The prevalence of gastroesophageal reflux disease is estimated to be as high as 20% in the United States, and up to 50% of these patients remain symptomatic on proton pump inhibitor (PPI) therapy. Unfortunately, the clinical approach to understand the mechanism of nonresponse is not standardized, and patients will often undergo various esophageal function tests: 1) pH-impedance, 2) wireless pH monitoring over 96 hours, 3) high-resolution impedance manometry (HRIM), and 4) mucosal impedance. Currently significant controversy exists regarding the best technique, optimal study protocol and treatment approach for the PPI non-responder (PPINR) group, resulting in inappropriate resource utilization and a failure to provide effective personalized care. As such, PPINRs contribute to a large healthcare burden in the United States.
The first aim of our study is to identify the relevant physiologic parameters of the aforementioned diagnostic tools in their ability to predict PPI requirement. Subsequently, in aim two these results will be applied to guide the formal development of a clinical algorithm for the management of PPINRs with personalized clinical pathways based on mechanism of treatment failure. We will first perform a prospective comparison trial of 240 PPINR subjects at two centers over a 4 year period. Subjects will complete symptom questionnaires and undergo diagnostic testing (pH-impedance on PPI therapy, HRIM, 96-hour wireless pH monitoring off of PPI therapy and mucosal impedance). Those who have a positive pH study and/or resume PPI therapy will receive escalation of acid suppression therapy with dexlansoprazole. Experiments 1a & 1b will compare the ability of 96-hour wireless pH monitoring vs pH impedance to predict PPI requirement and response to dexlansoprazole, respectively. Experiment 1c will explore whether mucosal impedance is equivalent to 96-hour wireless pH monitoring in predicting PPI requirement. Lastly, Experiment 1d will determine whether HRIM metrics can be utilized to determine reflux burden, mechanism and response to treatment. Next, we will develop quality measures for reflux testing in order to develop a simplified management strategy for the PPINR group. The RAND/UCLA Appropriateness Methodology will be utilized with an expert working group to develop formal validated quality measures for reflux testing based on results from aim 1 in addition to the available literature & evidence. This will be conducted over twelve-months (years 4 to 5).

Public Health Relevance

Gastroesophageal reflux disease (GERD) is an increasingly common medical condition affecting up to twenty percent of the adult US population. Despite the fact that treatment with proton pump inhibitors (PPI) is extremely effective, up to 30-50% of patients are unsatisfied with their response and continue to have refractory symptoms. This proposal seeks to identify physiologic parameters that are related to PPI therapy requirement and response to escalation of PPI therapy, and apply these results to guide the formal development of a clinical algorithm for the management of patients who are not responsive to PPI therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Yadlapati, Rena; Tye, Michael; Keefer, Laurie et al. (2018) Psychosocial Distress and Quality of Life Impairment Are Associated With Symptom Severity in PPI Non-Responders With Normal Impedance-pH Profiles. Am J Gastroenterol 113:31-38
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Alexeeva, Olga; Keswani, Rajesh N; Pandolfino, John E et al. (2018) Electronic Clinical Decision Support Tools for Obesity and Gastroesophageal Reflux Disease: The Provider's Perspective. Am J Gastroenterol 113:916
Yadlapati, Rena; Pandolfino, John E; Alexeeva, Olga et al. (2018) The Reflux Improvement and Monitoring (TRIM) Program Is Associated With Symptom Improvement and Weight Reduction for Patients With Obesity and Gastroesophageal Reflux Disease. Am J Gastroenterol 113:23-30
Yadlapati, Rena; Tye, Michael; Roman, Sabine et al. (2018) Postprandial High-Resolution Impedance Manometry Identifies Mechanisms of Nonresponse to Proton Pump Inhibitors. Clin Gastroenterol Hepatol 16:211-218.e1
Carlson, D A; Kathpalia, P; Craft, J et al. (2018) The relationship between esophageal acid exposure and the esophageal response to volumetric distention. Neurogastroenterol Motil 30:
Yadlapati, Rena; Hungness, Eric S; Pandolfino, John E (2018) Complications of Antireflux Surgery. Am J Gastroenterol 113:1137-1147
Yadlapati, Rena; Craft, Jenna; Adkins, Christopher J et al. (2018) The Upper Esophageal Sphincter Assist Device Is Associated With Symptom Response in Reflux-Associated Laryngeal Symptoms. Clin Gastroenterol Hepatol 16:1670-1672
Yadlapati, R; Ciolino, J D; Craft, J et al. (2018) Trajectory assessment is useful when day-to-day esophageal acid exposure varies in prolonged wireless pH monitoring. Dis Esophagus :
Hillman, L; Yadlapati, R; Thuluvath, A J et al. (2017) A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease. Dis Esophagus 30:1-15

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