Elif Saritas Yuksel, MD, and Michael F. Vaezi, MD, PhD, MSc (Epi)
Dr. Saritas Yuksel is a Research Assistant in the Division of Gastroenterology, Hepatology, and Nutrition at Vanderbilt University Medical Center in Nashville, Tennessee. Dr. Vaezi is a Professor of Medicine; Clinical Director of the Division of Gastroenterology, Hepatology, and Nutrition; and Director of the Center for Swallowing and Esophageal Disorders, all at Vanderbilt University Medical Center.
Address correspondence to: Dr. Michael F. Vaezi, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, C2104-MCN, Nashville, TN 37232; Tel: 615-322-3739; Fax: 615-322-8525; E-mail: Michael.vaezi@vanderbilt.edu
Abstract: Gastroesophageal reflux disease (GERD) can present with a wide variety of extraesophageal symptoms that are usually difficult to diagnose because of the absence of typical GERD symptoms (ie, regurgitation or heartburn). The diagnostic process is further complicated by the lack of a definitive test for identifying GERD as the cause of extraesophageal reflux symptoms. Due to the low predictive value of upper endoscopy and pH testing—as well as the lack of reliability of the symptom index and symptom association probability—extraesophageal reflux disease is still an area of investigation. This paper discusses recent developments in this field, with special emphasis on new diagnostic modalities and treatment options.
Gastroesophageal reflux disease (GERD) is among the most common diseases encountered by primary care physicians and gastroenterologists in the Western world, and this condition is increasing in prevalence.1 The predominant symptoms of GERD are heartburn and regurgitation; however, patients may also present with atypical symptoms such as chronic cough, asthma, and laryngitis, which are often referred to as extraesophageal manifestations of GERD (Figure 1). Extraesophageal reflux (EER) symptoms can occur with or without typical GERD symptoms, which, in the latter setting, may delay the diagnosis of reflux. The term “laryngopharyngeal reflux” (LPR) is often used by otolaryngologists to describe laryngeal findings of irritation in patients with chronic throat symptoms, including cough, hoarseness, throat clearing, dysphonia, and globus pharyngeus.2,3
Despite the use of different terminology, the same pathophysiologic factor is believed to be responsible for subjective patient symptom reports and objective findings. GERD contributes to extraesophageal syndromes via a direct mechanism (aspiration) or an indirect (vagally mediated) mechanism.4-8 The extent of gastroduodenal reflux within the esophageal lumen may be classified as either high or distal.9 High esophageal reflux is reflux that traverses the esophagus and induces cough or laryngeal irritation by direct pharyngeal or laryngeal stimulation or aspiration, causing a tracheal or bronchial response. In distal esophageal reflux, cough or throat symptoms may be produced by a vagally mediated, tracheal-bronchial reflex.9,10 Embryologic studies have shown that the esophagus and bronchial tree share a common embryologic origin and neural innervation via the vagus nerve. Changes in the pressure gradient between the abdominal and thoracic cavities during the act of coughing may lead to a cycle of cough and reflux.10,11 A disturbance in any of the normal protective mechanisms—such as a disruption of the mechanical barrier for reflux (ie, the lower esophageal sphincter [LES]) or the presence of esophageal dysmotility—may allow noxious gastroduodenal contents to come into direct contact with the larynx or airway.12,13
This paper will discuss recent developments in the field of EER, with special emphasis on new diagnostic modalities and treatment options.
Chronic Cough
Chronic cough, which is defined as cough lasting more than 8 weeks, is a condition commonly evaluated by physicians in the United States.14,15 In nonsmoking patients who have normal chest radiograph findings and are not taking angiotensin-converting enzyme (ACE) inhibitors, the most common causes of chronic cough include postnasal drip syndrome (PNDS), asthma, GERD, and chronic bronchitis; these 4 conditions may account for up to 90% of chronic cough cases (Figure 2).16 The diagnosis of GERD-associated chronic cough may be challenging, as many patients do not exhibit typical reflux symptoms. It has been estimated that up to 75% of patients with GERD-associated chronic cough do not display classic symptoms of reflux (ie, heartburn and regurgitation).6,17,18 The diagnostic process is further complicated by the lack of a test that definitively identifies GERD as the cause of chronic cough. Esophagogastroduodenoscopy (EGD) and 24-hour esophageal pH monitoring have several inherent problems when used to evaluate reflux as a cause of chronic cough. It is difficult to use EGD as a diagnostic tool for reflux-associated cough because of the frequently poor correlation between esophagitis findings and cough. For example, in a study of 45 patients with chronic cough, Baldi and colleagues reported classic reflux symptoms in 55% of patients, but only 15% of the study population had EGD-confirmed esophagitis.16 Therefore, EGD has a low sensitivity for establishing a link between chronic cough and esophageal findings. Most patients with chronic cough have normal endoscopy findings.
