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(Chest. 2005;128:2458-2464.)
© 2005 American College of Chest Physicians

Citric Acid Cough Threshold in Patients With Gastroesophageal Reflux Disease Rises After Laparoscopic Fundoplication*

Dariusz Ziora, MD, PhD; Wojciech Jarosz, MD; Józef Dzielicki, MD; Jacek Ciekalski, MD; Andrzej Krzywiecki, MD, FCCP; Szymon Dworniczak, MD and Jerzy Kozielski, MD, PhD, FCCP

* From the Department of Lung Diseases and Tuberculosis (Drs. Ziora, Krzywiecki, Dworniczak, and Kozielski) and Laparoscopic Surgery Center (Drs. Dzielicki and Ciekalski), Medical University of Silesia, Zabrze; and Municipal Hospital of Pulmonary Diseases (Dr. Jarosz), Chorzow, Poland.

Correspondence to: Dariusz Ziora, MD, PhD, Department of Lung Diseases and Tuberculosis, Medical University of Silesia, 41-803 Zabrze, Koziolka 1, Poland; e-mail: ftpulmza{at}slam.katowice.pl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Background: It has been reported that antireflux surgery can diminish chronic cough due to gastroesophageal reflux disease (GERD) that is resistant to pharmacologic therapy. The aim of this study was the assessment of citric acid cough threshold (CACT) in patients with chronic cough due to GERD before and 3 months after laparoscopic Toupet fundoplication.

Methods: Thirty subjects (20 women and 10 men; median age, 45.3 years) with chronic cough due to GERD and 15 healthy volunteers underwent cough challenge with doubling concentrations of citric acid. Twenty subjects with GERD, a group of 14 women and 6 men (mean age, 45.5 years), underwent the same protocol 3 months after laparoscopic fundoplication. Daytime and nighttime cough score questionnaires (verbal category descriptive score) were completed in all groups.

Results: The geometric mean of CACT was significantly lower in GERD patients (9.62 mg/mL) than in healthy volunteers (50.8 mg/mL, p < 0.001). The results of cough score measurement significantly improved within 2 weeks after laparoscopic surgery. In 13 weeks of postoperative follow-up, cough disappeared or was greatly improved in 14 of the 20 patients (70%); in 3 other patients, cough resolved partially. In three patients. there was no improvement in cough. Cough challenge after surgery revealed a significant increase in mean cough threshold, from 8.28 to 19.03 mg/mL (p < 0.05).

Conclusions: The results suggest that GERD influences CACT, which was significantly lower in GERD patients compared to healthy subjects. A significant correlation was found between subjective and objective measurements of cough in GERD patients. We found laparoscopic fundoplication to be objectively beneficial in GERD-induced chronic cough, as it reduced the CACT.

Key Words: chronic bronchitis • chronic cough • citric acid • cough questionnaire • cough threshold • esophageal pH monitoring • gastroesophageal reflux disease


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Gastroesophageal reflux disease (GERD) is among the most common causes of chronic cough in all age groups, exceeded in frequency only by postnasal drip syndrome and asthma.1 Moreover, chronic cough can be the sole presenting manifestation of GERD.23 However, up to 75% patients with GERD-induced cough may have no GI symptoms.4 Studies56 have shown that antireflux surgery, ie, laparoscopic fundoplication, can improve GERD-related symptoms including chronic cough resistant to intensive pharmacotherapy. Little is known about the relationship between cough threshold and subjective assessment of cough intensity in GERD patients, especially after laparoscopic fundoplication. In our preliminary study7 in a group of GERD patients with chronic cough before antireflux surgery, we observed the relationship between subjective and objective evaluations of cough and means of citric acid cough threshold (CACT) values. We also proved the safety of the CACT evaluation procedure.

The aim of our study was to objectively assess cough reflex sensitivity by estimating the CACT in patients with GERD-induced chronic cough. We examined the influence of treatment by laparoscopic fundoplication on cough itself and cough threshold in those patients. We also investigated the relationship between subjective (cough questionnaire) and objective (CACT) assessments of cough severity in patients with GERD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Subjects
Group 1: GERD Patients With Chronic Cough:
Thirty nonsmoking patients (10 men and 20 women; mean age, 45.3 years; range, 20 to 70 years) with at least a 3-month history of chronic cough due to GERD. Mean duration of cough was 36 months (range, 3 to 180 months). In all patients, reflux esophagitis was endoscopically interpreted by criteria of Sonnenberg and coworkers.8 Twenty-four–hour esophageal pH monitoring using sound (G-9011 Digitrapper MK III; Syntetics; Solothurn, Switzerland) was performed and interpreted according to Irwin and co-workers.9 GERD-related cough was recognized when the following criteria proposed by Irwin and co-workers9 were met: (1) any gastroesophageal reflux parameter in the distal esophagus above normal physiologic values, ie, > 51 acidic reflux events, four or more acidic reflux events lasting > 4 min, pH < 4 over > 4.4% of the total time of measurement, longest supine and upright reflux events lasting > 5.6 min and > 16.8 min, respectively; and/or (2) a reflux event that appeared to induce a cough.

