SEARCH

SEARCH BY CITATION

Keywords:

  • 24-h pharyngo-esophageal impedance and pH monitoring;
  • chronic cough;
  • gastro-esophageal reflux disease;
  • swallowing-induced pharyngeal reflux;
  • weakly acidic pharyngeal gas reflux

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

Background  Gastro-esophageal reflux disease (GERD)-related chronic cough (CC) may have multifactorial causes. To clarify the characteristics of esophagopharyngeal reflux (EPR) events in CC patients whose cough was apparently influenced by gastro-esophageal reflux (GER), we studied patients with CC clearly responding to full-dose proton pump inhibitor (PPI) therapy (CC patients).

Methods  Ten CC patients, 10 GERD patients, and 10 healthy controls underwent 24-h ambulatory pharyngo-esophageal impedance and pH monitoring. Weakly acidic reflux was defined as a decrease of pH by >1 unit with a nadir pH >4. In six CC patients, monitoring was repeated after 8 weeks of PPI therapy. The number of each EPR event and the symptom association probability (SAP) were calculated. Symptoms were evaluated by a validated GERD symptom questionnaire.

Key Results  Weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR only occurred in CC patients, and the numbers of such events was significantly higher in the CC group than in the other two groups (P < 0.05, respectively). Symptom association probability analysis revealed a positive association between GER and cough in three CC patients. Proton pump inhibitor therapy abolished swallowing-induced acidic/weakly acidic EPR, reduced weakly acidic gas EPR, and improved symptoms (all P < 0.05).

Conclusions & Inferences  Most patients with CC responding to PPI therapy had weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR. A direct effect of acidic mist or liquid refluxing into the pharynx may contribute to chronic cough, while cough may also arise indirectly from reflux via a vago-vagal reflex in some patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

Many aerodigestive tract conditions are thought to be associated with gastro-esophageal reflux disease (GERD) and have been referred to as supraesophageal complications of GERD,1 but the cause-and-effect relationship between these conditions and GERD remains controversial. For example, many studies have shown that patients with reflux laryngitis, i.e., chronic laryngitis caused by gastro-esophageal reflux (GER), have significantly increased esophagopharyngeal reflux (EPR) on 24-h esophagopharyngeal pH monitoring, although some studies did not detect such an increase.2–6 Moreover, some normal subjects also displayed EPR in these studies and the normal range of EPR on pharyngeal pH monitoring has not yet been established. Recently, Kawamura et al.7 demonstrated by 24-h pharyngo-esophageal impedance and pH monitoring that weakly acidic gas EPR is significantly increased in patients with reflux laryngitis. Reflux of acidic mist from the stomach into the pharynx may be detected as weakly acidic gas EPR that causes pharyngeal injury.8 However, the laryngeal findings associated with reflux laryngitis are also controversial. Contact ulcers, nodules, granulomas, erythema, and edema of the larynx have been reported as features of reflux laryngitis,9,10 but erythema and edema can also be found in normal healthy volunteers.11 Therefore, there is a risk of overdiagnosing reflux laryngitis that could result in a poor response to acid suppression therapy.12,13 Reflux laryngitis may have multifactorial causes, i.e., not only GERD, but also laryngeal injury secondary to smoking, excessive alcohol intake, allergies, asthma, viral infections, or vocal abuse.14

Chronic cough (CC), i.e., cough lasting more than 8 weeks, is one of the most common symptoms of reflux laryngitis. Chronic cough has more than 30 known causes15 and GERD is one of the most common,16–18 but it is difficult to diagnose GERD-related CC accurately. Gastro-esophageal reflux disease-related CC may also have multiple causes and it has been reported that more than 50% of CC patients had cough due to GERD plus another cause,19 whereas only 35–57% of patients with GERD-related CC respond to proton pump inhibitor (PPI) therapy.20,21 In addition to acidic GER, weakly acidic and non-acidic GER can also elicit cough, so therapy directed solely at acid suppression might not improve GERD-related cough.22,23 Sifrim et al.23 studied the relationship between GER and cough in 22 CC patients using 24-h simultaneous ambulatory pressure, pH, and impedance monitoring. They identified a subgroup of patients with CC that was clearly associated with weakly acidic GER. This study included patients with CC that had clearly responded to PPI therapy, and we performed 24-h pharyngo-esophageal impedance and pH monitoring in order to clarify the characteristics of EPR events in CC patients whose cough was apparently influenced by GER.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

