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Reflux related cough, asthma and laryngitis are frequently encountered and are considered part of extraoesophageal syndromes. The diagnosis of extraoesophageal reflux is difficult due to the lack of gold standard diagnostic criteria. Esophagogastroduodenoscopy and esophageal pH monitoring are inadequate diagnostic tools for due to poor sensitivity and specificity. For this reason, empirical PPI therapy is recommended as an initial approach to diagnose and treat the potential underlying cause of these symptoms in patients without alarm symptoms. Diagnostic testing with esophageal pH and/or impedance monitoring and esophageal motility testing is usually reserved for those who continue to be symptomatic despite a trial of therapy with PPIs. Recent developments have increased our understanding of this difficult to treat group of patients but more research into reflux related extraoesophageal symptoms are needed to better diagnose and treat this group.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Gastroesophageal reflux disease (GERD) is a common disease that is often diagnosed based on typical symptoms of heartburn and regurgitation. In addition to these more classic manifestations, GERD is increasingly associated with extra-esophageal symptoms, including chronic cough, asthma, laryngitis, and dental erosions. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. For those who improve with PPIs, GERD is the presumed etiology, but for those who remain unresponsive to such therapy, further diagnostic testing with impedance/pH monitoring may be necessary in order to exclude refractory acid or weakly acid reflux. In those with normal test results despite PPI therapy and continued symptoms, causes other than GERD may be pursued. Recent data suggest that in patients with extra-esophageal symptoms, objective findings of moderate-sized hiatal hernia and moderate reflux on pH testing may predict response to acid suppressive therapy. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal symptoms and continued PPI therapy in this group is not recommended.
OBJECTIVES/HYPOTHESIS - Ambulatory esophageal impedance monitoring is commonly employed to assess for nonacid reflux in patients with extraesophageal reflux. We aimed to determine if on therapy impedance data can be predicted from off therapy upper endoscopy, manometry, or pH parameters.
STUDY DESIGN - Prospective Cohort Study.
METHODS - Patients with extraesophageal reflux symptoms and either partial- or nonresponders to twice-daily PPI underwent impedance monitoring on twice-daily PPI, as well as manometry, upper endoscopy, and 48-hour wireless pH monitoring off acid-suppressive medications for 1 week. Percent time pH < 4 and number of reflux episodes were obtained. Multivariable linear regression was used to determine association between the impedance data on therapy and upper endoscopy, manometry, and pH parameters measured off therapy.
RESULTS - Seventy-five patients (77% female, median BMI 29, 38% with hiatal hernia, and 19% with esophagitis) were studied both on and off therapy. Thirty-five percent had abnormal impedance monitoring on therapy and 84% had abnormal pH testing off therapy. There was no significant (P = 0.184) overall correlation between total number of impedance events and the baseline physiologic parameters of hiatal hernia, degree of acid reflux, or manometric findings, with only weak correlation (r = 0.54, P = 0.045) with % time pH < 4 among patients with esophagitis.
CONCLUSIONS - In patients with suspected extraesophageal reflux refractory to PPI therapy, impedance measures on therapy cannot be predicted from traditional baseline esophageal physiologic parameters. We recommend caution regarding over-interpretation of impedance data.
LEVEL OF EVIDENCE - 2b.
Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.
Gastroesophageal reflux disease (GERD) is the main etiological factor behind the recent rapid increase in the incidence of esophageal adenocarcinoma. During reflux, esophageal cells are exposed to bile at low pH resulting in cellular damage and inflammation, which are known to facilitate cancer development. In this study, we investigated the regulation of p73 isoform, ΔNp73α, in the reflux condition. Previous studies have reported that ΔNp73 exhibits anti-apoptotic and oncogenic properties through inhibition of p53 and p73 proteins. We found that direct exposure of esophageal cells to bile acids in an acidic environment alters the phosphorylation of ΔNp73, its subcellular localization and increases ΔNp73 protein levels. Upregulation of ΔNp73 was also observed in esophageal tissues collected from patients with GERD and Barrett's metaplasia, a precancerous lesion in the esophagus associated with gastric reflux. c-Abl, p38 MAPK, and IKK protein kinases were identified to interact in the regulation of ΔNp73. Their inhibition with chemotherapeutic agents and siRNA suppresses ΔNp73. We also found that pro-inflammatory cytokines, IL-1β and TNFα, are potent inducers of ΔNp73α, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic ΔNp73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.
OBJECTIVES - Extraesophageal symptoms are common manifestations of gastroesophageal reflux disease (GERD). Lack of a definitive diagnostic or treatment standards complicate management, which often leads to multiple specialty consultations, procedures, pharmaceuticals and diagnostic tests. The aim of this study was to determine the economic burden associated with extraesophageal reflux (EER).
METHODS - Direct costs of evaluation were estimated for patients referred with symptoms attributed to EER between 2007 and 2011. Medicare payment for evaluation and management and pharmaceutical prices was used to calculate first year and overall costs of evaluating and treating extraesophageal symptoms attributed to reflux.
RESULTS - Overall, 281 patients were studied (cough (50%), hoarseness (23%), globus/post-nasal drainage (15%), asthma (9%), and sore throat (3%)). Over a median (interquartile range) of 32 (16-46) months follow-up, patients had a mean (95% confidence interval) of 10.1 (9.4-10.9) consultations with specialists and underwent 6.4 (3-9) diagnostic procedures. Overall, the mean initial year direct cost was $5,438 per patient being evaluated for EER. Medical and non-medical components contributed $5,154 and $283. Of the overall cost, 52% were attributable to the use of proton pump inhibitors. During the initial year, direct costs were 5.6 times higher than those reported for typical GERD ($971). A total of 54% of patients reported improvement of symptoms. Overall cost per improved patient was $13,700.
