Cough regardless of etiology and duration is the

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1 GASTROENTEROLOGY 2010;139: CLINICAL Acoustic Cough Reflux Associations in Chronic Cough: Potential Triggers and Mechanisms JACLYN A. SMITH,* SAMANTHA DECALMER,* ANGELA KELSALL,*, KEVIN McGUINNESS,*, HELEN JONES,* SIMON GALLOWAY, ASHLEY WOODCOCK,*, and LESLEY A. HOUGHTON, *Respiratory Research Group, The University of Manchester, Manchester; University Hospital of South Manchester NHS Foundation Trust, Manchester; and Neurogastroenterology Unit, The University of Manchester, Manchester, United Kingdom See related article, Lam PKY et al, on page 770 in CGH; see editorial on page 716. BACKGROUND & AIMS: Central sensitization is thought to play a role in chronic cough and might explain the temporal association between cough and gastroesophageal reflux (GOR) in patients in whom non-gor causes have been excluded. Using our novel simultaneous acoustic cough recording and impedance/ph monitoring technique, we aimed to explore this further by assessing such temporal associations and their relationship to the acidity, duration, and proximal extent of reflux and the presence of erosive disease and cough reflex sensitivity in unselected patients (ie, including non-gor causes) with chronic cough. METHODS: Twenty-four hour ambulatory acoustic cough monitoring with simultaneous impedance/ph recording was carried out in 71 unselected patients with chronic cough, aged years (47 female). In addition, all patients underwent cough reflex sensitivity testing to citric acid, and 66 patients underwent gastroscopy. Temporal associations between cough and reflux were expressed using the symptom association probability. RESULTS: Seventy percent of patients exhibited temporal associations, with 48% having a positive symptom association probability (SAP R-C ) for cough preceded by reflux (mainly distal), 56% a positive symptom association probability (SAP C-R(2min) ) for reflux preceded by cough, and 32% both. Moreover, SAP R-C positive patients had a more sensitive cough reflex (P.03) but similar esophageal reflux exposure and erosive disease, together with similar prevalence of extraesophageal causes of cough compared with SAP R-C negative patients. Reflux immediately following cough was rare. CONCLUSIONS: Cough temporally associates with reflux irrespective of proposed diagnoses, may be self-perpetuating in some patients, and is likely to be driven by central processes. Keywords: Cough; Gastroesophageal Reflux; Impedance/Ph Monitoring; Symptom Association Probability. View this article s video abstract at Cough regardless of etiology and duration is the commonest symptom for which patients seek medical attention. 1 Moreover, chronic cough is estimated to affect 11% 20% of the population, 2 has a high socioeconomic impact, 3 and results in significant reduction in quality of life. 4 Proposed causes of chronic cough include gastroesophageal reflux, rhino-sinusitis, and asthma, 5 although recent studies suggest that targeting such mechanisms with drugs only results in approximately half of patients reporting symptom relief. 6 For example, placebo controlled trials of antireflux therapy in cough patients with either concomitant typical gastroesophageal reflux (GOR) symptoms 7 or proven GOR 8 11 have been far from encouraging. Convergence of vagal afferents from the esophagus and respiratory tract in the brain stem has led to the suggestion of the possibility of an esophageal-bronchial reflex. This is supported by the findings that acid infused into the distal esophagus of patients with chronic cough increased the frequency of coughing 12 and cough reflex sensitivity. 13 Moreover, the fact that esophageal acid had no effect on cough reflex sensitivity in patients with objectively confirmed gastroesophageal reflux disease without cough 13 would suggest that the esophagealbronchial reflex maybe sensitized in patients with chronic cough. Whether central or peripheral mechanisms are responsible for sensitization of this reflex is unknown. The presence of microscopic inflammatory changes in the esophagus 14 and small intestine 15 of some patients with chronic cough and other airways diseases, however, could theoretically lead to both processes. As a result of afferent nerve convergence, sensitization within the brain Abbreviations used in this paper: 95% CI, 95% confidence interval; BMI, body mass index; C5, 5 coughs; CT, computerized tomography; GOR, gastroesophageal reflux; IQR, interquartile range; LOS, lower esophageal sphincter; SAP, symptom association probability; SAP C-R, SAP for cough followed by reflux; SAP R-C, SAP for reflux followed by cough; SAP C-R (2 min/10 sec), SAP within a 2 minute/10 second time window by the AGA Institute /$36.00 doi: /j.gastro

2 September 2010 COUGH-REFLUX ASSOCIATION IN CHRONIC COUGH 755 stem is also likely to increase the neural receptive field to include innervation from a variety of sites, such as the esophagus and nose, from which coughing could be triggered and may explain why different pathologies are associated with chronic cough. Furthermore, sensitization of a central mechanism might explain why reflux that was mainly confined to the distal esophagus appears to temporally associate with cough in a significant proportion of cough patients in whom non-gor (ie, extraesophageal) causes had been excluded Indeed very few reflux events appeared to reach the proximal esophagus, making central sensitization rather than microaspiration a more likely cause of cough. 16 Whether similar associations between reflux and cough exist in all chronic cough patients (ie, including those with extraesophageal causes) is unknown, but the presence of such associations would be supportive of a sensitized central mechanism playing a major role in chronic cough. The reverse sequence of cough causing reflux has also been shown to occur in a minority of patients in which again extraesophageal causes had been excluded, 18 but these were few and appeared not to contribute significantly to esophageal reflux. 