Patients with definite and inconclusive evidence of reflux according to Lyon consensus display similar motility and esophagogastric junction characteristics

Background/Aims: The role of esophageal high-resolution manometry (HRM) within Lyon consensus phenotypes, especially patients with inconclusive gastroesophageal reflux disease (GERD) evidence, has not been fully investigated. In this multicenter, observational study we aim to compare HRM parameters in patients with GERD stratified according to the Lyon consensus. Methods: Clinical and endoscopic data, HRM and multichannel intraluminal impedance-pH (MII-pH) studies performed off proton pump inhibitor therapy in patients with esophageal GERD symptoms were reviewed. Lyon consensus criteria identified pathological GERD, reflux hypersensitivity, functional heartburn, and inconclusive GERD. Patients, with inconclusive GERD were further subdivided into 2 groups based on total reflux numbers (≤ 80 or \u3e 80 reflux episodes) during the MII-pH recording time. Results: A total of 264 patients formed the study cohort. Pathological GERD and inconclusive GERD patients were associated with higher numbers of reflux episodes, lower mean nocturnal baseline impedance (MNBI) values, and a higher proportion of patients with pathologic MNBI compared to functional heartburn ( Conclusion: Esophageal motor parameters on HRM are similar between pathologic and inconclusive GERD according to the Lyon consensus

Clinical Picture of Gastroesophageal Reflux Disease in Children

Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, is a normal physiologic process occurring several times per day in healthy infants, children, and adults. The majority of GER episodes occur in the postprandial period, last in <3 min, and cause few or no symptoms. Conversely, when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications, we talk about “gastroesophageal reflux disease (GERD).” Distinguishing physiologic GER from GERD may often be tricky for clinicians, especially in infants. The typical presentation of GERD includes the following symptoms: recurrent regurgitation, vomiting, weight loss or poor weight gain, excessive crying and irritability in infants, heartburn or chest pain, ruminative behavior, hematemesis, and dysphagia. Besides these esophageal symptoms, there is a set of extra-esophageal symptoms, mainly respiratory, which may occur along with typical symptoms or may represent the only clinical picture of GERD: odynophagia, wheezing, stridor, cough, hoarseness, dental erosions, and apnea/apparent life-threatening events (ALTEs). While infantile GER tends to resolve spontaneously and does not deserve pharmacological treatment, GERD management includes lifestyle changes, pharmacologic therapy, and surgery. Therefore, a proper diagnosis of these two conditions, besides other possible conditions mimicking reflux, is crucial in order to target the treatment, avoiding the overuse of antacid drugs that currently represents a major source of concern

Long-term Follow-up After Esophageal Atresia Repair: Gastrointestinal morbidity in children and adults

This thesis aims to optimize long-term gastrointestinal follow-up of EA patient

The use of impedance pH measurements to determine the effect of gastro-oesophageal reflux in patients with idiopathic pulmonary fibrosis and cystic fibrosis

