382 salivary pepsin in patients with refractory gerd: double blinded assessment of test sensitivity,...

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prior to GES correlated with symptoms during the test for nausea (NGES r=0.61; p<0.001, DGES r=0.70; p<0.0001), stomach fullness (NGES r=0.47; p<0.001, DGES r=0.60; p<0.001), and bloating (NGES r=0.62; p<0.001, DGES r=0.66; p<0.001). Conclusions: Symptom severity recorded during GES is higher in DGES than NGES patients for stomach fullness, abdominal pain, and bloating. There is a good correlation between symptoms recorded during GES and during daily life as recorded by the PAGI-SYM for 2 weeks prior to the test. 381 Intercellular Space Distance Is Increased in Refractory Heartburn Patients with GERD But Not Those with Functional Heartburn (FH): A Study Using Impedance-pH and Electron Microscopy Marcelo F. Vela, Brandon M. Craft, Neeraj Sharma, Janice Freeman, Debra Hazen-Martin INTRODUCTION: Refractory heartburn despite maximal acid suppression may be due to ongoing GERD as documented by endoscopy or reflux monitoring, or it may represent Functional Heartburn (FH), i.e. symptoms in the absence of objective evidence of GERD. Multichannel Intraluminal Impedance and pH (MII-pH) detects both acid and nonacid reflux and is useful for evaluating reflux and its association to symptoms in acid suppressed patients. Intercellular space distance (ISD) of esophageal epithelium measured by electron microscopy (EM) is a marker of epithelial damage present in both erosive and non-erosive reflux disease. AIM: Compare ISD in healthy controls and two groups of patients with refractory heartburn: those with objective evidence of GERD on endoscopy and/or 24-hour MII-pH, and those with Functional Heartburn (FH). METHODS: Patients with persistent heartburn despite BID PPI underwent MII-pH on therapy and endoscopy with biopsies for ISD measurement by Electron Microscopy (EM). Patients with esophagitis (EE) or abnormal MII-pH defined by increased esophageal acid exposure time (AET) or a positive symptom index (SI), i.e. >50% heartburn events associated with a reflux episode, were categorized as GERD; those with normal testing were considered FH. Healthy controls without GERD symptoms and a normal 24-h pH study underwent endoscopy with esophageal biopsies for ISD measurement. ISD determined in all subjects by transmission EM of esophageal biopsies at 5,000x magnifica- tion using computer-assisted morphometry (Image J software). 10 measurements of ISD taken in each of 10 micrographs; mean ISD was the average of these 100 measurements. RESULTS: 10 healthy controls, 10 FH, and 14 GERD patients (8 SI-positive, 2 SI-positive + AET, 2 EE, 1 AET, 1 EE + AET) studied. Results shown in the table. Mean ISD was significantly higher in GERD compared to controls (p = 0.007) and FH (p = 0.03). ISD numerically higher for FH compared to controls, but not statistically significant. CONCLU- SION: GERD but not FH patients with refractory heartburn have increased ISD, even though most GERD patients had normal endoscopy. ISD may be a helpful tool to discriminate GERD from FH. Implications for therapy may be that those with increased ISD need improved reflux control, while those with FH may benefit from non-GERD treatments (e.g. visceral analgesia). EE = Erosive Esophagitis, ISD = Intercellular Space Distance 382 Salivary Pepsin in Patients with Refractory GERD: Double Blinded Assessment of Test Sensitivity, Specificity, Positive and Negative Predictive Values Shih-Kuang S. Hong, Peter W. Dettmar, James C. Slaughter, Vicki Strugala, Marion Goutte, Michael F. Vaezi Background: There is increasing prevalence of patients with gastroesophageal reflux disease (GERD) who are refractory to aggressive acid suppression. Pepsin lateral flow test (LFT) is a non-invasive assay to detect salivary pepsin. It has 2 unique antibodies specific for human pepsin. In this double blind clinical study, we aimed to establish the following critical test characteristics for this assay: 1) sensitivity and specificity based on known pepsin presence or absence, 2) the prevalence of salivary pepsin in normal controls vs. GERD and extraeso- phageal reflux (EERD) patients, and 3) positive and negative predictive values (PPV and NPV) in symptomatic patients (GERD+EERD) on or off PPI therapy. Methods: 230 samples were analyzed by LFT with all assays double-blinded as to the source. Bench sensitivity and specificity were estimated using 54 pure water and 51 gastric juice samples. Saliva was collected from 51 healthy volunteers to serve as normal controls. For PPV and NPV calcula- tions in symptomatic patients, saliva was collected from 58 patients with gastroesophageal syndrome (Montreal Definition) and 16 patients with extraesophageal syndrome. Prevalence of positive salivary pepsin was determined in normal controls, GERD, and EERD groups. The two patient groups then underwent EGD, wireless pH monitoring and reflux questionnaire off therapy. PPV and NPV were calculated based on two True Positive definitions: A) positive pH or esophagitis or B) positive pH or esophagitis or presence of heartburn. Results: 1) ROC analysis revealed a sensitivity of 88% and a specificity of 87% based on samples of known pepsin presence. 