Gastroesophageal reflux disease (GERD) is defined by the presence of esophageal and extraesophageal symptoms because of a pathological reflux or a hypersensitivity to physiologic reflux and represents a common disease, with an increasing worldwide prevalence (1–3). Among extraesophageal symptoms, chronic cough significantly impairs the quality of life (4).
Nowadays, the clinical management of patients with suspected GERD-related chronic cough is challenging, and their response to adequate acid suppressive therapy is widely considered as unsatisfactory. It has been reported that the therapeutic gain, after a proper proton pump inhibitor (PPI) therapy, is greater in chronic cough patients with pathologic esophageal acid exposure or with concomitant typical symptoms than in those without (5). In this scenario, it is crucial in rigorous patient selection to better define the diagnosis and, therefore, to identify those patients likely to be responsive to PPIs.
Ambulatory multichannel intraluminal impedance-pH (MII-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 (6). It has been demonstrated that patients with chronic cough are characterized by a significantly higher number of refluxes than asymptomatic subjects (7). It should be recognized that the increased number of reflux episodes in patients with chronic cough may be caused by the cough bursts themselves, which may trigger the occurrence of reflux episodes by increasing the transdiaphragmatic pressure or facilitating transient lower esophageal sphincter relaxations (8,9). On the other hand, few data concerning the association between MII-pH variables and PPI response in suspected GERD-related chronic cough patients are available. It has been shown that the presence of a pathological esophageal acid exposure time (AET) or impedance baseline values may predict PPI response in chronic cough patients (10).
Esophageal chemical clearance, an important defence mechanism in GERD, has been evaluated with the postreflux swallow-induced peristaltic waves (PSPWs), i.e., the impedance drops propagating from the proximal to the distal esophagus and occurring within 30 seconds after a reflux event (11). Dividing the number of PSPWs by the number of reflux events, a new MII-pH variable, namely the PSPW index, has been obtained. The PSPW index assesses efficacy of esophageal chemical clearance, which consists of delivering salivary bicarbonate and epidermal growth factor into the distal esophagus. Recently, both PSPW index and the mean nocturnal baseline impedance (MNBI) values have been proposed as a new metric, able to increase the diagnostic yield of MII-pH in uncertain conditions (12). Furthermore, it has been showed that pathological MNBI and PSPW index values are associated to PPI responsiveness in patients with typical GERD symptoms (13). Indeed, no studies have evaluated the diagnostic yield and the association with PPI response of these novel MII-pH parameters in patients with suspected GERD-related chronic cough.
Finally, it has been shown that weak peristalsis with large breaks, observed using high-resolution manometry (HRM), characterizes a not negligible proportion of patients with chronic cough, directly influencing clearance of refluxed events (14,15).
The aim of the present investigation was, therefore, to evaluate in a large cohort of suspected GERD-related chronic cough patients, the diagnostic yield of conventional and new MII-pH parameters, and the role of MII-pH variables, HRM findings, and endoscopic and clinical characteristics in predicting PPI response.
MATERIALS AND METHODS
Demographic, clinical, and upper endoscopy findings together with ambulatory 24-hour MII-pH and HRM tracings from consecutive adult patients (age older than18 years), prospectively assessed in our Outpatients Unit (between January 2017 and December 2020) for suspected GERD-related cough as main symptom persisting for >8 weeks, were retrospectively evaluated.
Only patients who were nonsmokers and presenting 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 MII-pH monitoring, patients were evaluated with an ear, nose, and throat evaluation with fibrolaryngoscopy, spirometry, and methacholine test; those with a diagnosis of asthma and postnasal drip syndrome were excluded. Moreover, individuals with inadequate evaluation (equipment malfunction, poor study quality, and the presence of artifacts), evidence of achalasia, and/or esophagogastric junction (EGJ) outflow obstruction at HRM, Barrett's esophagus, eosinophilic esophagitis, connective tissue disease, psychiatric disease, a history of neoplasia, and previous foregut surgery were excluded.
The impact of chronic cough was assessed using the Fisman Cough Severity/Frequency Scores, a validated scale, administered in the presence of a senior investigator who 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; and 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).