16 The presence of such sequences per se in chronic cough nevertheless could lead to a self-perpetuating cycle of cough, increasing central sensitization and thus cough reflex sensitivity. However, the majority of studies assessing refluxcough associations have used a data logger and/or symptom diary to record coughs, which has been shown to significantly under-report the occurrence of coughing when compared with manometric techniques ,26 Indeed, even in those studies in which coughs have been detected manometrically, their identification during an ambulatory 24-hour recording may be poor, especially single rapid pressure changes that could represent either cough or artefact, such as clearing of the throat, and thus be rejected on a cautionary level by the observer. 26 None of these studies have assessed cough reflex sensitivity or the esophageal mucosa for evidence of erosive disease. The aim of this study was to investigate the temporal relationship between cough and reflux events over 24 hours using novel ambulatory cough sound recordings together with synchronized impedance/ph monitoring in unselected patients presenting with chronic cough. In addition, the relationship to the acidity, duration, and proximal extent of reflux and the presence of erosive disease and cough reflex sensitivity were explored. Patients and Methods Patients Seventy-eight consecutive patients (aged, years; 50 female) were recruited from the specialist cough clinic at the University Hospital of South Manchester NHS Foundation Trust. All patients were current nonsmokers (and exsmokers of 6 months) with normal chest radiographs, suffering from chronic cough (duration 8 weeks). Those taking angiotensin converting enzyme inhibitors, opiates (or other antitussive agents), with a recent respiratory tract infection ( 4 weeks), or with significant medical comorbidities were excluded. Proton pump inhibitors, H 2 receptor antagonists, and prokinetics were stopped 2 weeks prior to the study. Ethical approval was obtained from South Manchester Local Research Ethics Committee, and subjects provided written informed consent. Protocol and Study Design All patients were investigated for common causes of chronic cough by an algorithm similar to that outlined in the European Respiratory Society guidelines 27 (spirometry, methacholine challenge, sputum eosinophil counts, otolaryngology examination, and high resolution computerized tomography [CT] scan of thorax). In addition, all patients underwent assessment of their cough reflex sensitivity to citric acid, and 66 patients underwent upper gastrointestinal endoscopy. Within 6 weeks, patients attended the laboratory after an overnight fast and underwent esophageal manometry to locate the position of the lower esophageal sphincter (LOS). 28 An esophageal impedance/ph catheter (Laryngopharyngeal ComforTec; Sandhill Scientific Inc, Highlands Ranch, CO) was then passed trans-nasally and positioned such that the distal ph electrode was 5 cm above the LOS. The catheter was connected to a data logger (Sleuth system; Sandhill Scientific Inc, Highlands Ranch, CO) worn by the patients along with a custom-built sound recording device and lapel microphone (Vitalojak; Vitalograph Ltd, Buckingham, UK), and the subjects were allowed to return home. Patients were asked to report back to the laboratory 24 hours later for removal of the catheter and collection of the equipment. Diagnosis of Extraesophageal Disease Airways disease was diagnosed by assessment of eosinophilic inflammation (induction of sputum with measurement of the percentage of eosinophils) and bronchial hyper-responsiveness (methacholine challenge). Patients exhibiting both eosinophilic airway inflammation ( 3% eosinophils) and bronchial hyper-responsiveness (provocative concentration of methacholine causing a 20% fall in FEV 1 [PC 20 ] 8 mg/ml) were diagnosed with asthma, and those with eosinophilic airway inflammation without bronchial hyper-responsiveness were diagnosed with eosinophilic bronchitis. 29 Patients were diagnosed as having nasal disease if nasendoscopic examination revealed evidence of rhino-sinusitis, and any abnormality on high-resolution CT scan of the thorax was noted. Gastroscopy Gastroscopies were carried out under midazolam sedation following a 6-hour fast. The esophagus was

3 756 SMITH ET AL GASTROENTEROLOGY Vol. 139, No. 3 manner. 32 Doubling doses ( mol/l citric acid; Stockport Pharmaceuticals, Stockport, UK) were administered as single breath inhalations (KoKo dosimeter; Pds Instrumentation, Romsey, UK) with 3 placebo inhalations of normal saline randomly interspersed in a double blind manner. Following each inhalation, the number of coughs in the subsequent minute was counted by an experienced observer (A.K.) and recorded. The challenge was terminated once the citric acid had induced 5 or more coughs and the logarithmic (base 10) concentration provoking 5 coughs was recorded (logc5). Figure 1. Typical cough sound wave form that consists of 3 phases: (1) explosive phase corresponding to the sudden opening of the glottis with increase in air outflow and manifested as a sudden irregular noise-like wave form, inset A; (2) intermediate phase corresponding to a decrease in airflow accompanied by decreasing sound amplitude; and (3) voiced phase corresponding to a partial closure of the vocal cords, which then vibrate to produce a regular periodic sound, inset B. Insets show time-expanded waveforms (reproduced by kind permission of Kelsall et al 31 ). examined for macroscopic esophagitis graded 0 4 (Savary-Miller Criteria), and evidence of hiatus hernia or other structural abnormality documented. Objective Cough Measurements Cough frequency. Twenty-four hour ambulatory cough sound recordings were performed using a custombuilt validated recording device and microphone (Vitalojak; Vitalograph Ltd). 