Other causes of chronic cough were excluded in all patients according to the protocol described by Irwin and Madison.10 In all patients, we found normal chest radiographic findings, no changes on auscultation, and normal spirometric parameters: FEV1, FVC, and peak expiratory flow, expressed as predicted values according to Quanjer et al.11 Coexisting asthma was excluded by histamine and exercise provocation tests and negative skin-prick test results with common allergens. The patients with GERD had no history of chronic bronchitis and no exposition to irritants in the workplace. Postnasal drip syndrome was excluded by careful laryngologic examination. In all patients, bronchoscopy revealed no abnormalities of the bronchial tree. From this group, 20 previously described patients7 were classified for laparoscopic fundoplication (5 men and 15 women; mean age, 45.5 years; range, 20 to 70 years) with at least a 3-month history of chronic cough due to GERD. Mean duration of cough was 54 months (range, 3 to 180 months).

The indication for surgery was objective signs of GERD without improvement after 6 months of pharmacologic treatment. All of the patients either failed to respond to the maximal pharmacologic therapy of GERD, including high-dose proton pump inhibitors and a prokinetic drug administered simultaneously for at least 6 months, or, after temporary recovery, their cough returned when pharmacotherapy was discontinued. Patients completed their cough questionnaires 1 day every week for 3 months after surgery, describing their complaints from that day and the previous night. The last questionnaire score was completed 13 weeks after surgery, on the day when the second cough challenge with citric acid was performed. Twenty subjects with GERD and chronic cough later underwent surgical treatment by laparoscopic Toupet fundoplication. Details of the surgical procedure have been described elsewhere.1213

Healthy Volunteers:
Control subjects were recruited by local advertisement. This group consisted of 15 healthy, nonsmoking, nonatopic volunteers (8 men and 7 women; mean age, 37.5 years; range, 22 to 70 years) with normal spirometry and normal chest radiographic findings. None of the subjects from any group had been receiving angiotensin-converting enzyme inhibitors within the previous 3 months, or nonsteroidal antiinflammatory, antihistamine, antitussive, or sedative medications within the 5 days before the study. Antireflux pharmacologic therapy (if applicable) was discontinued at least 10 days before cough challenge. No history of respiratory tract infection within the previous past 6 weeks before cough challenge was noted.

Methods
Subjects from all groups completed a cough questionnaire with a verbal category descriptive (VCD) score described by Chang et al.14 The VCD score was assigned to a description for daytime and nighttime cough.

Daytime Score:
Daytime scores were calculated as follows: 0 = no cough; 1 = cough for one or two short periods only; 2 = cough for more than two short periods; 3 = frequent coughing but does not interfere with work or other activities; 4 = frequent coughing which interferes with work or other activities; and 5 = cannot perform most usual activities due to severe coughing.

Nighttime Score:
Nighttime scores were calculated as follows: 0 = no cough at night; 1a = cough on waking only; 1b = cough on going to sleep only; 2 = awakened once or awakened early due to coughing; 3 = frequent waking due to coughing; 4 = frequent coughs most of the night; 5 = distressing cough.

All subjects completed the cough questionnaire, assisted by one co-inhabiting person to describe the subject’s daytime and nighttime cough severity on the day and night before the cough challenge. The subjects then underwent CACT challenge according to the method described by Auffarth et al,15 adapted to the Asthma Provocation System (Jaeger; Wurzburg, Germany) as described previously.7 Cough challenges were performed at the same time of day, between 1 PM and 3 PM. All subjects ate breakfast by 9:00 AM and were asked not to eat or drink anything until the cough challenge was completed. On the day of the cough challenge, patients were not allowed to eat any food containing menthol or peppermint. The challenge was performed with a series of doubling concentrations of citric acid diluted in saline solution from 1 to 512 mg/mL at 18 to 20°C. Patients first inhaled saline solution followed by 16 breaths each of citric acid solution in increasing order. Citric acid was administered with a breath-activated dosimeter (output, 0.015 mL/s; Asthma Provocation System; Jaeger) for the period of 0.9 s of each breath, to achieve the same cumulative dose as in the original method.15 Patients were asked to breathe regularly with the frequency of normal tidal breathing. Each citric acid solution was inhaled in 16 breaths that lasted approximately 1 min, as described by Auffarth et al.15 This procedure was not accompanied by any adverse symptoms.