This study included 10 patients with CC responding to PPI therapy aged 49.0 ± 16.2 years (range: 24–74 years; three women and seven men: CC group), 10 GERD patients without signs or symptoms in the aerodigestive tract aged 42.9 ± 17.6 years (range: 20–73 years; two women and eight men: GERD group), and 10 healthy controls aged 32.2 ± 15.3 years (range: 22–72 years; four women and six men: control group). All subjects underwent 24-h simultaneous ambulatory pharyngo-esophageal impedance and pH recording. Patients were recruited from the outpatient clinic of the Department of Gastroenterology at Gunma University Hospital, while the healthy controls were recruited via advertisement. The CC patients were all referred to our department with the chief complaint of CC that had not responded to therapy for respiratory and/or ENT diseases. They were referred because of suspected GERD-related CC and were enrolled in this study consecutively. In all 10 CC patients, cough resolved after full-dose PPI therapy and recurred after cessation of PPI therapy. The GERD patients had suffered from heartburn at least once a week on average for the last 3 months or had erosive reflux esophagitis on endoscopic examination.24 This study was approved by the Institutional Review Board of Gunma University Hospital. Written informed consent was obtained from all subjects and the study was performed in conformity with the Declaration of Helsinki.

All subjects underwent upper gastrointestinal endoscopy. In the GERD group, the Los Angeles classification was grade B, A, or M in one, six, and three patients, respectively. According to the modified Los Angeles classification, grade M (minimal change) is defined as ‘erythema without sharp demarcation, whitish turbidity, and/or invisibility of vessels’.25 In the CC group, the classification was grade D, B, A, or M in one, one, four, and four patients, respectively. All of the healthy controls had normal endoscopic findings and no symptoms. None of the subjects had a history of gastrointestinal surgery. In six CC patients and seven GERD patients, these studies were performed before starting initial PPI therapy. In the remaining four CC patients (Cases 1, 5, 6, and 7 in Table 1) and three GERD patients, these studies were performed after suspending acid suppression therapy for at least 1 week. As PPI therapy for the CC group, omeprazole (20 mg day−1) was administered to four patients, rabeprazole (20 mg day−1) was given to four patients, and lansoprazole (30 mg day−1) was used for two patients. They all received the standard doses recommended in Japan.

Table 1.   Number of weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR events and the results of SAP analysis in each patient from the CC group
Case no.Age (year)GenderWeakly acidic gas EPRSwallowing-induced EPRSAP
AcidicWeakly acidicTotal
  1. EPR, esophagopharyngeal reflux; SAP, symptom association probability; CC, chronic cough.

 167F2000+
 243M3336
 356M2011
 449M2011
 563F3101
 646M0000+
 774M0213
 829M2011+
 939M1101
1024F6404

Just before performing manometry and 24-h monitoring, the symptoms of each subject were evaluated with the frequency scale for the symptoms of GERD (FSSG), which is a specific questionnaire for GERD that was developed in Japan and consists of 12 questions.26 Question 7 is related to supraesophageal symptoms and asks, ‘Do you have an unusual (e.g., burning) sensation in your throat?’ If the total score for the questionnaire was ≥8, GERD was diagnosed. This questionnaire is also useful for evaluating the response of GERD patients to treatment.

Impedance was recorded with a combined impedance and pH probe (Model ZAI-S62C12E, 13E, 14E; Sandhill Scientific Inc., Highlands Ranch, CO, USA) (Fig. 1). Before the study, the pH electrodes were calibrated with buffer solutions of pH 4.0 and 7.0. The probe was connected to an ambulatory data acquisition unit (Sleuth System; Sandhill Scientific Inc.), and the sampling frequency of both impedance and pH data was set at 50 Hz.

image

Figure 1.  Schematic representation of the short recording probe. In the short probe, the interval between the pharyngeal and esophageal pH sensors is 17 cm. When the pharyngeal pH sensor is placed 1 cm above the upper margin of the UES in a subject with an esophagus of 21 cm in length (interval between the upper margin of the UES and the LES), the esophageal pH sensor will be located exactly 5 cm above the upper margin of the LES. The interval between the pharyngeal and esophageal pH sensors in the medium and long probes is 20 cm and 23 cm, respectively. The short probe is used for an esophagus with a length of 20–22 cm, the medium probe is for an esophagus of 23–25 cm, and the long probe is for an esophagus of 26–28 cm. The interval between the impedance electrodes is 1.5 cm in the pharynx and 2 cm in the esophagus. Therefore, pharyngeal impedance was measured 1 and 2.5 cm above the upper margin of the UES and esophageal impedance was measured at 3, 5, 7, and 9 cm (within ±1 cm) above the upper margin of the LES.

Download figure to PowerPoint

Twenty-four-hour simultaneous ambulatory pharyngo-esophageal impedance and pH recording was started after fasting for at least 5 h. Esophageal manometry was employed to determine the location of the upper esophageal sphincter (UES) and the lower esophageal sphincter (LES). The probe was chosen depending on the length of the esophagus and was inserted transnasally under topical anesthesia (2% xylocaine jelly; AstraZeneca K.K., Osaka, Japan) and was fixed to the subject’s nose with tape so that the pharyngeal pH sensor was located 1 cm above the upper margin of the UES and the esophageal pH sensor was 5 cm above the LES (within ±1 cm). The position of the probe was confirmed by fluoroscopy. It was also confirmed that the pharyngeal pH sensor did not enter the esophagus on swallowing.