30 Briefly, this consists of a digital data logger recording sounds at a sample rate of 8 khz, 16-bit resolution and in wav format, which is a commonly used uncompressed sound file format. Cough was manually counted by S.D. and A.K. using software with an audiovisual display (CoolEdit2000; Syntrillium Software Corporation, Phoenix, AZ). Cough sounds were identified by audio recognition in association with appropriate sound wave form (Figure 1). Using this system, interobserver agreement was excellent (mean agreement, 0.3 cough sounds/hour; 95% limits of agreement, 2.1 to 1.1). Manual cough counting from digital sound recordings has also been previously validated against cough quantification from video recordings. 30 Coughing was expressed as both the number of explosive cough sounds per hour and total number of cough epochs per 24-hour recording. 31 A cough epoch was defined as a period of continuous coughing without a 2-second break, and the start and end time of each cough epoch was noted. Cough reflex sensitivity. A citric acid challenge was used to assess cough reflex sensitivity 32 and involves inhaling increasing concentrations of citric acid, which induces coughing in a dose-dependent, reproducible Esophageal Impedance/pH Monitoring Reflux was monitored over 24 hours using a multichannel impedance/ph recording system (Sleuth; Sandhill Scientific Inc) and esophageal catheter consisting of 2 ph electrodes (5 and 27 cm above the LOS) and 8 impedance electrodes (2, 4, 6, 8, and 10 cm, and 14, 16, and 18 cm comprising 6 recording pairs above LOS). Data were manually analyzed (Bioview Analysis; Sandhill Scientific Inc, Highlands Ranch, CO) for reflux episodes, defined as a rapid retrograde fall in impedance to 50% of baseline, in at least 2 consecutive channels of the distal 4 (abnormal 73 episodes in 24 hours 33,34 ). Reflux episodes associated with ph 4 were considered acid, whereas those with ph 4 were regarded as nonacid (ie, both weakly acid [ph 4 and 7] and weakly alkali [ph 7]). Previous studies have suggested that very few of the latter events occur 17 particularly in patients off treatment, 16 and, therefore, these were not assessed separately. The start and end times of each reflux event were noted, and the number of events in 24 hours was calculated. To ensure accurate synchronization of cough and impedance recordings, 2 time signals at the beginning and end were recorded on each device by simultaneously pressing the event marker on the impedance device and speaking into the audio recorder. Statistical Analysis Analyses were performed using SPSS, version 15.0 (SPSS, Inc, Chicago, IL), and the standard 5% level was used for statistical significance. Cough frequencies (both explosive cough sounds and epochs) and concentrations of citric acid provoking 5 coughs (C5) were log 10 transformed prior to analysis. The appropriate parametric/ nonparametric analyses were applied depending on data distribution and proportions of patients in particular subgroups compared using 2 or Fisher exact test. Analysis of Temporal Relationships The associations between cough epochs and reflux events were assessed using the method described by Weusten et al 35 for calculating the symptom association probability (SAP) between reflux events and patient reported reflux symptoms. Events were assumed to be associated in time if they occurred within the standard time win-

4 September 2010 COUGH-REFLUX ASSOCIATION IN CHRONIC COUGH 757 dow. 36 Data collected during mealtimes and drinks were excluded from the analysis because reflux could not be accurately evaluated during these periods. Reflux-cough associations. To assess the probability that reflux events were provoking cough, each 24- hour impedance trace was divided into 2-minute segments, and each segment was assessed for the presence of reflux and/or cough. All cough epochs were then assessed for reflux occurring in the preceding 2 minutes. A 2 by 2 contingency table was constructed tabulating the number of 2-minute segments with and without reflux vs those with and without cough, and Fisher exact test was used to calculate the probability (P) that the tabulated distribution had occurred by chance alone. The SAP for reflux followed by cough (SAP R-C ) was calculated as (1-P) 100%, and SAP R-C 95% was assumed to indicate a positive association. Cough-reflux associations. To assess the reverse process, ie, the probability that cough epochs were provoking reflux, each 24-hour sound recording was divided into both the conventional 2-minute segments 36 and the new shorter 10-second segments. Each segment was then assessed for the presence of cough epochs and/or reflux. All reflux events were then assessed for cough epochs occurring in the preceding 2 minutes/10 seconds, and Fisher exact test was used to calculate the probability statistic. The SAP for cough followed by reflux (SAP C-R (2 min/10 sec) ) could then be calculated as above, and a SAP C-R (2 min/10 sec) 95% assumed to indicate a positive association. Results Patients Of the 78 patients recruited, 71 had successful synchronized impedance/ph and ambulatory cough recordings (median age, 59.0 years [interquartile range (IQR), 51 64]; 47 [66.2%] female, body mass index [BMI] of 27.3 [IQR, ), cough duration 5.0 years [IQR, ]). All patients had a normal chest x-ray and normal pulmonary function (forced expiratory volume in 1 second [FEV 1 ] mean 101% [ 15.8] predicted and forced vital capacity (FVC) 112.5% [ 17.8%] predicted). Investigations for extraesophageal causes of cough found evidence of nasal disease in 25 (35.2%) of the patients, eosinophilic bronchitis in 8 (11.3%), asthma in 5 (7.0%); and 2 (2.8%) patients had CT scan evidence of minimal bronchiectasis. Of those patients with successfully synchronized impedance/ph and cough recordings, 66 underwent gastroscopy. The majority (79%) were shown to have no evidence of erosive disease, with the rest demonstrating either grade 1 (16.3%) or 2 (4.7%) esophagitis. In addition, 36% of patients were shown to have a hiatus