Ribolsi M., Guarino M.P., Tullio A., Cicala M. Post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance predict PPI response in GERD patients with extra esophageal symptoms. Digestive and Liver Disease. 52 (2020) 173–177.

Авторы: Ribolsi M. / Guarino M.P. / Tullio A. / Cicala M.

Post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance predict PPI response in GERD patients with extra esophageal symptoms

Mentore Ribolsi*, Michele Pier Luca Guarino, Alessandro Tullio, Michele Cicala

Department of digestive diseases, Campus Bio Medico University, Rome, Italy

Аннотация на русском языке

Abstract

Background: Mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index are able to increase the diagnostic yield of impedance-pH and are associated to proton pump inhibitor (PPI) response. Few data concerning these variables in patients with extra-esophageal symptoms (EES) are available.

Aims: To evaluate, in EES patients, the role of the conventional and new impedance-pH variables in diagnosing GERD and the predictive value of impedance-pH variables for PPI response.

Methods: Consecutive patients presenting suspected GERD-related EES underwent impedance-pH. Patients treated in the last six months with double dose PPI therapy were enrolled. The presence of concomitant typical symptoms was assessed.

Results: 239 EES patients were studied; 102 responders and 137 non-responders. Eighty-one (34%) were affected by non-erosive reflux disease (NERD), 61 (26%) presented reflux hypersensitivity (RH) and 97 (40%) were non-GERD. In NERD and RH groups, a significantly higher proportion of patients with pathological PSPW index or MNBI values compared to non-GERD group was observed. 24 (25%) non-GERD patients presented a pathological PSPW index and/or MNBI. Pathological PSPW index, MNBI and presence of typical symptoms were associated to PPI response.

Conclusions: MNBI and PSPW index measurement increases the diagnostic yield of impedance-pH; abnormal values are associated with a satisfactory response to acid-suppressive therapy in EES patients.

Keywords: Extra-esophageal symptoms, GERD, pH-impedance, PPI

* Corresponding author. E-mail address: m.ribolsi@ unicampus.it (M. Ribolsi).

ht tps://doi.org/10.1016/j.dld.2019.09.011 1590-8658/© 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.

1. Introduction

Gastro-esophageal reflux disease (GERD) is defined by the presence of esophageal and extra-esophageal symptoms (EES) due to a real pathological reflux or to a non-pathological reflux perceived as abnormal and represents a common disease, with an increasing worldwide prevalence. In particular, Western Europe, North America and South America display the highest prevalence rates (20–40%) [[1], [2], [3], [4]]. In addition to the typical symptoms (heartburn, regurgitation and non-cardiac chest pain), GERD may be characterized by EES, including chronic cough, asthma, laryngitis, and hoarseness [1].

Patients presenting only with suspected GERD-related EES represent a challenging group. In these patients, due to the poor sensitivity of endoscopy and pH monitoring, an empiric trial with proton pump inhibitors (PPIs) might be considered as the initial diagnostic step. Traditionally, in patients who benefit from PPI therapy, GERD could be considered as the presumed etiology. On the other hand, in the majority of patients who result unresponsive to anti-secretory therapy, further diagnostic testing with ambulatory 24 h pH-metric or 24 h multichannel intraluminal impedance-pH (MII-pH) monitoring is necessary. It has been demonstrated that 55–79% of patients with chronic hoarseness display abnormal acid exposure at distal esophagus [5]. Moreover, in patients with EES unresponsive to an appropriate acid suppressive therapy, non-acid reflux, detected by MII-pH, may play a role in symptom generation [6,7]. Sifrim et al. have demonstrated a positive association between chronic cough and weakly acidic reflux in a subset of patients [8,9]. In addition to the traditional acid exposure time and symptom-reflux association indexes, novel MII-pH variables have been recently proposed. It has been shown that the mean nocturnal baseline impedance (MNBI) value and the post-reflux swallow-induced peristaltic wave (PSPW) index are able to increase the diagnostic yield of MII-pH monitoring [10]. MNBI is a measure of the baseline impedance, low values might be a consequence of reflux-induced impairment of mucosal integrity even in the absence of macroscopic damages and its value is inversely related to acid exposure time [11,12]. It has been demonstrated that PPI-responsive non-erosive reflux disease (NERD) patients, with normal conventional MII-pH findings, are characterized by lower values of MNBI compared to PPI-refractory [13]. PSPW index assesses the efficacy of esophageal chemical clearance and is able to discriminate GERD from non-GERD subjects as well as NERD patients from functional heartburn [10].

