The manifestations of gastroesophageal reflux disease (GERD) have been classified into either esophageal or extraesophageal syndromes. Cough, reflux laryngitis, and asthma have been classified as extraesophageal syndromes, whereas reflux chest pain has been classified as a symptomatic syndrome of GERD. In extraesophageal syndromes, patients usually do not display the classic symptoms of reflux, such as heartburn and regurgitation. Upper gastrointestinal endoscopy and pH monitoring, when used to diagnose reflux in patients with symptoms not classic for GERD, have proved to have poor sensitivity and are often not diagnostically helpful. In contrast, an empiric trial of proton pump inhibitors is a well-established, cost-effective tool.
In 2006, an international consensus group developed the Montreal definition and classification of gastroesophageal reflux disease (GERD), and defined gastroesophageal reflux (GER) as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.” They found that GER is common, but has varying prevalence around the world, with Western Europe, North America, South America, and Turkey having the highest prevalence rates of approximately 10% to 20%.
The consensus group recognized that heartburn and regurgitation are common symptoms of typical reflux disease with the most common manifestation of esophageal injury being reflux esophagitis; however, they also noted that manifestations of GERD include both esophageal and extraesophageal syndromes ( Fig. 1 ). Reflux cough syndrome, reflux laryngitis syndrome, and reflux asthma syndrome were designated to be among the extraesophageal syndromes with an established association to GERD.
Potential ways in which GER may contribute to reflux cough, laryngitis, and asthma syndromes involves both direct (aspiration) and indirect (neutrally mediated) mechanisms. Reflux is thought to provoke cough by one of two mechanisms. These are classified as either “high” or “distal” esophageal reflux. The pathogenesis of “high” esophageal reflux involves refluxate that traverses the esophagus and induces cough either by direct pharyngeal or laryngeal stimulation or aspiration and causes a tracheal or bronchial cough response. In distal esophageal reflux, cough can be produced by a vagally mediated tracheal-bronchial reflex. Conversely, chronic cough caused by pressure gradient changes between the abdominal and thoracic cavities during the act of coughing may precipitate reflux and lead to a self-perpetuating cycle of cough and reflux. Similarly, in reflux-associated laryngitis, GER may contribute to laryngeal mucosal damage by direct aspiration of gastric contents. The laryngeal mucosa is more sensitive to gastric acid than the esophagus, and animal studies have shown that even small amounts of gastric refluxate may cause injury.
Reflux cough syndrome
Chronic cough, defined as cough greater than 3 weeks duration, is a common condition seen by physicians in the United States. In nonsmoking patients with a normal chest radiograph, not taking angiotension-converting enzyme (ACE) inhibitors, the most common causes of cough include postnasal drip syndrome, asthma, GER, and chronic bronchitis, and these four conditions may account for up to 90% of cases of chronic cough.
The evaluation of patients with chronic cough is not always straightforward, because patients may not have a single underlying cause of their cough, but instead may have several disorders that contribute to symptoms. For example, Poe and Kallay found that GER alone accounted for cough in 13% of their study population, whereas in 56% of patients, GER was a contributing factor to persistence of cough. Nonetheless, evaluation of chronic cough generally begins with the anatomic diagnostic protocol developed by Irwin and colleagues. This protocol evaluates chronic cough patients who have normal chest radiographs and not taking angiotension-converting enzyme inhibitors, for the three most common causes of cough: (1) postnasal drip syndrome, (2) asthma, and (3) GERD. Once the contributions of postnasal drip syndrome and asthma have been assessed, patients can then undergo evaluation for GERD.
The diagnosis of GER-associated chronic cough may be difficult because many patients do not exhibit typical reflux symptoms, and clinicians must maintain a high index of suspicion for the diagnosis. It is estimated that up to 75% of patients with GER-associated cough do not display classic symptoms of reflux (ie, heartburn and regurgitation). Everett and colleagues found that only 63% of patients studied displayed the classic symptoms of reflux. In contrast to classic symptoms, patients with GER-associated cough may describe a cough that occurs primarily during the day, in the upright position, during phonation, when rising from bed, or cough associated with eating. The process is further complicated by the fact that there is no diagnostic test that is definitive in identifying GER as a cause of chronic cough.