Although 24-hour esophageal pH monitoring has a 90% sensitivity for diagnosing abnormal esophageal acid exposure in patients with GERD, the use of this method is limited in patients with chronic cough, as its specificity in this population is as low as 66%.9,11,19-22 An important advantage of pH monitoring in chronic cough patients may be its ability to correlate esophageal reflux episodes with cough symptoms via the 2 most commonly used indices: symptom index (SI) and symptom association probability (SAP). However, a recent study conducted by Slaughter and associates concluded that both the SI and SAP can be overinterpreted and are prone to misinterpretation.23 The authors suggested that both the SI and SAP are essentially chance occurrences at best, except in patients with GERD that is refractory to proton pump inhibitor (PPI) therapy who have high rates of esophageal acid exposure.23 A recent study using an acoustic cough monitoring device showed that cough temporally associates with reflux, irrespective of proposed diagnoses, and cough may be self-perpetuating in some patients, likely due to central processes and not just reflux.24 Therefore, given the low predictive value of pH testing, the lack of reliability of the SI and SAP, and the lack of temporal association (which is not necessarily causal), the use of pH testing in patients with chronic cough may be problematic.
In patients with chronic cough suspected to be related to GERD, most experts recommend empiric PPI therapy, often via twice-daily dosing. This recommendation is solely based on open-label trials, as placebo-controlled studies have not shown a benefit with PPI therapy in this group. For example, Poe and Kallay found that 79% of patients with cough secondary to GERD experienced resolution of their symptoms following an empiric trial of PPI therapy.10 A study conducted by Baldi and colleagues suggested that once-daily PPI therapy in these patients may yield results similar to those associated with twice-daily PPI therapy.16 However, a meta-analysis of 5 placebo-controlled studies in adult patients with chronic cough found insufficient evidence in favor of PPI therapy.25 In agreement with the conclusions of this meta-analysis, 2 other recent randomized controlled studies did not find any benefits with PPI therapy compared to placebo in adults with chronic cough.26,27 Taken together, these studies show the uncertainty of the association between chronic cough and GERD, most likely due to poor diagnostic tests and, thus, inappropriate patient selection in controlled studies. In addition, we recently showed that the response to surgical intervention in patients with chronic cough may depend on the concomitant baseline presence of typical GERD symptoms (ie, heartburn and regurgitation).28
Recently, the term “sensory neuropathic cough” has been used to describe patients with recalcitrant cough in whom other causes, including GERD, have been excluded. This condition appears to result from a lowered stimuli response threshold (as with postherpetic neuralgic pain) and does not respond to usual therapies such as PPI therapy.29 Sensory neuropathic cough is sudden, occurs in episodes, and may be triggered by eating, talking, or deep breathing. This condition can result in rhinorrhea, vomiting, laryngospasm, and syncope or near-syncope.29 It has been estimated that up to 31% of patients with chronic cough may have sensory neuropathic cough.30 Recent studies have suggested that gabapentin can cause symptomatic improvement of this type of cough.31,32 Therefore, chronic cough patients in whom other causes have been excluded may experience some benefit with off-label use of a neuromodulator medication such as amitriptyline
(10 mg/day), gabapentin (100–900 mg/day), or pregabalin (maximum dose of 150 mg twice daily). Amitriptyline is a tricyclic antidepressant. Pregabalin and gabapentin are very similar in structure, as they are both analogs of gamma-aminobutyric acid (GABA), although they do not bind to GABA A or GABA B; instead, they bind to subunits of presynaptic calcium channels and decrease the release of the neurotransmitters glutamate, noradrenaline, and substance P.33
In conclusion, the evaluation of chronic cough should begin by assessing causes such as PNDS or asthma in patients with normal chest radiograph findings and no history of ACE inhibitor use. After these causes have been ruled out, an empiric trial of acid suppression should be administered via once-daily or twice-daily PPI therapy for no more than 12–16 weeks, which will likely identify and treat the majority of patients with reflux-associated chronic cough. Patients who are unresponsive to this trial should undergo tests to exclude large mechanical defects such as hiatal hernia (which could cause volume regurgitation), or they should be evaluated for lung-related issues. In patients without an obvious cause of cough and poor clinical response to the usual therapies, including PPI therapy, a trial of neuromodulator medications may help to control chronic symptoms.
Asthma
Asthma has a strong correlation with GERD, and it has been proposed that the conditions may induce each other (Figure 3). GERD may induce asthma via the vagally mediated or microaspiration mechanisms mentioned above. It has been suggested that asthma may induce reflux via several mechanisms. Exacerbation of asthma results in negative intrathoracic pressure (which may cause reflux), and the medications used to treat asthma (theophylline, b-agonists, and steroids) may reduce the pressure of the LES. GERD should be suspected in patients with asthma whose symptoms are worse after meals and in patients who do not respond to traditional asthma medications. Patients who have heartburn and regurgitation before the onset of asthma symptoms may also be suspected of having reflux-induced asthma symptoms.
