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Background: Chronic cough significantly impairs the quality of life. Although various studies focused on MNBI as assessed in the distal esophagus, scarce data are available on the clinical value of proximal measurements., Aim: To investigate the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response., Methods: Demographic, clinical, endoscopy findings, impedance-pH and HRM tracings from consecutive cough patients were evaluated. MNBI was calculated at proximal and distal esophagus., Results: One hundred and sixty four patients were included. In addition to traditional variables, when considering also the PSPW index or MNBI at 3 cm or 15 cm, the proportion of patients with pathological impedance-pH monitoring significantly increased. 70/164 patients were responders, while 94 (57.3%) were non-responder to double PPI dose (p < 0.05). Patients with pathologic MNBI at 3 cm and/or 15 cm as well as those with pathologic PSPW index were characterized by a significantly higher proportion of responders than that observed among patients with normal impedance-pH variables (p < 0.001). The proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). At multivariable model, pathological MNBI at both 3 cm and 15 cm as well as PSPW index were associated with PPI responsiveness. The strongest association with PPI response was observed for MNBI at 15 cm., Conclusions: The assessment of MNBI at proximal esophagus increases the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough., (© 2024 John Wiley & Sons Ltd.)

Introduction: Gastroesophageal reflux disease (GERD) severity increases with esophageal body hypomotility, but the impact of Chicago Classification (CC) v4.0 criteria on GERD diagnosis is incompletely understood., Methods: In patients with GERD evaluated with high-resolution manometry and pH-impedance monitoring, CCv3.0 and CCv4.0 diagnoses were compared., Results: In 247 patients, hypomotility diagnosis decreased from 45.3% (CCv3.0) to 30.0% (CCv4.0, P < 0.001). In contrast, within patients with ineffective esophageal motility, proportions with pathological acid exposure increased from 38% (CCv3.0) to 88% (CCv4.0); baseline impedance and esophageal clearance demonstrated similar findings ( P < 0.05 for each comparison)., Discussion: CCv4.0 hypomotility criteria are more specific in supporting GERD evidence compared with CCv3.0., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Impairment of esophageal mucosal integrity as assessed by low mean nocturnal baseline impedance (MNBI) measured in the distal esophagus increases the diagnostic yield of impedance-pH in patients with inconclusive GERD diagnosis as defined by Lyon criteria., Aim: To assess the diagnostic yield of MNBI measurement in the proximal esophagus, and its relationship with PPI response., Methods: Expert review of off-therapy impedance-pH tracings from consecutive patients with heartburn, 80 responders and 80 non-responders to label-dose PPI. Data were compared to those from 36 healthy controls using ROC analysis. Multivariate analysis was performed to measure the strength of association of MNBI with PPI response., Results: A threshold value of 2665 Ω was defined for proximal MNBI by ROC analysis, affording 91.7% sensitivity and 86.5% specificity. Proximal and distal MNBI were significantly lower in non-responder cases as compared to responders. Adding proximal MNBI positivity to pathologic (>6%) acid exposure time (AET) and positive symptom-reflux association, the proportion of patients with abnormal impedance-pH findings increased from 74/160 (46%) to 106/160 (66.3%) (p = 0.0016). Among the 12 patients with pathologic proximal MNBI as the only positive impedance-pH finding, 9 cases (75%) were PPI responders. According to multivariate analysis, AET and pathological distal and proximal MNBI were significantly associated with PPI response, the strongest association observed for proximal MNBI., Conclusions: Impedance baseline assessment in the proximal esophagus may increase the diagnostic yield of impedance-pH monitoring. Heartburn response to PPI is directly related to ultrastructural mucosal damage in the distal and in the proximal esophagus as well., (© 2023 John Wiley & Sons Ltd.)

Background: Anxiety may exacerbate GERD and FD symptoms perception and reduce quality of life. As many as 50% of patients with GERD symptoms have incomplete relief with PPI therapy, and psychological factors may influence PPI responsiveness., Aim: The potential relationship between anxiety, excessive air swallowing, and PPI responsiveness was evaluated., Methods: GERD patients with concomitant FD were prospectively evaluated. Validated structured questionnaires were used to evaluate anxiety, GERD, and FD symptoms. All patients were treated, within the previous year, with at least 8 weeks of standard dose PPI therapy., Results: One hundred sixty-one patients were included. Frequency of non-responders in patients with moderate/severe anxiety was significantly higher compared to patients with mild anxiety (62.7% vs. 37.3%, p < 0.01). Patients with moderate/severe anxiety displayed a significantly higher mean FD symptoms score value compared to patients with mild anxiety. A significantly higher mean number of air swallows were observed in patients with moderate/severe anxiety. At ROC analysis, air swallows and mixed reflux episodes were significantly associated with the presence of PPI refractoriness (AUC: 0.725, 95% CI: 0.645-0.805 and 0.768, 0.692-0.843). According to univariate analysis, an abnormal number of air swallows, mixed reflux episodes and presence of moderate/severe anxiety was significantly associated with PPI refractoriness., Conclusion: Our results, if confirmed in in a larger, prospective clinical and therapeutic study, demonstrate the usefulness of an up-front evaluation with anxiety questionnaire and esophageal testing in patients with a broad spectrum of upper gastrointestinal symptoms who fail to respond to PPI treatment, supporting the option of alternative treatment modalities., (© 2023 John Wiley & Sons Ltd.)

Introduction: GERD is a common disorder and is characterized by the presence of typical or atypical symptoms. In GERD patients, the presence of mucosal alterations in endoscopy is detected in up to 30% of individuals. The clinical presentation of GERD patients may be complex and their management is challenging, due to the heterogeneous clinical presentation. The present review has been performed searching all relevant articles in this field, over the past years, using PubMed database., Areas Covered: The diagnosis and management of GERD have been significantly improved in the last years due to the increasing availability of reflux monitoring techniques and the implementation of new procedures in the therapeutic armamentarium. Beside traditional impedance-pH variables, new metrics have been developed, increasing the diagnostic yield of reflux monitoring and better predicting the treatment response. Traditional pharmacological treatments include acid-suppressive-therapy and/or anti-acid. On the other hand, surgical treatment and, more recently, endoscopic procedures represent a promising field in the therapeutic approach., Expert Opinion: Diagnosis and treatment of GERD still represent a challenging area. However, we believe that an accurate upfront evaluation is, nowadays, necessary in addressing patients with GERD to a more accurate diagnosis as well as to the best treatment options.

