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* From the Departments of Medicine (Drs. Irwin, Zawacki, Wilson, and French) and Surgery (Dr. Callery), University of Massachusetts Medical School, Worcester, MA.
Correspondence to: Richard S. Irwin, MD, FCCP, U Mass Memorial Medical Center, University Campus, Division of Pulmonary, Allergy, and Critical Care Medicine, 55 Lake Ave North, Worcester, MA 01655; e-mail address: irwinr{at}ummhc.org
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Abstract |
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Methods: In a prospective, before-and-after interventional trial, we assessed the effects of antireflux surgery in eight patients whose chronic coughs were due to GERD resistant to intensive medical therapy. All patients met a profile predicting that cough was likely due to GERD and had an initial positive 24-h esophageal pH monitoring study, and then underwent serial 24-h esophageal pH monitoring on gradually intensified medical therapy until the percentage of time that esophageal pH was < 4 was zero and there were no acid reflux events > 4 min. The effects of medical and surgical therapy on cough were assessed clinically by a visual analog scale (VAS) and the Adverse Cough Outcome Survey (ACOS).
Results: Before surgery (median, 23.7 days), patients still complained of cough, VAS score was 73.1 ± 6.1, and ACOS score was 15.0 ± 1.1. After surgery (median, 41.2 days and 1 year), cough improved in all, VAS score decreased to 19.1 ± 8.3 and 22.6 ± 8.1 (p = 0.001), respectively, and ACOS score decreased to 2.0 ± 1.3 and 3.6 ± 2.3, respectively (p = 0.002).
Conclusions: Antireflux surgery can improve chronic cough due to GERD resistant to intensive medical therapy. There is a clinical profile that can predict when GERD is the likely cause of cough. GERD cannot be excluded on clinical grounds as the potential cause of cough. The term acid reflux disease, when applied to chronic cough due to GERD, can be a misnomer.
Key Words: chronic cough • chronic cough due to gastroesophageal reflux disease • nonacid reflux disease • treatment of cough due to gastroesophageal reflux disease
Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough in all age groups.1 When GERD is the cause of chronic cough, it has been prospectively shown that it can be "silent" from a GI standpoint up to 75% of the time,2 and there is a clinical profile that has predicted > 95% of the time when patients have silent GERD as the cause of their cough.1 2 Such patients (1) have normal or near-normal chest radiographic findings; (2) are not smoking or exposed to other environmental irritants; (3) are not receiving an angiotensin-converting enzyme inhibitor; (4) have either a negative methacholine inhalational challenge result or failure of their cough to improve with treatment for asthma; and (5) have not had cough improve with appropriate specific treatment for postnasal drip syndrome.1 2 Since the validation of this clinical profile, it has become clear that some investigators are diagnosing eosinophilic bronchitis with increasing frequency3 ; it is a corticosteroid-responsive cause of chronic cough that may present with the same clinical profile as silent GERD. Therefore, to maintain the high accuracy of the clinical profile to predict when silent GERD is causing chronic cough, patients must also be shown to (6) neither have sputum eosinophilia4 nor improvement in cough with inhaled, and in selected cases, systemic corticosteroid treatment.3
Medical therapy for GERD prior to the proton pump inhibition era led to resolution of chronic cough in 70 to 100% of adult patients.1 Successful therapy that included but was not limited to acid suppression with histamine type-2 antagonists sometimes did not start to improve cough in some patients for 2 to 3 months and the average time to complete resolution could take up to 179 days. Many concluded that better results would be obtained with proton pump inhibitors and the delay in improvement and failure for some patients to improve with medical therapy in these prior publications was due to use of the less potent acid-suppressing histamine type-2 antagonists. Based on results of a randomized, double-blind, placebo-controlled trial in a group of patients thought likely to have chronic cough due to GERD, Ours et al5 concluded that the "best diagnostic and therapeutic approach, after excluding asthma and postnasal drip syndrome, is empiric treatment for 2 weeks with a high dose proton pump inhibitor," implying that chronic cough cannot be due to GERD if patients fail to get better after 2 weeks of treatment with omeprazole, 40 mg, or an equivalent agent administered twice daily.