Epidemiologic studies, as well as physiologic testing with ambulatory 24-hour pH monitoring, have shown an association between asthma and GERD.34,35 In a study that evaluated the prevalence of GERD in asthma patients, Kiljander and associates found that 35% of GERD patients did not have typical reflux symptoms but did have abnormal esophageal acid exposure according to pH monitoring.34 Similarly, Leggett and coworkers conducted a study to assess GERD in patients with difficult-to-control asthma using 24-hour ambulatory pH monitoring with both distal probes (5 cm above the LES) and proximal probes (15 cm above the distal probes).36 The distal probes detected reflux in 55% of patients, and the proximal probes detected reflux in 35% of patients. Thus, reflux is a common occurrence in patients with asthma.
As is the case for most EER conditions, there is controversy regarding the benefit of PPI therapy in patients suspected of having reflux-induced asthma. Studies have used different endpoints to measure the efficacy of acid suppression therapy in this group: Some studies have employed objective measurements (such as improvement in forced expiratory volume [FEV1]), whereas other studies have relied on patient-reported questionnaires or a decrease in the need for asthma medications. Early trials reported improvements in pulmonary symptoms and function in patients treated with acid suppression therapy.37 In 1994, Meier and colleagues conducted a double-blind, placebo-controlled, crossover study that evaluated the pulmonary function of asthma patients treated with omeprazole 20 mg twice daily for 6 weeks.38 This study found that 27% of patients with reflux (4/15) had an increase in FEV1 of at least 20%.38
In another study, Sontag and associates divided 62 patients with GERD and asthma into 3 arms: control, medical treatment (ranitidine 150 mg 3 times daily), or surgical treatment (Nissen fundoplication).37 After a 2-year follow-up period, 75% of patients who received surgical treatment experienced improvement in nocturnal asthma exacerbations, compared to 9.1% of patients who received medical therapy and 4.2% of patients in the control group. Additionally, there was a statistically significant improvement in mean asthma symptom score but no improvement in pulmonary function or reduction in the need for medication among the groups. In a different study, Littner and coworkers followed 207 patients who had symptomatic reflux and received either placebo or PPI therapy twice daily for 24 weeks.39 The primary outcome of this study was daily asthma symptoms reported in patient diaries, and secondary outcomes were the need for rescue albuterol inhaler use, pulmonary function, asthma-associated quality of life, investigator-assessed asthma symptoms, and asthma exacerbations. The study showed that medical treatment of reflux did not reduce daily asthma symptoms or albuterol use and did not improve pulmonary function in asthma patients.39 Similarly, a study conducted by the American Lung Association Asthma Clinical Research Center randomized 412 patients with poor asthma control to either esomeprazole 40 mg twice daily or placebo.40 After 24 weeks of follow-up, the study found that PPI therapy had no treatment benefit for controlling asthma. Recently, a randomized controlled trial in children who had asthma, but not overt GERD, did not show an improvement in symptoms or lung function with lansoprazole therapy.41 A Cochrane review of GERD treatment for patients with asthma found only minimal improvement of asthma symptoms with reflux therapy.42 Nevertheless, a recent controlled trial in asthma patients suggested a therapeutic benefit with PPI therapy in the subgroup of asthma patients with both nocturnal respiratory symptoms and GERD symptoms.43 Therefore, the effect of reflux treatment on asthma control in patients with both conditions is not yet clear.
The current recommendation in patients with asthma (with or without concomitant heartburn or regurgitation) is similar to that for patients with chronic cough: an initial empiric trial of once-daily or twice-daily PPI therapy for 2–3 months. In patients who are responsive to therapy for both heartburn and/or asthma symptoms, PPIs should be tapered to the minimal dose necessary to control symptoms. In unresponsive patients, it may be necessary to test for reflux via pH testing and/or impedance/pH monitoring in order to measure reflux of acidic or nonacidic material, which could still be responsible for asthma exacerbation.
Laryngitis
GERD is implicated as an important cause of laryngeal inflammation.44 Common symptoms of this condition (which is referred to as LPR by otolaryngologists) include hoarseness, throat pain, the sensation of a lump in the throat, cough, repetitive throat clearing, excessive phlegm, difficulty swallowing, pain with swallowing, heartburn, and voice fatigue (Table 1). These symptoms are nonspecific and can also be seen in patients with PNDS or exposure to allergens, smoke, or other irritants.45 However, reflux is often implicated in many of these patients, given the chronicity of their symptoms and the laryngeal findings of erythema and edema. The most common laryngeal signs associated with LPR are listed in Table 2.