Background: The Lyon Consensus proposed a hierarchical approach to GERD diagnosis based on conventional and new impedance-pH metrics, namely acid exposure time (AET), number of reflux episodes, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI)., Aims: To define the value of conventional and new impedance-pH parameters as predictors of response to label-dose PPI in typical GERD., Methods: Consecutive adult patients with typical esophageal symptoms were prospectively studied with impedance-pH monitoring and treated with 8-week label-dose PPI. At the end of the PPI course, symptoms response was assessed., Results: Among 255 patients who entered the study, 168 (65.9%) reported symptom remission. At ROC analysis, both MNBI and PSPW index were significantly associated to PPI responsiveness with AUC of 0.783 and 0.801, respectively. Cut-off values of 1747Ω for MNBI and 50% for PSPW index were identified as discriminators between response and non-response to label-dose PPI. At multivariate analysis, MNBI, PSPW index, and AET >6% were efficient predictors of PPI responses (OR 3, 5.4 and 2.3, respectively). Number of reflux episodes did not predict PPI response., Conclusions: The novel MII-pH variables together with pathological are highly predictive of response of the typical GERD syndrome to label-dose PPI., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: On-therapy impedance-pH monitoring is recommended in patients with documented GERD and PPI-refractory heartburn in order to establish whether the unremitting symptom is reflux-related or not., Aims: To define on-PPI cut-offs of impedance-pH metrics allowing proper interpretation of on-therapy impedance-pH monitoring., Methods: Blinded expert review of impedance-pH tracings performed during double-dosage PPI, prospectively collected from 150 GERD patients with PPI-refractory heartburn and 45 GERD patients with PPI-responsive heartburn but persisting extra-esophageal symptoms. Acid exposure time (AET), number of total refluxes (TRs), post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI) were assessed. On-PPI cut-offs were defined and evaluated with ROC analysis and the area under curve (AUC)., Results: All the four impedance-pH metrics significantly differed between PPI-refractory and PPI-responsive heartburn cases. At ROC analysis, AUC was 0.73 for AET, 0.75 for TRs, 0.81 for PSPW index, and 0.71 for MNBI; best cut-offs were ≥1.7% for AET, ≥45 for TRs, ≤36% for PSPW index, and ≤ 1847 Ω for MNBI; AUC of such cut-offs was 0.66, 0.71, 0.73, and 0.68, respectively. Analysis of PSPW index and MNBI added to assessment of AET and TRs significantly increased the yield of on-therapy impedance-pH monitoring in the PPI-refractory cohort (97% vs. 83%, p < 0.0001). Notably, suboptimal acid suppression as shown by AET ≥1.7% was detected in 43% of 150 PPI-refractory cases., Conclusions: We have defined on-PPI cut-offs of impedance-pH metrics by which comprehensive assessment of impedance-pH tracings, including analysis of PSPW index and MNBI can efficiently characterize PPI-refractory GERD and support treatment escalation., (© 2023 John Wiley & Sons Ltd.)

Goals: The present study was aimed at evaluating the possible role of air swallowing in the association between gastroesophageal reflux disease (GERD) symptoms and concomitant functional dyspepsia (FD) and their role in GERD symptom persistence despite proton pump inhibitor (PPI) therapy., Background: It has been shown that individuals with excessive air swallowing experience FD. It has been also demonstrated that a consistent group of GERD patients not responding to PPI therapy swallow more air during mealtime and also have more mixed refluxes., Materials and Methods: Multichannel intraluminal impedance-pH tracings from consecutive patients were retrospectively evaluated. A validated structured questionnaire was used to evaluate GERD and concomitant FD symptoms. All patients were treated, within the previous year, with at least 8 weeks of standard-dose PPI therapy., Results: A total of 35 patients with conclusive GERD, 35 patients with reflux hypersensitivity, and 35 with functional heartburn were studied. A direct relationship was observed between the number of air swallows and of mixed refluxes ( R =0.64). At receiver operating characteristic curve analysis, air swallows and mixed refluxes were significantly associated to the presence of FD and PPI refractoriness. An air swallow cutoff of 107 episodes/24 hours was identified to discriminate patients with and without FD (sensitivity: 87%, specificity: 82.8%). A mixed reflux cutoff of 34 episodes/24 hours was identified to discriminate PPI responders from nonresponders (sensitivity: 84.8%, specificity: 69%). At multivariate analysis, an abnormal number of air swallows and of mixed refluxes were significantly associated to FD and PPI refractoriness., Conclusion: Our study highlights the relevant role of excessive air swallowing in eliciting both dyspepsia and refractoriness of typical GERD symptoms to PPI therapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Impedance-pH monitoring allows evaluation of esophageal chemical clearance, a response to reflux elicited by the esophago-salivary reflex, by means of the post-reflux swallow-induced peristaltic wave (PSPW) index; mucosal integrity can be evaluated by means of mean nocturnal baseline impedance (MNBI) and is regarded as a GERD marker. Currently, the relationship between PSPW index and MNBI has not yet been fully investigated and represents the aim of the present study., Methods: Impedance-pH tracings from consecutive patients were reviewed. ROC analysis and multivariate regression models were generated to evaluate the association between acid exposure time (AET), total refluxes (TRs), PSPW index, and MNBI. Patients were classified by means of AET thresholds and symptom-reflux association indexes into conclusive and inconclusive GERD, reflux hypersensitivity (RH), and functional heartburn (FH). Pathologic MNBI <2292 Ω was defined according to published outcome studies., Key Results: Two hundred and thirty patients constituted the study cohort. Overall, a significant direct correlation was observed between PSPW index and MNBI (0.759, p < 0.001). At ROC analysis, a PSPW index cut-off value of 53% was the best discriminator between normal from pathologic MNBI values (sensitivity 88%, specificity 86.4%). Considering AET cut-off of 4% or 6%, a sensitivity of 80.7% and 46% and a specificity of 62.5% and 93.2% were found, respectively. According to multivariate analysis, AET >4% and PSPW index value <53% or <61% were significantly associated with pathologic MNBI values., Conclusions and Inferences: Esophageal chemical clearance is a major defense mechanism against reflux and its impairment represents a major determinant of reflux-associated mucosal damage., (© 2022 John Wiley & Sons Ltd.)