hernia, in which esophagitis was found to be more common than in those without a hiatus hernia (P.004). Objective Cough Measurements Cough frequency. The geometric mean cough rate was 8.6 (95% confidence interval [CI]: ) cough sounds per hour, equating to a mean total of (95% CI: ) cough sounds and 59.2 (95% CI: ) cough epochs per 24 hours. Excluding periods during which impedance assessment of reflux was not possible, ie, meals, resulted in 53.8 (95% CI: ) analyzable cough epochs per 24 hours. Although there was a tendency for females to have a greater number of cough sounds per hour than males (geometric mean [GM] 10.0 [95% CI: ] vs GM 6.4 [95% CI: ], respectively; P.07), there was no difference in the number of cough epochs per 24 hours between men and women (GM 44.0 [95% CI: ] vs GM 59.5 [95% CI: ], respectively; P.18). In addition there was a trend for the number of cough epochs to increase with age (r 0.21; P.08). Cough-reflex sensitivity. Patients were shown to have a median logc5 of 0.9 Molar (M) (IQR, 1.2 to 0.5). Females had a more sensitive cough reflex than males (median, 0.9 M [IQR, 1.2Mto 0.6 M] vs median, 0.6 M [IQR, 9.0 to 0.0], respectively; P.001). LogC5 was not influenced by age (r 0.02, P.87). Esophageal Impedance/pH Measurements The mean number of reflux episodes was 67.7 (95% CI: ) per 24 hours, with 29 (37%) patients exhibiting reflux beyond the 95th percentile for controls ( 73 reflux episodes). 34 The number of reflux events was unaffected by age (r 0.04, P.74) or gender (P.81), and a median of 58.3% (IQR, ) were acid and 40.0% (IQR, ) nonacid. A median of 9.0 (IQR, ) reflux events (median, 17% [IQR, ]%) reached the proximal esophagus, with only 4 patients exceeding the normal reference range ( 30 events) 34 and none with an excess proportion of proximal events with respect to total number of reflux events ( 64%). 33,34 Temporal Associations Between Reflux and Cough Reflux-cough associations. Considering the cough epochs, the majority were not preceded by a reflux event (median, 66.7% [IQR, ] not preceded by reflux vs median, 33.3% [IQR, ] preceded by reflux: P.001). SAP R-C. A positive SAP R-C of cough preceded by reflux ( 95%) was present in 34 (47.9%) patients. SAP R-C positive patients exhibited a greater cough rate (geometric mean, 11.5 coughs/hour [95% CI: ] vs 6.6 [95% CI: ], respectively; P.016) and number of cough epochs per 24 hours (geometric mean, 65.8 [95% CI: ] vs 43.7 [95% CI: ], respectively; P.07) than SAP R-C negative patients. Moreover, in SAP R-C

5 758 SMITH ET AL GASTROENTEROLOGY Vol. 139, No. 3 Table 1. Comparison of Reflux Parameters in Patients With a Positive and Negative Symptom Association Probability for Reflux Preceding Cough Positive SAP R-C n 34 Negative SAP R-C n 37 P value Sex (% female) Age, y 58.3 ( 10.7) 55.6 ( 11.3).42 BMI 27.3 ( ) 27.3 ( ).77 Cough duration, y 6.0 ( ) 3.5 ( ).10 Cough reflex sensitivity to citric acid, 0.9 ( 1.2 to 0.6) 0.6 ( 1.1 to 0.3) 0.03 mol/l (logc5) Total number of reflux events 62 ( ) 69.5 (59 86).16 Acid 39.0 ( ) 36.0 ( ).31 Nonacid 23.0 ( ) 20.5 ( ).97 Number of proximal reflux events 9.0 ( ) 10.0 ( ).32 Proximal acid 0 (0 1.0) 0 (0 0.0).60 Proximal nonacid 9.0 (6.0 20) 10.0 (3.0 17).29 % Time ph ( ) 2.9 ( ).59 Nasal disease, % Eosinophilic bronchitis, % Asthma, % Bronchiectasis, % NOTE. Data expressed as a percentage of whole group or as median (interquartile range) except for Age, where values are mean ( standard deviation). SAP R-C, symptom association probability for reflux preceding cough. positive patients, a mean of 43.8% (95% CI: ) of the cough epochs followed a reflux event. There were no significant differences in the total number of reflux episodes (P.16), acid (P.31), or nonacid (P.97) reflux events or the number reaching more proximal regions of the esophagus (P.32) per 24 hours between patients with a positive and negative SAP R-C (Table 1). In addition, there were no differences in the proportion of subjects with impedance events beyond the 95th percentile for controls, ie, 73 (16/34 [47%] vs 11/37 [29.7%], respectively; P.15) or esophagitis (7/31 [23%] vs 5/35 [14%], respectively; P.62) between the 2 groups. However, SAP R-C positively correlated with the number of cough epochs (r 0.47, P.001) ie, patients with a higher symptom association were likely to have more cough events (unadjusted for other influences). Interestingly, SAP R-C positive patients also had a significantly more sensitive cough reflex to citric acid than SAP R-C negative patients (P.03) (Table 1), with this being unaffected following adjustment for the number of cough epochs and reflux events (P.023). In addition, cough duration, age, female/male ratio, and BMI were not different between the groups (P.10) (Table 1). Furthermore, SAP R-C positive patients were no more likely to have evidence of nasal disease, eosinophilic bronchitis, asthma, or bronchiectasis than SAP R-C negative patients (P.23) (Table 1). SAP for acid and nonacid reflux. When acid and nonacid reflux events were considered separately, identical numbers of patients (22 [31.4%]) had a positive SAP R-C for acid compared with nonacid reflux, both sequences being present in 17.1% (Figure 2). Note that, in 1 subject, reflux could not be classified as acid/nonacid because of detachment of reference electrode. Cough-Reflux Associations Considering the reflux events, the majority were not preceded by a cough epoch (2-minute window: 91.9% [IQR, ] not preceded by cough vs 8.1% [IQR, ] preceded by cough; P.001). SAP: 2-minute window. A positive SAP C-R (2 min) of reflux preceded by cough ( 95%) was present in 40 (56.3%) patients. SAP C-R (2 min) positive patients had a Figure 2. Venn diagram showing the percentage (number) of patients with positive symptom association probabilities for reflux preceding cough (SAP R-C ), for acid and nonacid reflux events. Note that, in 1 subject, reflux events could not be classified as acid/nonacid because of detachment of reference electrode.

