Proton Pump Inhibitor Nonresponders Research Articles

Mucosal integrity of the larynx and hypopharynx and the response to proton pump inhibitors in patients with laryngopharyngeal reflux.

To evaluate whether impairment of integrity of laryngeal and hypopharyngeal mucosa in laryngopharyngeal reflux (LPR) could be related to response to proton pump inhibitors (PPIs). Chronic hoarseness with Reflux Finding Score (RFS) > = 7 was evaluated using the Reflux Disease Questionnaire (RDQ) and Reflux Symptoms Index (RSI). Upper endoscopy was performed and samples of the laryngeal posterior commissure were collected to evaluate ex vivo laryngeal mucosal integrity by transepithelial resistance (TER) using Ussing chamber. In vivo, hypopharyngeal integrity was measured using intraluminal impedance. Clinical responders scored < 13 and had a drop of at least 50% in the initial RSI after 8 weeks of pantoprazole. Eighteen patients completed the protocol, Esophagitis was detected in 28% of the patients, and one patient presented acid exposure above 6%. After treatment, 66.67% responded to PPI. Laryngeal basal TER and TER drops after the weakly acidid challenge showed no difference between PPI responders and non-responders. Hypopharyngeal basal impedance was similar between the groups. After acid exposure test, there was a lower impedance in non-responders. In laryngopharyngeal reflux, hypopharyngeal mucosal integrity was lower in PPI non-responders. These preliminary results suggest that the weaker laryngopharyngeal mucosa in refractory LPR may require new therapies aimed at improving barrier function. N/A.

Post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance predict proton pump inhibitor response in patients with reflux hypersensitivity.

Post-reflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI) have been shown to influence proton pump inhibitor (PPI) response in GERD patients. However, currently, little data concerning these variables in patients with reflux hypersensitivity (RH) are available. In this study, we aimed to evaluate, in RH patients, the prevalence of PPI responders and nonresponders and investigate the predictive value of impedance-pH variables, including PSPW and MNBI, on responses to PPI. A total of 108 RH patients who met ROME IV criteria were prospectively recruited from June 2018 to December 2022. The prevalence of PPI responders/nonresponders was calculated, and impedance-pH variables were compared between the response and nonresponse groups. Multiple logistic regression was used to investigate predictors for PPI response. Among 108 patients with RH, 60 patients (55.56%) were the PPI responders, and 48 (44.44%) were the nonresponders. Compared with the nonresponders, the PPI responders had a lower PSPW index (47.05±4.43 vs 51.33±3.50, P=0.004) and a decreased value of MNBI (1866.68±390.62 vs 2181.14±338.42, P=0.017). Multivariate logistic regression revealed that only the pathologic PSPW index (OR: 2.064) and MNBI (OR: 1.800) significantly influenced PPI response. Nearly half of RH patients were PPI nonresponders. Impedance-pH monitoring was more valuable than pH-only monitoring in associating PPI response to reflux in RH patients owing to the appraisal of the PSPW index and MNBI.

Functional lumen imaging probe topography identifies patients with normal acid exposure and esophageal hypervigilance amongst proton-pump inhibitor non-responders.

Multiple factors contribute to symptom generation and treatment response in proton-pump inhibitor non-responders (PPI-NRs). We aimed to test whether PPI-NRs with normal acid exposure have a higher degree of esophageal hypersensitivity and hypervigilance and can be identified using functional lumen imaging probe (FLIP) topography at the time of endoscopy. Data from PPI-NRs whom underwent endoscopy, FLIP and wireless 96-h pH-metry were retrospectively analyzed. Patients were grouped according to acid exposure time (AET) as (a) 0days abnormal (AET > 6%), (b) 1-2days abnormal, or (c) 3-4days abnormal. The esophageal hypervigilance and anxiety scale (EHAS) score and other symptom scores were compared between groups. The discriminatory ability of the esophagogastric junction (EGJ) distensibility index (DI) and max EGJ diameter in identifying patients with 0days abnormal AET was tested via receiver-operating-characteristic (ROC) curve analysis. EHAS score was 38.6 in the 0days abnormal AET group, 30.4 in the 1-2days abnormal AET group (p = 0.073 when compared to 0days abnormal) and 28.2 in the 3-4days abnormal AET group (p = 0.031 when compared to 0days abnormal). Area-under-the-curve (AUC) for the DI in association with 0days AET > 6% was 0.629. A DI of < 2.8 mm2/mmHg had a sensitivity of 83.3%, and negative predictive value of 88% in classifying patients with 0days abnormal acid exposure (p = 0.004). FLIP complements prolonged wireless pH-metry in distinguishing the subset of PPI-NRs with completely normal acid exposure and a higher burden of esophageal hypervigilance. Proper identification of patients along the functional heartburn spectrum can improve overall surgical outcomes.

