Definition

Gastroesophageal reflux (GER) can impact the lung and is a cause of subacute and chronic cough. The esophagus and the lung share common embryonic foregut origins and vagal innervation.

In 1998, the American College of Chest Physicians (ACCP) published their first evidenced-based guideline concerning the diagnosis and management of chronic cough that included a systematic, diagnostic protocol.¹ These guidelines were updated in January 2006² and include an empiric integrative approach that can be easily implemented for individual patients.

These new guidelines define subacute cough as a cough lasting 3 to 8 weeks and chronic cough as a cough lasting more than 8 weeks in a nonsmoking, immunocompetent host. It also states that the subject should have a normal or stable chest radiograph and not be on medications that could cause chronic cough, including angiotensin-converting enzyme (ACE) inhibitors. Utilizing this systematic anatomic protocol allows the cause of chronic cough to be determined in 88% to 100% of cases. Specific therapy toward the cause of chronic cough leads to cough resolution in up to 98% of cases.¹ Subacute and chronic cough has more than 20 etiologies.^{1, 2, 3, 4, 5} Gastroesophageal reflux–related chronic cough is defined as a chronic cough that is improved or eliminated with GER-specific therapy^{1, 2, 3} (Table 1). Even though GER is a cause of subacute cough, this review focuses on chronic cough.

Table 1: Common causes of chronic cough^* (excluding ACE inhibitors)4, ⁵²

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History of Disease

Richard Irwin and colleagues⁵ initially noted that GER caused chronic cough in 1981. These investigators evaluated the spectrum and frequency of chronic cough causes. In 1981, GER was the fourth most common cause of chronic cough with a prevalence of 10%.⁵ With the advent of more sophisticated diagnostic and therapeutic options to identify subjects with GER, GER was found to be the cause of chronic cough in 36% to 41% of cases and is currently considered the second most common cause of chronic cough.⁶ Also, during the past 25 years researchers have elucidated physiologic mechanisms explaining how GER causes cough. Cough can also be elicited by nonacid GER.⁷

Epidemiology

When the diagnosis of GER-related cough is based on a favorable response to GER therapy, prospective before and after intervention studies show that GER is one of the most common causes of chronic cough in adults.³ In subjects with chronic cough, prevalence of GER-related chronic cough ranges from 5% to 41%, depending on how GER is defined.^{5, 6, 8, 9, 10, 11, 12, 13} Establishing a prevalence rate for GER-related cough is complicated by the fact that in many patients, cough can have more than one underlying cause. For instance, recent investigations reveal that chronic cough is caused by more than one condition in up to 62% of cases.¹ In combining reports, a single cause of chronic cough was found in 38% to 82%, two causes of cough were found in 18% to 62%, and three causes of cough were found in up to 42% of cases.¹ The three most common causes of chronic cough are upper airway cough syndrome (formerly referred to as postnasal drip), GER, and cough-variant asthma. In general, studies show that GER is a cause of chronic cough in approximately 25% of adults.¹⁴ These data depend partly on how the GER diagnosis is made. For instance, if GER is diagnosed by history, endoscopy, or barium esophagram, 10% of chronic cough patients have GER.⁵ However, if 24-hour esophageal testing is employed, GER is the cause of cough in 40% of patients.¹⁵ Esophageal GER symptoms are present in 6% to 10% of chronic cough patients; however, GER may be clinically silent from an esophageal standpoint. Irwin and colleagues⁵ found that 43% of patients with cough (that improved or was eliminated with GER therapy) denied heartburn and/or a sour taste in their mouth, which are common indicators of silent reflux. Kiljander and colleagues¹⁶ noted that 28% of patients with chronic cough that improved with GER therapy did not have typical GER symptoms. In another prospective study population, Irwin and colleagues¹⁷ noted that GER was clinically silent in 75% of GER-related chronic cough patients. In conclusion, GER is a cause of chronic cough in up to 41% of cases and is the second most common cause of chronic cough. Furthermore, GER is clinically silent in up to 75% of patients with GER-related chronic cough (cough improved with GER therapy).