The presence of concomitant typical esophageal symptoms (heartburn, regurgitation, and noncardiac chest pain) (17) was assessed with a validated structured questionnaire based on a 4-grade Likert-type scale (0 = none; 1 = mild/occasional; 2 = moderate/frequent; and 3 = severe/constant) (18). Typical symptoms were considered as troublesome if a score ≥2 was achieved.
Upper endoscopy was performed within 3 months before ambulatory MII-pH monitoring executed during our ambulatory evaluation. All procedures were performed after at least 2-week pharmacological wash out (17). MII-pH studies were preceded by esophageal HRM for the accurate location of the lower esophageal sphincter (LES). Grade C and D erosive esophagitis, according to the Los Angeles classification, were considered as diagnostic of severe erosive GERD disease (19).
All patients were treated, after the MII-pH, with at least 8 weeks of double dose PPI therapy (esomeprazole 40 mg b.i.d., pantoprazole 40 mg b.i.d., lansoprazole 30 mg b.i.d., and omeprazole 20 mg b.i.d.). After PPI treatment, patients were reassessed, and a significant cough improvement was considered as achieved if patients reported a Fisman Severity Score ≤1 (10). The study was approved by the Ethic Committee of Campus Bio Medico University, and written informed consent was obtained from all individuals before undergoing all investigations.
A catheter with 36 circumferential solid state pressure sensors located at 1-cm intervals was inserted, after an overnight fast, through an anesthetized nostril such that at least 3 distal pressure sensors were in the stomach. The manometric study was performed using ten 5 mL swallows of ambient temperature fluid at 30-second intervals in a semirecumbent position (20).
Each HRM study was evaluated using the following CCv3.0 criteria (21): (i) intact swallow: distal contractile integral (DCI) >450 mm Hg·cm−1·s−1, (ii) fragmented swallow: DCI >450 mm Hg·cm−1·s−1 with >5 cm breaks, (iii) weak swallow: DCI 100–450 mm Hg·cm−1·s−1, and (iv) failed swallow: DCI <100 mm Hg·cm−1·s−1. CCv3.0 diagnoses consisted of the following: (i) fragmented peristalsis: ≥50% fragmented swallows, (ii) ineffective esophageal motility (IEM): ≥50% of any combination of weak or failed swallows, and (iii) absent contractility: 100% failed swallows. Patients displaying >70% of weak swallows were also reported (22). EGJ morphology was determined by the relationship between LES and crural diaphragm; superimposed LES and crural diaphragm defined type 1 EGJ, type 2 was characterized by separation <3 cm, and type 3 by separation ≥3 cm (21).
24-Hour MII-pH monitoring
MII-pH was recorded using a 2.3 mm diameter polyvinyl catheter assembly containing a series of impedance electrodes, each 4 mm in axial length, spaced at 2 cm intervals, and a distal antimony pH electrode (Diversatek, Highlands Ranch, CO). The pH electrodes were calibrated using pH 4.0 and pH 7.0 buffer solutions before MII-pH monitoring. After esophageal manometry, the catheter was passed through the anesthetized nostril and positioned with the pH electrode 5 cm above the LES, and impedance electrodes at 3, 5, 7, 9, 15 and 17 cm proximal to the LES. MII-pH was always preceded by conventional manometry or HRM for the accurate location of the LES.
Event markers, corroborated with 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 (19). Reflux number was considered as abnormal if >58 during MII-pH monitoring, according to the value proposed in a recent multicenter study in western countries (23). Reflux-symptom association was assessed using symptom index (SI) and symptom association probability (SAP) for all reflux episodes using previously described methodology (24–26). MNBI was calculated by measuring baseline impedance values at 5 cm above LES, across stable nocturnal 10-minute periods (at or approximately 1:00 am, 2:00 am, and 3:00 am). The values from the 3 time periods for both levels were averaged to yield the MNBI for each channel. Values <2,292 Ω defined abnormal studies (27). PSPWs were defined as antegrade 50% drops in impedance, originating in the proximal esophagus and reaching the distal lumen within 30 s after reflux events. The PSPW index was calculated dividing the number of PSPWs by the number of reflux events (11,28). Normal values for PSPW index were used according to previously published standards (29). MNBI and PSPW index were calculated by the same operator that was blinded to the treatment outcome of each patient.
Data are presented as means and SD unless otherwise indicated. Comparisons between groups were assessed using the Fisher exact test. Group means were compared using 2-sample Student t tests.