However, based on previously published studies from our group in 19932 and Leite et al6 in 1996, we began to consider that intensive medical therapy for GERD, even with potent acid-suppressing medications, may fail to cure or improve chronic cough. In our prospective, before-and-after intervention trial,2 the intraesophageal infusion of 0.1 N HCL failed to provoke more coughs than 0.9% saline solution administered in a randomized, double-blind, standardized fashion in patients eventually shown to have cough due to GERD. Leite et al6 showed that there is a small but distinct subgroup of patients whose intragastric acidity persists despite treatment with omeprazole, 80 mg/d. Consequently, beginning in 1997, when patients fit the clinical profile suggesting that cough was likely due to GERD, we offered them antireflux surgery even when they had failed to improve with medical therapy or prior antireflux surgery, and we prospectively studied them before and after surgery. To date, eight patients continued to complain of cough despite total or near total esophageal acid suppression on intensive medical therapy; yet, cough was subsequently eliminated or improved following antireflux surgery. We report their results after a 1-year follow-up evaluation.
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Materials and Methods |
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Initial Cough Protocol
Patients were evaluated according to a previously validated, systematic, diagnostic protocol.7
When cough persisted following the initial evaluation that included a positive 24-h esophageal pH monitoring study,2
patients who fit the clinical profile, described above, that GERD was still the likely cause of their chronic cough were identified as being in need of intensification of antireflux medical therapy and further study. When cough did not improve after a minimum of 3 months of therapy, serial 24-h esophageal pH monitoring studies were performed monthly on gradually intensified doses of acid-suppressing medication until the percentage of 24 h that pH was < 4 dropped to zero. Lastly, when the patients expressed the opinion that their persisting cough was not sufficient for a satisfactory quality of life, they were evaluated for antireflux surgery, even if surgery had been previously performed.
Medical Treatment Regimen for GERD
Medical treatment consisted of a combination of the following: (1) an antireflux diet and other lifestyle modifications8
; (2) acid suppression with a proton pump inhibitor and/or histamine type-2 antagonist; and (3) prokinetic therapy that consisted of cisapride, metoclopramide, or bethanechol singly or in combination. The diet was low in fat (not more than 45 g/d) and included elimination of beverages and foods with a pH < 5, three meals a day without snacking, and not eating or drinking except for taking medications for 2 to 3 h prior to lying down. A head-of-bed elevation of four inches was only recommended for those patients shown to have supine, nocturnal reflux by 24-esophageal pH monitoring. The doses of acid-suppressing medications were intensified until the percentage of time that pH was < 4 was zero and there were no acid reflux events lasting > 4 min during a 24-h esophageal pH monitoring study while patients took their treatment regimen. A sustained weight loss of at least 5 lb plus documented acid suppression were used as indicators that patients were adhering to their treatment regimen.9
Preoperative Protocol
First, flexible bronchoscopy was performed to assess for laryngeal changes considered typical for GERD-induced injury10
and to rule out any suspected endobronchial comorbid disorders(s) that could be contributing to cough. Second, multiple GI evaluations were scheduled to assess for abnormalities that might preclude antireflux surgery (eg, esophageal cancer, severe esophageal dysmotility) or modify the surgical approach to be taken (eg, large intrathoracic hiatus hernia, short length of intra-abdominal esophagus, moderately severe esophageal dysmotility, and markedly prolonged gastric emptying). Evaluations included (1) a gastroenterology consultation; (2) barium esophagography; (3) a gastric emptying study with solids; (4) upper GI endoscopy; and (5) esophageal manometry.
Third, cough severity and the impact of cough on health-related dysfunction were assessed by having patients fill out two self-administered instruments. The Adverse Cough Outcome Survey (ACOS) determines the reasons why patients with chronic cough seek medical attention.11 Patients were asked to reply yes or no to 29 potential psychosocial and/or physical adverse occurrences. Patients were instructed to assess the severity of their cough using a visual analog scale (VAS) by marking a horizontally drawn 100-mm line where they perceived their cough to be since their last visit. The scale ranged from 0 to 100, corresponding to descriptors that ranged from none to very severe.