Gastro-esophageal reflux disease (GERD) occurs in about 25% of the general population. The complexity of the disease and the multiplicity of its clinical manifestations impair the availability of a singular diagnostic test. The majority of GERD patients do not have any endoscopically visible lesions, the so-called non-erosive reflux disease (NERD). This latter population consists of several subgroups characterized by: 1. excess of acid; 2. normal acid, but hypersensitivity to acid or weakly acidic reflux; 3. normal acid, but lack of any relationship between symptoms and reflux episodes. At present, 24-h impedance-pH monitoring represents the best diagnostic tool to detect abnormal reflux and to correlate symptoms to reflux episodes. Moreover, the recent adoption of novel impedance metrics, such as mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index, seem to be able to improve the diagnostic yield of 24-h impedance-pH monitoring, making this test the most accurate in diagnosis of GERD., Competing Interests: Conflict of interest statement ES declares lecture fees from Takeda, Janssen, MSD, Abbvie, Malesci, Sofar, and consulting fees from BMS, Gilead, Takeda, Janssen, MSD, Reckitt Benckiser, Sofar, Unifarco, SILA, Oftagest, Diadema; the remaining authors have no disclosures., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To validate Lyon Consensus criteria for diagnosing gastro-oesophageal reflux disease (GORD) by reflux monitoring., Design: Manual review of impedance-pH tracings from patients with proton pump inhibitor (PPI)-dependent heartburn, evaluated off PPI. Acid exposure time (AET) thresholds defined by the Lyon Consensus and impedance parameters were investigated, namely, total refluxes (TRs), postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI)., Results: The study included 488 patients, 178 (36%) with normal (<4%) AET, 89 (18%) with inconclusive (4%-6%) AET and 221 (45%) with abnormal (>6%) AET, alongside with 70 healthy controls. At receiver operating characteristic analysis, area under curve was 0.89, 0.95 and 0.89 for TRs, PSPW index and MNBI, respectively, and threshold values were 40, 50% and 2000 Ω; the 4% physiological AET threshold defined by the Lyon Consensus showed 100% specificity but 63% sensitivity. The thresholds defined for impedance parameters were validated against AET by means of ordered logistic regression, being in concordance with the 4% AET threshold (OR 2.5 for TRs, 18.9 for PSPW index and 5.7 for MNBI). TRs positivity and concordant PSPW index/MNBI positivity were found in 80%-90% of patients in the abnormal AET group, in 73%-74% of cases in the inconclusive AET group and in 28%-40% of cases in the group with normal AET., Conclusions: Our results show the overall validity of the Lyon Consensus approach to GORD diagnosis. Adding evaluation of impedance parameters, namely, TRs, PSPW index and MNBI to AET appraisal, substantially improves the diagnostic yield of reflux monitoring., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A hierarchical approach for gastro-oesophageal reflux disease (GERD) diagnosis by impedance-pH monitoring was proposed by the Lyon Consensus, based on acid exposure time (AET) and supportive impedance metrics., Aims: To establish the clinical value of Lyon Consensus criteria in the work-up of patients with proton pump inhibitory (PPI)-refractory heartburn., Methods: Expert review of off-therapy impedance-pH tracings from unproven GERD patients with PPI-refractory heartburn prospectively evaluated at referral centers. Impedance metrics, namely total reflux episodes, postreflux swallow-induced peristaltic wave index, and mean nocturnal baseline impedance, were assessed. Expert review of on-therapy preoperative impedance-pH tracings from a separate cohort of surgically treated erosive/nonerosive GERD cases., Results: Off-therapy, normal, inconclusive, and abnormal AET was found in 59%, 17%, and 23% of 317 cases. Supportive evidence of GERD was provided by abnormal impedance metrics in up to 22% and 62% of cases in the normal and inconclusive AET groups, respectively. Adding the cases with inconclusive AET and abnormal impedance metrics to the abnormal AET group, a significant increase in GERD evidence was observed (from 23% to 37% of cases, p < 0.0002). At the on-therapy presurgical evaluation, abnormal/inconclusive AET and supraphysiological values of impedance metrics showed ongoing reflux in 21% and 90% of 96 cases, respectively (p < 0.00001); a relationship between on-therapy ongoing reflux and PPI-refractory heartburn was confirmed by the favorable surgical outcome at 3-year follow-up, 88% of cases being in persistent off-PPI heartburn remission., Conclusions: Impedance-pH monitoring, off- and on-therapy, is of high clinical value in the work-up of patients with PPI-refractory heartburn., (© 2022 John Wiley & Sons Ltd.)

Introduction: Investigations conducted using conventional manometry and, recently, using high-resolution manometry (HRM), allowed us to explore the field of esophageal motility and understand the potential link between motor features and gastroesophageal reflux disease (GERD) pathogenesis. The management of patients with nonachalasic esophageal motor disorders is often challenging, due to the clinical heterogeneous presentation and the multifactorial nature of the mechanisms underlying symptoms., Areas Covered: Several studies, carried out using HRM, have better interpreted the esophageal motor function in patients with esophagogastric junction outflow obstruction (EGJOO), distal esophageal spasm (DES), hypertensive esophagus, and hypomotility disorders. Moreover, HRM studies have shown a direct correlation between reduced esophageal motility, disruption of the esophagogastric junction, and gastroesophageal reflux burden., Expert Opinion: Pathogenesis, clinical presentation, diagnosis, and treatment of nonachalasic esophageal motor disorders still represent a challenging area, requiring future evaluation by multicenter outcome studies carried out in a large cohort of patients and asymptomatic subjects. However, we believe that an accurate clinical, endoscopic, and HRM evaluation is, nowadays, helpful in addressing patients with nonachalasic esophageal motor disorders to optimal treatment options.

Background: Esophageal chemical clearance has been evaluated with the post-reflux swallow-induced peristaltic wave (PSPW) index. The factors triggering PSPW in Gastro-esophageal reflux disease (GERD) have not yet been investigated. This multicenter study was aimed at evaluating the characteristics of reflux episodes associated with PSPW occurrence in patients with typical GERD symptoms., Methods: Impedance-pH tracings from patients with typical reflux symptoms were analyzed. Sixteen healthy subjects were included for comparison. Multivariate analysis was performed to determine predictors of PSPW events., Key Results: Impedance-pH tracings from 60 patients and 16 healthy subjects were evaluated. A total of 3454 refluxes were recorded. In patients, comparing reflux episodes followed with those not followed by a PSPW, significantly higher proportions of acid (79% vs. 74%, p: 0.02), mixed (47% vs. 32%, p: 0.0001) and proximal refluxes (34% vs. 20%, p: 0.0001) were observed. A multivariate analysis, acid (OR: 1.3, 95% CI: 1.05-1.6), mixed (OR: 2, 95% CI: 1.6-2.3), and proximal (OR: 2.1, 95% CI: 1.7-2.5) refluxes were independently associated with PSPWs. Reflux episodes followed by a PSPW were characterized by a significantly higher bolus clearing time [(mean ± SD) 41 s ± 6 s vs. 30 s ± 5 s, p < 0.05] whereas nadir pH value of reflux events preceding PSPWs was tangentially but not significantly lower [(mean ± SD) 2.61 ± 1.22 vs. 2.74 ± 1.26, p: 0.057]., Conclusions and Inferences: Acid, mixed and proximal refluxes, and their duration are key factors in eliciting PSPWs. PSPW represents a response to reflux directly related to the potential harmfulness of reflux contents., (© 2021 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Introduction: The clinical management of chronic cough patients is challenging, and their response to proton pump inhibitors (PPIs) is considered as unsatisfactory. Few data concerning the association between impedance-pH variables and PPI response in these patients are available. Mean nocturnal baseline impedance (MNBI) and postreflux swallow-induced peristaltic wave (PSPW) index increase the diagnostic yield of impedance-pH in gastroesophageal reflux disease., Methods: Demographic, clinical, and endoscopy findings; impedance-pH; and high-resolution manometry tracings from consecutive patients assessed for cough were evaluated. Univariable and multivariable regression models were generated to evaluate the association between impedance-pH and high-resolution manometry findings, endoscopic and clinical characteristics, and PPI response., Results: A total of 178 patients were included. Eighty-four of 178 cough patients (47.2%) displayed grade C-D erosive esophagitis or were characterized by a pathological acid exposure time (AET) and/or positive symptom association probability/symptom index. When also considering MNBI and PSPW, 135 of 178 patients (75.8%) were characterized by the evidence of reflux disease (P < 0.001). Eighty patients (44.9%) had cough responding to PPIs, whereas 98 (55.1%) were nonresponders (P = 0.071). At the receiver operating characteristic analysis, both PSPW index and MNBI were associated to PPI responsiveness. MNBI and PSPW index showed higher sensitivity in predicting PPI response compared with AET and symptom association probability/symptom index. The area under the curves of MNBI and PSPW index were significantly higher than that of AET (P < 0.01 for both comparisons). When patients were stratified according to AET and excluding those with erosive esophagitis, pathological MNBI or PSPW index, hiatal hernia, and hypomotility features were associated to PPI response in all groups., Discussion: Our results demonstrate the usefulness of an up-front esophageal testing in discriminating reflux-related cough patients and predicting PPI response., (Copyright © 2021 by The American College of Gastroenterology.)

