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Original Research: Signs and Symptoms of Chest Diseases |

Chronic CoughMicroaspiration and Chronic Cough: Relationship Between Microaspiration, Gastroesophageal Reflux, and Cough Frequency FREE TO VIEW

Samantha Decalmer, PhD; Rachel Stovold, PhD; Lesley A. Houghton, PhD; Jeff Pearson, PhD; Chris Ward, PhD; Angela Kelsall, PhD; Helen Jones, MPhil; Kevin McGuinness, PhD; Ashley Woodcock, MD; Jaclyn A. Smith, PhD
Author and Funding Information

From the Respiratory Research Group (Drs Decalmer, Houghton, Kelsall, McGuinness, Woodcock, and Smith and Ms Jones), Faculty of Medicine and Human Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, England; the Applied Immunobiology and Transplantation Research Group (Drs Stovold, Pearson, and Ward), Institute of Cellular Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, England; the Division of Gastroenterology and Hepatology (Dr Houghton), College of Medicine, Mayo Clinic, Jacksonville, FL; and the National Institute for Health Research Translational Research Facility in Respiratory Medicine (Drs Kelsall and Woodcock), University Hospital of South Manchester, Manchester, England.

Correspondence to: Jaclyn A. Smith, PhD, University of Manchester, ERC Bldg, Second Floor, Wythenshawe Hospital, Manchester, M23 9LT, England; e-mail: jacky.smith@manchester.ac.uk


Funding/Support: This study was funded by a grant from the Moulton Charitable Trust. Dr Smith was funded by a Stepping Stones Fellowship from Manchester University followed by a Medical Research Council Clinician Scientist Fellowship [Grant G0701918].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(4):958-964. doi:10.1378/chest.12-0044
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Background:  Microaspiration is often considered a potential cause of cough. The aim of this study was to investigate the relationship between microaspiration, the degree and type of gastroesophageal reflux, and the frequency of coughing in patients with chronic cough.

Methods:  One hundred patients with chronic cough (mean [± SD] age, 55.8 years [± 11.0 years]; 65 women) and 32 healthy volunteers (median age, 43.5 years [interquartile range (IQR), 30-50.8 years]; 16 women) were recruited. Patients with chronic cough performed 24-h objective cough frequency with simultaneous esophageal impedance/pH monitoring and measurement of pepsin concentrations in sputum and BAL. Twelve healthy volunteers underwent bronchoscopy/BAL, and 20 underwent impedance/pH monitoring.

Results:  Patients with chronic cough had significantly more reflux episodes than healthy volunteers (median, 63.5 reflux episodes [IQR, 52.5-80.0] vs 59.0 [IQR, 41.8-66.0]; P = .03), although the absolute difference was small, and there was no difference in numbers of events extending into the proximal esophagus (median, 17.2% [IQR, 8.0%-26.0%] vs 20.3% [IQR, 5.1%-32.1%]; P = .36). BAL pepsin levels were also similar in chronic cough to control subjects (median, 18.2 ng/mL [range, 0-56.4 ng/mL] vs 9.25 ng/mL [range, 0-46.9 ng/mL]; P = .27). Sputum but not BAL pepsin weakly correlated with the number of proximally occurring reflux events (r = 0.33, P = .045) but was inversely related to cough frequency (r = −0.52, P = .04). Sputum pepsin was, therefore, best predicted by combining the opposing influences of cough and proximal reflux (r = 0.50, P = .004).

Conclusions:  Proximal gastroesophageal reflux and microaspiration into the airways have limited roles in provoking chronic cough. Indeed, coughing appears to be protective, reducing pepsin concentration in the larger airways of patients with chronic cough.