Mean Nocturnal Baseline Impedance and Post-reflux Swallow-induced Peristaltic Wave Index Could Identify Gastroesophageal Reflux Disease but pH-Impedance Metrics Alone Might Not Correlate With Proton Pump Inhibitor Response in Chinese Patients With Typical Reflux Symptoms.

Background/AimsLyon consensus differentiates acid exposure time (AET) as physiological, borderline, and pathological. Mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave index (PSPWi) are believed to increase diagnostic yield of gastroesophageal reflux disease (GERD) and correlate with symptom outcome of proton pump inhibitor (PPI) treatment. We aim to explore the clinical characteristics and the correlation of pH-impedance parameters with PPI response in Chinese patients with different AET levels.MethodsWe retrospectively investigated 177 patients with typical reflux symptoms who received esophageal function tests. The demographics, GERD questionnaire scores, the proportion of esophagitis and PPI responders, and manometric and pH-impedance parameters were compared among patients with AET < 4%, 4-6%, and > 6%. In patients with AET ≥ 4%, manometric and pH-impedance parameters were compared between PPI responders and non-responders.ResultsAmong 177 patients, 69 (39.0%) had AET 4-6%, and 53 (29.9%) had AET > 6%. The demographics, esophagogastric junction type, and occurrence of ineffective esophageal motility were similar between patients with AET 4-6% and > 6%, but different from AET < 4%. MNBI and PSPWi were different among different AET levels, but similar between PPI responders and non-responders in patients with AET ≥ 4%.ConclusionsIt is reasonable to set 4% as a threshold to define pathological AET in Chinese patients. MNBI and PSPWi could identify GERD patients, but may not correlate with PPI response of Chinese GERD patients.

Value of pH Impedance Monitoring While on Twice-Daily Proton Pump Inhibitor Therapy to Identify Need for Escalation of Reflux Management

Acid exposure time (AET) and reflux episode thresholds from the Lyon Consensus may not apply for pH impedance studies performed while on proton pump inhibitor (PPI) therapy. We aimed to determine metrics from "on PPI" pH impedance studies predicting need for escalation of therapy. De-identified pH impedance studies performed while on twice-daily PPI (Diversatek, Boulder, CO) in healthy volunteers (n= 66, median age 37.5 years, 43.9% female), and patients with proven gastroesophageal reflux disease (GERD) (European heartburn-predominant cohort: n= 43, median age 57.0 years, 55.8% female; North American regurgitation-predominant cohort: n= 42, median age 41.6 years, 42.9% female) were analyzed. Median values and interquartile ranges for pH impedance metrics in healthy volunteers were compared with proven GERD patients with and without 50% symptom improvement on validated measures. Receiver operating characteristic (ROC) analyses identified optimal thresholds predicting symptom response. Both conventional and novel reflux metrics were similar between PPI responders and nonresponders (P ≥ .1 for each) despite differences from healthy volunteers. Combinations of metrics associated with conclusively abnormal reflux burden (AET >4%, >80 reflux episodes) were seen in 32.6% and 40.5% of heartburn and regurgitation-predominant patients, respectively, 57.1% and 82.4% of whom reported nonresponse; and 85% with these metrics improved with invasive GERD management. On ROC analysis, AET threshold of 0.5% modestly predicted nonresponse (sensitivity, 0.62; specificity, 0.51; P= .22), and 40 reflux episodes had better performance characteristics (sensitivity, 0.80; specificity, 0.51; P=.002); 79% with these metrics improved with invasive GERD management. Combinations of abnormal "on PPI" pH impedance metrics are associated with PPI nonresponse in proven GERD patients, and can be targeted for treatment escalation, including surgery, particularly in regurgitation-predominant GERD.