6 September 2010 COUGH-REFLUX ASSOCIATION IN CHRONIC COUGH 759 Table 2. Comparison of Reflux Parameters in Patients With a Positive and Negative Symptom Association Probability for Cough Preceding Reflux Positive SAP C-R n 40 Negative SAP C-R n 31 P value Sex (% female) Age, y 59.0 ( ) 58.0 ( ).90 BMI 27.3 ( ) 27.3 ( ).68 Cough duration, y 6.0 ( ) 4.0 ( ).51 Cough reflex sensitivity to citric acid, 0.9 ( 1.2 to 0.6) 0.6 ( 1.2 to 0.3).36 mol/l (logc5) Total number of reflux events 70.5 ( ) 62.0 ( ).04 Acid 37.0 ( ) 34.0 ( ).45 Nonacid 24.0 ( ) 20.0 ( ).21 Number of proximal reflux events 11.0 ( ) 7.0 ( ).035 Proximal acid 0 (0 1.8) 0 (0 0).002 Proximal nonacid 11.0 ( ) 6.5 ( ).06 % Time ph ( ) 3.2 ( ) 1.0 Nasal disease, % Eosinophilic bronchitis, % Asthma, % Bronchiectasis, % NOTE. Data expressed either as a percentage of whole group or as median and interquartile range. SAP C-R, symptom association probability for cough preceding reflux. greater total number of reflux episodes (P.04) and were more likely to exhibit proximal reflux (P.035) than SAP C-R (2 min) negative patients (Table 2). However, SAP C-R (2 min) positive patients were no more likely to exhibit acid (P.45) or nonacid (P.21) reflux events or impedance events beyond the 95th percentile for controls (ie, 73) (18/40 [45%] vs 9/31 [29%], respectively; P.17), esophagitis (7/36 [19%] vs 5/30 [17%], respectively; P.65), or hiatus hernia (12/36 [33%] vs 15/30 [50%], respectively; P.21) than SAP C-R (2 min) negative patients. In SAP C-R (2 min) positive patients, a mean of 23.7% (95% CI: ) of the reflux events followed cough epochs. Moreover, the number of cough epochs (GM, 74.4 [95% CI: ] vs 44.1 [95% CI: ], respectively; P.011) and cough sound rate (10.7 per hour [95% CI: ] vs 6.51 [95% CI: ], respectively; P.031) were significantly higher in SAP C-R(2min) positive than negative patients. However, cough reflex sensitivity and the incidence of nasal disease, eosinophilic bronchitis, asthma, and bronchiectasis were no different between the 2 groups (P.31) (Table 2). Subjects with a positive SAP C-R(2min) were of similar age and had a similar BMI, cough duration, and proportion of females to males compared with those with a negative SAP C-R(2min) (P.45) (Table 2). SAP: 10-second window. When the time window for the association of cough preceding reflux was reduced to 10 seconds, it was found that reflux events rarely immediately followed coughing. A positive SAP C-R (10 sec) association was now only present in 17 patients (23.9%) and accounted for only 4 (IQR, 3 5) reflux events per 24 hours, ie, a median of 5.7% (IQR, 4.5% 7.3%) of reflux events (P.05 compared with window of 2 minutes). Patients who were SAP C-R (10 sec) positive were no more likely to have evidence of hiatus hernia than SAP C-R (10 sec) negative patients (20/50 [40.0%] vs 7/16 [43.8%], respectively; P 1.00). Coexistence of Reflux-Cough and Cough-Reflux Associations For the 2-minute window, 71.8% of subjects had reflux-cough and/or cough-reflux associations, with 32.4% exhibiting both processes (Figure 3). Those exhibiting both processes had a greater geometric cough rate (13.3 coughs/hour [95% CI: ]) than those with reflux-cough associations alone (7.9 coughs/hour [95% CI: ], P.11), cough-reflux associations alone (7.6 [95% CI: ], P.05), or neither (5.8 coughs/ Figure 3. Venn diagram showing the percentage (number) of patients with significant reflux-cough associations (SAP R-C positive) and coughreflux associations (SAP C-R positive).