M.D. ThesisIntroduction For many decades gastrooesophageal reflux has been implicated in patients suffering from lung disease and in lung allograft injury. From the early 1970s studies have taken place investigating reflux in idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). However, these early studies were small and used primitive techniques to assess reflux. In addition, the role of microaspiration secondary to reflux has often been postulated as a cause of deteriorating lung function in these patients but has been under studied. It is also known that many of these patients require a lung transplant due to end-stage lung disease. Asymptomatic reflux and aspiration may be associated with allograft dysfunction post lung transplant. Early anti-reflux surgery has been suggested to improve long-term survival by treating reflux. This thesis reports a prospective assessment of reflux/aspiration in patients with IPF and CF. In addition, the study reports the largest European series of fundoplication in lung transplant patients. Methods Over a 2 year period patients with IPF and CF were recruited from specialist clinics. All patients completed objective assessment of oesophageal physiology using manometry and impedance-pH. Symptom and quality of life assessment using RSI, Demeester and GIQLI questionnaires were performed on all patients at the time of recruitment. For those patients taking proton pump inhibitor, questionnaires were done ‘on’ and ‘off’ their medication. IPF patients then had a bronchoscopy and lavage (BAL) whilst CF patients produced sputum. Cytospins of the BAL and sputum were produced and differential cell counts were performed and the cells were stained with Oil Red O and Prussian Blue (Perls). ELISA and mass spectrometry assays were also performed on the samples for pepsin and bile salts respectively. Lung transplant patients attended for impedance-pH studies over 3 years and those with symptomat ic reflux or reflux and deteriorating lung function were referred for a laparoscopic fundoplication. Lung function assessment, symptom and quality of life questionnaires were performed before surgery and at 6 weeks and 6 months after surgery Results IPF Patients: Thirty eight patients with IPF were initially approached and 29 consented to be studied. Nine patients dropped out from the study after consent. Twenty patients with IPF completed both the oesophageal physiology and BAL aspects of the investigation. In 12 patients there was objective evidence of reflux including 6 patients with proximal reflux. 60% of patients had an abnormal RSI score whilst taking a PPI and scores for the other questionnaires were not significantly different ‘on’ and ‘off’ PPI. Lung function was not related to the degree of reflux. The principal cell type identified was macrophages and both Oil Red O and haemosiderin scores were well above the normal range. Bile salts were detectable in 17/20 IPF patients but the levels were not higher than the normal range. 11/20 patients had higher than normal levels of pepsin in the BAL. CF Patients: Twenty-six patient with CF consented to the study but 15 dropped out. Eleven CF patients attended for oesophageal investigation and each provided 2 samples of sputum. 9/11 had reflux, including five with proximal reflux. All patients were taking acid- suppression medication and questionnaire assessments were abnormal whilst on their medication with 82% still having a GIQLI score below 121 despite medication for reflux. Twenty one samples of sputum were processed altogether. The principal cell type was neutrophils. Bile salts were detectible in all samples but these were at very low concentrations. Elevated pepsin was seen in 7/11 sputum samples with the median concentration ten times above the normal level. Lung Transplant Patients 16 lung transplant patients with symptomatic reflux or deteriorating lung function and reflux on impedance-pH had a laparoscopic fundoplication. Symptom questionnaire and quality of life assessment was significantly improved in all patients. Half the patients had presented with declining lung function and all showed an improvement in respiratory function after surgery. Summary We have demonstrated that reflux is present in patients with IPF, CF and in patients after lung transplant. Using impedance-pH we have identified patients with proximal reflux. The presence of reflux appears to affect the patients’ quality of life and despite PPI therapy the majority still had symptoms. High levels of haemosiderin stained macrophages in IPF indicate oxidative stress which may or may not be secondary to reflux. Pepsin levels are elevated in both IPF and CF patients, possibly indicating microaspiration. Conclusion Despite PPI therapy there is significant reflux in IPF and CF identifying a clinical gap in patient treatment that should be considered in management. Our results in the post lung- transplant group indicate there is a role for surgery in treating reflux and potentially reducing microaspiration. This has been shown to stabilise lung function in this cohort and may have implications for the treatment of reflux in patients with lung disease before transplantation.The Joint Research Scientific Executive Committee of the Newcastle Healthcare Charity (RVI/NGH) & Newcastle upon Tyne Hospitals NHS Charity The Northern Oesophagogastric Uni

Surgical Management of Gastroesophageal Reflux in Children: Risk Stratification and Prediction of Outcomes

Introduction: Since the 1980s fundoplication, an operation developed for adults with hiatus hernia and reflux symptoms, has been performed in children with gastroesophageal reflux disease (GORD). When compared to adult outcomes, paediatric fundoplication has resulted in higher failure and revision rates. In the first chapter we explore differences in paradigm, patient population and outcomes. Firstly, symptoms are poorly defined and are measured by instruments of varying quality. Secondly, neurological impairment (NI), prematurity and congenital anomalies (oesophageal atresia, congenital diaphragmatic hernia) are prevalent in children. / Purpose: To develop methods for stratifying paediatric fundoplication risk and predicting outcomes based on symptom profile, demographic factors, congenital and medical history. / Methods: Study objectives are addressed in three opera: a symptom questionnaire development (TARDIS:REFLUX), a randomised controlled trial (RCT) and a retrospective database study (RDS). TARDIS: REFLUX: In the second chapter, digital research methods are used to design and validate a symptom questionnaire for paediatric GORD. The questionnaire is a market-viable smartphone app hosted on a commercial platform and trialed in a clinical pilot study. / RCT: In the third chapter, the REMOS trial is reported. The trial addresses the subset of children with NI and feeding difficulties. Participants are randomized to gastrostomy with or without fundoplication. Notably, pre- and post-operative reflux is quantified using pH-impedance. / RDS: In the fourth chapter, data mining and machine learning strategies are applied to a retrospective paediatric GORD database. Predictive modelling techniques applied include logistic regression, decision trees, random forests and market basket analysis. / Results and conclusion: This work makes two key contributions. Firstly, an effective methodology for development of digital research tools is presented here. Secondly, a synthesis is made of literature, the randomised controlled trial and retrospective database modelling. The resulting product is an evidence-based algorithm for the surgical management of children with GORD

Deglutizioni multiple ripetute come test per la definizione della riserva funzionale esofagea: studio prospettico con HRM

