) that was blinded to treatment outcome.

2.3 | Statistical analysis

Data are presented as means and standard deviation (SD) unless otherwise indicated. Comparisons between groups were assessed using the Fisher's exact test and ANOVA with Bonferroni correction, when appropriate. The ability of impedance-pH variables to separate PPI responsive from PPI refractory cough patients was assessed by means of receiver operating characteristic (ROC) analysis. Sensitivity and specificity were therefore calculated.

Multivariable regression models were generated to evaluate the factors predictive of PPI responsiveness. Significance was achieved when the p value was <0.05. Statistical analysis was performed using SPSS 27.0 software (SPSS Inc., Chicago, IL, USA).

3 | RESULTS

3.1 | Demographic, clinical, endoscopic, HRM, and impedance-pH findings

A total of 324 patients with cough were evaluated. Among them, 48 did not complete the PPI trial, 14 had evidence of asthma, 44 were smokers, 27 were using angiotensin-converting enzyme inhibitors, nine presented evidence of esophageal EGJ outflow obstruction, and 18 had impedance-pH or HRM tracings with presence of artifacts. Therefore, a total of 164 patients with suspected GERD-related chronic cough were included in the study (mean age: 46 years, range: 21–72 years); 88 (53.7%) were female, and 55 (33.5%) had concomitant typical GERD symptoms (Table 1). Presence of grade B-C-D erosive esophagitis was observed in 16 (9.8%) patients. Thirty-six out of 164 cough patients (22%) displayed grade B-C-D erosive esophagitis or were characterized by a pathological AET. According to AET and/or SAP/SI, 51 patients (31.1%) had a pathological impedance-pH study. In addition to traditional variables, when considering also the PSPW index or MNBI at 3 cm or 15 cm, the proportion of patients with pathological impedance-pH monitoring significantly increased (Table 2). Eighteen out of 52 (34.6%) patients with pathological distal MNBI and 22/69 (31.9%) patients with pathological proximal baseline had concomitant typical GERD symptoms (p: NS). According to the Fisman score assessed before PPI therapy, mean cough severity and frequency in patients with normal versus pathologic proximal baseline were: 1.4 ± 0.3 and 3.2 ± 1.1 versus 3.1 ± 1.1 and 6.2 ± 2.4; p < 0.01 for all comparisons. No correlation was observed between AET and cough severity/frequency scores (R: 0.23 and 0.27, respectively) while a good correlation was observed between cough severity/ frequency scores and proximal MNBI (R: 0.82, 0.87) or PSPW index (R: 0.71, 0.75).

3.2 | Comparison between PPI-responsive and PPI-refractory cases with cough

According to the Fisman severity score, 70 (42.7%) out of the 164 patients with cough responded to PPIs, while the remaining 94 (57.3%) reported an unfavorable response following the double PPI dose (p < 0.05). Typical GERD symptoms were more frequently observed in responders compared to nonresponders [34 out of 70 (43%) vs. 21 out of 94 (21%); p < 0.001].

FIGURE 1. ROC curves for impedance-pH variables.

The majority of patients with AET >6% as well as slightly less than half of those with positive SAP/SI had cough responding to PPI (Table 3). The majority of patients with only AET between 4% and 6% were nonresponders (Table 3). Patients with pathologic MNBI at 3 cm and/or 15 cm as well as those with pathologic PSPW index were characterized by a significantly higher proportion of PPI responders than that observed among patients with all impedance-pH variables in the normal range (Table 3) (p < 0.001 for all comparisons). ROC analysis allowed to calculate sensitivity and specificity values for impedance-pH variables (Figure 1). The proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). Mean values of MNBI at both 3 cm and 15 cm were significantly lower in responders than in nonresponders (p < 0.001 for all comparisons) (Figure 2).