Background: The Lyon Consensus delineates impedance-pH parameters that can demonstrate/exclude gastro-oesophageal reflux disease (GERD). In patients with acid exposure time between 4% and 6%, GERD diagnosis has been considered inconclusive. In these cases, mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index may either confirm or refute GERD diagnosis and represent predictors of proton pump inhibitor (PPI) response., Aims: To investigate the diagnostic yield of MNBI and PSPW index and their relationship with PPI response in patients with inconclusive GERD diagnosis., Methods: Review of impedance-pH tracings from PPI responder/non-responder patients with typical reflux symptoms. Multivariate regression analysis was performed to determine the association of MNBI and PSPW index to PPI response., Results: Among 233 patients evaluated, 145/233 (62.2%) were PPI responders; 62 had conclusive and 65 inconclusive evidence of GERD, 46 had reflux hypersensitivity, and 60 functional heartburn. Abnormal MNBI and PSPW index were significantly more frequent in inconclusive GERD as compared to the functional heartburn group (P < 0.001). Within the inconclusive GERD group, 35/65 (54%) patients were PPI responders and displayed a significantly higher proportion of cases with pathological MNBI or PSPW index as compared to non-responders (32/35 [91.4%] and 30/35 [85.7%] vs 9/30 [30%] and 7/30 [23.3%], P < 0.001). By multivariate analysis, pathological PSPW index and/or MNBI values were significantly associated with PPI response in all groups., Conclusions: The present study highlights the value of MNBI and PSPW index as adjunctive metrics in characterising patients with inconclusive evidence of GERD and identifying those responsive to PPI treatment., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Following acid perfusion, esophageal pH is restored by swallowed bicarbonate-containing saliva secreted in response to a vagal esophago-salivary reflex. At impedance-pH monitoring, the post-reflux swallow-induced peristaltic wave (PSPW) index puts into relationship timely post-reflux swallows with the number of reflux events: Low values typify reflux-related heartburn (RRH) and lack of on-therapy improvement characterizes proton pump inhibitor (PPI) failure. Considerable esophageal pH increments associated with PSPWs could demonstrate the occurrence of esophago-salivary reflex in clinical setting, while its relevance could be shown by lower esophageal pH increments in PPI-refractory RRH., Methods: Prospective multicenter study in patients with PPI-refractory or PPI-responsive RRH evaluated with off-PPI impedance-pH monitoring. Increments in pH associated with PSPWs were measured and the mean calculated to obtain the PSPW-associated ∆pH., Key Results: The mean PSPW-associated ∆pH in 294 RRH patients was 1.2 ± 0.7 and was lower in 137 PPI-refractory (1.0 ± 0.6) than in 157 PPI-responsive (1.5 ± 0.6) cases (p < 0.0001). Lower PSPW-associated ∆pH was independently related to PPI failure at multivariable logistic regression analysis (OR 0.16, 95% CI 0.09-0.26). At ROC analysis, comparing PPI-refractory to PPI-responsive cases the AUC for PSPW-associated ∆pH was 0.76 (95% CI 0.71-0.82), the best cutoff value being 1.2., Conclusions and Inferences: Considerable PSPW-associated pH increments demonstrate the occurrence of esophago-salivary reflex in clinical setting. Lower increments in PPI-refractory RRH cases show the clinical relevance of esophago-salivary reflex, confirming that PSPW represents a defense mechanism against reflux. PSPW-associated ∆pH can efficiently predict PPI response in patients undergoing off-therapy impedance-pH monitoring., (© 2021 John Wiley & Sons Ltd.)

Background: Postreflux swallow-induced peristaltic wave (PSPW) on pH-impedance monitoring and contraction vigor on high-resolution manometry (HRM) both assess esophageal peristaltic response. We aimed to evaluate relationships between PSPW and esophageal peristalsis on HRM in the context of reflux disease in this multicenter cohort study., Methods: pH-impedance and HRM studies performed on patients with persisting reflux symptoms were reviewed from 6 centers (5 in Europe and 1 in US). Total, upright and supine acid exposure time (AET) were evaluated from pH-impedance studies; PSPW index (PSPWI) and mean nocturnal baseline impedance (MNBI) were calculated using standard methodology. Esophageal body contraction vigor was analyzed using distal contractile integral (DCI), and DCI ratio > 1 between single swallows and multiple rapid swallows (MRS) defined presence of contraction reserve. Student's t test, ANOVA, and linear regression were utilized to investigate relationships between PSPW, contraction vigor, and contraction reserve., Key Results: Of 296 patients (52.8 ± 0.8 yr, 63% F), median PSPWI was 0.475. Only 24.0% had intact DCI; the remainder had varying degrees of hypomotility. As hypomotility increased, PSPWI and MNBI decreased significantly, while total AET and reflux episodes had an inverse response (P ≤ .002 for each). MRS data were available in 167 (56.4%), 72.5% had contraction reserve. MRS cohorts with normal PSPWI had significantly lower reflux burden compared to low PSPWI, regardless of presence or absence of contraction reserve (P ≤ .001)., Conclusions and Inferences: PSPWI correlates with esophageal hypomotility and reflux burden, and complements clinical reflux evaluation. Intact PSPW is more relevant to esophageal reflux clearance than contraction reserve., (© 2020 John Wiley & Sons Ltd.)

Introduction: The management of gastro-esophageal reflux disease (GERD) patients is often complex as the clinical presentation is heterogeneous and the mechanisms underlying symptoms are multifactorial. In the past decades, investigations conducted with conventional manometry and, above all, the more accurate high resolution manometry (HRM), helped us in exploring the field of esophageal motility and in understanding the link between motor features and GERD pathogenesis., Areas Covered: Several studies carried out with conventional manometry and HRM have confirmed a relevant role of esophageal motor function in GERD pathogenesis. In particular, HRM studies have shown a direct correlation between impaired esophageal body motility, disruption of the esophagogastric junction and reflux burden. These findings impact the clinical and therapeutical management of GERD patients. Moreover, HRM findings might be helpful in evaluating patients with proton pump inhibitor (PPI) resistance and inconclusive evidences of GERD., Expert Opinion: The relationship between esophageal motility and GERD pathogenesis needs to be further evaluated by multicenter outcome studies involving a large number of GERD patients and healthy controls. However, other more promising areas could be progressed.