Direct laryngeal exposure to injurious gastroduodenal contents is likely the pathophysiologic mechanism for the development of LPR. However, the relative importance of the specific agent(s) responsible is subject to debate. Earlier studies suggested that pepsin may be the main cause of LPR symptoms; however, later studies suggested the
co-importance of acid, pepsin, and bile acids.3,7,46,47 There has recently been an increase in articles examining the role of pepsin in LPR patients. Some publications have suggested that an important contributor to LPR may be the reflux of pepsin into the larynx, with subsequent pepsin transfer into the cytoplasm of laryngeal cells and its later activation in cell organelles with lower pH than that of the lumen.48 Dilation of intercellular spaces (DIS) has been reported to be an early morphologic marker in GERD, reflecting the alteration of esophageal mucosal integrity. However, recent studies assessing DIS in patients suspected of LPR and GERD have not shown a difference in epithelial space separation between patients and controls, thus questioning the uniform reflux-related epithelial presence of DIS.49 E-cadherin may play an important role as a cellular adhesion molecule in mucosal integrity. There is some evidence that e-cadherin expression may be decreased in the laryngeal tissue of LPR patients.50 However, it is not apparent whether the decrease is due to reflux or an inflammatory response to reflux.
Recent studies have suggested the importance of carbonic anhydrase (CA) isoenzymes (I, II, and III) in laryngeal protection and their role in LPR patients.51,52 CA enables the esophagus or larynx to defend against acidic refluxate by producing bicarbonate. The expression of CA III has been demonstrated to vary in laryngeal biopsies obtained from different locations in LPR patients.51 CA III expression is decreased in the vocal folds of LPR patients, but it is increased in the posterior commissure, with the degree of increase based on the severity of the patient’s symptoms.53,54 The difference may be attributed to the fact that the larynx contains both squamous and respiratory epithelium, which react differently to reflux.3
Laryngoscopy is an important tool for the diagnosis of reflux-associated laryngeal symptoms; however, the most common laryngoscopic findings of LPR patients are often highly subjective, nonspecific, and present in many individuals without GERD (Table 2).55-58 For example, Milstein and coworkers highlighted the nonspecific nature of laryngeal evaluation in a study of 52 nonsmoking volunteers with no history of otolaryngology abnormalities or GERD.57 This asymptomatic healthy group underwent both rigid and flexible video laryngoscopy. The authors found at least 1 sign of tissue irritation in 93% of patients via flexible video laryngoscopy and 83% of patients via rigid video laryngoscopy. Additionally, the findings were dependent on the technique. Laryngeal signs were more commonly reported via flexible transnasal laryngoscopy than via rigid transoral examination.57 The high prevalence of laryngeal irritation in healthy volunteers—combined with the variability of the diagnosis based on the methods used—highlights the uncertainty associated with laryngeal signs in LPR patients.
Ambulatory pH monitoring is also commonly used in the diagnosis of LPR. However, this method lacks sensitivity and specificity for LPR. Hypopharyngeal and proximal esophageal pH monitoring have sensitivities of 40% and 55%, respectively.59,60 Variability has been reported in the literature regarding placement of proximal and hypopharyngeal pH probes (eg, 15 cm above the LES, within the upper esophageal sphincter [UES], or above the UES). Also, gastroenterologists utilize manometry to guide placement, whereas otolaryngologists position pH probes via laryngoscopic visualization. This difference results in heterogeneous findings and uncertainty regarding their clinical utility. For example, a study with LES-referenced proximal catheter placement did not reveal an association between reflux and extraesophageal symptoms.61 Therefore, pH studies are confusing, rather than informative, in LPR patients, and further studies are needed to better define the role of pH studies in this disorder.