Among patients with inconclusive GERD, responders were characterized by a significantly higher proportions of individuals with pathologic MNBI at 3 cm or 15 cm compared with nonresponders (p < 0.0001 for all comparisons) while, among patients with AET <4% and SAP/SI in the normal range, responders were characterized by a significantly higher proportions of individuals with pathologic PSPW index as well as pathologic MNBI at 3 cm or 15 cm compared with nonresponders (p < 0.001 for all comparisons) (Figure 3).

FIGURE2. Mean values of MNBI at (A) 3 cm and (B) 15 cm in responders and non-responders.

FIGURE 3. Proportion of individuals with pathological MNBI or PSPW index in responders and non-responders patients with indefinite GERD vs those with normal impedance-pH. Column with the same color were compared. Fisher exact test was used to compare the different proportion and asterisk highlight a significantly difference. (*p < 0.05).


Considering all cases, at multivariable model pathological MNBI at both 3 cm and 15 cm as well as PSPW index were associated with PPI responsiveness whereas pathological AET, positive SAP/SI and pathological number of reflux episodes were not (Table 4). The strongest association with PPI response was observed for MNBI measured at 15 cm.

4 | DISCUSSION

This is the first investigation aimed at exploring the diagnostic yield of MNBI assessed at proximal esophagus as well as its relationship with PPI response in patients with troublesome chronic cough. The recent Lyon Consensus proposes shared criteria for GERD diagnosis, delineating impedance-pH parameters useful for establishing, or ruling out the presence of reflux disease[24] including MNBI assessed only in the distal esophagus. In this study, we confirm the clinical value of distal MNBI[9–16] in the cumbersome setting of chronic cough it increases the diagnostic yield of impedance-pH monitoring, with pathological values associated with PPI responsiveness. Moreover, our study shows that proximal MNBI measurement allows to discriminate reflux-related cough even better than distal MNBI, in accordance with our recent findings obtained in GERD patients with typical symptoms.

As far as the potential association between distal and proximal MNBI and PPI response is concerned, in our series patients with cough responding to PPIs are characterized by a significantly higher proportion of individuals with pathological MNBI at both levels in comparison with nonresponders. Interestingly, the proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). Results from the multivariate analysis showed that detection of pathological MNBI values either at 3 cm or 15 cm as well as pathological PSPW index were significantly associated to PPI response; notably, the strongest association was observed for proximal MNBI.

Our results highlight that pathological proximal MNBI values may be particularly useful in patients with cough and inconclusive GERD diagnosis. In our series of patients responding to PPIs, although characterized by unsatisfactory evidences of GERD at impedance-pH monitoring, pathological MNBI at proximal esophagus was the most common observed pathological variable, revealed in 76% of cases. The choice of our MNBI cutoffs was based on previous studies on large cohort of Italian patients, since there are significant regional differences in AET and number of reflux episodes, partially related to differences in diet, meal time and composition. Furthermore, it is also possible that genetic mechanisms might be responsible for microscopic ultrastructure alterations of esophageal epithelium, thus affecting the MNBI values.

Nowadays, it is widely acknowledged that GERD may contribute to cough occurrence indirectly due to vagal stimulation, triggered by the activation of the esophageal sensory nerve endings or due to microaspiration of gastric content. In this scenario, it is possible to speculate that, in the presence of an impaired epithelial integrity as confirmed by pathological MNBI,[30,31] the noxious component of refluxate diffuses through the paracellular pathway into the esophageal epithelium, the latter morphologically characterized by dilated intercellular spaces, thus activating the vagal afferents and, in turn, eliciting cough bursts. It has been demonstrated that a proper course of omeprazole therapy is able to induce a complete recovery of dilated intercellular diameters together with reflux symptoms relief.[32] Conceivably, a similar mechanism induces cough improvement in those patients with evidence of pathological MNBI values, particularly in the proximal esophagus, as confirmed by our results. Reasonably, the high diagnostic sensitivity and high predictive value of PPI responsiveness showed by proximal MNBI may be due to reflux-induced increased permeability in the proximal esophageal mucosa, in turn leading to an enhanced vagal stimulation.