Pathophysiology

Two major pathophysiologic mechanisms play a role in GER-related chronic cough including an esophagotracheobronchial cough reflex and microaspiration. Furthermore, nonacid gastric refluxate may contribute to cough. Cough can also induce GER episodes, causing a cough/GER self-perpetuated cycle that may further potentiate chronic cough. Esophageal dysmotility may also play a role.

Many investigators note the presence of an esophagotracheobronchial cough reflex. Irwin and colleagues,¹⁸ using dual probe esophageal pH testing, noted that cough occurred simultaneously with acid instillation in the distal esophagus 28% of the time compared to 6% of the time with acid in the proximal esophagus. Ing and colleagues¹⁹ noted that distal esophageal acid occurred simultaneously with coughing in 78% of cough episodes, without evidence of aspiration on chest radiographs or laryngeal examinations. In a randomized controlled study, Ing and colleagues²⁰ also examined the afferent pathway of the cough reflex, showing an increase in cough frequency with esophageal acid compared to esophageal infusions of normal saline. Blocking the afferent limb of the cough reflex with esophageal lidocaine inhibited acid-induced cough. Blocking the efferent limb of the cough reflex with inhaled ipratropium (an anticholinergic agent) also inhibited cough, but esophageal ipratropium did not inhibit the cough reflex. This supports the presence of a vagally mediated cough reflex.²⁰ With this neural reflex mechanism, refluxate into the esophagus is thought to be a sufficient stimulus to cause cough.²¹

There are also local axonal reflexes between the esophagus and the trachea that can impact cough.²² For instance, Ferrari and colleagues²² noted that the capsaicin inhalation cough threshold is lower in subjects with GER but without cough, compared to controls, irrespective of the presence of esophagitis, suggesting that GER may decrease the cough threshold. Capsaicin polarizes C-fibers in the afferent neurons, so neuroinflammatory mediators may also come into play.

So why does GER cause cough in some individuals but not in others? Potential theories abound, including different response characteristics of esophageal receptors and primary afferents, altered responsiveness of the cough center in the central nervous system, local release of protussive neurotransmitters, and microaspiration. Further research is needed to investigate these possibilities.

Furthermore, GER can stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract (as in the larynx) without aspiration, or by irritating the lower airway respiratory tract by macroaspiration or microaspiration into the lung, or GER may irritate the lower airway respiratory tract by macroaspiration or microaspiration.

Rolla and colleagues²³ examined seven subjects with GER and chronic cough, and seven subjects with GER but without cough. They noted that those with chronic cough had higher laryngitis scores, decreased lower esophageal sphincter (LES) pressures and upper esophageal sphincter (UES) pressures, higher esophageal acid contact times, and more prolonged esophageal acid clearance times, compared to subjects with GER but without cough. Laryngitis scores were inversely proportional to the provocative dose of histamine required to produce five coughs. Furthermore, laryngitis scores and the provocative dose findings improved with GER therapy.²³ Benini and colleagues²⁴ performed bronchial biopsies in six subjects with GER-related chronic cough showing evidence of airway inflammation with epithelial desquamation, with inflammatory cells, including monocytes.

Paterson and Murat²⁵ observed microaspiration into the hypopharynx in nine of 15 chronic cough patients. Notably, many GER-related chronic cough patients had evidence of laryngeal injury. This is further evidenced by Phua and colleagues,²⁶ who examined laryngopharyngeal sensitivity testing in 15 GER-related chronic cough patients and 10 normal controls. Laryngopharyngeal sensitivity threshold was higher in the GER-related chronic cough patients (9.5 mmHg) compared to control subjects (3.7 mmHg). Thus, the sensory integrity of the laryngopharynx is impaired in GER-related chronic cough patients, which could predispose to aspiration.

Esophageal dysmotility may also be important. Kastelik and colleagues²⁷ noted that esophageal dysmotility is common in patients with GER-related chronic cough. They noted that 67% of chronic cough patients had abnormal esophageal manometry. Furthermore, esophageal dysmotility was the only esophageal abnormality found in one-third of patients. These patients had normal esophageal acid contact times. At this point it is not known whether esophageal dysmotility is an adverse occurrence due to GER, or whether it contributes to GER in these patients.