Symptoms associated with reflux cough syndrome include
Cough occurs during day
Cough in upright position
Cough during phonation
Cough when rising from bed
Cough associated with eating
Common tests used to diagnose classic GERD include upper gastrointestinal (UGI) endoscopy, 24-hour esophageal pH-metry, and acid suppression with proton pump inhibitor (PPI) therapy. UGI endoscopy and 24-hour esophageal pH-metry have some inherent problems when used to evaluate reflux as a cause of chronic cough. UGI endoscopy is a commonly used diagnostic modality in patients suffering with classic symptoms of GERD, and is used to evaluate the presence of esophagitis and other mucosal abnormalities. The difficulty in using this test as a diagnostic tool in reflux-associated cough is that there is often poor correlation between findings of esophagitis on endoscopy, patient symptoms, and results of other tests used to diagnose reflux-associated cough. For example, Baldi and colleagues evaluated 45 patients suffering from chronic cough with UGI endoscopy. A total of 55% of their study group complained of classic reflux symptoms (heartburn or regurgitation); however, only 15% of the study population had endoscopy-proved esophagitis.
The 24-hour esophageal pH monitoring, previously considered the gold standard for diagnosing GER, has at best a sensitivity of 90%; however, it has limitations in patients with chronic cough, and is shown to have a specificity as low as 66% in this population. In patients with chronic cough, rather than evaluating total esophageal acid contact time, the best use of this test is correlation of reflux episodes with cough symptoms. Baldi and colleagues used this technique in their study evaluating patients with reflux-associated chronic cough. They found 53% of the patients had pathologic reflux; however, when compared with other, less invasive tests, such as treatment with PPIs, esophageal pH-metry was believed to have a low diagnostic gain. This is supported in a study by Ours and colleagues, which found that pH monitoring was not a “reliable predictor of acid reflux–induced chronic cough” because only 35% of patients in their study population with abnormal pH-metry responded to PPI therapy.
The effectiveness of PPI therapy to treat acid reflux–associated chronic cough is well established, and is shown through a prospective, randomized, placebo-controlled trial by Ours and colleagues. This study used a 2-week course of twice a day omeprazole therapy to treat GER-induced chronic cough, and found this method to be more reliable than other evaluations (pH testing) in diagnosing patients with GER-associated chronic cough. The authors subsequently suggested that the cost-effectiveness of using empiric PPI treatment for GER-associated cough was superior to other diagnostic modalities, such as 24-hour pH monitoring. The use of empiric therapy of PPIs to diagnose and treat GER-associated chronic cough has also been studied by Poe and Kallay, who were able to diagnose 79% of patients with cough secondary to GER with resolution of symptoms after empiric trial of PPI therapy.
Most experts recommend twice daily initial dosing of PPIs in patients with chronic cough. Baldi and colleagues, however, evaluated the use of once and twice dosing. In this study, patients were treated with a 4-week open-label course of lansoprazole, 30 mg twice a day, and monitored for response. Patients who responded were then treated with either lansoprazole, 30 mg once a day, or lansoprazole, 30 mg twice a day, for 12 weeks. There was no significant difference in symptom improvement between the two dosing regimens. A total of 60% of patients reported relief of cough after 12 weeks. Notably, this study found that 82% of patients who initially responded with the 4-week trial of twice a day PPI therapy noted complete symptoms relief after the further 12 weeks of therapy with lansoprazole, 30 mg twice a day. In contrast, only 23% of patients who did not respond after the initial 4 weeks of therapy obtained complete symptom relief. This study suggests that, to be efficacious, patients should be treated for an extended period of time with PPI therapy. Those who are likely to achieve complete response, however, notice improved symptoms after a shorter duration.
The evaluation of GER-associated chronic cough should begin with determination of other causes of chronic cough, such as postnasal drip syndrome and asthma. Once the contributions of these disorders have been ruled out, an empiric trial of acid suppression with twice a day PPI therapy for 12 to 16 weeks identifies and treats most patients with reflux-associated chronic cough.
Reflux laryngitis syndrome
It is estimated that approximately 10% of all patient visits to ear-nose-throat physicians are related to chronic laryngitis, and GER is implicated as an important cause of laryngeal inflammation. The prevalence of this diagnosis has increased in recent years. Common reported symptoms of this condition, also termed “laryngopharyngeal reflux” (LPR), include hoarseness, throat pain, sensation of a lump in the throat, cough, repetitive throat clearing, excessive phlegm, difficulty swallowing, pain with swallowing, heartburn, and voice fatigue. Although these symptoms are common in patients with suspected reflux laryngitis, they are nonspecific and can also be seen in patients with postnasal drip and environmental exposures to allergens or other irritants, such as smoke.