The ability of MII-pH variables to separate PPI responsive from PPI refractory cough patients was assessed by means of a receiver operating characteristic analysis with a calculation of the area under the curve (AUC). Paired comparisons between AUCs were performed with an adjustment of critical P values using Bonferroni correction. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for all MII-pH variables.
Multivariable regression models were generated to evaluate in all patients the factors predictive of PPI responsiveness. The choice of the variables to be included in the multivariable model was first made by identifying the variables significantly associated with the outcome in univariable models. Subsequently, we proceeded with stepwise logic. The significance level for maintaining the single term in the model was P ≤ 0.2. Multivariable regression models were also generated to evaluate the factors predictive of PPI responsiveness in patients stratified according to AET levels (AET >6%, AET between 4% and 6%, and AET <4%) and excluding those with grade C-D erosive esophagitis.
Significance was achieved when the P value was <0.05. Statistical analysis was performed using SPSS 27.0 software (SPSS, Chicago, IL).
Demographic, clinical, endoscopic, HRM, and MII-pH findings
A total of 388 cough patients were evaluated. Among these, 50 did not complete the PPI trial, 24 had evidence of asthma, 54 were smokers, 41 were using angiotensin-converting enzyme inhibitors, 12 presented evidence of esophageal EGJ outflow obstruction, and 29 had MII-pH or HRM tracings with the presence of artefacts. Therefore, a total of 178 patients with suspected GERD-related chronic cough were included in the study (mean age: 46 years, range: 21–72 years); 91 (51.1%) were women and 55 (31%) had concomitant typical GERD symptoms. The presence of grade C-D erosive esophagitis or hiatal hernia (type 2/3 EGJ at HRM) was observed in 14 (7.8%) and 31 (17.4%) patients, respectively. Twenty-four cough patients (13.5%) had evidence of hypomotility features at HRM (18 patients with IEM and 6 with fragmented peristalsis). Among patients those with IEM, 7 displayed >7 weak swallows. Eighty-four of 178 cough patients (47.2%) displayed grade C-D erosive esophagitis or were characterized by a pathological AET and/or positive SAP/SI. When also considering MNBI and PSPW index, 135 of 178 patients (75.8%) were characterized by evidence of reflux disease (P < 0.001).
Responder and nonresponder cough patients
According to the Fisman Severity Score, 80 (44.9%) of the 178 patients had cough responding to PPIs, whereas the remaining 98 (55.1%) reported an unfavorable response after the double dose of PPI treatment (P = 0.071). Responder patients showed a mean Fisman Severity Score value significantly lower after PPI therapy, whereas no significant difference was observed in nonresponders before and after the treatment (Figure 1a). The mean Fisman Frequency Score value was significantly lower after acid suppressive therapy in responders, whereas no significant difference was observed in nonresponders before and after PPIs (Figure 1b).
Typical GERD symptoms were more frequently observed in responders compared with nonresponders (34of 80 [43%] vs 21 of 98 [21%]; P = 0.0033). MNBI values were 1,775 Ω (±674 Ω) in responders and 2,508 Ω (±732 Ω) in nonresponders (P < 0.001); mean PSPW index values were 33% (±14) in responders and 52% (±23) in nonresponders (P < 0.001). Individual MNBI and PSPW values displayed a slight overlap between responders and nonresponders (Figures 2 and 3).
Most patients with grade C-D erosive esophagitis or with AET >6% and slightly less than half of those with positive SAP/SI had cough responding to PPI (Table 1). Patients with an AET between 4% and 6% and pathologic MNBI and/or PSPW index were characterized by a significantly higher proportion of responders than those observed among patients with only AET between 4% and 6% (Table 1). Patients with only pathologic MNBI and/or PSPW index were characterized by a significantly higher proportion of responders than those observed among patients with all MII-pH variables in the normal range (Table 1). Most patients with type 2/3 EGJ or hypomotility features had cough responding to PPI therapy (Table 1). All except 2 patients with severe IEM were responding to PPI treatment.
At the receiver operating characteristic analysis, both PSPW index and MNBI were associated to PPI responsiveness (Figure 4). The AUC of the model based on AET was 0.613 (95% confidence interval 0.571–0.654). AUCs of MNBI and PSPW index were significantly higher than that of AET (P < 0.01 for both comparisons). According to the proposed cutoff values, MNBI and PSPW index showed higher sensitivity in predicting PPI response compared with AET and SAP/SI (Table 2).