7 760 SMITH ET AL GASTROENTEROLOGY Vol. 139, No. 3 hour [95% CI: ], P.004). Furthermore, the incidence of extraesophageal disease was no greater in any of the groups (SAP C-R (2 min) positive only, 61.5%; SAP R-C positive only, 45.5%; SAP C-R (2 min) and SAP R-C positive, 40.9%; neither, 42.1%: P.69). Discussion This is the first study to investigate the temporal relationship between cough and reflux events using a validated ambulatory sound recording device to register the precise timing and occurrence of actual cough sounds together with synchronized impedance/ph recordings of acid and nonacid reflux in a large group of unselected patients presenting with chronic cough. Using this novel approach and 2-minute window, we have shown that, even in unselected patients presenting with chronic cough, 70% exhibited temporal associations between cough and reflux, with a similar proportion of patients (50%) having a positive SAP R-C for cough preceded by reflux and positive SAP C-R (2 min) for reflux preceded by cough. Reduction of the SAP C-R time window to 10 seconds markedly reduced the number of cough-reflux associations, suggesting that reflux rarely immediately followed cough events. However, with a 2-minute window, almost one third of patients exhibited both SAP R-C reflux-cough and SAP C-R (2 min) cough-reflux associations, raising the possibility of a self-perpetuating cycle maintaining chronic cough. Of particular note, our findings that SAP R-C positive patients (1) had no greater esophageal exposure to reflux, with little reaching proximal regions; (2) were no more likely to exhibit erosive disease; but (3) did have a more sensitive cough reflex than SAP R-C negative patients supports a central neuronal sensitization process linking reflux to cough. Despite studying an unselected group of chronic cough patients, many of whom had concomitant extraesophageal disease, we found that nearly half of the patients had a positive SAP R-C for cough preceded by reflux. This is significantly higher than that previously reported in similarly large powered studies (ie, 30% 36%) 16,18 where patients were only included if extraesophageal disease had been excluded. It might have been expected that, in our study of unselected patients, a much smaller percentage would have been SAP R-C positive. These observations along with the fact that SAP R-C positive patients have a similar prevalence of extraesophageal disease together with similar esophageal exposure to reflux to SAP R-C negative patients suggest that reflux may trigger cough irrespective of patient diagnostic category. Our findings that SAP R-C positive patients have both an increased cough reflex sensitivity and cough rate compared with SAP R-C negative patients, despite comparable exposure of the esophagus to reflux, raises the possibility that SAP R-C positive patients have a sensitized esophagealbronchial reflex. The fact that SAP R-C positive patients were no more likely to have esophagitis (although microscopic changes cannot be excluded) and that the vast majority of reflux events was confined to the distal esophagus also supports a central rather than peripheral neuronal sensitization process linking reflux to cough. This confirms our previous findings that refluxate stimulating receptors in the larynx and/or airways (ie, microaspiration) is an unlikely cause. 37 However, the initial trigger that causes this sensitized state remains to be determined. As in previous studies, 16,17 we have shown that nonacid, as well as acidic reflux events, associate with cough (SAP R-C positive). Moreover, in our study, equal numbers of patients had significant acid and nonacid reflux cough associations, suggesting that the acidity of the refluxate maybe unimportant when stimulating an already sensitized esophageal-bronchial reflex. This may also explain partly the lack of efficacy of acid suppressing drugs in some patients 7 11 and why antireflux surgery has been shown to be beneficial in some studies. 20,21,38 A positive reflux association probability (SAP C-R (2 min) ) for cough preceding reflux occurred in 56% of patients. To date, only 1 previous study has reported a formally calculated SAP C-R using the 2-minute window, which was considerably lower (13.5%) than that demonstrated in our study. 18 These investigators, however, relied on the patient pressing an event marker on a data logger for documenting the timing of cough and ambulatory ph only for reflux detection in patients in whom extraesophageal disease had been excluded. Another study, again in patients in whom extraesophageal disease had been excluded and using the 2-minute widow, also reported cough-reflux sequences and suggested that these had a minimal effect on reflux. 16 In contrast, in the present study, SAP C-R (2 min) positive patients did have significantly more reflux events, including reflux events reaching more proximal regions of the esophagus and more coughing than SAP C-R (2 min) negative patients. Of note, patients who had both reflux-cough (SAP R-C ) and cough-reflux (SAP C-R (2 min) ) positive associations tended to exhibit the highest cough rates, raising the possibility of a self-perpetuating cycle maintaining cough in some patients. Reduction of the window to 10 seconds reduced the percentage of patients exhibiting a positive SAP C-R to approximately 24%. This accounted for very few of the reflux events when compared with the 2-minute window (6% vs 24%, respectively) and is in keeping with other studies suggesting that (in ambulatory subjects) straining is not a major factor in reflux Indeed, SAP C-R (10 sec) positivity was not associated with increased likelihood of hiatus hernia. Whether the high incidence of cough and reflux events in these subjects simply increased the probability of a positive SAP C-R (2 min) with a longer time window is difficult to gauge, but, despite some possible limitations, symptom association probability presently remains the most appropriate method to assess such associations and suggests that they were occurring more