In patients with chronic cough, the presence of a pathological acid exposure at distal esophagus and/or of a pathological impedance baseline value is associated with a greater probability of PPI response [14]. Moreover, results from the same study demonstrate that impedance baseline measurement increases the diagnostic yield of MII-pH in patients with conventional MII-pH variables in the normal range. These new variables, however, have been so far mainly investigated in patients with typical GERD symptoms and only few data on patients with EES are available. Moreover, their relationship with PPI response has not been elucidated in patients with EES. Aim of the present investigation was, therefore, to evaluate the role of the conventional and new MII-pH variables, including MNBI and PSPW index, in diagnosing GERD in endoscopy negative patients with EES; moreover, the predictivity of all MII-pH variables for PPI response has been evaluated in these patients.

2. Study design

Consecutive patients presenting suspected GERD-related EES symptoms, attending our outpatients Unit from December 2015 to December 2018, who underwent upper endoscopy in the last year before the evaluation, were considered eligible. Patients with hiatal hernia >2 cm, erosive esophagitis (grade A, B, C, D according to Los Angeles classification) and Barrett esophagus were excluded. EES included chronic laryngitis, hoarseness, dysphonia, globus, chronic pharyngitis, chronic cough and asthma. Patients using angiotensin-converting enzyme inhibitors, and/or presenting with significant or recent respiratory tract infections were excluded. All patients underwent a general ear, nose and throat examination and fibrolaryngoscopy, patients with chronic cough were evaluated with spirometry and methacoline test. Patients with a diagnosis of postnasal drip syndrome were excluded. Smokers were excluded. All patients filled out a standardized questionnaire (Reflux Disease Questionnaire, RDQ) to evaluate the overlapping presence of typical GERD symptoms [15].

Finally, only patients treated in the last six months before the evaluation with a double dose of PPI (Esomeprazole 80 mg, Omeprazole 40 mg, Pantoprazole 80 mg, Lansoprazole 60 mg o.d. for at least 8 weeks) were enrolled. The response of EES to PPI treatment was retrospectively evaluated and considered as non-satisfactory if symptom improvement was <50%. Enrolled patients underwent esophageal high resolution manometry and 24 h ambulatory MII-pH monitoring. If patients were receiving empirical acid suppression therapy or antitussive drugs, this medication was stopped at least two weeks before the MII-pH monitoring. The study was approved by the local Ethic Committee and written informed consent was obtained from all individuals.

2.1. Esophageal high resolution manometry

A catheter with 36 circumferential solid state pressure sensors, located at 1-cm intervals (MMS, HRIM, Enschede, The Netherlands) was inserted, in fasting conditions, through an anesthetized nostril. The catheter was placed in the upright, seated position with at least 3 distal pressure sensors positioned in the stomach. The manometric study was performed, with 10 saline (5 ml) swallows, at 30-s intervals, in each individual, in a semi-recumbent position.

2.2. MII-pH monitoring

The MII-pH assembly (Sandhill Scientific, Highlands Ranch, CO, USA) was positioned with the pH electrodes placed 5 cm above the lower esophageal sphincter, according to high resolution manometry, and at gastric level. In this position, impedance was measured at 3, 5, 7, 9, 15 and 17 cm above the lower esophageal sphincter. MII-pH was always preceded by esophageal manometry to exclude motor disorders according to Chicago criteria v3.0 [16]. Patients were asked not to lie down during the daytime, but only at their usual bedtime and were instructed to have 3 meals and 2 beverages at fixed times. Tracings were manually analyzed for reflux episodes. Event markers recorded occurrence of symptoms, meal times and changes in posture.