Recent studies have suggested that nonacid reflux may play a role in causing symptoms in patients who remain symptomatic despite aggressive acid suppression therapy.62-65 Studies assessing patients with heartburn and regurgitation, as well as patients with extraesophageal symptoms, have suggested that 10–40% of patients on twice-daily PPI therapy may have persistent nonacid reflux.64,66 However, causation is difficult to establish between these nonacid reflux events and persistent symptoms.67 A recent study found that abnormal impedance findings in patients on PPI therapy predict acid reflux in patients off therapy.68 The study also concluded that combined impedance/pH monitoring of patients with refractory reflux might provide the single best strategy for evaluating reflux symptoms in these patients. However, the clinical significance of abnormal impedance findings in this group of patients awaits further study. The most recent uncontrolled study in surgically treated patients suspected of having LPR found that impedance monitoring did not predict LPR symptom response to fundoplication, regardless of whether the patients were on or off therapy; important predictors of symptom response were the presence of hiatal hernia, significant acid reflux at baseline, and the presence of regurgitation concomitant with LPR symptoms.69
The Dx–pH measurement system (Respiratory Technology Corp.), which is a sensitive and minimally invasive device for detecting acid reflux in the posterior oropharynx, is increasingly being used in patients with LPR.70 This device uses a nasopharyngeal catheter (the Restech pH catheter) to measure pH in either liquid or aerosolized droplets (Figure 4). This device has a faster detection rate and time to equilibrium pH than traditional pH catheters. A recent, prospective, observational study in healthy volunteers developed normative data for this device at pH cutoffs of 4, 5, and 6 for the distal esophagus and oropharynx.71 Although initial studies of this device in LPR patients are encouraging, controlled studies are needed to assess its future role.70
Over the last few years, the detection of salivary pepsin has been advocated as an objective method for diagnosing reflux.72 Pepsin is a proteolytic enzyme secreted as pepsinogen from the chief cells in the gastric fundus and activated in acidic environments.73 Using an enzymatic method, Potluri and colleagues compared salivary pepsin activity with proximal and distal esophageal pH results in 16 reflux patients and noted a correlation between these pH values and salivary pepsin assay findings.72 The authors thus concluded that the salivary pepsin assay might be a noninvasive method of assessing proximal reflux. Although Ozmen and associates found a 100% sensitivity and a 92.3% specificity for the pepsin assay in the nasal lavage fluid of chronic rhinosinusitis patients, Printza and coworkers did not find any peptic activity in the saliva samples of 93 LPR patients.74,75 Using the Western blot technique to measure pepsin in sputum and salivary samples from patients with EER, Kim and colleagues reported a sensitivity and specificity of 89% and 68%, respectively, based on pH monitoring results.76
Recently, a novel, rapid, pepsin test (Peptest, Biomed) has also been used as a convenient, office-based, noninvasive, quick, inexpensive technique for the diagnosis of LPR. This lateral flow device (LFD) utilizes 2 monoclonal antibodies to human pepsin, and its results can be read in 5–15 minutes (Figure 5).77 In a recent, prospective, blinded study of the rapid LFD in 59 patients with objective GERD (based on esophagitis or abnormal pH testing) and 51 control subjects, we found positive and negative predictive values of 87% and 78%, respectively.78 The sensitivity and specificity of the assay were both 87% via
in vitro bench testing. Thus, this study suggests that the use of rapid LFD for detection of salivary pepsin has acceptable test characteristics in GERD patients. However, the clinical role of this assay in LPR patients is unknown and remains the subject of ongoing studies. Table 3 summarizes the advantages and disadvantages of commonly used diagnostic methods for detection of LPR.
PPI therapy is the standard of care when GERD is suspected to be the etiology of chronic throat symptoms. However, a recent, large-scale, multicenter study of
145 patients suspected of having LPR did not show a benefit in those treated with esomeprazole 40 mg twice daily for 4 months compared to placebo.59 The disappointing negative findings from this study and other controlled trials in LPR patients stem from the dilution effect of patients enrolled in these trials (Figure 6).79 Given the lack of a gold standard for diagnosing GERD in patients with LPR, many patients may not have had the disease for which they were being randomized. Otolaryngologists usually suspect GERD-related laryngitis based on symptoms (such as throat clearing, cough, and globus pharyngeus) and signs (such as laryngeal edema and erythema); however, these signs and symptoms are nonspecific for reflux. Patients who are unresponsive to PPI therapy may have either nonreflux-related causes or a functional component to their symptoms. The placebo response rate in LPR studies is approximately 40%, which is similar to that seen in studies of functional gastrointestinal disorders such as irritable bowel syndrome.80 Although clinical response to an empiric trial of PPIs does not prove a causal link, persistent response or symptom recurrence with the discontinuation of PPIs may be suggestive of GERD-related symptoms.
Some investigators argue that continued acid and/or pepsin-related injury to the larynx is the cause of symptoms, despite a lack of response to PPI therapy. Altman and coworkers evaluated the laryngeal tissue of
15 patients and found expression of the a and/or b subunits of H+/K+–ATPase, suggesting that proton pumps in laryngeal seromucinous glands and duct cells may play a role in the pathogenesis of LPR signs and symptoms.81 It has been suggested that laryngeal proton pumps may activate in response to reflux or other causes of inflammation or infection in order to preserve intracellular pH and, thus, viability. An alternative explanation for the lack of response to PPI therapy in LPR patients is that reflux may be intermittent and/or may occur in low volumes. Proponents argue that the larynx is highly sensitive to acid, so even low levels of acid may result in laryngeal signs and symptoms without abnormal findings on endoscopy, pH tests, or impedance monitoring.82 Other doctors have suggested that pepsin can cause cellular damage even in nonacid environments.53,83 For example, Golgi complex and mitochondrial damage have been demonstrated in laryngeal tissue exposed only to pepsin. Moreover, studies have shown pepsin-related alterations in laryngeal gene expression in nonacid conditions, as well as specific receptor-mediated membrane transfer of pepsin.48,84 The above arguments may be appealing and academically thought-provoking; however, they do not explain why patients continue to be symptomatic despite aggressive therapy such as surgical fundoplication.85,86 This procedure should correct any reflux of nonacid materials, including pepsin and/or low-volume acid, to the larynx. The role of surgical intervention in patients who are refractory to PPI therapy is evolving. The most recent study conducted in this area suggests that baseline regurgitation, hiatal hernia, and moderate-to-severe acid reflux (defined as >10% when
pH <4) predict symptomatic response to surgery.28
Therefore, patients who are suspected of having LPR but who do not have any warning symptoms or signs should initially be treated with empiric PPI therapy for 1–2 months. If symptoms improve, the therapy may need to be prolonged for up to 6 months to allow healing of laryngeal tissue, after which time the dosage should be tapered to the smallest amount that still results in continued response. In unresponsive patients, impedance and/or
pH monitoring may be the best alternative to rule out reflux as the cause of continued symptoms and to move forward by considering other causes.