Trial registry:  ISRCTN Register; No.: ISRCTN62337037; URL: www.isrctn.org

Figures in this Article

Gastroesophageal reflux is the primary diagnosis in 5% to 41% of patients presenting with chronic cough.1 One of the proposed mechanisms whereby reflux is believed to cause coughing is via microaspiration of refluxate into the airways and/or larynx.2 Whether elevated levels of reflux are necessary for microaspiration to occur or whether even normal levels of reflux can pass into the airways to cause coughing is unclear.

Studies in children with unexplained respiratory symptoms and gastroesophageal reflux disease have shown them to have elevated levels of pepsin in their proximal airways (ie, trachea).3 In spite of this, other studies comparing chronic cough with lung transplant patients have suggested that although pepsin concentrations in the distal airways (ie, bronchoalveolar) are elevated in acute transplant rejection, they appear to be normal in chronic cough.4 This is supported by a recent larger study that showed patients with chronic cough to have similar levels of pepsin and bile acid in induced sputum to healthy control subjects.5

However, none of these studies objectively assessed gastroesophageal reflux, the presence of nonacid as well as acid reflux, or, probably most importantly, whether any reflux reached the proximal esophagus. Moreover, the number of patients studied was often small and the severity of their disease, in terms of frequency of coughing, not determined. This may be important, as the act of coughing may itself cause reflux, as suggested by the observation that in 24% of patients with chronic cough, reflux followed coughing events (within 10 s) more frequently than would be expected by chance alone.6 Indeed, the act of sputum induction by coughing has been shown to increase saliva pepsin concentration.7 Whether the frequency of coughing is related to the frequency of reflux events, their proximal extent, or the degree of microaspiration is unknown. The aim of this study was, therefore, to investigate whether patients with chronic cough exhibit microaspiration as measured by the concentration of pepsin in their proximal (sputum) and distal (BAL) airways and to explore the relationships between pepsin concentrations and the amount and proximal extent of gastroesophageal reflux and the frequency of coughing.

Subjects

Consecutive patients referred to a specialist cough clinic were approached. All patients were nonsmokers with normal chest radiographs, suffering from chronic cough (> 8 weeks). Those using angiotensin-converting enzyme inhibitors, opiates (or other antitussives), with significant comorbidity, or with a recent respiratory tract infection (< 4 weeks) were excluded. Proton pump inhibitors, H2 receptor antagonists, and prokinetics were stopped 2 weeks prior to the study.

Two groups of healthy volunteers were also studied to provide control data; one group underwent bronchoscopy, and the other had esophageal reflux monitoring (described later). Volunteers with a history of reflux symptoms were excluded. Ethical approval was obtained from the local research ethics committee, and subjects provided informed written consent (North and South Manchester Research Ethics Committees [LREC References 05/Q1403/117 and 08/H1009/63]).

Procedures

Patients were investigated for common causes of chronic cough by an algorithm similar to that outlined in the British Thoracic Society guidelines8 (spirometry,9 flow-volume loops, methacholine challenge,10 sputum eosinophil counts,11 otolaryngology examination). To assess microaspiration, reflux, and cough, patients additionally underwent simultaneous 24-h cough and esophageal reflux monitoring, bronchoscopy, and sputum induction with pepsin analysis of BAL fluid and sputum supernatant. All procedures were carried out over a period of approximately 6 weeks. The study procedures were carried out in the same order for all patients: pulmonary function, sputum induction, cough monitoring with pH/multichannel intraluminal impedance, bronchoscopy with BAL, nasendoscopy, and gastroscopy. Tests were performed at approximately 1-week intervals.

Sputum Induction:

Sputum induction was by inhalation of 5% hypertonic saline (Stockport Pharmaceuticals) delivered by ultrasonic nebulizer (Sonix 2000; Clement Clarke International Limited).12 Following processing of selected sputum with dithiothreitol, the resultant supernatant was stored at −80°C.

Bronchoscopy and BAL:

Bronchoscopy was performed under conscious sedation with topical lidocaine applied to the nose, larynx, and airways.13 BAL samples were collected from the right middle lobe (three aliquots, 60 mL of normal saline), centrifuged (4°C, 400g for 10 min), and the supernatant frozen (−80°C).