2.3. Data analysis

Reflux events were detected and classified as liquid, mixed liquid-gas, and pure gas reflux episodes. Reflux episodes were classified as symptom-related if they occurred ≤2 min before the onset of the symptom. Symptom association probability (SAP) index was calculated according to described criteria [17]. Endoscopy negative patients with an acid exposure time (AET) >6% of total recording time or with an AET between 4% and 6% but presenting a total reflux number >80 episodes, were defined as having NERD; patients with positive SAP and with AET <4% or AET between 4% and 6% but presenting a total reflux number ≤80 episodes were reflux hypersensitivity (RH) patients; finally patients with both normal AET <6%, total reflux number ≤80 and SAP negative were classified as non-GERD patients [18]. A PSPW was defined as an antegrade 50% drop in impedance occurring within 30 s after a reflux event, starting in the most proximal impedance channel, reaching the most distal impedance channel, and followed by at least 50% return to the baseline. PSPW index was, therefore, obtained dividing the number of PSPWs by the total number of reflux events [19]. MNBI was assessed from the most distal impedance channel during night-time period. Three 10-min time periods (around 1.00 am, 2.00 am, and 3.00 am) were selected and the mean was calculated to obtain the MNBI; time periods including swallows, refluxes and pH drops were not considered [20]. According to previous published criteria, cut-off values for PSPW index and MNBI were 61% and 2292 Ω, respectively [21].

2.4. Statistical analysis

Data are expressed as mean ± standard deviation (SD). The comparisons of groups were assessed by means of Fisher’s exact tests. Group means were compared using ANOVA with Bonferroni correction. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) of MNBI, PSPW index, AET, SAP and presence of typical symptoms for predicting response to PPI in EES patients were calculated. Multivariate statistical analysis was performed, in order to assess, independently, the association between each MII-pH variable, presence of typical symptoms, and the PPI response. Significance was achieved when the p value was <0.05. Statistical analysis was performed using SPSS 16.0 software (SPSS Inc., Chicago, IL, USA).

3. Results

Of 344 eligible patients, 105 were excluded (57 smokers, 22 with A-B-C-D erosive esophagitis, 13 with post-nasal drip, 6 with absent contractility, 3 with distal esophageal spasm and 4 with outflow obstruction). Therefore, 239 EES patients were included in the study. The frequency of each EES in the studied population is depicted in Fig. 1. The majority of patients presented chronic cough, pharyngitis and globus; 91 out of the 239 patients (38%) also presented typical symptoms.

Fig. 1. Frequency of each EES in the studied population. The majority of patients presented chronic cough, pharyngitis and globus; 91 out of the 239 patients (38%) also presented typical symptoms.
EES: extra-esophageal symptoms.

Among the included patients, 102 (43%) were responders and 137 (57%) non-responders to previous PPI treatments. No significant differences were found between responders and non-responders in terms of mean age, sex and BMI. Among responders, the proportion of patients presenting also typical symptoms was significantly higher than that in non-responders. Demographic and clinical data are shown in Table 1.

Table 1.
Demographic and clinical characteristics in responder and non-responder patients.

	Responders (n. 102)	Non-responders (n. 137)
Male/female (n.)	48/54	61/76
Age (mean ± SD)	48 (±19.4)	51 (±21.3)
BMI (mean ± SD)	22.4 (±2.1)	23.1 (±1.9)
Presence of typical symptoms [n. (%)]	49 (48%)*	42 (31%)

BMI: body mass index. SD: standard deviation.
* p < 0.05.


3.1. High resolution manometry findings

According to high resolution manometry, among the 239 EES patients, 197 presented normal motility. Thirty-one of the remaining 42 patients presented diagnosis of ineffective esophageal motility and 11 patients showed evidence of fragmented peristalsis.