Fourth, following the collection of data, patients were seen in consultation by our surgeon (M.P.C.) who had been specifically trained and was experienced in performing a wide spectrum of laparoscopic and open antireflux operations. Fifth, the patient was offered antireflux surgery when the multidisciplinary evaluation team (R.S.I., J.K.Z., and M.P.C.) by consensus recommended surgery.
Upper GI Evaluations
These were performed and interpreted according to previously published methods. Barium esophagography was performed according to the method of Levine and Laufer12
; results were considered positive for pathologic gastroesophageal reflux (GER) when reflux to the midesophagus or higher was demonstrated. Reflux esophagitis was endoscopically interpreted according to the criteria of Sonnenberg and coworkers.13
Patients underwent esophageal manometry after an overnight fast; any medications that might have affected lower esophageal sphincter (LES) pressures or amplitudes of esophageal body contractions were discontinued 72 h before the procedure. Manometry was performed and interpreted in standard fashion14
using a four-channel, solid-state catheter (Konigsberg Instruments; Pasadena, CA) with a diameter of 4 mm and possessing pressure sensors (120° offset) located 7, 12, and 17 cm from the distal tip. The normal range for LES pressure in our laboratory is 14 to 34.5 mm Hg. Dysmotility disorders that would contraindicate a fundoplication included diffuse esophageal spasm, achalasia, or diffuse, severe hypoperistalsis of the body of the esophagus. Moderately severe hypoperistalsis of the body of the esophagus would not contraindicate a modified fundoplication. Gastric emptying study with solids (technetium-tagged scrambled eggs) was performed according to the method of Mettler and Guiberteau.15
If the stomach emptied 
50% of the meal in < 90 min, the study finding was considered normal.
Twenty-four-hour esophageal pH monitoring was performed and interpreted as we have previously described.2 16 After determining the location of the gastroesophageal junction by barium esophagraphy, a 2.5 mm in diameter monocrystalline catheter with two antimony pH electrodes at the distal tip and 15 cm proximal to the tip (Medtronic; Minneapolis, MN) was transnasally inserted into the esophagus under fluoroscopic guidance. After the pH sensor had been placed 5 cm above the gastroesophageal junction, the catheter was secured at the nose and attached to a pH recording device with patient event marker button (Digitrapper; Medtronic, Minneapolis, MN). Prior to insertion, catheters and Digitrappers were calibrated using pH buffers 1.00 and 7.00. During the monitoring period, patients filled out a standardized event diary and activated the event marker buttons to correspond to the recorded entries. They were allowed unrestricted ambulation and a normal diet except for abstinence from foods and beverages having pH values known to be < 5.
After completing the monitoring period, the catheters were removed and Digitrapper interfaced with a personal computer and printer for displaying and charting of collected data. The tracings were analyzed by a diagnostic software package (EsopHogram, version 5.70C2; Gastrosoft; Milwaukee, WI) and by hand for the following: (1) calibration curves of pH 1.00 and 7.00; (2) number of acid reflux events; (3) longest upright and supine acid reflux events in minutes; (4) fraction of time that pH was < 4; (5) number of acid reflux events lasting > 4 min; (6) number of coughs; and (7) number of times cough appeared to be induced by an acid event (ie, pH < 4). The beginning of an acid reflux event was defined by a fall in pH to < 4, the end by a rise to pH > 5. A cough was considered to be induced by acid reflux when the cough was preceded by a drop in pH to < 4 and the cough occurred within 3 min of the drop.
Twenty-four-hour esophageal pH monitoring was considered consistent with GERD as the cause of cough when the following criteria were met: (1) any GER parameter in the distal esophagus was above normal physiologic values (eg, < 51 acid reflux events, 
4 acid reflux events lasting > 4 min, < 4.4% of total time pH < 4, and < 5.6 min and 16.8 min for longest supine and upright acid reflux events, respectively; and/or (2) a reflux event appeared to induce a cough.