2) 6/51 (12%) control subjects, 13/58 (22%) in GERD group, and 4/16 (25%) in EERD pts tested positive (p=NS). There was no difference in the prevalence of positive pepsin on (16%) or off (14%) PPI therapy (p=NS). Patients with esophagitis or abnormal pH had higher prevalence of positive salivary pepsin assay (45% and 33%, respectively). PPV and NPV based on each true positive definitions and the disease prevalence is shown in Table 1. Conclusion: 1) Salivary pepsin assay was only positive in 45% of known esophagitis and 33% of those with abnormal pH. 2) Given lower disease prevalence defined by esophagitis or abnormal pH (48%, Def. A), if the pepsin assay returns positive, the probability of disease increases to 65% in contrast to defining the disease by adding A-63 AGA Abstracts heartburn, which increases disease prevalence to 84% (Def. B) thus obviating the need for any additional test. Table 1 383 Optimization of the Reflux-Symptom Association Statistics in Infants Taher Omari, Andrea Schwarzer, Michiel P. van Wijk, Stamatiki Kritas, Lisa McCall, Sibylle Koletzko, Geoffrey Davidson Introduction: Symptom association probability (SAP) is the best available measure for dia- gnosis of a causal relationship between bolus gastroesophageal reflux (GER) and symptoms during pH-impedance monitoring. Current association criteria for calculation of SAP are optimised for symptoms of heartburn in adults. Infants, however, demonstrate a different symptom profile and their symptoms are usually recorded by a parent or guardian. The aim of this study was to establish the optimal reflux-symptom association time window for SAP calculations in infants with typical GERD symptoms. Methods: 10 infants (2-8 months) referred for investigation were enrolled. GER episodes were recorded using a pH-impedance probe which remained in place for 48h. During the test, cough, irritability/crying and regurgitation were marked. Impedance recordings for the 0-24h and 24-48h period were analysed for the occurrence of bolus reflux episodes. SAP was calculated using automated reporting software (Bioview) which enabled the time window used for SAP calculations to be modified. An SAP of 95% was considered to be a diagnostically positive result. Day to day variability in SAP was assessed by calculating the 95% limits of agreement (mean difference±1.96 standard deviation of differences) and their confidence intervals. This approach provides an interval within which 95% of the differences between measurement periods are expected to lie(1). The optimal time window for SAP calculation was defined by the interval that produced the least variation in the 95% limits of agreement. Results: The number of bolus GER recorded on days 1 and 2 was 73±9 vs 69±11 respectively and correlated from day to day in individual patients (Spearman rank correlation r=0.75, p= 0.0108). The occurrence of symptom episodes did not differ from day to day (21±3 vs 15±3 cough episodes, 38±8 vs 33±8 crying episodes and 6±3 vs 8±3 regurgitation episodes respectively). The least variability in SAP was found using time windows of 2min for cough, 2-5min for crying and 2-5 min for regurgitation (graph). Conclusion: In infants, SAP findings based on standard GER-symptom association criteria of 2min appear to be optimal for typical symptoms of GERD. (1)Bland J & Altman D. Statistical Methods in Medical Research 1999;8:135. 384 Predictive Validity and Responsiveness of the Mayo Dysphagia Questionnaire- 30 for the Outcome of Dysphagia Dawn L. Francis, Felicity Enders, Michael D. Crowell, K.Robert Shen, Robert C. Miller, Catherine R. Weiler, Rayna Grothe, Judith L. McElhiney, Gianrico Farrugia, Melissa M. Kuntz, Nancy Diehl, Matthew R. Lohse, Amindra S. Arora, Darlene E. Graner, Nicholas J. Talley, G. Richard Locke, Joseph A. Murray, Jeffrey A. Alexander, Timothy J. Beebe, Adil A. Abdalla, Joanna M. Peloquin, April Grudell, Ganapathy A. Prasad, Yvonne Romero Background: The Mayo Dysphagia Questionnaire 30 Day (MDQ-30) has been shown to have excellent reproducibility and concurrent validity. It is important for the questionnaire to demonstrate predictive validity and be responsive; that responses correlate with objective findings at endoscopy and that items on the questionnaire change in the direction one expects when symptoms change. Methods: We have been distributing the MDQ-30 to adult participants in 5 research studies over the past two years. Cases have an esophageal stricture < 15 mm diameter at baseline and controls do not. Patients with reflux esophagitis and esophageal neoplasm were excluded. Results: To create the Dysphagia Score (DS), 117 participants, 22 with stricture [mean age 70 years, 16 (73%) male] were compared to 95 controls [mean age 61, 51 (54%) male]. Eleven of 22 with stricture had endoscopy (EGD) on two occasions, 7 of whom completed the MDQ-30 twice, and could be used to assess responsiveness. Predictive validity. The best model to differentiate patients with stricture from those without used four items: impaction, solid food dysphagia, severity of dysphagia over the past 30 days, and took into account food avoidance and food modification, with an area under the ROC curve of 0.85. Many patients reveal they avoid certain food stuffs, like fibrous meats, or modify their food (e.g. dunk bread into hot coffee) to facilitate swallowing. DS > 60 were 91% sensitive for stricture, while scores < 6 were 97% specific for stricture (a score less than 6 virtually excluded the presence of a stricture). DS > 24 are 87.5% sensitive and 78.4% specific for the presence of a stricture < 15 mm diameter. Responsiveness. In two patients, the stricture remained the same diameter (9 to 9, and 9.7 to 10 mm) and their DS remained stable (39 to 39, and 39 to 39). In 2 patients the stricture diameter improved from 9 to 16 mm, and 12 to 15 mm, and their DS improved in the same direction (from 61 to 2, and 32 to 10, respectively). In one patient the diameter AGA Abstracts