Pepsin Analysis:

A plate enzyme-linked immunosorbent assay, based on a monospecific antibody to porcine pepsin, was developed (details provided in e-Appendix 1).4,14 Pepsin concentrations determined using a porcine pepsin standard were adjusted for human/porcine differences in antibody binding.

Ambulatory Cough Monitoring:

Twenty-four-hour ambulatory cough sound recordings were performed using a custom-built recording device and microphone (VitaloJAK; Vitalograph). Cough was manually counted by trained observers and expressed as the number of explosive cough sounds per hour.15

Esophageal Impedance/pH Monitoring:

Reflux events were monitored over 24 h using a multichannel impedance/pH system (Sleuth; Sandhill Scientific) and esophageal catheter (Laryngopharyngeal ComforTec; Sandhill Scientific). Mealtimes were documented by the patients and excluded from the analysis. The esophageal catheter consisted of two pH electrodes (5 and 22 cm above the lower esophageal sphincter [LOS]) and eight impedance electrodes (at 2, 4, 6, 8, and 10 cm, and 14, 16, and 18 cm, composing six recording pairs) and was passed transnasally and positioned such that the distal pH electrode was 5 cm above the manometrically determined LOS. Data were manually analyzed for reflux episodes, defined as a rapid retrograde fall in impedance to 50% of baseline, in at least two consecutive channels of the distal four (abnormal > 73 episodes in 24 h16,17). Reflux episodes associated with a pH < 4 were considered acid, whereas those with pH > 4 were regarded as nonacid (ie, both weakly acid [pH > 4 and < 7] and alkali [pH > 7]). Proximal reflux events were defined as those traversing the most proximal impedance electrode pair (16 and 18 cm), and such events were classified as acid/nonacid depending on the pH detected at the proximal pH electrode (22 cm above LOS). Events not reaching this level or interrupted by a swallow were considered distal (abnormal proximal reflux > 30 events in 24 h17).

Statistical Analysis

Cough frequencies were normalized by logarithmic transformation. Comparisons between patients with cough and control subjects for pepsin concentrations and reflux parameters were made with Mann-Whitney and independent samples t testing. The interactions between cough frequency, reflux events, and pepsin concentrations were explored using parametric and nonparametric correlations and linear regression analysis, adjusting for the effects of age and sex18 (SPSS, version 16.0; IBM and Prism Version 5.0; GraphPad Software, Inc).

At the time of study design, no data were available upon which to base a power calculation of the detectable differences in pepsin levels between patients with chronic cough and control subjects. However, a retrospective power calculation was performed to determine the differences in pepsin concentration that could be identified by a study of this size.

Subjects
Chronic Cough:

Out of 241 consecutive patients attending the clinic with chronic cough, 132 met the inclusion criteria, and 100 were recruited to the study (Fig 1). Of the 132 eligible patients, 24 decided not to take part, five were subsequently diagnosed with medical comorbidities that excluded them, two had spontaneous resolution of their cough, and one ex-smoker resumed smoking. Of these, 81% were referred from pulmonary specialists and the rest from primary care. Patient characteristics and the numbers undergoing each procedure are summarized in Table 1 and Figure 1. Investigations to identify potential causes of cough apart from gastroesophageal reflux identified rhinosinusitis in 36 patients, asthma in eight, eosinophilic bronchitis in 10, bronchiectasis in six, and sarcoidosis in one patient. No patients were smokers, but 38% were ex-smokers (median smoking history of 7.8 pack-years [IQR, 3.4-17.0], median abstinence of 20.5 years [IQR 12-30 years]).

Table Graphic Jump Location
Table 1 —Subject Characteristics

Data are expressed as mean (± SD) unless otherwise stated. BHR = bronchial hyperresponsiveness to methacholine; IQR = interquartile range; PC20 = provocative concentration of methacholine inducing a 20% fall in FEV1; PND = postnasal drip.