Postoperative Protocol
The postoperative evaluations consisted of follow-up clinical evaluations, and having patients again fill out the ACOS and VAS instruments. Clinical evaluations were planned to take place 1 week following discharge and monthly as needed. They were undertaken in our ambulatory clinic for patients living locally, or by telephone for patients living outside of our area. Cough severity and health-related dysfunction assessments were planned to occur after the effects of surgery had fully disappeared and at 1 year.
Statistical Analyses
Analyses consisted of paired t tests, Spearman’s correlation, and averaged multivariate testing by repeated-measures analysis of variance using a statistical software package (SPSS 9.0 for Windows; SPSS; Chicago, IL). The 0.05 level of significance was used throughout.
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Results |
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Because all eight patients fit the clinical profile that suggested that GERD was the likely cause of their cough, they underwent antireflux surgery with subsequent elimination or improvement of cough in all. They represent our study group, consisting of seven women and one man, with a mean age of 54.2 ± 10.8 years (range, 39.2 to 72.2 years) and complaining of cough when initially seen for 77.8 ± 69.6 months (range, 2 to 180 months). None were obese. Following surgery (median, 41.2 days), six of eight patients stated that their coughs had disappeared as a problem; two of eight patients indicated that their coughs had noticeably improved. These favorable responses were maintained at 1 year and are reflected in the improvements in cough severity VAS and health-related dysfunction ACOS scores presented below. Long-term follow-up by telephone during the month of July 2001 revealed that these favorable responses had been maintained, depending on the individual patient, from 2.5 to 4 years following the anniversary date of the surgery.
Results of Preoperative Evaluations
Clinically, cough was the chief complaint in all patients; initially, three of eight patients had no GI symptoms. While five patients initially had one or more typical GI reflux symptoms prior to any medical therapy, these symptoms were only brought out during specific questioning. The effects on cough and GI reflux symptoms of antireflux medical therapy (Table 1
) that decreased the percentage of esophageal acid (ie, pH < 4) in 24 h to 0 were as follows: GI symptoms remained absent and cough unchanged in two of eight patients; previously absent GI symptoms appeared and cough remained unchanged in one of eight patients; GI symptoms and cough partially improved but did not disappear in two of eight patients; GI symptoms disappeared but cough did not improve in three of eight patients.
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Effects of Antireflux Surgery on Cough Severity and Health-Related Dysfunction due to Chronic Cough
The results of VAS scores, a reflection of cough severity, and ACOS scores, a reflection of health-related dysfunction due to cough, were obtained at three time points, before surgery (median, 23.7 days), after surgery when patients had fully recovered from the effects of surgery (median, 41.2 days), and 1 year following surgery (Fig 1
). Over time, surgery significantly decreased VAS scores from a mean ± SE of 73.1 ± 6.1 to 19.1 ± 8.3 to 22.6 ± 8.1 (p = 0.001) and ACOS scores from 15.0 ± 1.1 to 2.0 ± 1.3 to 3.6 ± 2.3. The improvement initially noted approximately 3 weeks after surgery was dramatic and consistently noted in all patients initially and was sustained at 1 year. VAS scores had decreased 75.7% ± 24.3% in the short term after surgery and 64.4% ± 37.7% at 1 year. ACOS scores had decreased by 84% ± 29.6% in the short term after surgery and 78.9% ± 37.1% at 1 year. Over time, VAS and ACOS scores correlated significantly with each other (r = 0.88, p = 0.004).