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Page 1: 382 Salivary Pepsin in Patients with Refractory GERD: Double Blinded Assessment of Test Sensitivity, Specificity, Positive and Negative Predictive Values

prior to GES correlated with symptoms during the test for nausea (NGES r=0.61; p<0.001,DGES r=0.70; p<0.0001), stomach fullness (NGES r=0.47; p<0.001, DGES r=0.60; p<0.001),and bloating (NGES r=0.62; p<0.001, DGES r=0.66; p<0.001). Conclusions: Symptomseverity recorded during GES is higher in DGES than NGES patients for stomach fullness,abdominal pain, and bloating. There is a good correlation between symptoms recordedduring GES and during daily life as recorded by the PAGI-SYM for 2 weeks prior to the test.

381

Intercellular Space Distance Is Increased in Refractory Heartburn Patientswith GERD But Not Those with Functional Heartburn (FH): A Study UsingImpedance-pH and Electron MicroscopyMarcelo F. Vela, Brandon M. Craft, Neeraj Sharma, Janice Freeman, Debra Hazen-Martin

INTRODUCTION: Refractory heartburn despite maximal acid suppression may be due toongoing GERD as documented by endoscopy or reflux monitoring, or it may representFunctional Heartburn (FH), i.e. symptoms in the absence of objective evidence of GERD.Multichannel Intraluminal Impedance and pH (MII-pH) detects both acid and nonacid refluxand is useful for evaluating reflux and its association to symptoms in acid suppressed patients.Intercellular space distance (ISD) of esophageal epithelium measured by electron microscopy(EM) is a marker of epithelial damage present in both erosive and non-erosive reflux disease.AIM: Compare ISD in healthy controls and two groups of patients with refractory heartburn:those with objective evidence of GERD on endoscopy and/or 24-hour MII-pH, and thosewith Functional Heartburn (FH). METHODS: Patients with persistent heartburn despiteBID PPI underwent MII-pH on therapy and endoscopy with biopsies for ISD measurementby Electron Microscopy (EM). Patients with esophagitis (EE) or abnormal MII-pH definedby increased esophageal acid exposure time (↑AET) or a positive symptom index (SI), i.e.>50% heartburn events associated with a reflux episode, were categorized as GERD; thosewith normal testing were considered FH. Healthy controls without GERD symptoms and anormal 24-h pH study underwent endoscopy with esophageal biopsies for ISD measurement.ISD determined in all subjects by transmission EM of esophageal biopsies at 5,000xmagnifica-tion using computer-assisted morphometry (Image J software). 10 measurements of ISDtaken in each of 10 micrographs; mean ISD was the average of these 100 measurements.RESULTS: 10 healthy controls, 10 FH, and 14 GERD patients (8 SI-positive, 2 SI-positive+ ↑AET, 2 EE, 1 ↑AET, 1 EE + ↑AET) studied. Results shown in the table. Mean ISD wassignificantly higher in GERD compared to controls (p = 0.007) and FH (p = 0.03). ISDnumerically higher for FH compared to controls, but not statistically significant. CONCLU-SION: GERD but not FH patients with refractory heartburn have increased ISD, even thoughmost GERD patients had normal endoscopy. ISD may be a helpful tool to discriminateGERD from FH. Implications for therapy may be that those with increased ISD needimproved reflux control, while those with FH may benefit from non-GERD treatments (e.g.visceral analgesia).