3.2. MII-pH data

Among 239 EES patients, 65 patients presented an AET value >6% and 16 patients an AET value between 4% and 6% and a total reflux number >80; therefore 81 (34%) patients were classified, according to MII-pH, as NERD. Sixty-one out of the 239 EES patient (26%) presented only a positive SAP for extra-esophageal symptom (RH patients). The remaining 97 EES patients (40%), having both negative AET and SAP, were finally classified as non-GERD patients. Forty-two out of 61 RH patients (69%) displayed a positive SAP for cough episodes. MII-pH data in the three patient groups are summarized in Table 2. Mean number of total reflux, mixed and proximal reflux were comparable among the three groups. NERD patients presented a significantly higher mean acid reflux number compared to RH and non-GERD patients.

Table 2.
MII-pH findings in NERD, RH and non-GERD patients.

	NERD patients (n. 81)	RH patients (n. 61)	Non-GERD (n. 97)
Reflux number (mean ± SD)	61.2 (±28)	54.4 (±20)	52.3 (±21)
Acid reflux (mean ± SD)	29 (±14)*	17 (±11)	14 (±9)
Mixed reflux (mean ± SD)	32 (±19)	28 (±15)	26 (±11)
Proximal reflux (mean ± SD)	34 (±14)	29 (±11)	27 (±9)
PSPW index (mean ± SD)	35 ± 7%	42 ± 9%	72 ± 12%*
Pathologic PSPW index [n. (%)]	68 (84%)*	44 (72%)*	21 (21%)
MNBI (mean ± SD)	1347 ± 214 Ω	1624 ± 287 Ω	2545 ± 324 Ω*
Pathologic MNBI [n. (%)]	71 (88%)*	37 (61%)*	12 (12%)

NERD: non-erosive reflux disease. RH: reflux hypersensitivity. GERD: gastro-esophageal reflux disease. PSPW: post-reflux swallow-induced peristaltic wave. MNBI: mean nocturnal baseline impedance. SD: standard deviation.
* p < 0.01.


In NERD and RH groups, a significantly higher proportion of patients with pathological PSPW index or MNBI values compared to non-GERD group (according to the traditional variables) was observed. Mean PSPW index and MNBI values were significantly lower in NERD and RH patients compared to non-GERD.

However, in the non-GERD group according to the traditional variables, 21 out of 97 (21%) patients presented a pathological PSPW and 12 out of 97 (12%) a pathological MNBI value. A total of 24 (25%) non-GERD patients presented a pathological PSPW index and/or MNBI value.

3.3. PPI response

Among the 239 EES patients, 102 were responders and 137 non-responders to previous PPI treatments. Mean number of total reflux episodes, mixed and proximal reflux were comparable between the two groups. Responder patients presented a significantly higher mean acid reflux number compared to non-responder patients.

Fifty-two out of 102 (51%) responder and 29/137 (21%) non-responder patients presented AET >6% or between 4–6% and a total reflux number >80 episodes (p < 0.001). Thirty-five out of 102 (34%) responder and 26/137 (19%) non-responder patients presented a positive SAP (p < 0.05). Fifty-five out of 102 responder (54%) and 36/137 non-responder patients (26%) presented concomitant typical GERD symptoms.

Responder patients showed significantly lower mean PSPW index and MNBI values compared to non-responders. Moreover, the proportion of patients displaying pathologic PSPW index or MNBI values was significantly higher in responders. Results are summarized in Table 3. Among the 24 non-GERD patients, defined according to the traditional variables but with a pathological PSPW index and/or MNBI, 20 (83%) were responders to previous PPI therapy.

Table 3.
MII-pH findings in responder and non-responder patients.

	Responders (n. 102)	Non-responders (n. 137)
Reflux number (mean ± SD)	54.5 (±19)	56.7 (±21)
Acid reflux (mean ± SD)	29 (±14)*	13 (±11)
Mixed reflux (mean ± SD)	29 (±19)	31 (±15)
Proximal reflux (mean ± SD)	31 (±14)	28 (±11)
PSPW index (mean ± SD)	28 ± 6%	69 ± 9%*
Pathologic PSPW index [n. (%)]	77 (75%)*	56 (41%)
MNBI (mean ± SD)	1218 ± 184 Ω	2414 ± 337 Ω*
Pathologic MNBI [n. (%)]	71 (70%)*	59 (43%)*

PSPW: post-reflux swallow-induced peristaltic wave. MNBI: mean nocturnal baseline impedance. SD: standard deviation.
* p < 0.01.