8 September 2010 COUGH-REFLUX ASSOCIATION IN CHRONIC COUGH 761 often than by chance alone. Cough-reflux associations occurring in a 2-minute window are unlikely to be strain induced; therefore, we speculate that these associations may be neuronally based, similar to the reflux-cough associations. Cross sensitization of the upper gastrointestinal tract and airway via the central convergence of vagal afferents may allow coughing episodes (or the stimuli precipitating cough events) to, for example, increase the probability of transient lower esophageal sphincter relaxations and thus reflux, even up to several minutes after coughing. The triggers for cough that is not preceded by reflux (ie, SAP R-C negative patients, 52.1% of patients) cannot be determined from this study but does not appear to be attributable to an increased incidence of extraesophageal disease because this was similar across all patient subgroups. Indeed, even in SAP R-C positive patients, on average 56% of coughs were not preceded by reflux. Such triggers, however, may originate from the variety of environmental stimuli that are known to initiate and exacerbate coughing, such as temperature changes, perfume, air fresheners, smoke, and dust. 42 Given these potential different triggers and anatomic locations at which they act (ie, airways rather than esophagus), perhaps more than one mechanism is responsible for initiating cough in patients with chronic cough. As in our previous studies, 31,43,44 we have shown that, using an ambulatory acoustic recording device to register the precise timing and occurrence of actual cough sounds, we detect on average 2 3 times as many coughs epochs (ie, bursts or bouts) than has previously been reported with esophageal manometry 16 18,26 and 6 18 times as many as when patients press an event marker on a data logger ,26 Because manometry has not been compared with acoustic measures of cough, the reasons for these discrepancies are uncertain. As discussed earlier, perhaps it is difficult to identify coughs using esophageal manometry. Alternatively, the patients recruited to our study may have had more severe disease, although the patients recruited for Blondeau et al s manometric study 16 were recruited from a similar specialist chronic cough clinic to ours. Finally, in the present study, we did not record typical symptoms suggestive of reflux, such as heartburn, chest pain, and regurgitation, because Smout et al have shown that the patients with a positive SAP for typical reflux symptoms preceded by objective reflux are not necessarily those with a positive SAP R-C for cough preceded by objective reflux. 18 Thus, typical reflux symptoms are not useful when trying to determine the temporal association between cough and reflux. In addition, even though we have shown significant associations between cough and reflux, causality cannot be established until successful interventions are available. Currently, effective antitussive drugs are unavailable, and, although a number of agents have been shown to reduce transient lower esophageal sphincter relaxations, these have not been assessed in chronic cough. 45 In conclusion, using novel ambulatory acoustic cough monitoring with simultaneous impedance/ph recordings, we have shown that, irrespective of possible underlying cause, reflux can temporally associate with cough. The lack of association with degree/proximal extent of reflux and erosive disease, but link to increased cough reflex sensitivity, suggests that a sensitized central mechanism may be facilitating reflux-induced cough and cough-induced reflux. Furthermore, the presence of a similar incidence of cough preceding reflux points to the possible existence of a self-perpetuating cycle maintaining chronic cough. In addition, these results may partly explain the poor efficacy of traditional drugs, such as those targeting gastric acidity in the treatment of chronic cough. References 1. Schappert SM, Burt CW. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, Vital Health Stat ; 159: Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008;371: Morice AH, McGarvey L, Pavord I. Recommendations for the management of cough in adults. Thorax 2006;61(Suppl 1):i French CL, Irwin RS, Curley FJ, et al. Impact of chronic cough on quality of life. Arch Intern Med 1998;158: Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis 1981;123: Haque RA, Usmani OS, Barnes PJ. Chronic idiopathic cough: a discrete clinical entity? Chest 2005;127: Jaspersen D, Diehl KL, Geyer P, et al. Omeprazole in refluxassociated chronic persistent cough. Endoskopie Heute 1999; 12: Ours TM, Kavuru MS, Schilz RJ, et al. 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: Eherer AJ, Habermann W, Hammer HF, et al. Effect of pantoprazole on the course of reflux-associated laryngitis: a placebocontrolled double-blind crossover study. Scand J Gastroenterol 2003;38: Ing A. Chronic cough. Respirology 1997;2: Chang AB, Lasserson TJ, Kiljander TO, et al. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ 2006;332: Ing A, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am J Respir Crit Care Med 1994;149: Javorkova N, Varechova S, Pecova R, et al. Acidification of the oesophagus acutely increases the cough sensitivity in patients with gastro-esophageal reflux and chronic cough. Neurogastroenterol Motil 2008;20: Young EC, Decalmer S, Galloway S, et al. The majority of chronic cough patients exhibit evidence of oesophageal inflammation (abstract). Am J Respir Crit Care Med 2009;179:A Wallaert B, Desreumaux P, Copin MC, et al. Immunoreactivity for interleukin 3 and 5 and granulocyte/macrophage colony-stimu-