EE = Erosive Esophagitis, ISD = Intercellular Space Distance

382

Salivary Pepsin in Patients with Refractory GERD: Double Blinded Assessmentof Test Sensitivity, Specificity, Positive and Negative Predictive ValuesShih-Kuang S. Hong, Peter W. Dettmar, James C. Slaughter, Vicki Strugala, MarionGoutte, Michael F. Vaezi

Background: There is increasing prevalence of patients with gastroesophageal reflux disease(GERD) who are refractory to aggressive acid suppression. Pepsin lateral flow test (LFT) isa non-invasive assay to detect salivary pepsin. It has 2 unique antibodies specific for humanpepsin. In this double blind clinical study, we aimed to establish the following critical testcharacteristics for this assay: 1) sensitivity and specificity based on known pepsin presenceor absence, 2) the prevalence of salivary pepsin in normal controls vs. GERD and extraeso-phageal reflux (EERD) patients, and 3) positive and negative predictive values (PPV andNPV) in symptomatic patients (GERD+EERD) on or off PPI therapy. Methods: 230 sampleswere analyzed by LFT with all assays double-blinded as to the source. Bench sensitivity andspecificity were estimated using 54 pure water and 51 gastric juice samples. Saliva wascollected from 51 healthy volunteers to serve as normal controls. For PPV and NPV calcula-tions in symptomatic patients, saliva was collected from 58 patients with gastroesophagealsyndrome (Montreal Definition) and 16 patients with extraesophageal syndrome. Prevalenceof positive salivary pepsin was determined in normal controls, GERD, and EERD groups. Thetwo patient groups then underwent EGD, wireless pHmonitoring and reflux questionnaire offtherapy. PPV and NPV were calculated based on two True Positive definitions: A) positivepH or esophagitis or B) positive pH or esophagitis or presence of heartburn. Results: 1)ROC analysis revealed a sensitivity of 88% and a specificity of 87% based on samples ofknown pepsin presence. 2) 6/51 (12%) control subjects, 13/58 (22%) in GERD group, and4/16 (25%) in EERD pts tested positive (p=NS). There was no difference in the prevalenceof positive pepsin on (16%) or off (14%) PPI therapy (p=NS). Patients with esophagitisor abnormal pH had higher prevalence of positive salivary pepsin assay (45% and 33%,respectively). PPV and NPV based on each true positive definitions and the disease prevalenceis shown in Table 1. Conclusion: 1) Salivary pepsin assay was only positive in 45% ofknown esophagitis and 33% of those with abnormal pH. 2) Given lower disease prevalencedefined by esophagitis or abnormal pH (48%, Def. A), if the pepsin assay returns positive,the probability of disease increases to 65% in contrast to defining the disease by adding

A-63 AGA Abstracts

heartburn, which increases disease prevalence to 84% (Def. B) thus obviating the need forany additional test.Table 1

383

Optimization of the Reflux-Symptom Association Statistics in InfantsTaher Omari, Andrea Schwarzer, Michiel P. van Wijk, Stamatiki Kritas, Lisa McCall,Sibylle Koletzko, Geoffrey Davidson