During the 24-h ambulatory study, subjects performed their usual activities and could eat without restriction. They were instructed to press the event marker on the data recorder for meals, body position changes, and symptoms (such as coughing, belching, heartburn, and regurgitation).

After monitoring was completed, data were transferred to a personal computer and manually analyzed with BioView Version 5.1.0 software (Sandhill Scientific Inc.) by an investigator who was blinded to each subject’s name and group. Meal times were excluded from data analysis.

Changes of impedance corresponding to GER events were defined from the results of previous human studies.7,27–29 Criteria for identifying EPR events from impedance changes have been reported previously.7,8 A liquid EPR event was defined as a decrease of impedance by ≥50% from baseline and to <1200 Ω preceded by or concurrent with an esophageal liquid reflux event. Gas EPR was defined as an abrupt increase of impedance occurring simultaneously or almost simultaneously (±1 s from the proximal esophageal impedance change) with a proximal esophageal gas or mixed reflux event. Mixed EPR was defined as a combination of the gas and liquid patterns.

When pharyngeal pH data were assessed, an acidic reflux event was defined as a decrease of pH from above 4 to below 4 preceded by or concurrent with a decrease in esophageal pH to below 4.4 A weakly acidic pharyngeal reflux event was defined as a decrease of pH by >1 pH unit with a nadir pH >4 preceded by or concurrent with a decrease of esophageal pH by at least 1 unit. Non-acid pharyngeal reflux was defined as a pH change of less than 1 pH unit.

In six CC patients, 24-h monitoring and the FSSG questionnaire were repeated while on PPI therapy after 8 weeks of full-dose PPI treatment.

Results are presented as the mean ± standard error (SE), unless stated otherwise. Reflux events in the pharynx, mid esophagus (9 cm above the LES), and distal esophagus (5 cm above the LES) were compared among the groups. Reflux events were also stratified by whether subjects were upright or recumbent at the time of the event. Analysis of variance (anova), followed by multiple pairwise comparisons with Tukey’s correction or the Holm–Sidak method, was employed to assess differences in the number of reflux events among the three groups. When a non-parametric test was appropriate, the Kruskal–Wallis test was employed, followed by Tukey’s multiple pairwise comparison test. The paired t-test and Wilcoxon signed rank test were employed to compare data between subjects on and off PPI therapy. When a non-parametric test was used, results are presented as the median with the range in parenthesis. In all analyses, < 0.05 was considered to indicate statistical significance. In the CC group, symptom association probability (SAP) analysis with 2-min time window was performed to assess the relationship between GER and cough events identified by the event marker.23

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

Pharyngeal reflux events

Reflux events detected from impedance and pH changes  In all subjects, only gas EPR was observed in the pharynx. In the GERD, CC, and control groups, there were 28.9 ± 4.8, 33.1 ± 6.5, and 20.5 ± 5.0 gas EPR events during the 24-h recording period, respectively, with no significant differences among the groups. Acidic gas EPR was not detected in any subject. Weakly acidic gas EPR was only observed in the CC group. The number of such events in the GERD, CC, and control groups was 0 (0–0), 2 (1–6), and 0 (0–0), respectively, being significantly higher in the CC group (P < 0.05, Fig. 2). The number of non-acidic gas EPR events in the GERD, CC, and control groups was 28.0 (8–52), 28.5 (11–74), and 16.5 (3–53), respectively, showing no significant difference among the three groups. A representative example of recordings from the combined impedance and pH probe indicating weakly acidic gas EPR is shown in Fig. 3.

image

Figure 2.  Comparison of the number of weakly acidic (A) and non-acidic (B) gas EPR events among the CC group, GERD group, and control group. (A) There was a significantly greater number of weakly acidic gas EPR events in the CC group [2 (1–6)] than in the GERD group [0 (0–0)] or the control group [0 (0–0)] (P < 0.05). (B) There was no significant difference in the number of non-acidic gas EPR events among the three groups. Bars represent median values. CC: chronic cough, GE: GERD, C: control.

Download figure to PowerPoint

image

Figure 3.  Weakly acidic gas EPR during acidic esophageal mixed reflux in a patient with chronic cough. A diagram of the recording probe is shown on the left. The distal esophageal pH and pharyngeal pH began to decrease almost simultaneously, but the nadir pharyngeal pH did not reach 4, unlike the esophageal pH (short arrows). Esophageal impedance decreased by more than 50% and the change was propagated in the retrograde direction, signifying liquid reflux (horizontal bars), which was preceded by an abrupt increase in impedance signifying gas reflux (arrowheads). Pharyngeal impedance also increased abruptly, signifying gas reflux (arrowheads).