Symptoms associated with reflux laryngitis syndrome include
Hoarseness
Throat pain
Sensation of lump in throat
Cough
Repetitive throat clearing
Excessive phlegm
Difficulty swallowing
Heartburn
Voice fatigue
Two tests commonly used in the diagnosis of GER-associated laryngitis include 24-hour pH monitoring and laryngoscopy. The role of pH monitoring in establishing a relationship between GER and LPR is not clear, and its application in the diagnosis of reflux laryngitis is not as useful. Initially, it was considered that patients with symptoms of laryngitis, thought to be reflux related, would be shown to have more reflux events into the upper esophageal and hypopharyngeal areas. A recent review of studies evaluating pharyngeal reflux in normal patients demonstrated, however, that anywhere from 19% to 43% of normal patients can be expected to have pharyngeal reflux. Additional data have shown that only 54% of patients with suspected LPR have abnormal acid exposure throughout the esophagus. Furthermore, a recent review by Joniau and colleagues of pH monitoring in patients with reflux laryngitis found no statistical difference between the prevalence of pharyngeal reflux in symptomatic patients versus normal controls.
Some have argued that the use of pH monitoring in patients with suspected reflux laryngitis may be of limited value because symptoms may be caused by nonacid reflux. Intraluminal impedance testing is a method used for detecting nonacid reflux. This test detects reflux events based on changes in resistance to electrical current flow between electrodes placed in the esophagus. The use of this test for assessing nonacid reflux as a cause of symptoms in patients with suspected reflux laryngitis is uncertain at this time, however, and is in need of future investigation.
Laryngoscopy is one of the most common tests used to diagnose GERD-related laryngitis; however, its diagnostic usefulness is uncertain. The initial relationship between GER and laryngitis was suggested it the 1960s, when laryngoscopy demonstrated vocal cord ulcerations in the larynx of symptomatic patients with GERD. Since that time other signs of laryngeal irritation, such as posterior cricoid erythema, vocal cord erythema and edema, and arytenoid erythema and edema, have been used to diagnose and subsequently treat patient with GER-associated laryngitis. The use of nonspecific markers, however, has increased the sensitivity of laryngoscopy in detecting abnormalities at the cost of specificity with regards to GER as the cause of laryngeal inflammation.
In 2007, Vavricka and colleagues evaluated the prevalence of specific laryngopharyngeal changes associated with GERD in patients with known GERD versus normal patients. In this study, the laryngopharyngeal regions of 132 patients, found to have reflux esophagitis lesions on endoscopy, and 132 normal subjects were compared. Laryngeal examinations were videotaped and later reviewed by an otorhinolaryngologist and three gastroenterologists, blinded to the esophageal findings and to each other’s ratings. Ten specific areas of the laryngopharyngeal region were evaluated. These structures included
Posterior pharyngeal wall
Interarytenoid bar
Posterior commissure
Posterior cricoid wall
Arytenoids complex
True vocal fords
False vocal cords
Anterior commissure
Epiglottis
Aryepiglottic fold
Investigators found that the prevalence of laryngopharyngeal lesions thought to be related to GERD was the same in both patient groups. Lesions of the posterior pharyngeal wall, which included erythema, edema, and cobblestoning, showed a statistically significant higher prevalence in GERD patients as compared with the control group. This, and other studies, suggests that the lack of specific laryngeal signs on laryngoscopy makes overdiagnosing reflux laryngitis a real possibility.
Because GER is believed to play a causative role in the symptoms of many patients with chronic laryngitis, PPIs have been commonly used as therapy. A prospective, noncontrolled, unblinded study by Kamel and colleagues in 1994 found that 96% of patients with suspected reflux laryngitis had symptomatic improvement with PPI treatment. More recent data to support these findings are lacking. A recent large multicenter 16-week study of 145 patients suspected of having LPR did not show a benefit in those treated with esomeprazole, 40 mg twice a day, compared with placebo. Patients were eligible if they had a history of one or more chronic laryngeal symptoms (throat clearing, globus, sore throat, or hoarseness) and laryngoscopic signs indicating reflux laryngitis. To date, there have been seven randomized, placebo-controlled trials examining the efficacy of PPI treatment for LPR ( Table 1 ). A recent meta-analysis, examined these seven randomized controlled trials and found no significant symptom reduction with PPI therapy compared with placebo ( Fig. 2 ).