Introduction: Symptom association probability (SAP) is the best available measure for dia-gnosis of a causal relationship between bolus gastroesophageal reflux (GER) and symptomsduring pH-impedance monitoring. Current association criteria for calculation of SAP areoptimised for symptoms of heartburn in adults. Infants, however, demonstrate a differentsymptom profile and their symptoms are usually recorded by a parent or guardian. The aimof this study was to establish the optimal reflux-symptom association time window for SAPcalculations in infants with typical GERD symptoms. Methods: 10 infants (2-8 months)referred for investigation were enrolled. GER episodes were recorded using a pH-impedanceprobe which remained in place for 48h. During the test, cough, irritability/crying andregurgitation were marked. Impedance recordings for the 0-24h and 24-48h period wereanalysed for the occurrence of bolus reflux episodes. SAP was calculated using automatedreporting software (Bioview) which enabled the time window used for SAP calculations tobe modified. An SAP of ≥95% was considered to be a diagnostically positive result. Dayto day variability in SAP was assessed by calculating the 95% limits of agreement (meandifference±1.96 standard deviation of differences) and their confidence intervals. Thisapproach provides an interval within which 95% of the differences between measurementperiods are expected to lie(1). The optimal time window for SAP calculation was definedby the interval that produced the least variation in the 95% limits of agreement. Results:The number of bolus GER recorded on days 1 and 2 was 73±9 vs 69±11 respectively andcorrelated from day to day in individual patients (Spearman rank correlation r=0.75, p=0.0108). The occurrence of symptom episodes did not differ from day to day (21±3 vs 15±3cough episodes, 38±8 vs 33±8 crying episodes and 6±3 vs 8±3 regurgitation episodesrespectively). The least variability in SAP was found using time windows of 2min for cough,2-5min for crying and 2-5 min for regurgitation (graph). Conclusion: In infants, SAP findingsbased on standard GER-symptom association criteria of 2min appear to be optimal for typicalsymptoms of GERD. (1)Bland J & Altman D. Statistical Methods in Medical Research1999;8:135.

384

Predictive Validity and Responsiveness of the Mayo Dysphagia Questionnaire-30 for the Outcome of DysphagiaDawn L. Francis, Felicity Enders, Michael D. Crowell, K.Robert Shen, Robert C. Miller,Catherine R. Weiler, Rayna Grothe, Judith L. McElhiney, Gianrico Farrugia, Melissa M.Kuntz, Nancy Diehl, Matthew R. Lohse, Amindra S. Arora, Darlene E. Graner, Nicholas J.Talley, G. Richard Locke, Joseph A. Murray, Jeffrey A. Alexander, Timothy J. Beebe, AdilA. Abdalla, Joanna M. Peloquin, April Grudell, Ganapathy A. Prasad, Yvonne Romero

Background: The Mayo Dysphagia Questionnaire 30 Day (MDQ-30) has been shown tohave excellent reproducibility and concurrent validity. It is important for the questionnaireto demonstrate predictive validity and be responsive; that responses correlate with objectivefindings at endoscopy and that items on the questionnaire change in the direction oneexpects when symptoms change. Methods: We have been distributing the MDQ-30 to adultparticipants in 5 research studies over the past two years. Cases have an esophageal stricture< 15 mm diameter at baseline and controls do not. Patients with reflux esophagitis andesophageal neoplasm were excluded. Results: To create the Dysphagia Score (DS), 117participants, 22 with stricture [mean age 70 years, 16 (73%) male] were compared to 95controls [mean age 61, 51 (54%) male]. Eleven of 22 with stricture had endoscopy (EGD)on two occasions, 7 of whom completed the MDQ-30 twice, and could be used to assessresponsiveness. Predictive validity. The best model to differentiate patients with stricturefrom those without used four items: impaction, solid food dysphagia, severity of dysphagiaover the past 30 days, and took into account food avoidance and food modification, withan area under the ROC curve of 0.85. Many patients reveal they avoid certain food stuffs,like fibrous meats, or modify their food (e.g. dunk bread into hot coffee) to facilitateswallowing. DS > 60 were 91% sensitive for stricture, while scores < 6 were 97% specificfor stricture (a score less than 6 virtually excluded the presence of a stricture). DS > 24 are87.5% sensitive and 78.4% specific for the presence of a stricture < 15 mm diameter.Responsiveness. In two patients, the stricture remained the same diameter (9 to 9, and 9.7to 10 mm) and their DS remained stable (39 to 39, and 39 to 39). In 2 patients the stricturediameter improved from 9 to 16 mm, and 12 to 15 mm, and their DS improved in thesame direction (from 61 to 2, and 32 to 10, respectively). In one patient the diameter

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