Summary
GERD commonly presents with EER symptoms. Patients may or may not also have the typical GERD symptoms of heartburn and/or regurgitation. In this group of patients, empiric acid suppression therapy is indicated if there are no warning symptoms. A lack of response to acid suppression therapy necessitates diagnostic testing with pH and/or impedance monitoring. However, due to limited outcome studies, the role of the latter test alone is currently uncertain. New diagnostic modalities and treatment options discussed in this paper may be helpful in patients who continue to be symptomatic despite acid suppression therapy.
References
1. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005;54:710-717.
2. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991;101(4 pt 2 suppl 53):1-78.
3. Wood JM, Hussey DJ, Woods CM, Watson DI, Carney AS. Biomarkers and laryngopharyngeal reflux. J Laryngol Otol. 2011;125:1218-1224.
4. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900-1920; quiz 1943.
5. Field SK, Evans JA, Price LM. The effects of acid perfusion of the esophagus on ventilation and respiratory sensation. Am J Respir Crit Care Med. 1998;157(4 pt 1):
1058-1062.
6. Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastro-esophageal reflux. Am J Respir Crit Care Med. 1994;149:160-167.
7. Adhami T, Goldblum JR, Richter JE, Vaezi MF. The role of gastric and duodenal agents in laryngeal injury: an experimental canine model. Am J Gastroenterol. 2004;99:2098-2106.
8. Tuchman DN, Boyle JT, Pack AI, et al. Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology. 1984;87:872-881.
9. Stanghellini V. Relationship between upper gastrointestinal symptoms and lifestyle, psychosocial factors and comorbidity in the general population: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST). Scand J Gastroenterol Suppl. 1999;231:29-37.
10. Poe RH, Kallay MC. Chronic cough and gastroesophageal reflux disease: experience with specific therapy for diagnosis and treatment. Chest. 2003;123:679-684.
11. Irwin RS. Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 suppl):80S-94S.
12. Johnson DA. Medical therapy of reflux laryngitis. J Clin Gastroenterol. 2008;42:589-593.
13. Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease. Clin Cornerstone. 2003;5:32-38, discussion 39-40.
14. Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol. 1999;94:3131-3138.
15. Schappert SM. National ambulatory medical care survey: 1991 summary. Adv Data. 1993;230:1-16.
16. Baldi F, Cappiello R, Cavoli C, Ghersi S, Torresan F, Roda E. Proton pump inhibitor treatment of patients with gastroesophageal reflux-related chronic cough: a comparison between two different daily doses of lansoprazole. World J Gastroenterol. 2006;12:82-88.
17. Laukka MA, Cameron AJ, Schei AJ. Gastroesophageal reflux and chronic cough: which comes first? J Clin Gastroenterol. 1994;19:100-104.
18. Everett CF, Morice AH. Clinical history in gastroesophageal cough. Respir Med. 2007;101:345-348.
19. Chandra KM, Harding SM. Therapy insight: treatment of gastroesophageal reflux in adults with chronic cough. Nat Clin Pract Gastroenterol Hepatol. 2007;4:604-613.
20. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis. 1990;141:640-647.
21. Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic, and pathogenetic aspects. Chest. 1993;104:1511-1517.
22. McGarvey LP, Heaney LG, Lawson JT, et al. Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax. 1998;53:738-743.
23. Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2011;9:868-874.
24. Smith JA, Decalmer S, Kelsall A, et al. Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroenterology. 2010;139:754-762.
25. Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev. 2005;(2):CD004823.
26. Faruqi S, Molyneux ID, Fathi H, Wright C, Thompson R, Morice AH. Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study. Respirology. 2011;16:1150-1156.
27. Shaheen NJ, Crockett SD, Bright SD, et al. Randomised clinical trial: high-dose acid suppression for chronic cough—a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33:225-234.
28. Francis DO, Goutte M, Slaughter JC, et al. Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux. Laryngoscope. 2011;121:1902-1909.
29. Bastian RW, Vaidya AM, Delsupehe KG. Sensory neuropathic cough: a common and treatable cause of chronic cough. Otolaryngol Head Neck Surg. 2006;135:17-21.