Download figure to PowerPoint

A total of 21 weakly acidic pharyngeal gas EPR events were observed in the CC group, including 16 events that occurred during acidic mixed reflux in the distal esophagus, four events during weakly acidic esophageal gas reflux, and one event during weakly acidic esophageal mixed reflux. Seventeen events (81%) were associated with a belch event marker. Nineteen of the 21 weakly acidic gas EPR events occurred in the upright position during the postprandial period [12–220 min (mean: 91 min, median: 66 min) after the previous meal].

Reflux events detected by pH changes alone  In the CC group, 18 EPR events were only detected from pH changes. The decrease in pH always coincided with swallowing that was confirmed by pharyngeal impedance changes (swallowing-induced EPR), and these events always occurred during acid liquid or mixed reflux in the mid esophagus. From the onset of the decrease in pharyngeal pH, both pharyngeal impedance values also began to fall to approximately 0 Ω, with upper pharyngeal impedance starting to decline slightly earlier. These changes were brief and were always followed by esophageal clearance, suggesting that these impedance changes were related to swallowing. A pattern of liquid EPR was not detected by monitoring impedance changes during these events. Eleven of the 18 events involved acidic reflux (Figs 4A and S2) and the other seven events involved weakly acidic reflux (Figs 4B and S3). All events occurred in the upright position during the postprandial period from 2 to 200 min (mean: 74 min; median: 64 min) after the previous meal. These events were never observed in the GERD and control groups, but occurred in eight of the CC patients. The number of events was significantly higher in the CC group [1 (0–6)] than in the GERD group [0 (0–0)] or the control group [0 (0–0)] (P < 0.05).

image

Figure 4.  Swallowing-induced acidic EPR (A) and weakly acidic EPR (B) during acidic esophageal liquid reflux in a patient with chronic cough. During both events, the changes in esophageal impedance indicate reflux of liquid (horizontal bars) that is acidic (short arrow). At both pharyngeal sites, impedance decreased to around 0 Ω, with the decline starting slightly earlier at the upper sensor. These changes were brief and were always followed by esophageal clearance, suggesting that these impedance changes were related to swallowing (arrowhead). Simultaneously, with the decrease in pharyngeal impedance, pharyngeal pH started to decline (arrowhead) due to acidic reflux (A) or weakly acidic reflux (B), but the pharyngeal impedance data did not show any evidence of liquid reflux. After these two events, the subject pressed the event marker for regurgitation.

Download figure to PowerPoint

Weakly acidic gas EPR events and swallowing-induced EPR events detected in each patient in the CC group are listed in Table 1. Eight patients (Cases 1–5, 8–10) had weakly acidic gas EPR, and eight (Cases 2–5, 7–10) showed acidic and/or weakly acidic swallowing-induced EPR. Thus, a total of nine patients displayed acidic and/or weakly acidic EPR events, while one patient had pure non-acidic gas EPR.

Relationship between GER and cough

The patient with pure non-acidic gas EPR (Case 6 in Table 1) showed a positive association between GER and cough on SAP analysis, as did two other patients (Cases 1 and 8). These three patients predominantly had cough induced by reflux. Cough only occurred during acidic esophageal reflux in Case 1, during both weakly acidic and non-acidic esophageal reflux in Case 6, and during both acidic and weakly acidic esophageal reflux in Case 8. In Cases 1 and 6, reflux-induced cough mainly occurred in the upright position during the postprandial period. In Case 8, reflux-induced cough occurred in the upright position during the interdigestive period.

Evaluation of symptoms by the FSSG

The total FSSG score of the GERD, CC, and control groups was 11.2 ± 1.6, 11.1 ± 1.7, and 5.2 ± 2.4, respectively, showing no significant differences. The score for Question 7 was 0.5 ± 0.2, 1.9 ± 0.5, and 0.1 ± 0.1, respectively, being significantly higher in the CC group than in the other two groups (P < 0.05).

Reflux events in the distal esophagus

Reflux events occurring in the mid and distal esophagus are summarized in Table 2. Reflux events affecting the distal esophagus tended to be more frequent in the GERD and CC patients than in the controls (P = 0.054). Mixed reflux events, acidic reflux events, and acidic mixed reflux events were all significantly more frequent in the GERD and CC patients than in the controls (all P < 0.05). Most reflux events occurred in the upright position. The median percentage of reflux events that occurred in the upright position was of 89% (69–100%) in the GERD group, 96% (81–100%) in the CC group, and 99% (71–100%) in the control group (P = 0.093).

Table 2.   Reflux events of each type and each level of acidity in the mid and distal esophagus
 Mid esophagusDistal esophagus
GERDCCControlP-valueGERDCCControlP-value
  1. Data are presented as mean ± SE. For non-parametric data, the median (range) in addition to the mean ± SE is shown.

  2. *GERD vs control; CC vs control and GERD vs control.