Nonacid GER may also impact chronic cough. Irwin and colleagues¹⁷ noted that esophageal acid and saline caused cough at the same frequency, so acid may not be the sole cough mediator. Furthermore, GER-related cough does not always resolve despite control of esophageal acid with aggressive medical therapy and may require fundoplication for resolution.^{28, 29} Sifrim and colleagues⁷ verified that nonacid GER events do occur in chronic cough patients. They examined 28 chronic cough patients with combined esophageal pH and impedance and examined the temporal association between cough and acid events (pH <4), weakly acidic events (pH <7), and alkaline events (pH 7). Of 98 GER-cough episodes, 65% involved acid GER, 29% involved weakly acidic GER, and 6% involved alkaline GER, verifying that both weakly acidic and nonacid GER are temporally associated with cough.

There may also be a self-perpetuating positive feedback cycle between cough and GER, where cough actually precipitates GER.²⁰ For instance, cough can cause a pressure gradient differential between the abdomen and the thorax leading to a functional decrease in LES pressure. Furthermore, cough can potentially trigger transient LES relaxations. Swallowing- related LES relaxations may also predispose to GER in the distal esophagus. The GER then initiates the distal esophagotracheobronchial reflex, leading to coughing episodes and potentially a cough-GER cycle. Although cough-induced GER episodes are observed in 24-hour esophageal pH tracings, the mechanism by which GER episodes are triggered by coughing is still not fully elucidated.²⁰

Clinical Features

Clinical features of a cough that is at least partially caused by GER include a chronic cough associated with symptoms of GER such as heartburn or regurgitation. Worsening of cough may be noted when eating foods that decrease LES pressure (peppermint, chocolate, alcohol). Using a prospective study design, Mello and colleagues¹⁵ found that detailed questions about cough characteristics, sputum production, and timing were not useful in determining the underlying cause of cough.

Many patients with cough that is at least partially caused by GER do not have esophageal GER symptoms. Irwin and Madison⁴ describe the clinical profile of patients with chronic cough owing to "silent" reflux. This clinical profile is based on post hoc analysis of four prospective intervention studies.^{5, 8, 15, 30} This clinical profile includes individuals with chest radiographs that are normal or that have stable nonsignificant findings, individuals who are not exposed to environmental irritants, and individuals who are nonsmokers who do not take ACE inhibitors or other medications that can cause chronic cough. Furthermore, symptomatic asthma has been ruled out either by the cough not being improved with aggressive therapy or negative methacholine inhalation challenge test. Upper airway cough syndrome (postnasal drip syndrome) has been ruled out, with the cough failing to improve with first-generation H₁-antagonist therapy and a sinus computed tomography (CT) scan showing no evidence of sinusitis. Furthermore, nonasthmatic eosinophilic bronchitis has been ruled out either by the cough not being improved on inhaled or systemic corticosteroids, or absence of eosinophils in sputum cytology. These individuals fit the clinical profile for patients having silent GER. Table 2 illustrates these points.

Table 2: Patient profile for patients with clinically silent gastroesophageal reflux (GER)-related chronic cough1, ^{2, 52}

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History

In patients with chronic cough, the characteristic and timing of the cough are not helpful in the clinical evaluation of cough that is at least partially caused by GER.^{15, 30} All patients with chronic cough should be asked about the presence of typical esophageal GER symptoms including regurgitation, heartburn, and dysphagia. Other extraesophageal manifestations of GER may be present including hoarseness, globus, sore throat, and dysphonia. Some patients note hoarseness and cough after eating. More commonly, patients present with a daytime cough that is nonproductive and is long-standing—up to 58 months in duration.³⁰ Patients may notice that their cough is exacerbated by certain asthma medications that promote GER including theophylline, inhaled ₂-adrenergic agonists, oral corticosteroids, progesterone, calcium channel blockers, anticholinergic agents, morphine, and meperidine.^{31, 32, 33, 34} Many patients have asymptomatic GER.¹⁸

Physical Examination Findings

In patients with GER-related chronic cough, physical examination findings are commonly normal. Pulmonary examination does not reveal wheezing, rales, or findings consistent with other pulmonary diseases that can cause cough. Patients may cough during examination, especially with continued respiratory effort. Evidence of laryngeal inflammation may be found on upper airway endoscopy. Patients with GER-related chronic cough do not have findings of postnasal drip in their upper airway.