9 762 SMITH ET AL GASTROENTEROLOGY Vol. 139, No. 3 lating factor of intestinal mucosa in bronchial asthma. J Exp Med 1995;182: Blondeau K, Dupont LJ, Mertens V, et al. Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther 2007;25: Sifrim D, Dupont L, Blondeau K, et al. Weakly acidic reflux in patients with chronic unexplained cough during 24-hour pressure, ph, and impedance monitoring. Gut 2005;54: Bogte A, Bredenoord AJ, Smout AJ. Diagnostic yield of oesophageal ph monitoring in patients with chronic unexplained cough. Scand J Gastroenterol 2008;43: Wunderlich AW, Murray JA. Temporal correlation between chronic cough and gastroesophageal reflux disease. Dig Dis Sci 2003; 48: Patterson N, Mainie I, Rafferty G, et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol 2009;43: Tutuian R, Mainie I, Agrawal A, et al. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest 2006; 130: Mainie I, Tutuian R, Agrawal A, et al. Fundoplication eliminates chronic cough due to nonacid reflux identified by impedance ph monitoring. Thorax 2005;60: Agrawal A, Roberts J, Sharma N, et al. Symptoms with acid and nonacid reflux may be produced by different mechanisms. Dis Esophagus 2009;22: Avidan B, Sonnenberg A, Schnell TG, et al. Temporal associations between coughing or wheezing and acid reflux in asthmatics. Gut 2001;49: Schnatz PF, Castell JA, Castell DO. Pulmonary symptoms associated with gastroesophageal reflux: use of ambulatory ph monitoring to diagnose and to direct therapy. Am J Gastroenterol 1996;91: Paterson WG, Murat BW. Combined ambulatory esophageal manometry and dual-probe ph-metry in evaluation of patients with chronic unexplained cough. Dig Dis Sci 1994;39: Morice AH, Fontana GA, Sovijarvi AR, et al. The diagnosis and management of chronic cough. Eur Respir J 2004;24: Houghton LA, Atkinson W, Whorwell PJ, et al. Effects of cilomilast, a selective phosphodiesterase 4 inhibitor, on esophageal motility and ph, and orocecal and colonic transit: two singlecenter, randomized, double-blind, placebo-controlled, two-part crossover studies in healthy volunteers. Clin Ther 2006;28: Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160: Smith JA, Earis JE, Woodcock AA. Establishing a gold standard for manual cough counting: video versus digital audio recordings. Cough 2006;2: Kelsall A, Decalmer S, Webster D, et al. How to quantify coughing: correlations with quality of life in chronic cough. Eur Respir J 2008;32: Morice AH, Fontana GA, Belvisi MG, et al. ERS guidelines on the assessment of cough. Eur Respir J 2007;29: Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and ph monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99: Zerbib F, des Varannes SB, Roman S, et al. Normal values and day-to-day variability of 24-h ambulatory oesophageal impedance-ph monitoring in a Belgian-French cohort of healthy subjects. Aliment Pharmacol Ther 2005;22: Weusten BL, Roelofs JM, Akkermans LM, et al. The symptomassociation probability: an improved method for symptom analysis of 24-hour esophageal ph data. Gastroenterology 1994;107: Lam HG, Breumelhof R, Roelofs JM, et al. What is the optimal time window in symptom analysis of 24-hour esophageal pressure and ph data? Dig Dis Sci 1994;39: Stovold R, Forrest IA, Corris PA, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 2007;175: Mainie I, Tutuian R, Agrawal A, et al. Combined multichannel intraluminal impedance-ph monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg 2006;93: Penagini R, Schoeman MN, Dent J, et al. Motor events underlying gastro-oesophageal reflux in ambulant patients with reflux oesophagitis. Neurogastroenterol Motil 1996;8: Schoeman MN, Tippett MD, Akkermans LM, et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995;108: van Herwaarden MA, Samsom M, Smout AJ. Excess gastroesophageal reflux in patients with hiatus hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology 2000;119: McGarvey L, McKeagney P, Polley L, et al. Are there clinical features of a sensitized cough reflex? Pulm Pharmacol Ther 2009;22: Decalmer SC, Webster D, Kelsall AA, et al. Chronic cough: how do cough reflex sensitivity and subjective assessments correlate with objective cough counts during ambulatory monitoring? Thorax 2007;62: Kelsall A, Decalmer S, McGuinness K, et al. Sex differences and predictors of objective cough frequency in chronic cough. Thorax 2009;64: Dent J. Reflux inhibitor drugs: an emerging novel therapy for gastroesophageal reflux disease. J Dig Dis 2010;11: Received November 3, Accepted June 3, Reprint requests Address requests for reprints to: Jacky Smith, PhD, MRCP, Education and Research Centre, 2nd Floor, University Hospital of South Manchester, Southmoor Rd, Wythenshawe, Manchester, M23 9LT, United Kingdom. jacky.smith@manchester.ac.uk; fax (44) Conflicts of interest The authors disclose the following: Dr J. A. Smith has received remuneration for advice, and the department has also received financial support from GlaxoSmithKline, Pfizer, Schering Plough, Procter & Gamble, Vectura, and Sound Biotech. Professor A. Woodcock has received remuneration for advice, and the department has also received financial support from GlaxoSmithKline, Schering Plough, Astra Zeneca, and Chiesi Pharmaceutici. Dr L. A. Houghton has received remuneration for advice, and the department has also received financial support from Novartis Pharmaceuticals, GlaxoSmithKline, Pfizer, Solvay Pharmaceuticals, Danone Research, Clasado Ltd, Norgine, Kellogg s UK, and Ono Pharma UK Ltd. The remaining authors disclose no conflicts. Funding Supported by the Moulton Charitable Trust and by a Stepping Stones Award from the University of Manchester (to J.A.S.).