Diagnostic yield and reliability of post-prandial high-resolution manometry and impedance-ph for detecting rumination and supragastric belching in PPI non-responders.

Supragastric belching (SGB) and rumination are behavioral disorders associated with proton pump inhibitor (PPI) non-response and can be diagnosed using multichannel intraluminal impedance-pH (MII-pH) and post-prandial high-resolution impedance manometry (PPHRIM). This pilot study compared diagnostic yield and inter-rater agreement for SGB and rumination using MII-pH and PPHRIM. Three esophageal physiologists performed blinded interpretations of MII-pH and PPHRIM in 22 PPI non-responders. Raters selected from 4 diagnostic impressions (normal, GERD, behavioral disorders, GERD+behavioral disorders) without clinical context. Primary outcomes were diagnostic impressions compared against clinical gold standard impression, between raters, and between test modalities. Following a 28-month wash-out period, raters re-interpreted MII-pH with clinical context and under consensus definition of diagnostic criteria. Compared to gold standard, rater accuracy for presence of behavioral disorders ranged from 45 to 77% on MII-pH and 45-59% on PPHRIM. On MII-pH, inter-rater agreement was fair for diagnosis (ĸ0.32, p<0.01) and suboptimal for presence of behavioral disorders (ĸ0.13, p=0.14). On PPHRIM, inter-rater agreement was suboptimal for both diagnosis (ĸ0.03, p=0.34) and presence of a behavioral disorder (ĸ-0.22, p=0.96). Inter-rater agreement improved in post hoc MII-pH interpretations. Rumination was more frequently identified on PPHRIM (23, 35%) compared to MII-pH (7, 11%). Diagnostic accuracy and inter-rater agreement are higher for MII-pH than PPHRIM, and behavioral disorders are more frequently identified on PPHRIM. Identifying behavioral disorders on MII-pH and PPHRIM has implications for clinical evaluation of PPI non-response; clinical context is essential for accurate study interpretation. Further work is needed to standardize definitions and interpretations.

High-resolution Manometry Determinants of Refractoriness of Reflux Symptoms to Proton Pump Inhibitor Therapy.

Background/AimsImpaired esophageal motility and disrupted esophagogastric junction (EGJ) on high-resolution manometry (HRM) have been associated with increased reflux severity in gastroesophageal reflux disease (GERD) patients. However, there are limited data evaluating HRM parameters in proton pump inhibitors (PPI) non-responders.MethodsClinical and endoscopic data, HRM and multichannel intraluminal impedance-pH studies performed of PPI therapy in patients with typical GERD symptoms were reviewed from 3 international centers. Frequency of GERD symptoms was assessed on and off PPI therapy in both non-responders (< 50% symptom improvement on PPI therapy) and responders. Rome IV definitions identified non-erosive reflux disease, reflux hypersensitivity, and functional heartburn. Univariate and multivariate analyses were performed to determine predictors of non-response.ResultsOf 204 patients, 105 were PPI non-responders and 99 were responders. Non-responders showed higher EGJ contractile integral values, and a lower frequency of type II and III EGJ morphology (P ≤ 0.03 for each comparison). Esophageal body diagnoses on HRM (fragmented peristalsis, ineffective esophageal motility, or absent peristalsis) did not predict non-response. On multivariate analysis, non-pathological acid exposure time (OR, 2.5; 95% CI, 1.2-5.0; P < 0.001), normal mean nocturnal baseline impedance values (OR, 2.7-2.4; 95% CI, 1.0-6.1; P < 0.05), normal EGJ contractile integral values (OR, 3; 95% CI, 1.3-7.4; P = 0.012), and presence of type I EGJ morphology (OR, 1.9; 95% CI, 1.0-3.4; P = 0.044) were associated with an unfavorable response to PPIs.ConclusionsIntact EGJ metrics on HRM complement normal reflux burden in predicting non-response to PPI therapy. HRM has value in the evaluation of PPI non-responders.