Laboratory Findings

There are two potential reasons for performing laboratory evaluations in patients with chronic cough caused by GER. One is to rule out other causes of chronic cough and the other is to evaluate for the presence of GER.

As part of the workup for chronic cough, the following evaluations are helpful^{1, 2, 4, 35}

• Chest radiograph to ensure that no underlying pulmonary parenchymal disease is present such as interstitial lung disease.
• High-resolution CT chest scan to delineate other pulmonary parenchymal causes of chronic cough (including bronchiectasis).
• Spirometry before and after bronchodilator therapy with an inhaled ₂-agonist, methacholine challenge test, or peak expiratory flow rate monitoring to evaluate for asthma.
• Sinus CT scan to evaluate for sinusitis and upper airway cough syndrome (postnasal drip syndrome).
• Upper airway examination with nasal endoscopy for evaluation of sinusitis and upper airway syndrome (postnasal drip syndrome).
• Cardiac evaluation for the possibility of pulmonary edema.
• Sputum cytology for eosinophils to evaluate for nonasthmatic eosinophilic bronchitis.
• Bronchoscopy when there is an indication for bronchoscopy (such as a suspicion of an endobronchial anatomical abnormality), a suspicion of a secondary underlying pulmonary process, or to evaluate the source of hemoptysis.
• Pertussis evaluation is useful in selected patients: nasopharyngeal aspirate for Bordetella pertussis culture, noting a fourfold increase in immunoglobulin G (IgG) or IgA, and antibodies to Bordetella pertussis.

The American College of Chest Physicians evidence-based cough guidelines can guide physicians through this complicated workup.^{1, 2, 4} From a gastroenterologist's point of view, most of this workup is performed by a pulmonologist, allergist, or a primary care physician. Often a gastroenterologist evaluates chronic cough patients who have failed aggressive GER medical therapy or those in whom there is a question of whether GER is adequately controlled. Gastroenterologists may also see patients with complicated GER, and chronic cough patients considering surgical fundoplication.

Laboratory evaluation for GER-related chronic cough includes an empiric proton pump inhibitor (PPI) trial, esophageal manometry, and pH testing on and off GER medication.³⁵

Esophageal testing may also be useful in identifying patients with GER-related chronic cough, especially in the 75% of patients who are asymptomatic from an esophageal standpoint. Esophageal manometry is helpful in some cases. Kastelik and colleagues²⁷ reported esophageal manometrics and pH testing in 34 patients with GER-related cough defined by cough resolution with GER-directed therapy. They defined esophageal dysmotility as the presence of nonperistaltic contractions 30% of the time, or a contraction amplitude of <15 cm of water, or an LES pressure of <10 cm of water. They noted that 21% of patients had normal esophageal pH and manometry variables, whereas 79% had at least one abnormal esophageal test. Sixty-seven percent of patients had abnormal esophageal manometry with 42% having an LES pressure of <10 cm of water. Interestingly, 32% had abnormal manometry with normal esophageal pH variables, which means that these individuals would not have been identified based on esophageal pH criteria. This study verifies that esophageal dysmotility is common in GER-related chronic cough patients, and that esophageal dysmotility may be the only abnormality in more than one-third of these patients. Esophageal manometrics may also be useful in evaluating the operative status of patients with GER-related chronic cough.

Esophageal pH testing is also useful. Prospective trials examining the role of 24-hour esophageal pH testing show that it has a sensitivity of approximately 90% and a specificity ranging from 66% to 100% in chronic cough patients.^{8, 17, 30} Temporal correlation between esophageal acid and cough provides key information. Kastelik and colleagues²⁷ noted a temporal cough correlation in 87% of subjects. They defined cough correlation as esophageal pH <4 simultaneously or within 5 minutes preceding a cough. Irwin and colleagues¹ noted that esophageal pH testing in GER-related chronic cough patients had positive and negative predictive values of 83% and 90%, respectively. Wunderlich and Murray³⁵ examined the symptom association index (SAI) in chronic cough patients. The SAI is equal to 1 minus the probability of a falsely significant relationship between cough and episodes (as determined by Fisher exact test) times 100. The SAI is a more sensitive measure of temporal association. Further work needs to be done to evaluate the accuracy of the SAI. Irwin and colleagues¹⁷ found that correlation of cough episodes with simultaneous GER events is more helpful than esophageal acid contact times alone, which may be normal in patients with chronic cough responsive to GER therapy. There are potential problems with correlating cough with esophageal acid in that Paterson and Murat²⁵ monitored cough by esophageal manometry. Coughing causes marked changes in pleural pressure that can be monitored with esophageal manometry. They noted that subjects reported only 10% of manometrically determined coughs when esophageal pH and manometry were measured simultaneously.