Background: Mean nocturnal baseline impedance (MNBI) augments the diagnostic yield of multichannel intraluminal impedance-pH (MII-pH) monitoring. While acid exposure time (AET) correlates with MNBI, it remains unclear whether esophageal motility affects MNBI values. The present study was aimed at evaluating the respective roles of esophageal motor function and AET on MNBI., Methods: High-resolution manometry (HRM) studies and ambulatory 24-hour MII-pH monitoring tracings were retrospectively analyzed from consecutive endoscopy-negative GERD patients with typical symptoms responsive to previous acid-suppressive therapy from three tertiary care centers. Univariate and multivariate analyses were performed to determine predictors of pathologic MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES)., Key Results: Patients with pathological AET displayed lower MNBI values at 3 cm and 5 cm (P < .01) compared to patients with non-pathological AET. Similarly, significantly lower MNBI values were also noted at both sites with type 3 EGJ compared to type 1 EGJ (P ≤ .02 for each comparison), and with absent contractility compared to normal peristalsis (P ≤ .02 for each comparison). On multivariate analysis, the presence of type 2 or 3 EGJ and absent contractility were associated with a significantly higher probability of pathological MNBI values at 3 cm and 5 cm above the LES., Conclusions and Inferences: Disruption of the EGJ and absent contractility on HRM are both associated with lower MNBI values. HRM findings complement reflux testing using MII-pH monitoring., (© 2019 John Wiley & Sons Ltd.)

Background: Association between proportions of hypomotile swallows on esophageal high-resolution manometry (HRM) and esophageal reflux burden remains incompletely understood. We investigated relationships between hypomotility, acid exposure time (AET), and mean nocturnal baseline impedance (MNBI) on ambulatory reflux monitoring., Methods: Clinical data, HRM, and ambulatory pH-impedance studies (performed off acid suppression) from patients with persisting reflux symptoms were reviewed from five international centers. AET (abnormal > 6%) and MNBI (abnormal < 2292 ohms) were extracted from pH-impedance studies. Distal contractile integral (DCI) designated esophageal peristalsis into normal (DCI > 450 mmHg.cm.s), fragmented (DCI > 450 mmHg.cm.s with breaks > 5 cm), weak (DCI 100-450 mmHg.cm.s), and failed (DCI < 100 mm mmHg.cm.s) sequences. Univariate and multivariate analyses were performed to identify motor associations of abnormal reflux burden., Key Results: Of 351 patients (52.1 ± 0.8 years, 67%F), 29.3% had AET > 6% and 61.8% had MNBI < 2292 ohms. On univariate analysis, both fragmented peristalsis and IEM associated with abnormal AET (P ≤ .01) and MNBI (P ≤ .03); reflux burden was more profound with >70% fragmented as well as ineffective sequences compared to ≤70% for each (P < .05 for each comparison). When weak and failed sequences within IEM were separately analyzed, ≥50% failed sequences predicted abnormal AET (P ≤ .009), and ≥50% weak sequences did not (P = .14). On multivariate regression, ≥50% failed sequences predicted abnormal AET (P = .02), and >70% ineffective sequences trended strongly (P = .069); >70% ineffective sequences predicted abnormal MNBI (P = .046), and >70% fragmented sequences trended strongly (P = .076)., Conclusions and Inferences: Breaks in esophageal peristaltic integrity seen with fragmented and failed sequences are more relevant to abnormal esophageal acid burden than weak sequences., (© 2019 John Wiley & Sons Ltd.)

Background: Mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index are able to increase the diagnostic yield of impedance-pH and are associated to proton pump inhibitor (PPI) response. Few data concerning these variables in patients with extra-esophageal symptoms (EES) are available., Aims: To evaluate, in EES patients, the role of the conventional and new impedance-pH variables in diagnosing GERD and the predictive value of impedance-pH variables for PPI response., Methods: Consecutive patients presenting suspected GERD-related EES underwent impedance-pH. Patients treated in the last six months with double dose PPI therapy were enrolled. The presence of concomitant typical symptoms was assessed., Results: 239 EES patients were studied; 102 responders and 137 non-responders. Eighty-one (34%) were affected by non-erosive reflux disease (NERD), 61 (26%) presented reflux hypersensitivity (RH) and 97 (40%) were non-GERD. In NERD and RH groups, a significantly higher proportion of patients with pathological PSPW index or MNBI values compared to non-GERD group was observed. 24 (25%) non-GERD patients presented a pathological PSPW index and/or MNBI. Pathological PSPW index, MNBI and presence of typical symptoms were associated to PPI response., Conclusions: MNBI and PSPW index measurement increases the diagnostic yield of impedance-pH; abnormal values are associated with a satisfactory response to acid-suppressive therapy in EES patients., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction : Gastroesophageal reflux disease (GERD) is a very common and often debilitating disease. In the broad spectrum of GERD phenotypes, three main groups may be traditionally distinguished: 1) patients only affected by esophageal and/or extra-esophageal symptoms; 2) patients with erosive esophagitis and 3) patients with further complications. Areas covered : This review provides an overview on the current classifications of GERD patients, and their impact on their management. Expert opinion : In 2017, the GERD Consensus Working Group focused the attention on patients unresponsive to PPIs. In this scenario, a diagnosis of GERD might be confirmed by evident signs of erosive esophagitis and the finding of pH or multichannel intraluminal impedance-pH tests, such as more than 6%. The 'Lyon Consensus' panel of experts confirmed that positive indices of reflux-symptom association, without other altered parameters, represent reflux hypersensitivity. GERD requires a customized management; it is crucial to assess frequency and severity of symptoms and their response to an optimal course of therapy as well as to explore the endoscopic alterations and consider other diagnoses responsible for persistent symptoms.

Background: The real size of the gastro-oesophageal reflux disease (GERD) population not responding to proton pump inhibitor (PPI) therapy has still not been fully elucidated. Causes of PPI refractoriness include incorrect diagnosis and lack of adherence to therapy, in terms of incorrect dosage and timing., Aims: To evaluate the prevalence of refractoriness to optimal PPI therapy and the contribution of non-erosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn, to PPI refractoriness. The association of functional GI symptoms in non-responders was evaluated., Methods: Frequency and severity of GERD symptoms (heartburn, regurgitation, chest pain), dysphagia, belching, epigastric pain, postprandial distress, irritable bowel syndrome (IBS), globus, and ear nose and throat (ENT) symptoms were evaluated in patients previously classified as non-responders. Patients with at least one of the oesophageal symptoms with a frequency ≥3 /week were treated with esomeprazole 40 mg once daily for 8 weeks and then re-evaluated. Non-responders (patients with oesophageal symptoms ≥3 times per week) underwent 24 hour multichannel intraluminal impedance-pH monitoring., Results: Of 573 consecutive patients, 92 with oesophageal symptoms and classified as PPI-refractory underwent the esomeprazole trial; 60 did not respond. IBS, epigastric pain, and post-prandial distress episodes were associated with a poor response on multivariate analysis. NERD, reflux hypersensitivity, and functional heartburn patients constituted 32%, 42%, and 26%, respectively of the PPI-refractory group., Conclusions: True refractoriness in patients with GERD symptoms attending a secondary care setting is lower than previously reported. Following a careful history and optimal PPI dosing, the rate of refractoriness was 20%. True NERD constitutes only a third of the PPI-refractory group., (© 2018 John Wiley & Sons Ltd.)