Immunohistochemical expression of filaggrin is decreased in proton pump inhibitor non-responders compared with proton pump inhibitor responders of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an allergic gastrointestinal disease that features eosinophilic infiltration of esophageal mucosa, but the role of barrier dysfunction of the epithelium in its pathogenesis remains to be elucidated. Clinically, EoE is divided into proton pump inhibitor-non-responders (PPI-NR) and PPI-responders (PPI-R). Our main aims were to investigate the differences of expression of epidermal differential complex (EDC) proteins and desmoglein that are considered to play important roles in formation of the epidermal skin barrier between these two conditions and to seek the usefulness of the differences in pathological diagnosis. Conventional histopathological findings and allergic background were also compared. Twenty-nine PPI-NR and 44 PPI-R were recruited, and 35 reflux esophagitis patients were also enrolled. After clinical information and histopathological findings were reviewed, immunohistochemical expression of EDC proteins (filaggrin, loricrin, and involucrin) and desmoglein in all three groups were examined and semi-quantitatively scored. Regarding allergic conditions, the prevalence of asthma was significantly higher in PPI-NR than in PPI-R. Other allergic conditions showed no differences. Histopathological findings did not exhibit the statistical difference between PPI-NR and PPI-R. However, immunostaining score of filaggrin in PPI-NR was significantly lower than in PPI-R, although the expressions of involucrin, loricrin and desmoglein demonstrated no differences. The results suggest a role of reduced filaggrin expression in the difference of effectiveness of PPI treatment between PPI-NR and PPI-R. Moreover, immunohistochemical determination of filaggrin expression in EoE patients could be informative in the clinical decision of how to treat the patients.

Surgical and endoscopic management options for patients with GERD based on proton pump inhibitor symptom response: recommendations from an expert U.S. panel

The objective of this study was to examine expert opinion and agreement on the treatment of distinct GERD profiles from surgical and therapeutic endoscopy perspectives. We used the RAND/University of California, Los Angeles Appropriateness Method over 6 months (July 2018 to January 2019) to assess the appropriateness of antireflux interventions among foregut surgeons and therapeutic gastroenterologists. Patients with primary atypical or extraesophageal symptoms were not considered. Patient scenarios were grouped according to their symptom response to proton pump inhibitor (PPI) therapy. The primary outcome was appropriateness of an intervention. Antireflux surgery with laparoscopic fundoplication (LF) and magnetic sphincter augmentation (MSA) were ranked as appropriate for all complete and partial PPI responder scenarios. Transoral incisionless fundoplication was ranked as appropriate in complete and partial PPI responders without a hiatal hernia. Radiofrequency energy was not ranked as appropriate for complete or partial responders. There was lack of agreement between surgery and interventional gastroenterology groups on the appropriateness of LF and MSA for PPI nonresponders. Rankings for PPI nonresponders were similar when results from impedance-pH testing on PPI therapy were available, except that LF and MSA were not ranked as appropriate for PPI nonresponders if the impedance-pH study was negative. This work highlights areas of agreement for invasive therapeutic approaches for GERD and provides impetus for further interdisciplinary collaboration and trials to compare and generate novel and effective treatment approaches and care pathways, including the role of impedance-pH testing in PPI nonresponders.

Optimal Biopsy Protocol to Evaluate Histological Effectiveness of Proton Pump Inhibitor Therapy in Patients with Eosinophilic Esophagitis

Objective: Recent guidelines propose that both proton pump inhibitor (PPI) responders and nonresponders are included in eosinophilic esophagitis (EoE). Although multiple biopsies should be required to diagnose EoE because of patchy distribution of esophageal eosinophils, it is unclear whether multiple biopsies are required to evaluate histological effectiveness of PPI therapy. This study aimed to determine the optimal biopsy protocol after PPI therapy in patients with EoE. Methods: Of 110 EoE patients, 22 PPI nonresponders were enrolled. Intraepithelial eosinophils were counted in areas of high density in multiple biopsy specimens after PPI therapy. The prevalence of esophageal eosinophilia and peak eosinophil counts after PPI therapy was analyzed according to the biopsy sites and endoscopic findings. Positive predictive value (PPV) was calculated according to the number of biopsies. Results: Of 124 biopsies, 59 (47.6%) specimens showed esophageal eosinophilia (≥15 per high-power field). Eosinophil counts were significantly higher in specimens from the lower esophagus than in those from the upper esophagus but not in those from the middle esophagus. Prevalence of esophageal eosinophilia was 76.2, 40.9, and 24.3% in the lower, middle, and upper esophagus respectively. PPI nonresponders were diagnosed in all cases with 4 biopsy specimens obtained from the lower and middle esophagus, showing that PPV for non-effectiveness of PPI therapy was 0.910 (95% CI 0.773–1.000). The prevalence of esophageal eosinophilia and peak eosinophil counts was higher in cases with white plaques and linear furrows. Conclusion: Multiple biopsies should be required to evaluate histological effectiveness of PPI therapy in patients with EoE. Four biopsies from the lower and middle esophagus may be sufficient.