FEV1 measurements were carried out 30 s and 90 s after completing every 16 breaths of every concentration intake. The inhalations were stopped when FEV1 had fallen by ≥ 20% from baseline. The interval between doses of each concentration was at least 5 min. One dose of 16 breaths of 0.9% NaCl solution was added in random order to each protocol to blind the study. Patients were told that some irritation of the throat could occur during inhalation, but they were not informed about cough being measured. The cough threshold was defined as the first concentration of citric acid causing at least two coughs or one cough salve, providing that the next (doubled) concentration, administered after 30 min, also led to at least two coughs. The challenge was discontinued in any subject who reached cough threshold after < 16 breaths of specific concentration of citric acid solution. Cough was observed and cough threshold was arbitrarily estimated by two independent observers. If no cough was observed, the cough threshold was set at 512 mg/mL. The study protocol was approved by the local Medical Ethics Committee, and written informed consent was obtained from all participants in the study.

Statistical Analysis
All calculations were performed using statistical software (Statistica; StatSoft; Cracow, Poland). The geometric mean cough threshold and SE of the geometric mean were calculated for each group of subjects. The CACTs were log-transformed before analysis. Log CACT values were compared by means (± SD, SEM) of the Mann-Whitney U test. The median of the cough questionnaire counts was calculated for every group. Spearman rank correlation was used to assess the following: (1) the association between cough severity by questionnaire and cough threshold value, and (2) the relationship between total reflux time in pH monitoring and cough threshold value. A paired Wilcoxon test was used for the comparison of spirometric values before and after cough challenge, and mean log cough thresholds before and after surgery. The 0.05 level of significance was used throughout.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
In two patients from group 1, chronic cough was the sole symptom of GERD. The rest of the subjects had, apart from cough, other symptoms of GERD (Table 1 ). Approximately 73% patients with GERD had, apart from chronic cough, at least two other symptoms, and 23% of patients had at least three other symptoms.


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  		Table 1. Characteristics of Esophageal and Extraesophageal Symptoms in the Whole Group of GERD Patients Compared to GERD Patients Classified for Surgical Treatment*

 
The geometric mean of citric acid cough threshold in the patients with GERD who were classified for surgical treatment (CACT ± geometric SEM, 8.28 ± 7.36 mg/mL) was significantly lower than it was in the healthy subjects (50.8 ± 17.42 mg/mL, p < 0.001). In the entire group of GERD patients, the mean total time of acid exposure (pH < 4) in 24-h esophageal pH monitoring was 9.04% (range, 4.0 to 18.8%). No significant correlation was found between the time of exposure to pH < 4 and the CACT value. Mean spirometric values of FEV1, FVC, peak expiratory flow (percentage of predicted), and mean expiratory flow at 50% of vital capacity measured 10 min after completing the cough challenge did not significantly change from the baseline in any group of subjects (data not shown).

Daytime and nighttime cough severity were measured by questionnaire in 20 patients from the GERD group after laparoscopic fundoplication. Measurements were taken every week for 13 weeks and concerned cough intensity of the day of the questionnaire (Fig 1 ) and the preceding night (Fig 2 ). The median daytime cough score severity before surgery was 3 points. Two weeks after fundoplication, the median decreased to 2 points; at the end of the study, the median was 1 point (Fig 1). The median nighttime cough score severity before surgery was 2 points. One week after fundoplication, the median was 1 point; 8 weeks after surgery, it reached 0 (Fig 2).



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  		Figure 1. Daytime cough score before and after surgery. Min = minimum; Max = maximum.

 


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  		Figure 2. Nighttime cough score before and after surgery. See Figure 1 for expansion of abbreviations.

 
Thirteen weeks after fundoplication, the CACT challenge was repeated. Ten patients had higher CACTs than before surgery. In seven patients, the values of cough threshold were unchanged. Three patients showed a slightly lower CACT than previously. The geometric mean of CACT (± geometric SEM) values measured 13 weeks after laparoscopic fundoplication (19.03 ± 13.83 mg/mL) was higher than before surgery (8.28 ± 7.36 mg/mL; Fig 3 ). CACT values and their geometric means compared to those of the healthy subjects are shown in Figure 4 .