AET and SAP were more specific in predicting PPI response, whilst PSPW index and MNBI showed higher sensitivity. Patients with a pathological AET, SAP, PSPW index or MNBI as well as patients with concurrent typical symptoms showed a significantly increased probability of PPI response (Table 4).

Table 4.
Sensitivity, specificity, PPV, NPV and relative risk of PPI response in the studied population.

	Sensitivity	Specificity	PPV	NPV	Relative risk (95% CI)
Pathologic AET	51%	79%	64%	68%	2 (1.5–2.7)
SAP positive	34%	81%	57%	62%	1.5 (1.1–2)
Pathologic PSPW index	75%	59%	58%	76%	2.4 (1.7–3.6)
Pathologic MNBI	71%	57%	56%	73%	1.9 (1.4–2.7)
Presence of typical symptoms	54%	26%	60%	68%	1.9 (1.4–2.5)

AET: acid exposure time. SAP: symptom association probability. PPV: positive predictive value. NPV: negative predictive value. PSPW: post-reflux swallow-induced peristaltic wave. MNBI: mean nocturnal baseline impedance. SD: standard deviation.

4. Discussion

The present study was aimed at evaluating, in patients with EES, the value of the conventional (AET and SAP) and of new MII-pH metrics, i.e. PSPW index and MNBI in diagnosing GERD; to this purpose, the relationship of all these MII-pH variables as well as of the concomitant presence of typical symptoms, with the probability of PPI response was assessed. Indeed, unlike in patients with typical symptoms, an empirical PPI test in this subset of patients with extra-esophageal symptoms is known to be disappointing [27,28]. Efforts have been made to carefully select patients presenting with EES, with or without concomitant typical symptoms, who, soon before the referral, underwent upper endoscopy and an appropriate PPI course. Moreover, in attempt to better characterize EES patients, we have adopted the new classification, according to the recent MII-pH criteria emerged from the Lyon consensus [18].

In our series, according to MII-pH findings, among all endoscopy-negative EES patients, 81 (34%) were NERD, 61 (26%) were affected by RH and 97 (40%) were classified as non-GERD patients. The reflux patterns in these groups were evaluated. The mean number of total, mixed and proximal reflux episodes were comparable among the three groups. However, NERD patients presented a significantly higher mean number of acid reflux episodes compared to the other groups. Results reported herewith also show that, in EES patients, traditional MII-pH variables are able to detect GERD in 60% of cases, in agreement with other reports: abnormal esophageal acid exposure has been revealed, in fact, in 55–79% of patients with chronic hoarseness [5]; Baldi et al. found that 53% of their series of chronic cough patients had pathologic reflux [22]. Moreover, it has been demonstrated that half of patients with asthma may present abnormal reflux, detected at ambulatory pH monitoring [[23], [24], [25]]. It has to be borne in mind that, particularly in patients with chronic cough, the causal mechanism of symptoms is uncertain as cough may produce reflux itself.

Results emerging from our study also show that NERD and RH groups were characterized by a significantly higher proportion of patients with pathological PSPW index or MNBI values compared to the non-GERD group. Moreover, mean PSPW index and MNBI values were significantly lower in NERD and RH patients compared to non-GERD patients. To our knowledge, this is the first study aimed at evaluating these new MII-pH variables in a large cohort of patients with EES. Our results are in agreement with those emerging from the currently available literature in patients with typical symptoms. Frazzoni et al. have demonstrated that the mean PSPW index and MNBI are significantly lower in NERD and RH patients compared to FH patients [26]. Moreover, the mean PSPW index and MNBI values observed in that study were similar to those obtained in our NERD, RH and non-GERD patients. In our non-GERD group, defined according to the traditional parameters, 24/97 (25%) patients presented a pathological PSPW index and/or MNBI. Of interest, the proportion of patients with a diagnosis of GERD, based on the conventional and/or the new MII-pH variables, increases from 60% to 69%. This finding is in keeping with the results obtained in patients with typical symptoms, although, as expected, the diagnostic yield of MNBI and PSPW index in EES is lower than that reported in patients with heartburn or regurgitation [21].