Goals: The present study was aimed at evaluating, in dysphagic patients, the role of high-resolution manometry (HRM) findings, presence of gastroesophageal reflux disease (GERD), and proton-pump inhibitor (PPI) therapy on dysphagia perception., Background: A relevant proportion of patients with nonobstructive dysphagia present normal esophageal HRM findings. Patients with GERD often complain of dysphagia and factors, such as hypersensitivity, might be involved in its occurrence., Study: In total, 37 nonerosive reflux disease (NERD) patients with only dysphagia (group 1) and 52 patients with both dysphagia and typical GERD symptoms (group 2) were evaluated with symptom scores, HRM combined with impedance and 24 hours impedance-pH monitoring. In total, 44 NERD patients, not presenting dysphagia, underwent the same protocol. A total of 22/37 group 1 patients [11 with pathologic acid exposure time (AET)] were treated with esomeprazole 40 mg oid for 4 weeks and were reassessed during the last week of therapy., Results: A total of 15/37 group 1 patients (40%), 27/52 group 2 patients (52%), and 19/44 (43%) NERD patients presented pathologic AET [P=not significant (NS)]. Group 1 patients with a pathologic AET showed a significantly lower mean distal contractile integral (DCI) and a significant correlation (ρ=-0.71) between individual DCI and total bolus transit time values. During PPI therapy, in group 1 patients with pathologic AET, the mean dysphagia score value decreased significantly [7.5 (range, 3 to 9) before, 4 (range, 2 to 6) during PPI; P<0.01)] and mean DCI value increased significantly., Conclusions: In total, 40% of dysphagic patients show a pathologic AET and reduced peristaltic vigor. In these patients, an adequate PPI therapy significantly decreases dysphagia frequency and severity and improves the esophageal peristaltic force.

Trans-sphincteric pressure gradient (TSPG) seems to play a relevant role in eliciting refluxes during transient lower esophageal sphincter relaxations (TLESRs). Intra-bolus pressure (IBP) is considered to be correlated to esophageal wall tone. We aimed to evaluate the relationship between IBP, TSPG during TLESRs and the dynamic properties of refluxate in gastroesophageal reflux disease. Sixteen non-erosive reflux disease (NERD), 10 erosive disease (ERD) patients and 12 healthy volunteers (HVs), underwent 24-hour impedance-pH monitoring and combined high-resolution manometry-impedance before and 60 minutes. After a meal, ERD patients presented a significantly lower mean IBP (4.7 ± 1.6 mmHg) respect to NERD patients (8.9 ± 2.8 mmHg) and HVs (9.2 ± 3.2 mmHg). NERD patients with physiological abnormal acid exposure time showed a mean IBP (10.4 ± 3.1 mmHg) significantly higher than that in NERD with pathological abnormal acid exposure time (5.1 ± 1.5 mmHg). The TSPG value was significantly higher during TLESRs accompanied by reflux than during TLESRs not associated with reflux, both in patients and in HVs. A significant direct correlation was found between IBP, TSPG and proximal spread of refluxes in patients and in HVs. Gastroesophageal reflux disease patients display different degrees of esophageal distension. An increased compliance of the distal esophagus may accommodate larger volumes of refluxate and likely facilitates the injuries development. Higher TSPG values appear to facilitate the occurrence of refluxes during TLESRs. In patients with NERD, higher TSPG and IBP values favor proximal spread of refluxate and hence may play a relevant role in symptom generation., (© 2015 International Society for Diseases of the Esophagus.)

Objective: Gastroesophageal reflux disease (GERD) represents one of the most common gastrointestinal disorders, but is still a challenge to cure. Proton pump inhibitors (PPIs) are currently the GERD's standard treatment, although not successful in all patients; some concerns have been raised regarding their long term consumption. Recently, some studies showed the benefits of inspiratory muscle training in increasing the lower esophageal sphincter pressure in patients affected by GERD, thereby reducing their symptoms., Materials and Methods: Relevant published studies were searched in Pubmed, Google Scholar, Ovid or Medical Subject Headings using the following keywords: "GERD" and physiotherapy", "GERD" and "exercise", "GERD" and "breathing", "GERD and "training"., Results: At the end of our selection process, four publications have been included for systematic review. All of them were prospective controlled studies, mainly based on the training of the diaphragm muscle. GERD symptoms, pH-manometry values and PPIs usage were assessed., Conclusions: Among the non-surgical, non-pharmacological treatment modalities, the breathing training on diaphragm could play an important role in selected patients to manage the symptoms of GERD.

Patients with esophageal symptoms potentially associated to esophageal motor disorders such as dysphagia, chest pain, heartburn and regurgitation, represent one of the most frequent reasons for referral to gastroenterological evaluation. The utility of esophageal manometry in clinical practice is: (1) to accurately define esophageal motor function, (2) to identify abnormal motor function, and (3) to establish a treatment plan based on motor abnormalities. With this in mind, in the last decade, investigations and technical advances, with the introduction of high-resolution esophageal manometry, have enhanced our understanding and management of esophageal motility disorders. The following recommendations were developed to assist physicians in the appropriate use of esophageal manometry in modern patient care. They were discussed and approved after a comprehensive review of the medical literature pertaining to manometric techniques and their recent application. This position statement created under the auspices of the Gruppo Italiano di Studio per la Motilità dell'Apparato Digerente (GISMAD), Società Italiana di Gastroenterologia ed Endoscopia Digestiva (SIGE) and Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) is intended to help clinicians in applying manometric studies in the most fruitful manner within the context of their patients with esophageal symptoms., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Gastro-oesophageal reflux disease (GERD) may contribute to the onset of chronic cough (CC); however, the multichannel intraluminal impedance-pH (MII-pH) monitoring is often within the normal range and the response to proton pump inhibitors (PPIs) unsatisfactory. The measure of impedance baseline (IB) increases the sensitivity of MII-pH in patients with typical symptoms., Aim: To evaluate the role of MII-pH variables, including IB, in predicting PPI response and to define the characteristics of the reflux pattern in CC patients., Methods: Prospectively selected CC patients suspected GERD-related underwent MII-pH monitoring and, therefore, received a double dose of PPIs for at least 6 weeks. Patients filled symptom scores before MII-pH and after PPI therapy. MII-pH data were compared with those obtained in 60 non-erosive reflux disease patients with typical symptoms., Results: A total of 156 CC patients entered the study: 68 (43.5%) responders and 88 (56.5%) nonresponders to PPIs. The number of reflux episodes was significantly higher in CC compared with that in typical symptoms patients. Nonresponder CC patients with a pathological acid exposure time (AET) and/or IB value were 43/88 (49%), while 15/88 (17%) presented only pathological AET (P < 0.001). CC patients with a pathological AET or IB, or with both a pathological AET and IB, showed a probability of PPI response twofold greater than patients with normal AET and IB., Conclusions: The presence of a pathological AET or pathological IB in CC patients is associated with a greater probability of PPI response. IB is a promising variable in patients with CC, as it increases the diagnostic yield of MII-pH and allows confirmation of the GERD diagnosis in these patients., (© 2014 John Wiley & Sons Ltd.)