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  		Figure 3. CACT before and after surgery (long bold line) and means (short bold lines) including three subgroups of patients in whom daytime and nighttime cough disappeared ({circ}), partially resolved ({triangleup}) [1 to 4 mg/mL; 16 to 16 mg/mL; 8 to 8 mg/mL] or unchanged ({square}) [8 to 64 mg/mL; 16 to 64 mg/mL; 2 to 1 mg/mL] after the surgery.

 


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  		Figure 4. Geometric mean of CACT before and after surgery, as compared to control subjects.

 
After 13 weeks of postoperative follow-up, cough either disappeared entirely or decreased in 14 of the 20 patients (70%) who underwent surgery; the cough resolved partially in 3 other patients. Of the three subjects who had no improvement in cough, cough reflex sensitivity decreased (CACT was raised) by two concentrations in two subjects, while in one subject cough reflex sensitivity increased (CACT decreased) by one concentration. However, from among three patients in whom cough reflex sensitivity increased after surgery, CACT decreased in two cases by two concentrations, and in one case by one concentration. In only one case did daytime cough not improve, whereas in two others it resolved completely. To summarize, from among six patients with GERD whose cough did not improve after surgery (meaning that cough resolved partially or that no improvement was observed), cough reflex sensitivity decreased (ie, CACT was raised) in four subjects, increased in one subject, and remained unchanged in one subject.

Thirteen weeks after surgery a significant negative correlation was found between nighttime cough severity by questionnaire and CACT values (R = – 0.6; p = 0.008). No correlation was found between improvement of both daytime and nighttime cough and increase in cough threshold after surgery in GERD patients (R = – 0.24, p = 0.30; R = – 0.37, p = 0.10, respectively).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Cough threshold assessments in other studies1617 have proved that patients with GERD are likely to acquire chronic cough. Although gross aspiration and microaspiration from proximal esophageal reflux can cause cough in most patients with GERD, chronic cough is likely to result from the presence of gastric acid in the distal esophagus stimulating a vagally mediated distal esophageal-tracheobronchial reflex. Some authors17 have suggested that patients with GERD, even without respiratory symptoms, had a reduced cough threshold, as measured by inhaled capsaicin, but this opinion requires confirmation. The phenomenon appears to be due to acid reflux irrespective of the presence of esophagitis, suggesting that entry of gastric acid into the distal esophagus, rather than esophageal mucosal damage, is the major cause of GERD-induced cough. CACT values in GERD patients significantly correlated with daytime cough severity questionnaire results in our study. No correlation was found between CACT values and nighttime cough score, but it might have been undetected due to the possible difficulty or differences in perception of night cough phenomenon in individuals: if the cough did not awaken the patient or his co-inhabitant, it might not have been noted in the diary.

The severity of cough can be measured in different ways. For example, the Adverse Cough Outcome Survey has been shown to be a good and reliable tool.5 Cough intensity in our study was described with the use of a cough questionnaire with a VCD score, estimated by Chang and coworkers14 to be more highly correlated to the objective measurement than is the visual analog scale. However, cough diaries or questionnaires are helpful in the subjective evaluation of cough intensity, while the objective assessment of cough may require a more scientific method, such as cough threshold challenge by citric acid or capsaicin.

Cough threshold challenge with citric acid solutions was well tolerated and safe; no significant fall in FEV1 during and after challenge was observed. To avoid tachyphylaxis,18 a citric acid solution of higher concentration was administered following a 30-min interval after reaching the CACT.

Effective therapy of GERD digestive symptoms may fail to achieve satisfactory and long-lasting improvement in GERD-induced cough. It is possible that antireflux medical therapy may require high doses of drugs and take a long time to bring expected benefits in cough control.1 Furthermore, chronic cough may not disappear despite successful elimination of esophageal acid.9 Thus, antireflux surgery is the only therapeutic alternative after failed pharmacologic therapy. Laparoscopic fundoplication has been accepted as a standard method of surgical treatment of GERD in recent years. There are two methods of fundoplication. The Nissen fundoplication method consists of a 360° wrap performed over a 56 to 60F bougie using the fundus of the stomach. The short gastric vessels are divided. Toupet fundoplication is a 200 to 270° wrap performed over a 56 to 60F bougie using the fundus of the stomach. The short gastric vessels are divided in this procedure as well.