Considering all patients, at univariable analysis, AET >6%, positive SAP/SI, pathological MNBI or PSPW index, erosive esophagitis, typical symptoms, hiatal hernia, and hypomotility features were associated to PPI response. According to the multivariable model, pathological MNBI or PSPW index, hiatal hernia. and hypomotility features were associated to PPI response, whereas positive SAP/SI and the pathological number of reflux episodes did not predict PPI response (Table 3).
At univariable analysis, when grade C-D erosive esophagitis, AET >6%, the presence of hiatal hernia, and typical symptoms were considered together with the presence of pathological MNBI and/or PSPW index displayed an higher association to PPI response instead of been considered alone (odds ratio [95% confidence interval]; 5.37 [2.75–10.06]; 5.8 [2.87–11.66]; 5.37 [3.65–15.32] and 3.91 [2.18–6.27], respectively).
When patients were stratified according to AET and excluding those with grade C-D erosive esophagitis, pathological MNBI, or PSPW index, hiatal hernia and hypomotility features were associated to PPI response in all groups, whereas the presence of positive SAP/SI and the pathological number of reflux episodes were not associated to PPI responsiveness (Table 4).
This study was aimed at evaluating the diagnostic yield of conventional and new MII-pH parameters and the role of MII-pH variables, HRM findings, and endoscopic characteristics in predicting PPI response in a large cohort of suspected GERD-related chronic cough patients. Data from consecutive, prospectively assessed patients for suspected GERD-related cough were retrospectively evaluated. We enrolled only those patients who, after a complete work-up, received an 8-week double dose PPI therapy, assessing the cough improvement after treatment.
This is the first investigation evaluating MNBI and PSPW index in a large group of patients with chronic cough as a dominant symptom. Our findings are in agreement with those obtained by Frazzoni et al. (12) demonstrating that, in patients with typical reflux disease, MNBI and PSPW index increase the diagnostic yield of MII-pH monitoring. Moreover, the results reported herewith are further corroborated by a recent study from our group showing that the novel MII-pH variables are pathological in a not negligible proportion of patients with ear, nose, and throat symptoms characterized by conventional MII-pH parameters in the normal range (30).
Of interest, in our series, the presence of pathological MNBI and/or PSPW index values is associated to an increased probability of response to PPIs. This finding is in agreement with a study by Frazzoni et al. (13), carried out in heartburn patients, demonstrating that AET, MNBI, and PSPW indexes were the only factors independently associated with PPI responsiveness, with abnormal values found, respectively, in 60%, 76%, and 92% of PPI-responsive cases. Moreover, mean PSPW index in our responders is similar to that obtained by Frazzoni et al. (13) in PPI-responsive patients, whereas mean PSPW index in nonresponders is comparable with that obtained in a recent study on healthy subjects (31).
Efforts were made to examine the added value of novel MII-pH variables in discriminating cough patients responding to an optimal PPI course. To this purpose, a multivariable model was developed, excluding patients with severe esophagitis and stratifying the remaining patients according to the AET value. According to our analysis, MNBI, PSPW index, the presence of hiatal hernia, and hypomotility features, detected at HRM, were associated to PPI response in all groups of patients with AET in the normal range (Table 4).
The results reported herewith show that the mean MNBI value was significantly lower in responders compared with nonresponders. It has been previously demonstrated that baseline impedance directly relates to ultrastructural changes of the esophageal epithelium (32–36). Nowadays, it is widely acknowledged that GERD may contribute to cough occurrence indirectly because of vagal stimulation, triggered by the activation of the esophageal sensory nerve endings. In this scenario, it is possible to speculate that 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 (37). Calabrese et al. (38) have demonstrated that a proper course of omeprazole therapy is able to induce a complete recovery of dilated intercellular diameters together with reflux symptoms relief. It is tempting to hypothesize that a similar mechanism induces cough improvement in those patients with an evidence of reflux disease at MII-pH, as confirmed by our results.