Esophageal pH testing can also be useful in documenting adequacy of GER therapy. Esophageal impedance integrated with pH can also be useful in evaluating the presence of nonacid GER in selected patients.⁷

The Bernstein test may be helpful in selected patients. Allen and Anvari³⁶ noted that a positive Bernstein test causing cough predicted cough response with surgical fundoplication. This test is not often used clinically. Barium esophagram can assess for the presence of hiatal hernia and GER, but it has a lower sensitivity than esophageal pH testing.¹ Esophageal endoscopy can be performed; however, most subjects do not have evidence of esophagitis, and esophageal endoscopy has a lower sensitivity than esophageal pH testing.¹ Radionuclide gastric emptying studies assess for delayed gastric emptying, although it is difficult to link GER and cough with this test. Evaluation of bronchoalveolar lavage (BAL) fluid and induced sputum for lipid-laden macrophages may be a marker of aspiration; however, it has a low specificity of 57%.³⁷ Parameswaran and colleagues³⁸ noted lipid-laden macrophages in induced sputum and found that their presence predicted the presence of oropharyngeal reflux as documented by dual-probe 24-hour esophageal and pharyngeal pH testing. The clinical usefulness of lipid-laden macrophages in induced sputum and BAL fluid has not been adequately assessed in chronic cough patients, so at this time, they do not play a major role in the diagnosis of GER-related chronic cough.

Differential Diagnosis

The differential diagnosis for GER-related chronic cough includes all potential causes for chronic cough as outlined in the ACCP evidence-based cough guidelines.^{1, 2, 3, 4} The three most common causes of chronic cough are:

• Upper airway cough syndrome (formerly postnasal drip syndrome)
• Gastroesophageal reflux
• Cough variant asthma

Cough is caused by more than one etiology in up to 62% of cases; thus, clinicians need to be vigilant about examining for other potential chronic cough causes.¹ Further information is detailed below (see Clinical Course and Complications), especially when cough does not resolve with GER therapy.

Diagnosis

Diagnostic strategies for GER-related chronic cough include careful history taking, keeping in mind that GER is clinically silent in many patients. An empiric trial of medical GER therapy is recommended as the first diagnostic test for GER-related cough. Poe and Kallay³⁹ used the anatomic diagnostic protocol in 214 subjects with chronic cough, where cough resolution was deemed successful. They noted that GER caused chronic cough in 31% of subjects, and GER-related chronic cough was clinically silent in 43% of subjects. Empiric GER therapy included lifestyle therapy, PPIs, and the addition of a prokinetic agent if dysphagia was present or if PPI therapy was unsuccessful. Empiric GER therapy successfully diagnosed and treated GER-related chronic cough in 79% of subjects. Cough resolution occurred within 4 weeks in 86% of subjects. In nonresponding patients, careful testing with esophageal pH testing is recommended.

Empiric GER therapy should be used in patients with esophageal GER symptoms as well as those who fit the clinical profile of "silent GER" as noted above (see Clinical Features). Empiric therapy includes dietary and lifestyle modifications, acid-suppressive therapy with the addition of a prokinetic agent, either initially or if there is no response to acid-suppressive therapy and dietary/lifestyle modifications. Cough response to empiric therapy should be assessed within 3 months. In patients who fail empiric therapy, it should not be assumed that GER has been ruled out as a cause of chronic cough. Objective investigation for GER is recommended because empiric GER therapy may not have been intense enough.³ Esophageal investigation with esophageal manometry and pH testing is useful if empiric therapy fails. A combination of esophageal pH and impedance testing may be useful in assessing for nonacid GER. Table 3 reviews the diagnostic strategies for GER-related chronic cough.