Control Subjects:

Thirty-two healthy volunteers were recruited; 12 healthy volunteers underwent bronchoscopy, and 20 underwent 24-h esophageal impedance/pH monitoring. Although the control subjects (median age 43.5 years [IQR, 30-50.8 years]) were younger than the patients (P ≤ .001), BMI (median 24.2 [IQR, 23.1-28.1]) and female to male ratios (50% female) were not significantly different.

Objective Cough Frequency

A median of 240 coughs (IQR, 107-383) were recorded over 24 h in the subjects with chronic cough, giving a cough rate of 10.4 coughs/h (range, 0.3-70.2). Cough rates were significantly influenced by age (r = 0.34, P < .001), with women tending to cough more frequently than men (P = .056).

Gastroesophageal Reflux

Seventy-eight patients with chronic cough and 20 healthy volunteers completed pH/impedance monitoring. Patients with chronic cough had significantly more reflux episodes than control subjects over 24 h (median, 63.5 reflux episodes [IQR, 52.5-80.0] vs 59.0 reflux episodes [IQR, 41.8-66.0]; P = .03), although the absolute difference was small, and the median value was within normal limits (< 73 episodes17). In both groups, more reflux episodes were acid than nonacid (chronic cough, P = .003; control subjects, P = .018) and there were no differences comparing the patients with control subjects (Table 2). Moreover, the majority (approximately 80%) of reflux episodes did not reach the proximal esophagus, and there was no difference between groups. Of those events reaching the proximal esophagus, most were nonacid (chronic cough, P < .001 and control subjects, P < .001) (Table 2). For data analyzed using only distal pH measures, see e-Appendix 1.

Table Graphic Jump Location
Table 2 —Comparison of Reflux Episodes in Patients With Chronic Cough and Healthy Volunteers

Data are expressed as medians (IQR) with all subtypes of reflux events shown as a percentage of the total number of reflux events detected (acid events, pH < 4; nonacid events, pH > 4). See Table 1 legend for expansion of abbreviation.

A significantly greater proportion of patients (29 [37.2%]) had abnormal numbers of distal reflux events (> 73 reflux events) compared with control subjects (2 [10.0%], P = .03). The proportion of patients exhibiting abnormal numbers of proximal reflux (> 30 events17), however, was low (5.5%) and similar to that in the control subjects (5.0%). Other than proximal reflux events, all other reflux parameters where unaffected by age, sex, and BMI. Men had more proximal reflux than women (median, 15.0 [IQR, 8.5-22.0] vs 7.0 [IQR, 3.0-15.0]; P = .004).

Pepsin in BAL and Induced Sputum

BAL samples were collected in 98 patients and 12 control subjects undergoing bronchoscopy. Ninety patient and 12 control samples were suitable for analysis, and mean percentage BAL returns were similar in both groups (mean [± SD], 49.1% [± 13.12%] and 45.0% [± 12.27%], respectively; P = .41). The concentration of pepsin measured in the BAL of patients (median, 18.2 ng/mL [range, 0-56.4 ng/mL]) was not significantly different from control subjects (median, 9.25 ng/mL [0-46.9 ng/mL]; P = .27) (Fig 2). Patients with either excessive numbers of reflux events (> 73 episodes) or excessive esophageal acid exposure (pH < 4 more than 4.2% of time) had similar BAL pepsin levels to those without excessive reflux (median, 20.5 ng/mL [IQR, 13.7-27.2 ng/mL] vs 18.2 ng/mL [IQR, 0.0-25.8 ng/mL]; P = .34; and median, 17.6 ng/mL [IQR, 12.2-24.3 ng/mL] vs 18.3 ng/mL [IQR, 0.0-28.3 ng/mL], P = .82). Moreover, induced sputum pepsin concentrations in the patients (median, 17.3 ng/mL [0-55.4 ng/mL]), were very similar to and directly correlated with BAL pepsin concentration (r = 0.63, P < .001). BAL and sputum pepsin levels were unaffected by age, sex, or BMI.