Over the last two decades several evidences showed that the stimulation of the proximal esophageal mucosa is crucial for GERD symptom generation.[33,34] A lower perception threshold has been demonstrated in the proximal esophagus compared to distal and, finally more superficial afferent nerves have been found in the proximal and distal mucosa in NERD patients.[35,36]

It could be argued that our rate of PPI response in patients with cough is higher than that previously reported.[4,37] We may speculate that a careful patients selection, according to our inclusion and exclusion criteria, together with an up-front investigation of suspected GERD-related chronic cough patients with endoscopy, HRM and impedance-pH monitoring, performed off PPI with evaluation of conventional and novel metrics, contributed to select those patient more likely affected by reflux-related cough.

As far as we know, this is the first study assessing MNBI measured in the proximal esophagus in a large cohort of patients with chronic cough. Our results demonstrate that lower MNBI values at proximal level are an accurate marker of reflux-related cough, being also strongly associated with an increased probability of PPI response. We selected both PPI nonresponder and responder patients, the former requiring demonstration of GERD before advising treatment escalation and the latter needing documentation of reflux disease before confirming long-term PPI therapy, respectively: such enrolment criteria reflect clinical practice. Strengths of the present study are the number of patients included and rigorous selection process, excluding patients with other causes of cough and including an accurate endoscopic and functional assessment.

Some limitations could temper the strengths of our investigation. In particular, the retrospective nature of the study could be regarded as a bias: however, data collection was prospectively carried out for the whole study population at referral centers where criteria for patient assessment have long been standardized. Day-to-day variability of reflux testing and placebo effect might have underestimated the number of patients with reflux-related cough and overestimated the number of PPI responders, respectively. Compared to prolonged reflux testing, impedance-pH testing has lower sensitivity to pick up day-to- day variations of GERD and shorter recording period also decreases the number of symptom events for assessment of symptom-reflux association. We have assessed, in all patients, the presence of previously diagnosed psychiatric diseases, as well as the concomitant use of opioids, antidepressant and benzodiazepine. However, we are aware that few patients may have misdiagnosed anxiety and hypervigilance status. The assessment of proximal MNBI requires the execution of 24-h impedance-pH monitoring which results sometimes poorly tolerated, eliciting cough itself. Finally, symptom-reflux association indexes can be not accurate, particulary in this group of patients. It would be of interest to compare our results from those obtained by measuring proximal impedance baseline by mucosal impedance test, a simple through-the-scope procedure performed during endoscopy. The likely confirmation of our results by simply applying the mucosal test during endoscopy could corroborate the use of proximal MNBI as an upfront test in patients with cough, in order to avoid unnecessary PPI treatment, which may be very difficult to stop once commenced.

In conclusion, the present study shows that assessment of MNBI at proximal esophagus can increase the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough.

AUTHOR CONTRIBUTIONS

Mentore Ribolsi: planning and conducting the study, collecting and/or interpreting data, drafting the manuscript; Nicola De Bortoli, Marzio Frazzoni, Edoardo Savarino: collecting and/or interpreting data, drafting the manuscript; Lorenzo Marchetti: collecting and/or interpreting data; Michele Cicala: planning and conducting the study, drafting the manuscript. Each author has approved the final draft submitted.

FUNDING INFORMATION

No funding sources to declare.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ORCID

Mentore Ribolsi https://orcid.org/0000-0001-5102-1758
Nicola De Bortoli https://orcid.org/0000-0003-1995-1060
Marzio Frazzoni https://orcid.org/0000-0002-8608-1563

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How to cite this article: Ribolsi M, De Bortoli N, Frazzoni M, Marchetti L, Savarino E, Cicala M. Proximal esophageal impedance baseline increases the yield of impedance-pH and is associated with response to PPIs in chronic cough patients. Neurogastroenterology & Motility. 2024;36:e14775. doi:10.1111/nmo.14775

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