The Proton Pump Inhibitor Nonresponder: a Behavioral Approach to Improvement and Wellness.

Gastroesophageal reflux disease (GERD) is a difficult to treat medical condition, where nearly 40% of patients are refractory to standard medical intervention, which typically begins with a proton pump inhibitor (PPI). These PPI nonresponders represent a population of patients, where treatment planning must be individualized; multidisciplinary and psychiatric comorbidities should be considered. This review highlights treatment options that include neuromodulators, lifestyle, and psychological interventions for the PPI nonresponder. Mental health specialists in the field of psychogastroenterology can aid in the management of esophageal hypersensitivity, which can drive the symptom experience of a PPI nonresponder. Considerations for comorbid anxiety and depression in this population require careful assessment and treatment. Physicians are encouraged to create realistic expectations for symptom management and offer multidisciplinary options for treatment early in care. Patients will frequently benefit from working with a GI psychologist and find value in behavioral interventions.

Psychosocial Distress and Quality of Life Impairment Are Associated With Symptom Severity in PPI Non-Responders With Normal Impedance-pH Profiles.

Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes. This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient-reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: -acid exposure time (AET)/-symptom-reflux association (SRA), +AET, and -AET/+SRA; off PPI: functional (-AET/-SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (-AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ≥8. One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) -AET/-SRA, 42 (34%) +AET, and 11 (9%) -AET/+SRA. Among the -AET/-SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ≥8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ≥8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ≥8. Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance-pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors.

Review of antireflux procedures for proton pump inhibitor nonresponsive gastroesophageal reflux disease.

Up to 40% of patients with gastroesophageal reflux disease (GERD) report persistent symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for surgical and endoscopic therapies for the treatment of PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 45 unique articles specific to surgical and endoscopic therapies for PPI nonresponsive GERD were reviewed. Laparoscopic fundoplication (n = 19) provides symptomatic and physiologic relief out to 10 years, though efficacy wanes with time. Magnetic sphincter augmentation (n = 6) and transoral incisionless fundoplication (n = 9) improve symptoms in PPI nonresponders and may offer fewer side effects than fundoplication, though long-term follow-up is lacking. Radiofrequency energy delivery (n = 8) has insufficient evidence for routine use in treating PPI nonresponsive GERD. Electrical stimulator implantation (n = 1) and endoscopic mucosal surgery (n = 2) are newer therapies under evaluation for the treatment of GERD. Laparoscopic fundoplication remains the most proven therapeutic approach. Newer antireflux procedures such as magnetic sphincter augmentation and transoral incisionless fundoplication offer alternatives with varying degrees of success, durability, and side effect profiles that may better suit individual patients. Larger head-to-head comparison trials are needed to better characterize the difference in symptom response and side effect profiles.

Proton pump inhibitor-responsive esophageal eosinophilia: still a valid diagnosis?

To update rapidly evolving concepts regarding the controversial entity of 'proton pump inhibitor (PPI)-responsive esophageal eosinophilia,' referring to patients with clinical, endoscopic and histologic features of eosinophilic esophagitis (EoE) who achieve remission on PPI therapy. Up to half of pediatric and adult patients with typical EoE symptoms and histology achieve clinico-pathologic remission on PPI therapy, irrespective of whether esophageal pH monitoring demonstrates abnormal acid reflux. In patients with clinical and histologic features of EoE, genotypic and phenotypic features of PPI responders and nonresponders are virtually indistinguishable, and different from those of patients with gastroesophageal reflux disease. In PPI responders, PPIs effects on esophageal Th2 inflammation and gene expression are similar to those of topical steroids in PPI nonresponders. These therapies, along with diets, recently have been shown to be potentially interchangeable in two small series. Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal eosinophilia and esophageal symptoms that resolve with PPI therapy have phenotypic, molecular, mechanistic, and therapeutic features indistinguishable from similar patients who do not respond to PPIs. These patients with PPI responsiveness should be considered within the spectrum of EoE.