Figure Jump LinkFigure 2. Comparisons of BAL pepsin concentrations in healthy control subjects and patients with chronic cough. Median, interquartile range, and range are displayed.Grahic Jump Location

A retrospective power calculation suggested that a study with 90 patients, 12 control subjects, and an SD in pepsin concentration of ± 12.8 ng/mL would be able to detect a true difference in pepsin concentration between groups ± 11.2 ng/mL with probability (power) of 0.8.

Relationships Between Reflux, Pepsin, and Cough Frequency
Cough and Reflux:

The total number of reflux events in the distal esophagus significantly predicted log cough frequency (P = .01) when adjusted for age (P < .001) and sex (P = .011), with these variables explaining a total of 26.6% of the variance in objective cough frequency. It is notable that in contrast, the number of reflux events reaching the proximal esophagus did not predict cough frequency. The relationship between impedance and cough events was not significantly influenced by either esophageal acid exposure (% time pH < 4) or the presence of an excessive number of reflux events.

Cough and Pepsin:

Log cough frequency was inversely related to sputum pepsin concentration (r = −0.52, P = .04); that is, patients with higher cough frequency had lower sputum pepsin concentrations. However, BAL pepsin concentration did not predict cough frequency.

Reflux and Pepsin:

The number of distal reflux events was not correlated with sputum pepsin (r = 0.25, P = .08), whereas the number of proximal reflux events significantly predicted sputum pepsin concentration (r = 0.33, P = .045). In contrast, there was no correlation between BAL pepsin and the number of proximal or distal reflux events.

Reflux, Pepsin, and Cough:

When the relationship between proximal reflux and sputum pepsin concentration was adjusted for the frequency of coughing, the correlation became stronger and highly significant (r = 0.50, P = .004). These relationships are summarized in Figure 3.

To our knowledge, this is the first study to show that unselected patients with chronic cough do not have significant amounts of reflux into their proximal esophagus or pepsin in their airways, despite having more reflux per se compared with healthy volunteers. Moreover, patients with abnormal levels of reflux had no more pepsin in the airways compared with those with normal reflux. These observations, along with the fact that the frequency of coughing was not related to the number of proximal reflux events and that coughing actually tended to reduce sputum pepsin concentration, would suggest that refluxate entering the airway is unlikely to be a significant contributing factor in the majority of patients presenting with chronic cough.

In this large study, only 5.5% of patients with chronic cough exhibited increased reflux in their proximal esophagus, which was similar to healthy volunteers (5%) and supports earlier studies.17,19 Airway pepsin levels in these patients, however, were no higher than the rest of the patients. Moreover, significant laryngopharyngeal stimulation and/or inflammation also seems unlikely given that (1) the majority of proximal reflux events were nonacid (pH > 4) and that in a canine model of laryngeal injury,20 these caused minimal inflammation compared with exposure to pepsin at pH 1 to 2; (2) conscious guinea pigs do not cough in response to inhalation of gastric juice pH 2 (Brendan Canning, PhD, personal communication, January 2012); and (3) in the present study, proximally occurring reflux events were unrelated to the frequency of coughing.

Despite the lack of correlation between cough frequency and either proximal reflux events or pepsin levels, there was a correlation between cough frequency and the number of distal reflux events. This may be explained by our observation that there is a temporal relationship between cough and distal reflux events (using a 2-min window) in 71.8% of patients with chronic cough,6 which, together with the observation that these patients have increased cough reflex sensitivity, suggests a centrally sensitized mechanism may be linking reflux to cough.