| Study Author (Country, Year) | PPI Used | Duration | Inclusion Criteria | Exclusion Criteria | GI Endoscopy | pH Monitoring | Outcome Measured |
|---|---|---|---|---|---|---|---|
| Vaezi (USA 2005) | Esomeprazole, 40 mg BID | 16 wk | LSx for 3 moLPR on laryngoscopy | Heartburn >3/wk, PPI in 2 wk | Optional | Optional | 50% reduction in symptoms |
| Steward (USA 2004) | Rabeprazole, 20 mg BID | 8 wk | LSx for >4 wk LPR on laryngoscopy | Gastrointestinal surgeryPPI in 1 mo | Optional | Optional | 50% reduction in global symptom score |
| El-Serag (USA 2001) | Lansaprazole, 30 mg BID | 12 wk | LSx for >3 wk LPR on laryngoscopy | Infection, cancer, previous gastrointestinal surgery | Yes | Yes | Complete symptom resolution |
| Eherer (Austria, 2003) | Pantoprazole, 40 mg BID | 12 wk | Hoarseness for 2 mo (+) pH test | Optional | Yes | 50% reduction in global symptom score | |
| Wo (USA 2005) | Pantoprazole, 40 mg QD | 12 wk | LSx for 3 d/wk (+) pH test | Optional | Yes | 50% reduction in global symptom score | |
| Havas (Australia 1999) | Lansaprazole, 30 mg BID | 12 wk | Postpharyngolaryngitis | Central nervous system disorder, chronic obstructive pulmonary disease, pre-existing acid suppression, severe esophagitis | Yes | Yes | 50% reduction in global symptom score |
| Noordzij (USA) 2001 | Omeprazole, 40 mg BID | 8 wk | LSx for 3 moLPR four episodes | Infection, cancer, allergies | Optional | Yes | 50% reduction in global symptom score |
The disappointing findings from placebo-controlled studies in LPR are in part explained by current limitations in the diagnostic evaluation of chronic laryngitis. Otolaryngologists usually suspect GERD-related laryngitis based on such symptoms as throat clearing, cough, and globus, and such signs as laryngeal edema and erythema. Such symptoms and signs are nonspecific for GERD and may be caused by infection or postnasal drip, whereas laryngeal edema and erythema are prevalent in the general population without specific symptoms. Because there is no gold standard in the diagnosis of GERD-related laryngitis, patients with these symptoms or signs are likely misdiagnosed as having LPR. In placebo-controlled studies of this group of patients many may actually not have GERD, which reduces the power of the study to detect differences. As such, this group of unresponsive patients may have a possible functional component to their symptoms. The placebo response rate of approximately 40% in LPR studies is similar to that seen in irritable bowel syndrome and other functional gastrointestinal disorders.
Given the negative findings of controlled trials, uncontrolled studies are the current basis for the treatment recommendations in patients with LPR. This group of patients should initially be treated with empiric PPI therapy for an initial duration of 1 to 2 months. If symptoms improve the therapy may need to be prolonged up to 6 months to allow healing of laryngeal tissue, after which the dose should be tapered to the minimal dose of acid suppression needed to control symptoms. In unresponsive patients, testing with impedance or pH monitoring on therapy may be the best alternative to rule out reflux as the cause of persistent symptoms followed by a search for other potential etiologies.
Reflux laryngitis syndrome
It is estimated that approximately 10% of all patient visits to ear-nose-throat physicians are related to chronic laryngitis, and GER is implicated as an important cause of laryngeal inflammation. The prevalence of this diagnosis has increased in recent years. Common reported symptoms of this condition, also termed “laryngopharyngeal reflux” (LPR), include hoarseness, throat pain, sensation of a lump in the throat, cough, repetitive throat clearing, excessive phlegm, difficulty swallowing, pain with swallowing, heartburn, and voice fatigue. Although these symptoms are common in patients with suspected reflux laryngitis, they are nonspecific and can also be seen in patients with postnasal drip and environmental exposures to allergens or other irritants, such as smoke.