Belching

Supragastric belching is the most important factor in the etiology of excessive belching complaints. Supragastric belching is a belching disorder with a behavioral origin. The standard diagnosis is made by monitoring the esophageal impedance. Supragastric belching has been shown to be associated with globus, as well as reflux symptoms in proton pump inhibitor non-responders in gastroesophageal reflux disease; however, the pathophysiology of supragastric belching in patients with gastroesophageal reflux disease or functional dyspepsia has not been clarified. Patient education with behavioral therapy is the treatment of choice in isolated supragastric belching. On the other hand, the best management of supragastric belching associated with globus, gastroesophageal reflux disease, and dyspepsia remains to be studied.

Reply

We thank Dr Furnari and colleagues for their interest in our paper.1Cheng F.K.F. et al.Clin Gastroenterol Hepatol. 2015; 13: 867-873Google Scholar They raise 2 excellent points for discussion. The first is in regards to categorizing nonerosive reflux disease based on normal endoscopic findings of esophageal mucosa and number of reflux episodes on 24-hour pH and impedance monitoring without taking into account symptom association analysis. We agree that the number of reflux episodes alone may be less than ideal to assess for nonerosive reflux disease. In fact, this is what prompted Johnson and DeMeester2Johnson L.F. et al.Am J Gastroenterol. 1974; 63: 325-332Google Scholar to develop a score that incorporates other parameters besides reflux episodes. Our study classification differs from Savarino et al3Savarino E. et al.Am J Gastroenterol. 2008; 103: 2685-2693Google Scholar in that we used the results of impedance testing early in the categorization of patients with reflux who had a normal 24-hour pH score and a normal endoscopy. This method focuses on the objective role of testing rather than reliance on patient symptoms, in which limitations exist in the accuracy of patient reporting. One study showed that patients do not report most of their symptoms during the 24-hour testing period.4Kavitt R.T. et al.Am J Gastroenterol. 2012; 107: 1826-1832Google Scholar Furthermore, both symptom index and symptom association probability may be overinterpreted in patients with gastroesophageal reflux disease with day to day variability.5Slaughter J.C. et al.Clin Gastroenterol Hepatol. 2011; 9: 868-874Google Scholar, 6Vela M.F. et al.Am J Gastroenol. 2013; 108: 1658-1659Google Scholar These indices are also primarily used to assess patients with gastroesophageal reflux disease, but not in those who fail to respond to proton pump inhibitors7Wiener G.J. et al.Am J Gastroenterol. 1988; 83: 358-361Google Scholar, 8Weusten V.L. et al.Gastroenterology. 1994; 107: 1741-1745Google Scholar and are suboptimal in predicting response to therapy as outcome.9Taghavi S.A. et al.Gut. 2005; 54: 1067-1071Google Scholar Finally, the only data evaluating response to surgery in proton pump inhibitor–nonresponders are uncontrolled,10Frazzoni M. et al.Surg Endosc. 2013; 27: 2940-2946Google Scholar and more high-quality outcome studies are needed. The second point is that an impedance cutoff value of 73 reflux episodes may overestimate the number of patients classified as hypersensitive esophagus or with functional symptoms. The 73 episodes as the cutoff value for reflux episodes is in accordance with the American College of Gastroenterology guidelines.11Hirano I. et al.Am J Gastroenterol. 2007; 102: 668-685Google Scholar In a Belgian-French study, the 95% of reflux episodes is 75, nearly identical to US studies.12Shay S. et al.Am J Gastroenterol. 2004; 99: 1037-1043Google Scholar, 13Tutuian R. et al.Gastroenterology. 2006; 130: A171Google Scholar, 14Moawad F.J. et al.Aliment Pharmacol Ther. 2013; 37: 1011-1018Google Scholar Furnari et al refer to an Italian study that demonstrated the 95% value as 54 reflux episodes in a cohort that may have been influenced by consuming a Mediterranean diet.15Zentilin P. et al.Dig Liver Dis. 2006; 38: 226-232Google Scholar Although we agree that a lower cutoff value may reduce the number of false-positive episodes during testing, further high-quality studies on normal impedance values need to be performed before uniformly standardizing a lower cutoff value. The other implication is patients without acid reflux may be referred for antireflux surgery rather than be treated with a pain modulator. However, data for fundoplication in non–acid reflux, particularly in the absence of reduced lower esophageal sphincter pressure, are scarce and generally we do not advocate this as an initial approach to the management of non–acid reflux. Caution About Overinterpretation of Number of Reflux Episodes in Reflux Monitoring for Refractory Gastroesophageal Reflux DiseaseClinical Gastroenterology and HepatologyVol. 14Issue 7PreviewWe read with great interest the study by Cheng et al,1 who investigated patients with gastroesophageal reflux disease (GERD) refractory to antisecretory therapy by means of endoscopy and impedance-pH monitoring off-therapy and concluded that roughly half of these patients referred for testing actually underwent investigations and received medications with no evidence of GERD; they were affected by functional heartburn, functional disorders other than heartburn, or by undetermined disorders. These data confirm previous studies2,3 on the importance of investigating refractory patients and also emphasize the need of stopping antisecretory therapy to reduce overuse of proton pump inhibitors. Full-Text PDF