30. O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med. 1994;150:374-380.
31. Lee B, Woo P. Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment. Ann Otol Rhinol Laryngol. 2005;114:253-257.
32. Mintz S, Lee JK. Gabapentin in the treatment of intractable idiopathic chronic cough: case reports. Am J Med. 2006;119:e13-e15.
33. Halum SL, Sycamore DL, McRae BR. A new treatment option for laryngeal sensory neuropathy. Laryngoscope. 2009;119:1844-1847.
34. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest. 1999;116:1257-1264.
35. Ahmed T, Vaezi MF. The role of pH monitoring in extraesophageal gastroesophageal reflux disease. Gastrointest Endosc Clin N Am. 2005;15:319-331.
36. Leggett JJ, Johnston BT, Mills M, Gamble J, Heaney LG. Prevalence of gastroesophageal reflux in difficult asthma: relationship to asthma outcome. Chest. 2005;127:1227-1231.
37. Sontag SJ, O’Connell S, Khandelwal S, et al. Asthmatics with gastroesophageal reflux: long-term results of a randomized trial of medical and surgical antireflux therapies. Am J Gastroenterol. 2003;98:987-999.
38. Meier JH, McNally PR, Punja M, et al. Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study. Dig Dis Sci. 1994;39:2127-2133.
39. Littner MR, Leung FW, Ballard ED 2nd, Huang B, Samra NK; Lansoprazole Asthma Study Group. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest. 2005;128:1128-1135.
40. American Lung Association Asthma Clinical Research Centers; Mastronarde JG, Anthonisen NR, Castro M, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360:1487-1499.
41. Writing Committee for the American Lung Association Asthma Clinical Research Centers; Holbrook JT, Wise RA, Gold BD, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307:373-381.
42. Gibson PG, Powell H, Coughlan J, et al. Limited (information only) patient education programs for adults with asthma. Cochrane Database Syst Rev. 2002;(2):CD001005.
43. Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006;173:1091-1097.
44. Vaezi MF. Laryngitis and gastroesophageal reflux disease: increasing prevalence or poor diagnostic tests? Am J Gastroenterol. 2004;99:786-788.
45. Diamond L. Laryngopharyngeal reflux—it’s not GERD. JAAPA. 2005;18:50-53.
46. Samuels TL, Johnston N. Pepsin as a causal agent of inflammation during nonacidic reflux. Otolaryngol Head Neck Surg. 2009;141:559-563.
47. Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117:1036-1039.
48. Johnston N, Wells CW, Blumin JH, Toohill RJ, Merati AL. Receptor-mediated uptake of pepsin by laryngeal epithelial cells. Ann Otol Rhinol Laryngol. 2007;116:934-938.
49. Vaezi MF, Slaughter JC, Smith BS, et al. Dilated intercellular space in chronic laryngitis and gastro-oesophageal reflux disease: at baseline and post-lansoprazole therapy. Aliment Pharmacol Ther. 2010;32:916-924.
50. Reichel O, Mayr D, Durst F, Berghaus A. E-cadherin but not beta-catenin expression is decreased in laryngeal biopsies from patients with laryngopharyngeal reflux. Eur Arch Otorhinolaryngol. 2008;265:937-942.
51. Axford SE, Sharp N, Ross PE, et al. Cell biology of laryngeal epithelial defenses in health and disease: preliminary studies. Ann Otol Rhinol Laryngol. 2001;110:1099-1108.
52. Gill GA, Johnston N, Buda A, et al. Laryngeal epithelial defenses against laryngopharyngeal reflux: investigations of e-cadherin, carbonic anhydrase isoenzyme III, and pepsin. Ann Otol Rhinol Laryngol. 2005;114:913-921.
53. Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J. Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope. 2004;114:2129-2134.
54. Johnston N, Bulmer D, Gill GA, et al. Cell biology of laryngeal epithelial defenses in health and disease: further studies. Ann Otol Rhinol Laryngol. 2003;112:481-491.
55. Kendall KA. Controversies in the diagnosis and management of laryngopharyngeal reflux disease. Curr Opin Otolaryngol Head Neck Surg. 2006;14:113-115.
56. Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice. 2002;16:564-579.
57. Milstein CF, Charbel S, Hicks DM, Abelson TI, Richter JE, Vaezi MF. Prevalence of laryngeal irritation signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique (rigid vs. flexible laryngoscope). Laryngoscope. 2005;115:2256-2261.
58. Vavricka SR, Storck CA, Wildi SM, et al. Limited diagnostic value of laryngopharyngeal lesions in patients with gastroesophageal reflux during routine upper gastrointestinal endoscopy. Am J Gastroenterol. 2007;102:716-722.
59. Vaezi MF, Richter JE, Stasney CR, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope. 2006;116:254-260.
60. Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol. 1997;92:825-829.