In our series, hypomotility features and the presence of type 2/3 EGJ, observed at HRM, were more frequent in responders and, according to multivariable analysis, were associated to a favorable PPI response. It has been shown that patients with large breaks of esophageal peristalsis were more likely to have cough as a presenting symptom than those without (14,15). It is also known that impairment of esophageal motility and the presence of hiatal hernia, observed at HRM, are correlated with higher reflux burden (39) and to PPI response (40).
Our results show that the presence of positive SAP and/or SI seems not to be very useful in chronic cough patients. It is known that both SAP and SI represent MII-pH indexes assessing the temporal relationship between symptoms and reflux episodes. However, the diagnostic limits of these variables have long been recognized in patients with typical symptoms (41). Moreover, it has also been demonstrated that some heartburn patients with normal AET and SAP/SI are responders to PPI therapy (42). Finally, it has to be taken into consideration that SAP/SI accuracy in assessing cough-reflux association is limited because it is particularly challenging for patients to mark each cough episode during MII-pH monitoring. MNBI and PSPW index represent novel MII-pH variables proposed to overcome the limits of AET and SAP/SI, and their diagnostic efficiency has repeatedly been demonstrated in patients with typical symptoms.
It could be argued that our rate of cough patients responding to PPI treatment is higher than that previously reported. We may speculate that a careful patient 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 MII-pH monitoring, performed off PPI, can help to select those patients likely to be affected by true GERD and responsive to an optimal PPI course. In this scenario, our results confirm the relatively low yield of PPI trial in chronic cough patients and highlight the incremental value of esophageal testing using conventional together with novel MII-pH parameters (10–13,27,35).
To our knowledge, this is the first study focused, in a large group of suspected GERD-related chronic cough patients, on the diagnostic yield of conventional and new MII-pH parameters as well as the role of MII-pH variables, HRM findings, and endoscopic and clinical characteristics in predicting PPI response. Strengths of this study are the number of patients included and rigorous selection process, including the endoscopic and functional assessment. However, some limitations temper the strength of our findings, the main limitation relating to retrospective patient evaluation and data analysis, although data collection was prospectively carried out for the whole study population. Our cutoff values of MNBI and PSPW are higher than those recently reported in healthy volunteers (23), although in keeping with most of published studies in an Italian population (10–13,43). Moreover, a special MII-pH catheter incorporating proximal impedance sensors close to the upper esophageal sphincter would have been useful is evaluating cough patients. Finally, the day-to-day variability of reflux testing and the placebo effect may have overestimated our number of responder patients (18).
The routine clinical approach to suspected GERD-related chronic cough patients is an empirical PPI course, initiating the workup only in those not responding. However, the widely shown low rate of responders implicates that a high number of nonresponder patients keep PPIs only for symptoms, with mutual frustration of both patients and clinicians. Our results may lead to the conclusion that, in clinical practice, an objective confirmation of GERD after an accurate patient selection and evaluation with endoscopy, HRM, and MII-pH is needed to address to PPI therapy in those patients who will likely respond, encouraging to discontinue unavailing prolonged treatments in nonresponder cough patients without evidence of reflux disease.
CONFLICTS OF INTEREST
Guarantor of the article: Mentore Ribolsi, MD, PhD.
Specific author contributions: M.R.: planning and conducting the study, collecting and/or interpreting the data, and drafting the manuscript. M.P.L.G., P.B., A.A., and A.T.: drafting the manuscript. T.P.: data analysis. M.C.: planning and conducting the study and drafting the manuscript. Each author has approved the final draft submitted.
Financial support: None to report.
Potential competing interests: None to report.
WHAT IS KNOWN
- ✓ Chronic cough significantly impairs the quality of life, and the diagnosis of gastroesophageal reflux disease in cough patients is challenging.
- ✓ Response to adequate acid suppressive therapy is widely considered as unsatisfactory in chronic cough patients.
- ✓ Few data concerning the association between impedance-pH variables and proton pump inhibitor (PPI) response in these patients are available.
WHAT IS NEW HERE
- ✓ Novel variables increase the diagnostic yields of impedance-pH in detecting gastroesophageal reflux disease in chronic cough patients and predict PPI response.
- ✓ Pathological mean nocturnal baseline impedance or postreflux swallow-induced peristaltic wave, hiatal hernia, and hypomotility features are associated to PPI response.
- ✓ An up-front esophageal testing is useful in discriminating reflux-related cough patients and predicting PPI response.
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