  3. CC, chronic cough; GERD, gastro-esophageal reflux disease.

Total63 ± 1154 ± 6733 ± 6<0.05*71 ± 1458 ± 737 ± 60.054
 Acidic26 ± 427 ± 66 ± 2<0.0529 ± 430 ± 77 ± 2<0.05
 Weakly acidic8 ± 29 ± 29 ± 20.9499 ± 310 ± 310 ± 20.983
 Non-acidic29 ± 1018 ± 418 ± 50.77933 ± 1218 ± 420 ± 50.725
14.5 (6–103)14 (7–39)15 (4–58)16.5 (6–123)14.5 (7–39)18 (4–58)
Mid/distal ratio (%)91 ± 294 ± 288 ± 30.203    
Liquid21 ± 1113 ± 44 ± 10.22530 ± 1417 ± 58 ± 20.205
 Acidic7 ± 29 ± 31 ± 0.50.05411 ± 311 ± 42 ± 0.80.063
 Weakly acidic3 ± 12 ± 11 ± 0.40.9744 ± 23 ± 12 ± 0.60.863
0.5 (0–12)1 (0–9)1 (0–3)2 (0–15)1 (0–12)1 (0–5)
 Non-acidic11 ± 82 ± 0.52 ± 0.90.49615 ± 102 ± 0.74 ± 10.569
1.5 (0–86)1.5 (0–5)0 (0–8)2.5 (0–105)1.5 (0–7)3 (0–9)
Gas22 ± 521 ± 422 ± 40.99216 ± 416 ± 420 ± 40.765
 Acidic4 ± 13 ± 12 ± 0.70.0640.2 ± 0.10.4 ± 0.20.4 ± 0.40.612
3.5 (0–11)3 (0–11)0.5 (0–7)0 (0–1)0 (0–2)0 (0–4)
 Weakly acidic2 ± 0.64 ± 16 ± 10.1083 ± 0.85 ± 26 ± 10.220
 Non-acidic15 ± 414 ± 314 ± 30.98313 ± 412 ± 313 ± 30.942
10.5 (3–44)9 (5–36)14 (4–36)8.5 (3–38)9 (5–29)13.5 (4–31)
Mixed20 ± 320 ± 37 ± 2<0.0526 ± 425 ± 410 ± 3<0.05
 Acidic14 ± 215 ± 34 ± 1<0.0518 ± 318 ± 35 ± 2<0.05
 Weakly acidic3 ± 22 ± 0.71 ± 0.60.5233 ± 23 ± 12 ± 0.70.666
1 (0–15)2 (0–7)0 (0–5)1.5 (0–18)2.5 (0–10)1.5 (0–6)
 Non-acidic3 ± 12 ± 0.62 ± 10.5285 ± 14 ± 13 ± 20.381
2.5 (0–11)3 (0–4)1 (0–14)3.5 (0–13)3.5 (0–10)1.5 (0–19)

In the GERD, CC, and control groups, there were 15.4 ± 5.4, 19.7 ± 4.8, and 14.8 ± 4.6 reflux events associated with a belch event marker, respectively (P = 0.748). These were always mixed or gas reflux events, with mixed reflux events being more common in the GERD and CC groups than in the controls (57.6 ± 7.3% and 62.9 ± 8.8%vs 34.6 ± 8.9%, P = 0.062).

Reflux events in the mid esophagus

In the mid esophagus, reflux events were significantly more frequent in the GERD patients than in the controls (P < 0.05), while mixed reflux events were significantly more frequent in the GERD and CC patients than in the controls (P < 0.05). Assuming that the acidity of the refluxate was the same in the distal and mid esophagus, acidic reflux events and acidic mixed reflux events were significantly more frequent in the GERD and CC groups than in the controls (all P < 0.05). The ratio of the number of mid to distal esophageal reflux events did not show any significant differences among the three groups.

The distribution of reflux events with different physical properties along the esophagopharyngeal axis is shown in Figure S1 for all groups.

pH changes in the distal esophagus

The mean percentage of time in the 24-h monitoring period during which the distal esophageal pH was <4.0 was 4.1% (1.1–17.2%) in the GERD group, 2.0% (0.06–15.2%) in the CC group, and 0.3% (0–1.2%) in the control group. The acid exposure time was significantly longer in the GERD and CC groups than in the controls (P < 0.05).