61. McCollough M, Jabbar A, Cacchione R, Allen JW, Harrell S, Wo JM. Proximal sensor data from routine dual-sensor esophageal pH monitoring is often inaccurate. Dig Dis Sci. 2004;49:1607-1611.
62. Vaezi MF. Reflux-induced laryngitis (laryngopharyngeal reflux). Curr Treat Options Gastroenterol. 2006;9:69-74.
63. Sifrim D, Blondeau K. Technology insight: the role of impedance testing for esophageal disorders. Nat Clin Pract Gastroenterol Hepatol. 2006;3:210-219.
64. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398-1402.
65. Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483-1487.
66. Vaezi MF, Hicks DM, Ours TM, Richter JE. ENT manifestation of GERD: a large prospective study assessing treatment outcome and predictors of response. Gastroenterology. 2001;120:A636.
67. Vaezi MF. Laryngitis: from the gastroenterologist’s point of view. In: Vaezi MF, ed. Extraesophageal Reflux. San Diego, Calif: Plural Publishing, Inc; 2009:37-47.
68. Pritchett JM, Aslam M, Slaughter JC, Ness RM, Garrett CG, Vaezi MF. Efficacy of esophageal impedance/pH monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy. Clin Gastroenterol Hepatol. 2009;7:743-748.
69. Fletcher KC, Goutte M, Slaughter JC, Garrett CG, Vaezi MF. Significance and degree of reflux in patients with primary extraesophageal symptoms. Laryngoscope. 2011;121:2561-2565.
70. Wiener GJ, Tsukashima R, Kelly C, et al. Oropharyngeal pH monitoring for the detection of liquid and aerosolized supraesophageal gastric reflux. J Voice. 2009;23:498-504.
71. Sun G, Muddana S, Slaughter JC, et al. A new pH catheter for laryngopharyngeal reflux: normal values. Laryngoscope. 2009;119:1639-1643.
72. Potluri S, Friedenberg F, Parkman HP, et al. Comparison of a salivary/sputum pepsin assay with 24-hour esophageal pH monitoring for detection of gastric reflux into the proximal esophagus, oropharynx, and lung. Dig Dis Sci. 2003;48:
1813-1817.
73. Piper DW, Fenton BH. pH stability and activity curves of pepsin with special reference to their clinical importance. Gut. 1965;6:506-508.
74. Ozmen S, Yücel OT, Sinici I, et al. Nasal pepsin assay and pH monitoring in chronic rhinosinusitis. Laryngoscope. 2008;118:890-894.
75. Printza A, Speletas M, Triaridis S, Wilson J. Is pepsin detected in the saliva of patients who experience pharyngeal reflux? Hippokratia. 2007;11:145-149.
76. Kim TH, Lee KJ, Yeo M, Kim DK, Cho SW. Pepsin detection in the sputum/saliva for the diagnosis of gastroesophageal reflux disease in patients with clinically suspected atypical gastroesophageal reflux disease symptoms. Digestion. 2008;77:201-206.
77. Strugala V, McGlashan JA, Watson MG, Morice AH, Granier B, Dettmar PW. Detection of pepsin using a non-invasive lateral flow test for the diagnosis of extra-esophageal reflux—results of a pilot study. Gut. 2007;56:A212.
78. Saritas Yuksel E, Hong SK, Strugala V, et al. Rapid salivary pepsin test: blinded assessment of test performance in gastroesophageal reflux disease. Laryngoscope. 2012;122:1312-1316.
79. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101:2646-2654.
80. Patel SM, Stason WB, Legedza A, et al. The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005;17:332-340.
81. Altman KW, Waltonen JD, Hammer ND, Radosevich JA, Haines GK 3rd. Proton pump (H+/K+-ATPase) expression in human laryngeal seromucinous glands. Otolaryngol Head Neck Surg. 2005;133:718-724.
82. Merati AL, Lim HJ, Ulualp SO, Toohill RJ. Meta-analysis of upper probe measurements in normal subjects and patients with laryngopharyngeal reflux. Ann Otol Rhinol Laryngol. 2005;114:177-182.
83. Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease. Ann Otol Rhinol Laryngol. 2006;115:47-58.
84. Johnston N, Wells CW, Samuels TL, Blumin JH. Rationale for targeting pepsin in the treatment of reflux disease. Ann Otol Rhinol Laryngol. 2010;119:547-558.
85. Ratnasingam D, Irvine T, Thompson SK, Watson DI. Laparoscopic antireflux surgery in patients with throat symptoms: a word of caution. World J Surg. 2011;35:342-348.
86. Swoger J, Ponsky J, Hicks DM, et al. Surgical fundoplication in laryngopharyngeal reflux unresponsive to aggressive acid suppression: a controlled study. Clin Gastroenterol Hepatol. 2006;4:433-441.