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Discussion |
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First, we have confirmed that antireflux surgery can improve chronic cough due to GERD that is resistant to intensive medical therapy. While others have come to a similar conclusion,20 21 22 the medical treatment regimens used in these previous studies were not as intensive as ours. For instance, Fitzgerald et al20 prescribed dietary and lifestyle changes; cimetidine, 300 mg qid, or ranitidine 150, mg bid; plus metoclopramide, 10 mg, before meals and an antacid, 30 mL, at bedtime. While DeMeester et al21 did not provide the specifics of the medical regimens on which their patients failed to improve, they briefly mentioned that their patients "were unresponsive to therapy with antacids or H2 [histamine type 2] blockers." Allen and Anvari22 prescribed bed elevation, an antireflux diet, unspecified prokinetic agent(s) and dose, and omeprazole in doses varying from 40 to 80 mg/d. While our medical treatment regimens summarized in Table 1 included enough acid-suppression medication to totally or near totally eliminate intraesophageal acid during 24-h esophageal pH monitoring, such was not determined to be the case in the three cited studies.20 21 22 While it is possible that even further intensification of prokinetic and/or acid-suppressing medications in our patients would have been required to eliminate or substantially improve their coughs, we did not think that it was likely or that we were justified in trying to do so because our patients had not been responding to gradually increasing doses of these types of medications.
Second, we have prospectively confirmed that there is a clinical profile that predicts when patients are likely to have GERD as the cause of their chronic cough. When we initially prospectively assessed this profile, it was reported in a study of 12 patients with chronic cough due to GERD whose coughs disappeared with medical therapy.2 GERD was silent from a GI standpoint in nine patients. In this study, we prospectively extended the observation to a group of eight highly selected patients in whom we made sure that we had ruled out eosinophilic bronchitis before surgery and whose coughs disappeared or substantially improved following antireflux surgery after initially failing to respond or disappear with intensive medical therapy and prior antireflux surgery in four patients. While antireflux surgery has yielded a long-term favorable effect on cough in all eight of the subjects reported herein, the surgical outcome data at 1 year in our larger group of patients show that surgery will not cure all patients predicted to have chronic cough due to GERD. The favorable outcome in the 21 patients who had not previously undergone antireflux surgery before referral to us is presently 86%.23 Because this clinical profile has only been prospectively validated in a relatively small number of patients to date and it is not a perfect predictor that cough will improve or disappear with antireflux surgery, we suggest caution in using it to recommend antireflux surgery. Before making the recommendation, we evaluate each patient, without deviation, according to the testing and treatment protocols that we have outlined and referred to in our "Materials and Methods" section and only when our patients understand clearly that surgery may not cure their cough.
While it is possible that the 14% of patients who met the profile in our larger group23 failed to improve with antireflux surgery because GERD was not the cause of their cough, it is also possible that cough is still due to GERD but failed to be controlled by surgery. Theoretically, antireflux surgery may fail to control coughing because (1) the surgery may not be effective for technical reasons and/or the appropriate operation(s) was not performed as we noted in four of our patients; or (2) the site and pathway where GERD is provoking cough may be so sensitive that even the markedly diminished refluxing that takes place following surgery is enough to induce cough. As we continue to follow and reevaluate our larger cohort of patients, we hope to collect additional data that will support or refute these speculations.
Third, GERD cannot be excluded on clinical grounds alone as the potential cause of chronic cough. For example, we have shown that there can be a dissociation in improvement in GI symptoms and chronic cough with intensive medical therapy. In three of eight patients (38%), GI symptoms disappeared while cough remained unchanged. We have also shown that properly performed antireflux surgery can significantly improve cough due to GERD when intensive medical therapy and prior antireflux surgery failed to do so. In addition to redoing Nissen fundoplication in two patients who had previously undergone this procedure, these two patients also underwent a gastric drainage procedure that had not been previously done. Consequently, when GI symptoms improve and cough does not, and when cough has persisted despite prior intensive medical therapy or surgery, it should not be assumed that cough cannot be due to GERD especially when patients fit the clinical profile that predicts that chronic cough is likely due to GERD.
Fourth, the term acid reflux disease when applied to chronic cough due to GERD can be a misnomer. At a time when acid suppression during 24 h of monitoring had eliminated acid reflux in three patients and near totally in five patients, cough did not improve in six of eight patients and partially improved to an unacceptable degree in two patients. Yet, following antireflux surgery, cough significantly improved or was totally eliminated in all of our patients over a 1-year period of time of prospective direct observation and 2.5 to 4 years of long-term follow-up by telephone. These findings suggested that cough in our patients was caused by nonacid rather than acid reflux disease.