Effects of PPI therapy in the CC group

Proton pump inhibitor therapy abolished swallowing-induced acidic and/or weakly acidic EPR in the six patients in the CC group, and significantly reduced the number of weakly acidic gas EPR events compared with the respective number off PPI therapy (1.3 ± 0.5 vs 0.3 ± 0.3, P < 0.05). Both the total FSSG score and the score on Question 7 after 8 weeks of PPI therapy were significantly lower than the respective scores off therapy (12.3 ± 2.3 vs 2.3 ± 1.1 and 2.2 ± 0.6 vs 1.7 ± 0.6, both P < 0.05). Simultaneous improvement of EPR and symptoms during PPI therapy suggested a close relationship between these symptoms and reflux events. The number of total reflux events in the mid and distal esophagus was not significantly different between the periods off and on PPI therapy. Proton pump inhibitor therapy significantly reduced the number of acidic mixed reflux events in the distal esophagus (from 15.5 ± 4.3 to 6.0 ± 3.1, P < 0.05), and significantly increased the number of non-acidic mixed reflux events in the mid esophagus (from 2.7 ± 0.8 to 5.8 ± 1.5, P < 0.05). Proton pump inhibitor therapy reduced the percentage of time at a pH <4.0 in the distal esophagus [from 2.0% (0.06–15.2%) to 0.03% (0–1.6%), P = 0.094].

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

One explanation for the poor response of GERD-related CC or reflux laryngitis to acid suppression therapy is that the symptoms of these patients have multiple causes. This study revealed the effect of one of these factors, i.e., acidic or weakly acidic EPR, in patients who were presumed to have GERD-related CC because they responded well to PPI therapy.

Shaker et al.30 reported that there were three mechanisms of EPR: (i) transient complete UES relaxation after belching (a major mechanism), (ii) spontaneous EPR associated with a low residual UES pressure, and (iii) swallowing when the esophagus contains residual acid. The first mechanism may explain the weakly acidic gas EPR events observed in this study, as all such events occurred during esophageal reflux of the gastric contents that included gas and 17 (81%) out of 21 events were accompanied by a belch event marker. In this study, acidic and weakly acidic EPR events were also caused by swallowing [mechanism no. (iii)]. It is unclear why swallowing-induced EPR events were only observed in the CC group, but reflexes such as the pharyngo-UES or laryngo-UES contractile reflex may have been impaired in these patients. The pharyngo-UES contractile reflex involves contraction of the UES after injection of a tiny volume of water into the pharynx, while the laryngo-UES contractile reflex involves UES contraction induced by puffing air onto the larynx. Such reflexes may be activated by pharyngeal or laryngeal reflux of gastric and/or esophageal contents, increasing the UES pressure and possibly preventing further entry of refluxate. Both reflexes are thought to be impaired in patients with supraesophageal complications of GERD,31,32 which may lead to refluxate entering the hypopharyngeal space during swallowing.

Among our 10 CC patients, nine had weakly acidic gas EPR events and/or swallowing-induced acidic/weakly acidic EPR events, while only one displayed pure non-acidic EPR events. Regarding the possible mechanisms by which reflux causes cough, two hypotheses have been suggested, including microaspiration of refluxate into the respiratory tract (direct effect) and stimulation of a vago-vagal reflex known as the esophageal-tracheobronchial cough reflex (indirect effect).33 Therefore, direct injury to the pharynx due to reflux of acidic/weakly acidic gastric contents may have caused CC in nine of our 10 CC patients. The one patient with pure non-acidic EPR events showed a positive association between GER and cough on SAP analysis, suggesting that this patient’s symptoms arose indirectly from reflux via a vago-vagal reflex. In two other patients, symptoms may have been caused by both the direct and indirect effects of reflux. This is possibly the first study to demonstrate that both direct and indirect effects of reflux can be associated with CC.

Direct injury to the pharynx by acidic refluxate is traditionally thought to occur in the recumbent position at night when the basal UES pressure is lower. In this study, however, acidic and/or weakly acidic EPR mainly occurred in the upright position during the postprandial period. Therefore, direct pharyngeal injury may take place postprandially in the upright position at the time when GER is most frequent.

Kawamura et al.7 performed ambulatory 24-h pharyngo-esophageal impedance and pH monitoring in patients with reflux laryngitis, GERD patients without signs or symptoms of aerodigestive disease, and healthy controls, and reported that the number of weakly acidic gas EPR events was significantly increased in the patients with reflux laryngitis. However, they also observed weakly acidic gas EPR in some GERD patients and controls, unlike our results. This difference could be related to the subject selection criteria, as patients with CC responding to PPI therapy may be more likely to have pharyngeal reflux than those with laryngoscopically diagnosed reflux laryngitis.

Sifrim et al.23 studied 22 patients with CC by ambulatory 24-h esophageal pressure/pH/impedance monitoring, and performed SAP analysis to assess the relationship between GER and cough.34,35 They used manometry for objective recognition of cough and concluded that CC was clearly associated with weakly acidic GER in a subgroup of patients. In this study, three patients showed a positive association on SAP analysis and cough occurred during weakly acidic GER in two of these three patients, so it can be suggested that weakly acidic GER plays an important role in some patients with CC, although we used the event marker for detection of cough and this method is subjective.