CONCLUSIONS - EER contributes substantially to health-care expenditures. In this cohort, the cost for initial year's evaluation and treatment of EER symptoms was quintuple that of typical GERD. Prescription costs and, in particular, proton pump inhibitors were the single greatest contributor to the cost of EER management.
BACKGROUND - Diagnostics for gastro-esophageal reflux disease (GERD) are suboptimal because of limited sensitivity. We performed in vitro and in vivo studies to systematically assess the performance characteristics of an oropharyngeal pH probe.
METHODS - In vitro studies compared the oropharyngeal probe with a standard pH catheter in liquid and aerosolized solutions, pH 1-7. The accuracy of measurements, deviation from target pH, and time to equilibrium pH were determined. Simultaneous distal esophageal pH measurements were obtained in 11 patients with GERD. Oropharyngeal and distal esophageal reflux parameters were measured for controls (n = 20), patients with GERD (n = 17), and patients with chronic laryngitis (n = 10).
KEY RESULTS - In the liquid phase, at pH 4-5, the oropharyngeal probe had less deviation from the target value than the standard catheter; deviation in the vapor phase was similar (0.4 pH units). Median (interquartile) time to reach equilibrium pH was significantly (P < 0.001) faster with the oropharyngeal than the standard probe. In comparing simultaneous distal esophageal pH characteristics, 96% of recordings with the new and standard probes were in agreement to within ± 1.0 pH unit; 71% of recordings were in agreement within ± 0.5 pH units. Patients with chronic laryngitis had significantly higher levels of oropharyngeal acid exposure at pH <4, <5, and <6, in the upright position than patients with GERD or controls (P < .001).
CONCLUSIONS & INFERENCES - Oropharyngeal pH monitoring appears to be more sensitive than traditional pH monitoring in evaluation of patients with extraesophageal reflux. It is a promising tool in evaluation of this difficult group of patients.
© 2013 Blackwell Publishing Ltd.
This article discusses the current state of knowledge regarding the relationship between gastroesophageal reflux disease (GERD) and pulmonary and ear/nose/throat manifestations of reflux and outlines the recent developments in the diagnostic and treatment strategies for this difficult group of patients. Upper gastrointestinal endoscopy and pH monitoring are poorly sensitive for diagnosing reflux in this group of patients. Instead it is recommended that in those without warning symptoms, an empiric trial of proton-pump inhibitors be the initial approach to diagnosing and treating the potential underlying cause of these extraesophageal symptoms.
Copyright © 2013 Elsevier Inc. All rights reserved.
Gastroesophageal reflux disease (GERD) is a common disease that is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms. In addition to the esophageal manifestations of heartburn and regurgitation, the role of GERD in causing extra-esophageal symptoms, such as laryngitis, asthma, cough, chest pain, and dental erosions, is increasingly recognized with renewed interest. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPI) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. In those who are unresponsive to such therapy, other diagnostic testing such as impedance/pH monitoring may be reasonable in order to exclude continued acid or weakly acid reflux. Recent data suggest that patients with extra-esophageal symptoms who have concomitant typical symptoms, moderate-sized hiatal hernia and moderate reflux on pH testing may respond better to acid suppressive therapy. This group only accounts for 20-30 % of patients commonly referred for suspected GERD. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal signs and symptoms and continued PPI therapy in this group is not recommended.
Gastroesophageal reflux disease is increasingly associated with ear, nose, and throat symptoms, including laryngitis. Many patients are unaware of the gastroesophageal etiology of their symptoms. A variety of criteria are used to diagnose this condition, including laryngoscopy, esophagogastroduodenoscopy, and the use of ambulatory pH and impedance monitoring. However, no test serves as the gold standard for the diagnosis given their lack of sensitivity and specificity for reflux disease. Numerous trials have assessed the role of proton pump inhibitor therapy in patients with laryngopharyngeal reflux and most have revealed no benefit to acid suppression over placebo. Despite many uncertainties there has been some progress regarding the role of acid-suppressive therapy as well as other agents in this unique group of patients. In this review we explore therapeutic options and their rationale for patients with laryngeal signs and symptoms.
OBJECTIVES - Patient reporting of symptom events during ambulatory reflux monitoring is commonly performed with little data regarding its accuracy. We employed a novel time-synchronized ambulatory audio recording of symptom events simultaneously with prolonged pH/impedance monitoring to assess temporal accuracy of patient-reported symptoms.
METHODS - An acoustic monitoring system was employed to detect cough events via tracheal and chest wall sounds and it was temporally synchronized with an ambulatory impedance/pH monitoring system. Patients were instructed to record their symptoms in the usual manner. Six separate observers independently listened to the 24-h audio recordings and logged the exact timing of each cough event. Patients were blinded to study design and the audio reviewers were blinded to their own reports and those of patients and other reviewers. Concurrence of audio recordings and patient-reported symptoms were tested for three separate time thresholds: 1, 2, and 5 min.
RESULTS - The median (interquartile range (IQR)) number of cough events by audio detection was significantly (P<0.001) higher than those reported by patients: 216 (90-275) and 34 (22-60), respectively. There was significantly (P<0.001) higher agreement among the audio recording listeners (substantial to almost perfect agreement; kappa=0.77-0.82) than between the audio recording and patient-reported symptoms (slight to fair agreement; kappa=0.13-0.27). Patients did not report 91, 82, and 71% of audible cough events based on 1-, 2-, and 5-min concordance time windows, respectively.
CONCLUSIONS - We found that patients do not report the majority of their symptoms during ambulatory reflux monitoring even within a 5-min time window of the true event and advise caution in clinical decision-making based solely on symptom indices.