Table 3: Diagnostic strategies for GER-related chronic cough

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Clinical Course and Complications

The clinical course of GER-related chronic cough is varied. In trials not using PPIs, cough resolution was prolonged and took up to 179 days.⁸ In trials using PPIs, cough resolution was much more rapid, and cough resolution occurred with 2 weeks; however, it took as long as 53 days in some patients.^{40, 41} This verifies that aggressive acid suppression should be initiated with twice-daily PPI before breakfast and dinner along with lifestyle modifications.

The major complications of GER-related chronic cough is cough nonresolution despite aggressive GER therapy. Table 4 displays potential reasons for cough nonresolution.⁴ These include inadequate acid control on GER therapy and breakthrough GER events. Another possibility is inadequate GER therapy duration. Furthermore, failure to adequately treat coexisting causes of cough that perpetuate the cough-GER cycle may result in cough nonresolution. One example would be of not treating cough variant asthma in the setting of GER. In a case report, omeprazole has been noted to induce cough.⁴² The package insert for omeprazole (Prilosec) shows that that 1.1% of patients on this medication report cough.⁴³ Nonacid GER may also cause cough.⁷ Often, GER symptoms improve before cough symptoms improve.

Table 4: Reasons for non-resolution of cough in GER-related chronic cough

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Treatment

Treatment for GER-related chronic cough includes lifestyle modification and weight loss, if the patient is obese. Aggressive acid-suppressive therapy utilizing a PPI with dosing 30 minutes before breakfast and 30 minutes before dinner should be initiated and continued until the cough improves or resolves. At that point, the clinician can decrease the PPI dosing to once a day or even switch to an H₂-blocker. Addition of a prokinetic agent is useful in patients who have cough nonresolution on high-dose PPI and in those with dysphagia.³⁹ In the nonresponders, esophageal pH testing while the patient is on GER medication can be useful. Selected patients may require surgical fundoplication for cough resolution. Mainie and colleagues⁴⁴ reported a case of a woman with chronic cough who underwent esophageal pH impedance monitoring in which nonacid reflux was present. Fundoplication resulted in cough resolution.

Surgical fundoplication may also relieve GER-related chronic cough. Allen and Anvari³⁶ examined predictors of cough response with surgical fundoplication. They examined 287 cough patients undergoing laparoscopic Nissen fundoplication with preoperatively performed endoscopy, Bernstein test, esophageal manometry with pH, a quality-of-life measurement, and a validated cough symptom score. All subjects were reevaluated postoperatively. Predictors for positive cough response in patients included a positive Bernstein test, a higher preoperative cough score, and a good cough response on PPI. Some subjects require surgical fundoplication for cough resolution.³⁶ In general, surgical fundoplication is recommended in chronic cough patients with cough improvement on PPI who are deemed good surgical candidates. Patients with nonacid GER documented by a combination of esophageal pH and impedance testing can also be considered for surgical fundoplication.⁴⁴ Endoscopic GER therapies have not been evaluated in GER-related chronic cough and should be considered experimental.

Outcomes

As previously mentioned, aggressive GER therapy results in cough improvement or cough resolution in most patients with GER-related chronic cough if the appropriate diagnostic/therapeutic protocol is followed. Multiple studies have examined cough outcome with aggressive medical and surgical GER therapy. Table 5 reviews prospective double-blind, placebo-controlled trials using a PPI. Although there is significant selection bias present in these studies, cough response was noted in at least 35% of subjects. Ours and colleagues⁴⁰ noted that cough resolution took approximately 14 days using omeprazole, 40 mg twice daily for 12 weeks. Kiljander and colleagues¹⁶ performed a crossover, placebo-controlled trial and noticed significant cough improvement after 8 weeks of omeprazole, 40 mg a day. There were some statistical issues relating to how the crossover design trial was evaluated. Chang and colleagues⁴⁵ examined the Cochrane Database and noted that GER was a causative factor of cough in up to 41% of patients. They performed a meta-analysis on five studies of adults using a PPI for 2 to 3 months. There was no difference in cough resolution in placebo versus treated patients. There was a significant improvement in cough scores with PPI therapy with a mean difference of -0.41 [95% confidence interval (CI) -0.75 to -0.07] in crossover trials. The authors noted significant heterogeneity in the study populations across trials and they had insufficient evidence for general recommendations, including GER treatment duration.