According to our results, among the 239 EES patients, 102 (43%) were responders and 137 (57%) non-responders to previous optimal PPI treatments. The proportion of non-responders was similar to that observed in a meta-analysis focused on patients with chronic cough [27]. In our series, responders and non-responders did not differ in terms of age, sex and BMI. However, among responders, the proportion of patients presenting concurrent typical symptoms was significantly higher than that in non-responders (48% vs 31%, p < 0.05), being this finding in keeping with previous investigations [29,30]. It is conceivable that the presence of typical symptoms increases the probability of having acid-related GERD thus leading, in this subgroup of patients, to a more favorable response to acid-suppressive therapy.

In our series, mean number of total, mixed and proximal reflux episodes were comparable between responders and non-responders. However, responder patients presented a significantly higher mean number of acid reflux episodes compared to non-responder patients. Fifty-two out of 102 (51%) responder and 29/137 (21%) non-responder patients were classified as having NERD. Thirty-five out of 102 (34%) responder and 26/137 (19%) non-responder patients presented RH (p < 0.05). Of interest, PPI responder patients showed significantly lower mean PSPW index and MNBI values compared to non-responders. Finally, the proportion of patients displaying pathologic PSPW index or MNBI values was significantly higher in responders (75 and 70% versus 41 and 43%, respectively). Results reported herewith show that AET and SAP are more specific in predicting PPI response, whilst PSPW index and MNBI show higher sensitivity. Moreover, a pathological AET, SAP, PSPW index or MNBI, independently, as well as the presence of concomitant typical symptoms, predict an increased probability of PPI response. Interestingly, the large majority of patients with normal AET and SAP but pathological MNBI and/or PSPW index values presented a satisfactory response to previous PPI therapies.

The new message emerging from the present study is that, in patients with predominant EES, MNBI and PSPW index are sensitive predictors of PPI response. This finding is in agreement with a study performed by Frazzoni et al., showing that, in patients with heartburn, AET, PSPW index and MNBI are independently associated with PPI-response and that PSPW index and MNBI are more strongly associated than AET to a favorable PPI response [13].

To our knowledge, this is the first study evaluating, in a large series of EES patients, the role of the new MII-pH metrics and their association with PPI response. Strengths of the present study are the number of patients included and their selection. However, this study is hampered by some limitations: PPI response has been evaluated retrospectively, moreover, it is well known that patients with EES represent a heterogeneous groups, including both patients with GERD and with different mechanisms of symptom generation. Moreover, the reliability of SAP in detecting a relationship between EES and reflux episodes still needs to be prospectively validated. Finally, the Lyon consensus classification is mainly based on patients with typical symptoms, and its use in patients with EES in questionable.

In summary, the present study demonstrates that the MII-pH variables, both conventional and new, are associated with a satisfactory response to acid-suppressive therapy in patients with EES. MNBI and PSPW index are able to increase the diagnostic yield of MII-pH, and their measurement is suggested in these patients, particularly when AET and SAP are in the normal range. Patients with all MII-pH variables in the normal range should be considered as not having GERD. These findings encourage to perform MII-pH in the diagnostic work-up of EES patients, and to consider an appropriate PPI treatment not only for patients with a proven GERD according to conventional MII-pH variables, but also for patients with pathologic values of PSPW index and MNBI.

Conflict of interest
None declared.

Guarantor of the article
Mentore Ribolsi.

Acknowledgemente
Authors are grateful to Mrs Marian Shields for help with the English style.

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