Supragastric belching.

Supragastric belching has recently gained recognition as a belching disorder of behavioral origin that can be accurately diagnosed on esophageal impedance monitoring. Its contribution to numerous other gastrointestinal disorders is beginning to be appreciated. Improved knowledge of its pathophysiology has enabled identification of therapeutic goals, some of which have been subject to formal study and demonstrated good outcomes. This review sets out to present and discuss new findings related to the improved understanding of the relationship between supragastric belching and other gastrointestinal disorders, as well as fresh concepts in terms of management. Supragastric belching is now shown to be associated with globus, as well as reflux symptoms in proton pump inhibitor nonresponders. Patients with supragastric belching experience higher frequency of belching events if they have concurrent esophageal hypomotility. Gum chewing and sleeve gastrectomy have no impact on supragastric belching. Pediatric studies suggest an overlap with aerophagia that is not observed in adults. Successful treatments trialed recently include psychoeducation and behavioral therapy delivered by a health psychologist with expertise in gastroenterology. With the foreseeable increase in recognition and diagnosis of pathological supragastric belching, there is a clear need to better understand its pathophysiology, especially in terms of its emerging importance in relation to other gastrointestinal disorders. Further study is justified to uncover additional therapeutic options for this benign but disabling condition.

Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux.

Genesis of persistent gastro-esophageal reflux symptoms despite proton pump inhibitor (PPI) therapy is not fully understood. We aimed at determining reflux patterns on 24-h pH-impedance monitoring performed on PPI and correlating impedance patterns and symptom occurrence in PPI non-responders. Seventy-eight PPI non-responder patients underwent 24-h pH-impedance monitoring on PPI. Reflux impedance characterization included gastric and supragastric belches and proximal extent of reflux. Symptoms were considered associated with reflux if occurring within 5min after a reflux event. Patients were classified into three groups: persistent acid reflux (acid esophageal exposure [AET] >5% of time), reflux sensitivity (AET <5%, symptom index [SI] ≥50%), and functional symptoms (AET <5%, SI <50%). Dominant impedance pattern was determined for each patient. Seven patients (9%) had persistent acid reflux, 28 (36%) reflux sensitivity, and 43 (55%) functional symptoms. A total of 4296 reflux events were identified (median per patient 45 [range 4-221]). Although liquid reflux was the most common pattern in all groups, patients with reflux sensitivity and functional symptoms had much more variability in their pattern profile with a large proportion being associated with gastric and supragastric belching. Only 417 reflux events (9.7%) were associated with symptoms. Reflux with a supragastric component and proximal extent were more likely to be associated with symptoms. The impedance reflux profile in PPI non-responders was heterogeneous and the majority of reflux events were not associated with symptoms. Thus, the treatment of PPI non-responders should focus on mechanisms beyond reflux, such as visceral hypersensitivity and hypervigilance.