Other possible explanations were not likely. Prospective documentation of sustained weight loss of at least 5 lb and the decrease in esophageal acid reflux events and contact times on serial 24-h monitoring studies culminating in the total/near-total elimination of acid essentially eliminated our concern that our patients were not receiving their acid-suppressing medications. While it is possible, we do not believe that it is likely that the improvement in our patients was due to placebo effect for the following reasons: (1) our patients had been complaining of a persistently troublesome cough for an average of approximately 6.5 years at the time they were initially referred to us; (2) previous treatment, including antireflux surgery by numerous other physicians, had failed; and (3) the dramatic and consistent improvement in all patients in cough severity and health-related dysfunction scores at a median of 41 days following surgery was maintained at 1 year, and longer by telephone follow-up. According to a review24 of the literature on distinguishing a placebo from a real treatment effect, we believe that we have satisfied the most important aspects in measuring a real benefit due to surgery in chronic, non-life-threatening disease such as chronic cough. We allowed > 6 months to elapse following surgery before assessing final benefit, and we measured the effects of elimination of cough with a validated instrument that reflects health-related quality of life and does not specifically mention surgery. If antireflux surgery had a favorable effect on cough in our patients by treating a disease other than GERD, we cannot conceive of what that disease might be.
While we have no doubt that some patients with chronic cough due to GERD have acid reflux disease,5 25 26 evidence is mounting that cough due to GERD is not always or solely mediated by acid.27 For example, in patients whose coughs were eventually shown to be due to GERD,2 an increasing number of coughs could not be provoked with acid during 30-min intraesophageal infusions of 0.1 N HCL compared to 0.9% saline solution, administered in a randomized, double-blind, standardized fashion. In this same study, failure of intraesophageal acid infusion to induce cough was supported by 24-h esophageal pH monitoring data; the number of coughs induced during acid infusion was negatively correlated with the number of acid reflux events in the distal esophagus (r = - 0.64, p = 0.01). Based on our previous work2 as well as present study, we believe that a cogent argument can be made for a nonacid mediator (eg, alkaline pH, pancreatic enzyme, bile, and esophageal dysmotility associated with reflux28 29 ) of GER-induced cough in some patients such as those reported here. This is a concept that is increasingly recognized in the literature.30
While it is not known whether nonacid reflux disease might provoke cough in different ways than acid reflux disease, we theorize that all reflux disease potentially stimulates cough via the same pathophysiologic pathways that have been reviewed elsewhere.31 On the basis of normal chest radiographic findings and the paucity and/or absence of endoscopic findings supporting reflux-induced laryngeal or hypopharyngeal injury or aspiration, we speculate that GERD was causing cough in our patients by stimulating an esophageal-bronchial reflex pathway.
Perspective
Based on our past2
25
and present work and that of others,5
23
26
32
33
we believe27
that (1) there are likely to be multiple potential mediators of cough including, but not limited to, acid in the gastric refluxate; and (2) which mediator(s) trigger(s) cough in some patients may differ from those in others. With respect to this multiple-mediator pathogenetic concept, perhaps there is a parallel that can be drawn between GERD and asthma. We know that there are multiple mediators of the inflammation of asthma including, but not limited to, leukotrienes. Although antileukotriene modifier agents are beneficial in many asthmatics, they are not uniformly so. Hopefully, in the near future, the availability of simultaneous 24-h esophageal monitoring of intraesophageal impedance and pH will allow us to more easily determine when nonacid reflux disease is the cause of a persistently troublesome cough.34
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Footnotes |
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Presented in part at the annual meeting of the American Thoracic Society, April 28, 1999, San Diego, CA.
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This article has been cited by other articles:
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  I Mainie, R Tutuian, S Shay, M Vela, X Zhang, D Sifrim, and D O Castell Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring Gut, October 1, 2006; 55(10): 1398 - 1402. [Abstract] [Full Text] [PDF]
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