Background: The diagnostic corroboration of the relationship between gastro-oesophageal reflux disease (GERD) and chronic cough remains challenging., Aims: To compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro-oesophageal reflux (GER)-related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER-related cough., Methods: Forty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2-3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance-pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups., Results: A significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 μm) and controls (0.5 ± 0.2 μm, P < 0.001), whereas there was no difference between GrC and GERD group (1 ± 0.3 μm, NS). No difference was found in the mean ISD between GrC children with or without pathological oesophageal acid exposure time (1 ± 0.3 vs. 0.9 ± 0.2 μm), and there was no correlation between ISD and any reflux parameter. Finally, there was no correlation between ISD and distal baseline impedance values (r:-0.35; NS)., Conclusions: In children with reflux-related cough, dilated intercellular space diameter appears to be an objective and useful marker of oesophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients where the diagnosis is uncertain. In children with reflux-related cough, baseline impedance levels have no role in identifying reflux-induced oesophageal mucosal ultrastructural changes., (© 2014 John Wiley & Sons Ltd.)

Background & Aims: Transient lower esophageal sphincter relaxations (TLESRs) contribute to episodes of reflux. Few studies have assessed the frequencies or compositions of TLESRs and reflux episodes in patients with reflux disease. We used combined high-resolution manometry and impedance monitoring to analyze reflux episodes and esophageal motility in these patients, compared with those of healthy individuals., Methods: We evaluated the frequency of TLESRs and the relationship between the reflux pattern and esophageal pressures during TLESRs in 14 patients with nonerosive reflux disease (NERD) and 11 controls. Study participants underwent combined high-resolution manometry and impedance monitoring before and 60 minutes after a solid and liquid meal. The diagnosis of NERD was confirmed by a 24-hour pH impedance test., Results: The frequency of TLESRs did not differ between patients with NERD and controls. In patients with NERD, TLESRs were associated more often with reflux episodes than in controls (93% ± 6% vs 66% ± 19%; P < .05). Patients with NERD had a higher percentage of pure liquid reflux episodes (33% ± 15% vs 10% ± 2%; P < .05), whereas controls had a higher percentage of mixed reflux episodes (45% ± 16% vs 67% ± 17% in patients with NERD; P < .05). Patients with NERD also had a higher percentage of reflux (liquid and mixed) associated with common cavities (74% ± 18% vs 50% ± 20% in controls; P < .05)., Conclusions: In contrast to previous studies, we found that TLESRs are associated more often with reflux in patients with NERD than control subjects; this association increases when only liquid and mixed refluxes are considered. These findings indicate that factors involved in the occurrence of reflux in patients with NERD during TLESRs are different from those in healthy subjects., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Ineffective esophageal motility is frequently observed in gastroesophageal reflux disease (GERD) patients but its clinical relevance remains controversial. In healthy subjects and in patients with nonobstructive dysphagia, it has been demonstrated, by means of high-resolution manometry (HRM), that long breaks of esophageal peristalsis predict delayed bolus clearance., Methods: HRM and 24-h multichannel impedance-pH (MI-pH) monitoring were performed in 40 GERD patients with no evidence of hiatal hernia. Total bolus clearing time (BCT) in upright and supine position and acid exposure time (AET) were calculated., Results: Of the 40 patients, 23 showed a pathological AET and 15 erosive reflux disease (ERD). Patients with a pathological number of large breaks were characterized by a significantly lower BCT value in the supine position and higher AET. In all, 10/15 ERD patients (67%) and 5/25 nonerosive reflux disease patients (20%) were characterized by an abnormal number of small or large breaks (P<0.05). ERD patients were characterized by significantly higher AET and BCT in the supine position., Conclusions: GERD patients with a pathological number of large breaks, assessed by HRM, are characterized by a significantly prolonged reflux clearance in the supine position and higher AET. ERD patients display a higher number of esophageal breaks that might explain the development of erosions.

Background: Non-erosive reflux disease (NERD) patients are more sensitive than erosive esophagitis patients to weakly acidic reflux and to the presence of gas in the refluxate. Intra-esophageal acid perfusion sensitizes esophageal receptors to mechanical and chemical stimuli., Methods: To establish whether acid sensitization plays a role in the perception of weakly acidic and mixed reflux episodes, 29 NERD patients, responders and 14 non-responders to proton pump inhibitors (PPIs), underwent pH-impedance monitoring. Non-responders repeated the study while on PPIs. To assess the effect of acid exposure on symptom perception, the time period with pH below 4 was measured in 15- and 30-minute time-windows preceding the onset of each reflux episode., Key Results: Considering weakly acidic and mixed refluxes, both in responder and non-responder patients (off PPIs), the symptomatic refluxes were preceded by a significantly higher cumulative acid exposure than the asymptomatic refluxes. In all patients, following acid reflux, the percentage of symptomatic weakly acidic reflux episodes was significantly higher than that of asymptomatic refluxes. Non-responder patients, off-treatment, were characterized by a lower proportion of weakly acidic reflux and mixed reflux episodes. In the non-responder patients on PPI, only mixed and weakly symptomatic reflux episodes were preceded by a higher cumulative acid exposure., Conclusions & Inferences: In NERD patients, spontaneous acid reflux enhances subsequent reflux perception, regardless of acidity or liquid/mixed composition of episodes; in non-responder patients on PPIs, only the perception of mixed and weakly acidic reflux episodes seems to be mediated by a preceding acid exposure., (© 2013 John Wiley & Sons Ltd.)

Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

Background and Aims: We sought to compare intercellular space diameter in children with non-erosive and erosive reflux disease, and a control group. We also aimed to characterize the reflux pattern in erosive and non-erosive reflux disease patients, and to explore the relationship between intercellular space diameter values and reflux parameters., Methods: Twenty-four children with non-erosive reflux disease, 20 with erosive reflux disease, and 10 controls were prospectively studied. All patients and controls underwent upper endoscopy. Biopsies were taken at 2-3 cm above the Z-line, and intercellular space diameter was measured using transmission electron microscopy. Non-erosive and erosive reflux disease patients underwent impedance-pH monitoring., Results: Mean intercellular space diameter values were significantly higher in both non-erosive (0.9 ± 0.2 μm) and erosive reflux disease (1 ± 0.2 μm) compared to controls (0.5 ± 0.2 μm, p<0.01). No difference was found between the two patient groups. Acid exposure time, the number of acid, weakly acidic and weakly alkaline reflux events did not differ between the two patient groups. No difference was found in the mean intercellular space diameter between non-erosive reflux disease children with and without abnormal acid exposure time (1 ± 0.3 vs. 0.9 ± 0.2 μm). No correlation was found between any reflux parameter and intercellular space diameter values., Conclusions: Dilated intercellular space diameter seems to be a useful and objective marker of oesophageal damage in paediatric gastro-oesophageal reflux disease, regardless of acid exposure. In childhood, different gastro-oesophageal reflux disease phenotypes cannot be discriminated on the basis of reflux pattern., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: It was recently shown that GERD patients have lower impedance baseline (IB) values than healthy controls and, that the esophageal acid exposure time (AET) correlates with IB levels., Goals: To explore the sensitivity of IB measurements in NERD patients, responders and non-responders to PPIs, when compared with pH-impedance (MII-pH) variables, and to evaluate whether this variable could represent a marker of GERD symptoms. Reproducibility and inter-observer agreement of IB measurement were also assessed. Study. MII-pH tracings from 44 NERD responders and 22 non-responders were analysed. Ten healthy volunteers underwent the same protocol. IB values were measured at the distal and proximal esophagus. IB was also analysed in a subgroup of patients and in controls with two methods and by two blinded operators., Results: Mean IB values at the distal esophagus were significantly lower in NERD patients than in controls. IB values did not differ between responders and non-responders. Of the 8 responders with negative AET and symptom association probability (SAP), 3 (37.5%) showed IB values lower than controls. IB values in responders with positive and negative SAP were similar (1832 (1596-2068) Ω vs 1667 (1361-1973) Ω, p: n.s.). No differences were found between the IB values measured with the two methods and the inter-observer agreement was good., Conclusions: IB is a promising and easy to calculate MII-pH variable and appears to increase the sensitivity of MII-pH monitoring. IB values cannot predict PPI response and are not associated with reflux perception in NERD patients.