Factors associated with nonresponse to proton pump inhibitors therapy in patients referred for esophageal pH-impedance monitoring.

Nonresponse to proton pump inhibitors (PPI) concerns up to 40% of patients treated for gastroesophageal reflux disease (GERD). Identifying predictive factors of nonresponse might help to optimize patients' treatment. The aim of this study was to determine clinical factors associated with nonresponse to PPI therapy in patients referred for pH-impedance monitoring. One hundred and sixty-eight consecutive patients (105 females, mean age 52 years, range 17-83) were included between October 2011 and May 2013. Before the realization of high-resolution manometry and 24-hour pH-impedance monitoring they completed a questionnaire including Rome III criteria for functional dyspepsia and irritable bowel syndrome (IBS). Comparisons between patients with and without PPI response were performed using chi-square or analysis of variance tests. One hundred and twenty-six patients (83%) were considered as PPI nonresponders and 26 (17%) as responders. No significant difference was observed for age and body mass index. No manometric and pH-impedance profiles were identified as associated with PPI response. The percentage of patients with functional dyspepsia and IBS was higher in PPI nonresponders patients than in responders (65.6% and 27.2%, respectively, vs. 38.5% and 7.7%, P = 0.01 and P = 0.03). This study confirms that functional digestive disorders are more frequent in patients with persistent GERD symptoms on PPI and they might be indicative of nonresponse to PPI therapy.

Mo1912 Phenotypes of PPI Non-Responders Using Esophageal pH-Impedance Monitoring: How Are They Different?

Introduction Different phenotypes of GERD-suspected patients who do not respond to proton pump inhibitor (PPI) therapy might be identified using pH-impedance monitoring. Our aim was to describe demographic, manometric and impedance patterns associated with phenotypes of PPI non-responders. Patients and methods PPI non-responders (without previous foregut surgery, scleroderma or achalasia) referred for 24-h esophageal pH-impedance monitoring on PPI were recruited. Demographic data, results of upper GI endoscopy and high resolution manometry were collected. Two investigators reviewed pH-impedance studies; a 3rd one arbitrated disagreements. Based on impedance pattern, reflux events were characterized as belch, supragastric belch, reflux starting with belch, reflux induced by supragastric belch, reflux associated with belch, reflux associated with supragastric belch, proximal liquid reflux, swallow-induced reflux, distal liquid reflux. Patients were classified into 3 groups: persistent acid reflux (acid esophageal exposure time (AET; esophageal pH 5% of total time), reflux sensitive esophagus (AET<5%, symptom index (SI)≥50%), and functional heartburn (AET<5%, SI<50%, absence of Barrett's esophagus). Data are presented as percentage or median (range) and compared using Chi2 or Mann Whitney test. Results Eighty PPI non-responders (30 males, mean age 51 years (range 19-76), mean body mass index (BMI) 29.5 kg/m2 (range 18.6-44.1)) were included. AET was 0.5% (0.0-35.5) of total time and median number of reflux events (liquid, gas or mixed) was 45 (4-221). Eight patients (10%) had persistent acid reflux, 29 (36.2%) reflux sensitive esophagus and 43 (53.8%) functional heartburn. Characteristics of these groups are described in Table 1. Patients with persistent acid reflux had less frequently normal esophageal motility than the other patients groups (29% vs 46%, p<0.01). Patients with reflux sensitive esophagus or functional heartburn tended to present more frequently supra-gastric belch than patients with persistent acid reflux (60% vs 25, p=0.067). Distribution of dominant impedance patterns is presented in the Table 2. Conclusions The mechanistic reflux profile in PPI non-responders is heterogeneous. Although liquid reflux events were the most common mechanism of reflux in all three PPI non-responder subtypes, patients with reflux sensitivity and functional heartburn had much more variability in their mechanistic profile with a large proportion being associated with both suband supra-gastric belching. These different mechanistic profiles may have clinical implications as therapy targeting the dominant mechanism in each patient may be more effective. Table 1