An additional novel and unexpected finding was the way in which gastroesophageal reflux, sputum pepsin, and cough frequency interacted (Fig 3). Rather than the expected finding that coughing would be associated with increased sputum pepsin, coughing appeared to improve clearance or prevent its entry into the airway. Thus, there appeared to be a balance between the opposing influences of proximal reflux and cough frequency on microaspiration. This maybe analogous to the observation that elderly patients taking angiotensin-converting enzyme inhibitors, which commonly induce coughing, are less susceptible to lower respiratory tract infections than patients not taking these medications,2124 supporting a protective role for enhanced cough.

Figure Jump LinkFigure 3. A summary of the relationships between esophageal reflux, objective cough frequency, and sputum pepsin in patients with chronic cough.Grahic Jump Location

There are some potential limitations with this study. Ideally the control subjects should have been better age-matched to the patients with chronic cough. However, a number of studies using both impedance and pH monitoring have suggested that age does not particularly influence the number and pattern of reflux events,25 and as the reflux rate in the present study was similar to that previously reported in healthy volunteers of a similar age (> 45 years),17 the age difference is unlikely to have significantly affected our results. Additionally, the gold standard method for assessing microaspiration has yet to be established. Some authors have measured pepsin concentration, whereas others have also assessed bile acids,26 which likely reflects duodenogastroesophageal reflux. Which components of the aspirate are most relevant to airway symptoms and/or disease is unknown, and how various assays compare with one another is still to be established. The microaspiration data presented in this study, however, are consistent with previous pepsin and bile acid findings in patients with cough and also support other studies suggesting that low levels of pepsin can be measured in the airways of even healthy volunteers.5,27

In conclusion, to our knowledge this is the first study to demonstrate that microaspiration into the airways has no, or limited, role to play in both unselected patients with chronic cough and those with objectively confirmed gastroesophageal reflux. Indeed, coughing appeared to be protective, reducing pepsin concentration in the larger airways. In addition, we have shown that the frequency of coughing is directly related to the total number of reflux events (of which the majority were confined to the distal esophagus), supporting our observations that reflux often temporally associates with cough,6 possibly via a centrally sensitized esophagobronchial reflex.

Author contributions: Dr Smith is guarantor of the manuscript.

Dr Decalmer: contributed to participant recruitment, performing bronchoscopies, analyzing of impedance/pH data, drafting of the manuscript, and final manuscript.

Dr Stovold: contributed to developing, validating, and performing the pepsin assays on the BAL and sputum samples and reviewing the final manuscript.

Dr Houghton: contributed to supervising impedance/pH data collection and revising and reviewing the final manuscript.

Dr Pearson: contributed to developing, validating, and performing the pepsin assays on the BAL and sputum samples and reviewing the final manuscript.

Dr Ward: contributed to developing, validating, and performing the pepsin assays on the BAL and sputum samples and reviewing the final manuscript.

Dr Kelsall: contributed to participant recruitment, cough sounds data collection/analysis, and reviewing the final manuscript.

Ms Jones: contributed to performing and analyzing impedance/pH studies, analyzing impedance data, and reviewing the final manuscript.

Dr McGuinness: contributed to performing cough sounds data analysis and synchronization with impedance/pH data and reviewing the final manuscript.

Dr Woodcock: contributed to study conception and design, supervising data collection, and reviewing the final manuscript.

Dr Smith: contributed to study conception and design, supervising data collection, performing bronchoscopies, carrying out the statistical analysis, and revising and reviewing the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs McGuinness, Woodcock, and Smith are inventors on a patent describing novel methods for cough detection and monitoring, owned by the University Hospital of South Manchester. They have an industrial collaboration and the University Hospital of South Manchester has a license agreement with Vitalograph to develop a commercial cough monitoring system (VitaloJAK). Drs Decalmer, Stovold, Houghton, Pearson, Ward, and Kelsall, and Ms Jones have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the study design, collecting of the data, analysis or interpretation of the data or in writing of this report.