Table 5: Outcomes of treatments with proton pump inhibitors in GER-related chronic cough in adults

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Surgical fundoplication outcomes for GER-related chronic cough are outlined in Table 6.^{28, 29, 36, 46, 47, 48, 49, 50, 51} Nine prospective studies include 689 subjects. Of these surgically treated subjects, 586 (85%) had a significant cough response.^{28, 29, 36, 46, 47, 48, 49, 50, 51} These studies have design weaknesses including lack of blinding, lack of controls, use of highly selected patient populations, and different postoperative follow-up procedures. Allen and Anvari⁵¹ examined long-term cough outcomes in 527 patients with chronic cough with follow-up for up to 5 years, using a validated cough scale. They noted at 6 months that 83% of patients had a cough response, with 52% of them having cough resolution and 31% having cough improvement. At 2 years, 74% had a cough response, with 43% having cough resolution and 31% having cough improvement. At 5 years, 79% of subjects had a cough response with 36% cured and 35% improved. This study shows that over a 5-year period there is a decrease in cough response. Although GER-related chronic cough generally has a good outcome, GER is a chronic disease, and cough may return when medications are stopped, so episodic and prolonged GER therapy may be required. Surgery may be considered in selected patients.

Table 6: Outcomes of surgical treatments in GER-related chronic cough in adults^*1

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Conclusion

Gastroesophageal reflux is the second most common cause of chronic cough in subjects who are nonsmokers with a normal chest radiograph, not exposed to airway irritants who do not take ACE inhibitors. Identifying GER as a cause of cough is difficult because GER is clinically silent in up to 75% of patients who had cough improvement with GER therapy. Furthermore, chronic cough is caused by more than one etiology in up to 62% of cases. Gastroesophageal reflux elicits cough through an esophagotracheobronchial reflex and by microaspiration of gastric content into the airway. Recently published evidence-based guidelines from the American College of Chest Physicians recommends an empiric trial of GER therapy to help identify and manage chronic cough due to GER. Esophageal testing can be considered in the cough nonresponders and in subjects considering fundoplication surgery. Nonacid GER requires esophageal impedance monitoring for identification, and often requires surgical therapy for resolution. Future research will identify better management tools for cough caused by GER.

• Esophageal motility > disordersSynopsis Clinical disorders of oral, pharyngeal and esophageal motilityReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthmaOverview Esophageal motility disordersReview Heartburn and esophageal painEndoscopic evaluation of esophageal motility disordersEsophageal manometryGastroesophageal reflux monitoring: pH and impedancePathophysiology of gastroesophageal reflux diseaseNonerosive reflux diseaseReflux esophagitis and peptic stricturesBarrett's esophagusBarrett's adenocarcinomaHiatus herniaEosinophilic esophagitisMedical management of gastroesophageal reflux diseaseEndoscopic therapy for gastroesophageal reflux diseaseSurgical therapy for gastroesophageal reflux diseasePathophysiology of achalasia and diffuse esophageal spasmMedical and endoscopic management of achalasiaSurgical treatment for achalasiaOral, pharyngeal and esophageal motility disorders in systemic diseasesOral, pharyngeal, and esophageal motor disorders in infants and childrenOral, pharyngeal and esophageal motor function in agingPharyngeal and esophageal diverticula, rings, and webs
• Gastroesophageal reflux disease > and chronic coughOverview Oral, pharyngeal and upper esophageal sphincter motility disordersReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthma
• Gastroesophageal reflux disease > laryngeal complicationsOverview Oral, pharyngeal and upper esophageal sphincter motility disordersReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthma
• Gastroesophageal reflux disease > and asthmaOverview Oral, pharyngeal and upper esophageal sphincter motility disordersReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthma
• Gastroesophageal reflux disease > pharyngeal complicationsReview Laryngeal and pharyngeal complications of gastroesophageal reflux diseaseGastroesophageal reflux and asthma