Symptoms associated with reflux laryngitis syndrome include
Hoarseness
Throat pain
Sensation of lump in throat
Cough
Repetitive throat clearing
Excessive phlegm
Difficulty swallowing
Heartburn
Voice fatigue
Two tests commonly used in the diagnosis of GER-associated laryngitis include 24-hour pH monitoring and laryngoscopy. The role of pH monitoring in establishing a relationship between GER and LPR is not clear, and its application in the diagnosis of reflux laryngitis is not as useful. Initially, it was considered that patients with symptoms of laryngitis, thought to be reflux related, would be shown to have more reflux events into the upper esophageal and hypopharyngeal areas. A recent review of studies evaluating pharyngeal reflux in normal patients demonstrated, however, that anywhere from 19% to 43% of normal patients can be expected to have pharyngeal reflux. Additional data have shown that only 54% of patients with suspected LPR have abnormal acid exposure throughout the esophagus. Furthermore, a recent review by Joniau and colleagues of pH monitoring in patients with reflux laryngitis found no statistical difference between the prevalence of pharyngeal reflux in symptomatic patients versus normal controls.
Some have argued that the use of pH monitoring in patients with suspected reflux laryngitis may be of limited value because symptoms may be caused by nonacid reflux. Intraluminal impedance testing is a method used for detecting nonacid reflux. This test detects reflux events based on changes in resistance to electrical current flow between electrodes placed in the esophagus. The use of this test for assessing nonacid reflux as a cause of symptoms in patients with suspected reflux laryngitis is uncertain at this time, however, and is in need of future investigation.
Laryngoscopy is one of the most common tests used to diagnose GERD-related laryngitis; however, its diagnostic usefulness is uncertain. The initial relationship between GER and laryngitis was suggested it the 1960s, when laryngoscopy demonstrated vocal cord ulcerations in the larynx of symptomatic patients with GERD. Since that time other signs of laryngeal irritation, such as posterior cricoid erythema, vocal cord erythema and edema, and arytenoid erythema and edema, have been used to diagnose and subsequently treat patient with GER-associated laryngitis. The use of nonspecific markers, however, has increased the sensitivity of laryngoscopy in detecting abnormalities at the cost of specificity with regards to GER as the cause of laryngeal inflammation.
In 2007, Vavricka and colleagues evaluated the prevalence of specific laryngopharyngeal changes associated with GERD in patients with known GERD versus normal patients. In this study, the laryngopharyngeal regions of 132 patients, found to have reflux esophagitis lesions on endoscopy, and 132 normal subjects were compared. Laryngeal examinations were videotaped and later reviewed by an otorhinolaryngologist and three gastroenterologists, blinded to the esophageal findings and to each other’s ratings. Ten specific areas of the laryngopharyngeal region were evaluated. These structures included
Posterior pharyngeal wall
Interarytenoid bar
Posterior commissure
Posterior cricoid wall
Arytenoids complex
True vocal fords
False vocal cords
Anterior commissure
Epiglottis
Aryepiglottic fold
Investigators found that the prevalence of laryngopharyngeal lesions thought to be related to GERD was the same in both patient groups. Lesions of the posterior pharyngeal wall, which included erythema, edema, and cobblestoning, showed a statistically significant higher prevalence in GERD patients as compared with the control group. This, and other studies, suggests that the lack of specific laryngeal signs on laryngoscopy makes overdiagnosing reflux laryngitis a real possibility.
Because GER is believed to play a causative role in the symptoms of many patients with chronic laryngitis, PPIs have been commonly used as therapy. A prospective, noncontrolled, unblinded study by Kamel and colleagues in 1994 found that 96% of patients with suspected reflux laryngitis had symptomatic improvement with PPI treatment. More recent data to support these findings are lacking. A recent large multicenter 16-week study of 145 patients suspected of having LPR did not show a benefit in those treated with esomeprazole, 40 mg twice a day, compared with placebo. Patients were eligible if they had a history of one or more chronic laryngeal symptoms (throat clearing, globus, sore throat, or hoarseness) and laryngoscopic signs indicating reflux laryngitis. To date, there have been seven randomized, placebo-controlled trials examining the efficacy of PPI treatment for LPR ( Table 1 ). A recent meta-analysis, examined these seven randomized controlled trials and found no significant symptom reduction with PPI therapy compared with placebo ( Fig. 2 ).
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