The proximal extent of reflux in GERD patients with supraesophageal complications is also controversial. Jacob et al.36 reported significantly more exposure of the proximal esophagus to acid in patients with reflux laryngitis, whereas Cool et al.37 did not find more frequent supraesophageal symptoms in patients who had abnormal proximal acid reflux. In this study, we did not perform impedance monitoring in the proximal esophagus, and the ratio of reflux events in the mid esophagus did not differ significantly between the CC group and the other two groups. In both the CC and GERD groups, we found significantly greater numbers of acidic mixed reflux events affecting the distal and mid esophagus than in the control group. The significant decrease in the number of acidic mixed reflux events in the esophagus with PPI therapy also supports their role as a cause of CC. Acidic mixed reflux is thought to mainly represent belching of gas with some acidic liquid, and the percentage of mixed reflux events associated with a belch event marker was higher in our GERD and CC groups than in the controls. Although there was no significant difference in the number of esophageal acidic mixed reflux events between the GERD and CC groups, EPR was only observed in the CC group. The association of EPR with cough among the CC patients may be related to differences in the extent of reflux into the proximal esophagus or differences in UES function (including impairment of reflexes).

During swallowing-induced pharyngeal reflux, the impedance electrodes failed to detect reflux of liquid contents, even though these electrodes were set at a lower position and the interval between electrodes was smaller in this study than in the previous study of Kawamura et al.7 in which the lower pharyngeal impedance couplet was located 2 cm above the upper margin of the UES and the electrodes in the pharynx were spaced at 2-cm intervals. This may have been due to limitations of the pharyngeal impedance sensor. Impedance must be measured by two electrodes separated by an interval of 1.5 cm, while pH can be measured with a single sensor. Moreover, the pharynx is wider than the distal esophagus, so more refluxate is needed for detection by impedance changes compared with pH changes.

In conclusion, ambulatory 24-h concurrent pharyngo-esophageal impedance and pH monitoring revealed that most patients with CC responding to PPI therapy had weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR into the pharynx, which mainly occurred during the postprandial period in the upright position. The cause of CC in most of our CC patients was suggested to be a direct effect of acidic mist or acidic liquid refluxing into the pharynx, while symptoms may also arise indirectly from reflux via a vago-vagal reflex in some patients. These results should be further confirmed by a placebo controlled trial. Furthermore, EPR should be studied in patients with CC not responding to PPI, in order to expand our understanding of the role of these events in chronic cough.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