Both surgical procedures are effective in correcting gastroesophageal reflux, but the laparoscopic Toupet fundoplication was found to be associated with a lower incidence of postoperative digestive complications, such as dysphagia, than was the laparoscopic Nissen operation.1213 The laparoscopic fundoplication approach offers the advantages of clear visualization, adequate dissection, and precise repair, along with the benefits associated with endoscopic surgery: diminished postoperative pain and discomfort, reduced hospitalization, and quicker return to normal activities. Toupet fundoplication may be preferable to the Nissen technique for many patients requiring surgical treatment of reflux disease; indications for this method have increased.192021222324

Chronic cough due to GERD can lead to potential physical and psychosocial complications, which can be observed as a decrease in health-related quality of life25 and sickness impact profile.5 The efficacy of surgical treatment of GERD for cough disorders has been observed in previous studies. Tibbling et al26 achieved clinical improvement and diminished cough intensity in 80% of operated patients with GERD and cough. Patti et al6 observed improvement in chronic cough in 74% of operated patients and in up to 83% of subjects with proven cough-reflux correlation in 24-h pH monitoring. Finally Novitsky et al5 achieved improvement in 86% of operated subjects. In our study, cough disappeared or was greatly improved in 14 of 20 operated patients (70%); in 3 other patients, it resolved partially within 13 weeks of postoperative follow-up. The total percentage of patients with improvement was 85%. Most of our patients noted a decrease in cough severity within several days after fundoplication. The median daytime and nighttime cough intensities decreased after 2 weeks and 1 week, respectively. This rapid decline of cough intensity after laparoscopy may be the result of weakening the esophageal-bronchial reflex postulated by Irwin et al.27 This observation underlines its possible leading role in generating cough in patients with GERD. According to Tibbling et al,26 expected benefits from surgery in chronic cough should be fully revealed within 6 months after surgery. Longer observation (3 years) did not reveal further benefits. The decline in cough severity and improvement of quality of life after surgery are reported to be stable for 1 year of follow-up.5 However, the results of our study suggest that despite fundoplication CACT measured 3 months after surgery is still lower in some patients than in healthy subjects. There is some difficulty in interpreting our results because of the mismatched gender proportions between our healthy subjects (8 men and 7 women) and our study group (5 men and 15 women). It is well recognized that cough reflex sensitivity is nearly four times greater in healthy women than in healthy men, both in young and middle-aged adults.2829

No correlation was found between improvement in either daytime or nighttime cough and increased cough threshold after laparoscopic fundoplication. We wonder if GERD-associated cough is actually due to increased cough reflex sensitivity induced by gastroesophageal reflux. This issue requires future investigations concerning relationship between GERD-induced cough, GERD-induced cough reflex hypersensitivity, and acid reflux.

It is difficult to state with certainty whether fundoplication per se influences cough reflex sensitivity, although our findings seem to confirm this hypothesis. More conclusive findings would require the examination of other group of GERD patients without cough who had undergone the surgery.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Since most of our subjects with GERD-induced chronic cough had previously not responded to pharmacologic antireflux therapy and recovered only following surgical intervention, we conclude that treatment by laparoscopic fundoplication should be considered for GERD with chronic cough. Finally, in confirming previous reports,45626 we conclude that laparoscopic fundoplication is beneficial in the treatment of GERD-induced chronic cough because it leads to an increase in cough threshold, probably by weakening the esophageal-bronchial reflex.

Each hypothesis of cough reflex phenomenon in GERD stipulates that it is necessary to irritate the esophageal mucosa to activate the GERD-dependent cough reflex. We suspect that such constant irritation of the esophageal mucosa by acidic or nonacidic refluxate may lead to a constant slight stimulation of cough receptors in the airways (probably via local neurohumoral connections). Thus, some subthreshold external cough stimuli may become a threshold stimulus strong enough to induce cough. Fundoplication restores normal anatomic and physiologic status and likely leads to a situation where the cough reflex is being stimulated occasionally by some trigger such as constant or recurrent exposure to acid or, in some cases, by irritation of the esophageal mucosa by nonacidic refluxate.27


   Footnotes
 
Abbreviations: CACT = citric acid cough threshold; GERD = gastroesophageal reflux disease; VCD = verbal category descriptive

This work was performed at the Department of Lung Diseases and Tuberculosis, Medical University of Silesia in Katowice.

Received for publication July 8, 2004. Accepted for publication May 11, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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