Other contributions: We thank all the patients and healthy volunteers who took part in the study. We also thank Julie Morris, BSc, Department of Medical Statistics, for statistical advice.

Additional information: The e-Appendix and e-Table can be found in the “Supplemental Materials” area of the online article.

IQR

interquartile range

LOS

lower esophageal sphincter

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Figures

Figure Jump LinkFigure 2. Comparisons of BAL pepsin concentrations in healthy control subjects and patients with chronic cough. Median, interquartile range, and range are displayed.Grahic Jump Location
Figure Jump LinkFigure 3. A summary of the relationships between esophageal reflux, objective cough frequency, and sputum pepsin in patients with chronic cough.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Subject Characteristics

Data are expressed as mean (± SD) unless otherwise stated. BHR = bronchial hyperresponsiveness to methacholine; IQR = interquartile range; PC20 = provocative concentration of methacholine inducing a 20% fall in FEV1; PND = postnasal drip.

Table Graphic Jump Location
Table 2 —Comparison of Reflux Episodes in Patients With Chronic Cough and Healthy Volunteers

Data are expressed as medians (IQR) with all subtypes of reflux events shown as a percentage of the total number of reflux events detected (acid events, pH < 4; nonacid events, pH > 4). See Table 1 legend for expansion of abbreviation.

References

Morice AH, Kastelik JA. Cough. 1: chronic cough in adults. Thorax. 2003;58(10):901-907. [CrossRef] [PubMed]
 
Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(suppl 1):80S-94S. [CrossRef]
 
Krishnan U, Mitchell JD, Messina I, Day AS, Bohane TD. Assay of tracheal pepsin as a marker of reflux aspiration. J Pediatr Gastroenterol Nutr. 2002;35(3):303-308. [CrossRef]
 
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(12):1298-1303. [CrossRef]
 
Grabowski M, Kasran A, Seys S, et al. Pepsin and bile acids in induced sputum of chronic cough patients. Respir Med. 2011;105(8):1257-1261. [CrossRef]
 
Smith JA, Decalmer S, Kelsall A, et al. Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroenterology. 2010;139(3):754-762. [CrossRef]
 
Ervine E, McMaster C, McCallion W, Shields MD. Pepsin measured in induced sputum—a test for pulmonary aspiration in children?. J Pediatr Surg. 2009;44(10):1938-1941. [CrossRef]
 
Morice AH, McGarvey L, Pavord I; British Thoracic Society Cough Guideline Group British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax. 2006;61(suppl 1):i1-i24. [CrossRef]
 
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Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax. 1983;38(10):760-765. [CrossRef]
 
Pavord ID, Pizzichini MM, Pizzichini E, Hargreave FE. The use of induced sputum to investigate airway inflammation. Thorax. 1997;52(6):498-501. [CrossRef]
 
Paggiaro PL, Chanez P, Holz O, et al. Sputum induction. Eur Respir J Suppl. 2002;37:3s-8s.
 
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Ward C, Forrest IA, Brownlee IA, et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax. 2005;60(10):872-874. [CrossRef]
 
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(1):175-179. [CrossRef]
 
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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(10):1011-1021. [CrossRef]
 
Kelsall A, Decalmer S, McGuinness K, Woodcock A, Smith JA. Sex differences and predictors of objective cough frequency in chronic cough. Thorax. 2009;64(5):393-398. [CrossRef]
 
Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D. Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther. 2007;25(6):723-732. [CrossRef]
 
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Ohkubo T, Chapman N, Neal B, Woodward M, Omae T, Chalmers J; Perindopril Protection Against Recurrent Stroke Sutdy Collaborative Group Perindopril Protection Against Recurrent Stroke Sutdy Collaborative Group. Effects of an angiotensin-converting enzyme inhibitor-based regimen on pneumonia risk. Am J Respir Crit Care Med. 2004;169(9):1041-1045. [CrossRef]
 
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NOTE:
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543