YS, HH, SK, MM, AN, HZ, and MK participated in the study design, data collection, and data analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information
  • 1
    Hogan WJ, Shaker R. Medical treatment of supraesophageal complications of gastroesophageal reflux disease. Am J Med 2001; 111: 197S201S.
  • 2
    Wiener GJ, Koufman JA, Wu WC, Cooper JB, Richter JE, Castell DO. Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-h ambulatory pH monitoring. Am J Gastroenterol 1989; 84: 15038.
  • 3
    Katz PO. Ambulatory esophageal and hypopharyngeal pH monitoring in patients with hoarseness. Am J Gastroenterol 1990; 85: 3840.
  • 4
    Shaker R, Milbrath M, Ren J et al. Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis. Gastroenterology 1995; 109: 157582.
  • 5
    Ulualp SO, Toohill RJ, Hoffmann R, Shaker R. Pharyngeal pH monitoring in patients with posterior laryngitis. Otolaryngol Head Neck Surg 1999; 120: 6727.
  • 6
    Shaker R, Bardan E, Gu C, Kern M, Torrico L, Toohill R. Intrapharyngeal distribution of gastric acid refluxate. Laryngoscope 2003; 113: 118291.
  • 7
    Kawamura O, Aslam M, Rittmann T, Hofmann C, Shaker R. Physical and pH properties of gastroesophagopharyngeal refluxate: a 24-hour simultaneous ambulatory impedance and pH monitoring study. Am J Gastroenterol 2004; 99: 100010.
    Direct Link:
  • 8
    Kawamura O, Bajaj S, Aslam M, Hofmann C, Rittmann T, Shaker R. Impedance signature of pharyngeal gaseous reflux. Eur J Gastroenterol Hepatol 2007; 19: 6571.
  • 9
    Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991; 101(Suppl. 53): 178.
  • 10
    Book DT, Rhee JS, Toohill RJ, Smith TL. Perspectives in laryngopharyngeal reflux: an international survey. Laryngoscope 2002; 112: 1399406.
  • 11
    Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002; 16: 56479.
  • 12
    Wo JM, Grist WJ, Gussack G, Delgaudio JM, Waring JP. Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a prospective study. Am J Gastroenterol 1997; 92: 21605.
  • 13
    Ormseth EJ, Wong RK. Reflux laryngitis: pathophysiology, diagnosis, and management. Am J Gastroenterol 1999; 94: 28127.
    Direct Link:
  • 14
    Richter JE, Hicks DM. Unresolved issues in gastroesophageal reflux-related ear, nose, and throat problems. Am J Gastroenterol 1997; 92: 21434.
  • 15
    Irwin RS, Boulet LP, Cloutier MM et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 114(Suppl. 2): 133S81S.
  • 16
    Palombini BC, Villanova CA, Araújo E et al. A pathogenic triad in chronic cough: asthma, postnasal drip syndrome, and gastroesophageal reflux disease. Chest 1999; 116: 27984.
  • 17
    O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med 1994; 150: 37480.
  • 18
    Kastelik JA, Aziz I, Ojoo JC, Thompson RH, Redington AE, Morice AH. Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J 2005; 25: 23543.
  • 19
    Poe RH, Kallay MC. Chronic cough and gastroesophageal reflux disease: experience with specific therapy for diagnosis and treatment. Chest 2003; 123: 67984.
  • 20
    Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94: 31318.
    Direct Link:
  • 21
    Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Chronic cough and gastro-oesophageal reflux: a double-blind placebo-controlled study with omeprazole. Eur Respir J 2000; 16: 6338.
  • 22
    Tutuian R, Mainie I, Agrawal A, Adams D, Castell DO. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest 2006; 130: 38691.
  • 23
    Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut 2005; 54: 44954.
  • 24
    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101: 190020.
    Direct Link:
  • 25
    Hongo M. Minimal changes in reflux esophagitis: red ones and white ones. J Gastroenterol 2006; 41: 959.
  • 26
    Kusano M, Shimoyama Y, Sugimoto S et al. Development and evaluation of FSSG: frequency scale for the symptoms of GERD. J Gastroenterol 2004; 39: 88891.
  • 27
    Silny J. Intraluminal multiple electric impedance procedure for measurement of gastrointestinal motility. J Gastrointest Motil 1991; 3: 15162.
  • 28
    Silny J, Knigge KP, Fass J, Rau G, Matern S, Schumpelick V. Verification of the intraluminal multiple electrical impedance measurement for the recording of gastrointestinal motility. J Gastrointest Motil 1993; 5: 10722.
  • 29
    Fass J, Silny J, Braun J et al. Measuring esophageal motility with a new intraluminal impedance device. First clinical results in reflux patients. Scand J Gastroenterol 1994; 29: 693702.
  • 30
    Shaker R, Dodds WJ, Hogan WJ, Arndoefer RC, Hofmann C, Dent J. Mechanisms of esophagopharyngeal acid regurgitation. Gastroenterology 1991; 100: A494.
  • 31
    Ulualp SO, Toohill RJ, Kern M, Shaker R. Pharyngo-US contractile reflex in patients with posterior laryngitis. Laryngoscope 1998; 108: 13547.
  • 32
    Kawamura O, Easterling C, Aslam M, Rittmann T, Hofmann C, Shaker R. Laryngo-upper esophageal sphincter contractile reflex in humans deteriorates with age. Gastroenterology 2004; 127: 5764.
  • 33
    Ing AJ, Ngu MC, Breslin AB. Chronic persistent cough and gastro-oesophageal reflux. Thorax 1991; 46: 47983.
  • 34
    Lam HG, Breumelhof R, Roelofs JM, Van Berge Henegouwen GP, Smout AJ. What is the optimal time window in symptom analysis of 24-hour esophageal pressure and pH data? Dig Dis Sci 1994; 39: 4029.
  • 35
    Weusten BL, Roelofs JM, Akkermans LM, Van Berge-Henegouwen GP, Smout AJ. The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology 1994; 107: 17415.
  • 36
    Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pH-metry in patients with ‘reflux laryngitis’. Gastroenterology 1991; 100: 30510.
  • 37
    Cool M, Poelmans J, Feenstra L, Tack J. Characteristics and clinical relevance of proximal esophageal pH monitoring. Am J Gastroenterol 2004; 99: 231723.
    Direct Link:

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Competing interests
  10. References
  11. Supporting Information

Figure S1. Esophagopharyngeal distribution of gastric refluxate with different physical properties. Each number represents percentage number of events that reached each site from the distal esophagus. Pha, pharynx; ME, middle esophagus; DE, distal esophagus.

Figure S2. Swallowing-induced acidic EPR. Zooming in the display revealed that the decrease started slightly earlier at the upper sensor. Moreover, there were similar pharyngeal impedance changes just before the event, which were apparently due to swallowing because esophageal clearance occurred consecutively.

Figure S3. Swallowing-induced weakly acidic EPR. Zooming in the display revealed that the decrease started slightly earlier at the upper sensor. Moreover, there were similar pharyngeal impedance changes just before the event, which were apparently due to swallowing because esophageal clearance occurred consecutively.

FilenameFormatSizeDescription
NMO_1658_sm_fs2.tif148KSupporting info item
NMO_1658_sm_fs3.tif156KSupporting info item
NMO_1658_sm_fs1.tif498KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.