Background: A distinction between symptomatic non-erosive reflux disease (NERD) and erosive esophagitis (EE) patients is supported by the presence of inflammatory response in the mucosa of EE patients, leading to a damage of mucosal integrity. To explore the underlying mechanism of this difference, we assessed inflammatory mediators in mucosal biopsies from EE and NERD patients and compared them with controls., Methods: Nineteen NERD patients, 15 EE patients, and 16 healthy subjects underwent endoscopy after a 3-week washout from PPI or H(2) antagonists. Biopsies obtained from the distal esophagus were examined by quantitative real-time polymerase chain reaction (qPCR) and multiplex enzyme-linked immunosorbent assay for selected chemokines and lyso-PAF acetyltransferase (LysoPAF-AT), the enzyme responsible for production of platelet-activating factor (PAF)., Key Results: Expression of LysoPAF-AT and multiple chemokines was significantly increased in mucosal biopsies derived from EE patients, when compared with NERD patients and healthy controls. Upregulated chemokines included interleukin 8, eotaxin-1, -2, and -3, macrophage inflammatory protein-1α (MIP-1α), and monocyte chemoattractant protein-1 (MCP-1). LysoPAF-AT and the chemokine profile in NERD patients were comparable with healthy controls., Conclusions & Inferences: Levels of selected cytokines and Lyso-PAF AT were significantly higher in the esophageal mucosa of EE patients compared with NERD and control patients. This difference may explain the distinct inflammatory response occurring in EE patients' mucosa. In contrast, as no significant differences existed between the levels of all mediators in NERD and control subjects, an inflammatory response does not appear to play a major role in the pathogenesis of the abnormalities found in NERD patients., (© 2012 Blackwell Publishing Ltd.)

Background: Baseline impedance measurement has been reported to be related to esophageal acid exposure and hypothesized to be a marker of microscopic changes of the esophageal mucosa. Aims of the study were to establish whether any relationship existed between the magnitude of intercellular space diameter (ISD) of esophageal mucosa and baseline impedance levels in children with gastro-esophageal reflux disease (GERD), and to compare baseline impedance levels between children with non erosive (NERD) and erosive (ERD) reflux disease., Methods: Fifteen children (median age: 11.2 years) with NERD, and 11 with ERD (median age: 9.6 years) were prospectively studied. All patients underwent upper endoscopy. Biopsies were taken 2-3cm above the Z-line, and ISD was measured using transmission electron microscopy. All patients underwent impedance pH-monitoring, and baseline impedance levels were assessed in the most distal impedance channel., Key Results: Mean (±SD) ISD did not differ between NERD (1.0±0.3μm) and ERD (1.1 ± 0.3 μm, ns). Considering all patients together, no correlation was found between distal baseline impedance and ISD (r: -0.15; ns). Conversely, negative correlations were found between distal baseline impedance and acid exposure time (r: -0.76; P<0.001), long-lasting reflux episodes (r: -0.78; P<0.001), acid reflux episodes (r: -0.62; P<0.001), and acid clearance time (r: -0.79; P<0.001). Distal baseline impedance was significantly lower in ERD [1455 (947-2338) Ω] than in NERD children [3065 (2253-3771) Ω; P<0.01]., Conclusions & Inferences:   In children with GERD baseline impedance levels are not useful in predicting reflux-induced ultrastructural changes in the esophageal mucosa, despite their ability to discriminate between NERD and ERD., (© 2012 Blackwell Publishing Ltd.)

Background: The sensitivity of 24-h pH monitoring is poor in non-erosive reflux disease (NERD). In NERD patients, the proximal extent of acid reflux is one of the main determinants of reflux perception. The present study was aimed to compare the diagnostic accuracy of acid exposure time (AET), at 5 cm above the lower esophageal sphincter, with those at 10 cm and at 3 cm below the upper esophageal sphincter as well as the reproducibility of these parameters., Methods: A total of 93 consecutive NERD patients, with typical symptoms responsive to proton pump inhibitor treatment, and 40 controls underwent esophageal manometry and multi-channel 24-h pH-test; 13 patients underwent the same study on two occasions. Symptom association probability (SAP) values were evaluated at each esophageal level., Key Results: The ROC curve indicates that the area under the curve was 0.79 at distal (SE=0.039), 0.87 (SE=0.032) at proximal (P=0.029 vs distal), and 0.85 (SE=0.033) at very proximal esophagus (P =0.148). AET showed a reproducibility of 61% (Kappa 0.22) at distal esophagus, 77% (Kappa 0.45) at proximal and 53% (Kappa 0.05) at very proximal esophagus. The percentage of patients with a positive SAP was not significantly different when assessed at the distal compared with the proximal esophagus., Conclusions & Inferences: In NERD patients, the diagnostic yield of the pH test is significantly improved by the assessment of AET at the proximal esophagus. As this variable seems to be less affected by the day to day variability, it could be considered a reliable and useful diagnostic tool in NERD patients., (© 2011 Blackwell Publishing Ltd.)

The mechanisms underlying symptoms in non-erosive reflux disease (NERD) remain to be elucidated. Non-erosive reflux disease patients appear to be more sensitive to intraluminal stimula than erosive patients, the proximal oesophagus being the most sensitive. In order to assess regional oesophageal changes in reflux acidity and sensitivity to reflux, according either to the acidity or the composition of the refluxate, combined multiple pH and multiple pH-impedance (pH-MII) was performed in 16 NERD patients. According to multiple pH-metry, 29% and 12% of reflux events reached the middle and proximal oesophagus respectively, and 35% and 19% according to conventional pH-MII (P < 0.05). The per-individual analysis confirmed the difference between the two techniques. According to combined distal and proximal pH-MII, approximately 30% of distal acid reflux became weakly acidic at the proximal oesophagus. In all patients, the frequency of symptomatic refluxes, both acid and weakly acidic, was significantly higher at the proximal, compared with distal oesophagus (25 +/- 8%vs 11 +/- 2% for acid reflux and 27 +/- 8%vs 8 +/- 2% for weakly acidic reflux; P < 0.05). Compared with multiple pH-metry, pH-MII shows a higher sensitivity in the detection of proximal reflux. As approximately 30% of acid reflux becomes weakly acidic along the oesophageal body, to better characterize proximal reflux, in clinical practice, combined proximal pH-impedance monitoring should be used. In NERD patients, the proximal oesophagus seems to be more sensitive to both acid and weakly acidic reflux.