INTRODUZIONE: L’introduzione della manometria ad alta risoluzione (HRM) nella pratica clinica e nella ricerca ha rappresentato un importante passo avanti nel definire e caratterizzare le anomalie motorie esofagee (come l’ineffective esophageal motility, IEM) nei pazienti con MRGE. L’utilizzo di test provocativi come le deglutizioni multiple ripetute (MRS), può aumentare la sensibilità nella diagnosi di tali anomalie. SCOPO DELLA TESI: Lo scopo di questo studio di tesi è quello di migliorare l’individuazione dei pazienti con IEM attraverso HRM prendendo in considerazione deglutizioni semplici di acqua (SS), deglutizioni multiple ripetute (MRS) ed il rapporto tra le due (MRS/SS ratio). MATERIALI E METODI: Sono stati arruolati 230 pazienti (101M e 129F) con pirosi non responsiva a farmaci (con o senza rigurgito e/o altri sintomi di MRGE). Tutti i soggetti sono stati sottoposti ad EGDS off-therapy, accurata anamnesi e successivamente HRM e MII-pH. La HRM è stata eseguita con registrazione dei valori basali all’EGJ, effettuazione di 10 SS e di 5 MRS. Per ogni deglutizione sono stati calcolati DCI, DL e IRP. Per valutare la riserva peristaltica esofagea è stato calcolato il MRS/SS ratio (rapporto tra la media dei valori del DCI per ogni MRS e quella per ogni SS non fallita). Tale valore è stato considerato normale quando >1. I pazienti sono stati raggruppati in 5 diversi gruppi in base alla percentuale di peristalsi fallite/deboli alle SS: Gruppo A≤30%; Gruppo B=40%; Gruppo C=50%; Gruppo D=60%; Gruppo E≥70%. La MII-pH ha valutato il numero ed il tipo di episodi di reflusso ed il tempo di esposizione all’acido (AET). Un AET <4.2% è stato considerato normale. Il numero totale dei reflussi è considerato normale se < 54. RISULTATI: L’andamento del DCI medio durante le SS ha mostrato un progressivo decremento dal gruppo A al gruppo D (p1 nei gruppi A, B e C e <1 nei gruppi D ed E (p<0.001). Dai dati di MII-pH è risultato un progressivo aumento del valore di AET con l’aumentare del numero di deglutizioni deboli o fallite (p<0.001). Una correlazione lineare inversa è stata evidenziata fra AET e DCI MRS (r=-0.601; p<0.001). DISCUSSIONE E CONCLUSIONI: Questo lavoro di tesi ha permesso di confermare l’utilità degli MRS nella diagnosi di IEM e nella valutazione della riserva funzionale esofagea. È stato infatti possibile osservare che la riserva esofagea va progressivamente riducendosi all’aumentare delle deglutizioni SS deboli o fallite. Secondo la Chicago Classification il 50% delle deglutizioni deboli o fallite è sufficiente per la diagnosi di IEM, ma al momento non ci sono dati che confermino l’utilità di questo cut-off. Dai risultati del nostro studio osserviamo infatti che solo quando la percentuale di deglutizioni deboli/fallite diventa del 60% è presente una reale caduta riserva esofagea contrattile, con MRS/SS ratio 5. Inoltre questo studio mette in evidenza la relazione diretta fra la presenza di un valore di AET alterato e la perdita di forza peristaltica (DCI) delle SS e delle contrazioni post-MRS, con correlazione inversa fra AET e MRS (p<0.001)

Gastro-oesophageal reflux, aspiration and anti-reflux surgery in a human lung transplant population

Introduction Asymptomatic gastro-oesophageal reflux and aspiration may be associated with allograft dysfunction post lung transplant. Early anti-reflux surgery has been advocated in selected patients and may improve long-term survival. Little has been published on this topic and the current evidence supporting this is flawed. The understanding of the pathophysiology of aspiration in lung transplant recipients is currently limited. This study reports a prospective analysis of reflux/aspiration immediately post-transplantation to date and its subsequent management. Methods Lung transplant recipients were recruited over 12 months. At one and six months post-transplantation, patients completed a reflux symptom index (RSI) questionnaire for symptoms of extra-oesophageal reflux and underwent objective assessment for reflux (manometry & pH/impedance). Testing was performed with subjects on maintenance proton pump inhibitor. Bronchoalveolar lavage fluid was assessed for pepsin, bile salts, interleukin-8 and neutrophils. Laparoscopic fundoplication was performed on selected patients. Subsequent laboratory based work was performed to determine the composition of gastric juice and to assess the effects of aspiration on primary bronchial epithelial cells and HT29-MTX goblet cells. Results 18 patients with a median age of 46 years (range 22-59) were studied. Manometry was abnormal in 8/18 (44%) patients. Seventeen patients completed 24 hour pHimpedance measurements. 12 of 17 (71 %) had evidence of GORD on pH-impedance monitoring. 3 of 12 (25%) of patients had exclusively weakly-acid reflux. A statistically significant correlation existed between proximal reflux events and neutrophilia at one month (n=13)(Spearman correlation r=0.52, p=0.03). Pepsin was detected in BALF signifying aspiration. Bile salts were rarely detected using 3 separate assays [sensitivity 0.1 /lmolll]. The prevalence of reflux increased over the first six months post-transplant despite a reduction in immunosuppression and normal lung function. Nine patients have subsequently undergone fundoplication for severe Xlil or symptomatic reflux. No major complications occurred. This was associated with improved quality of life and decreased symptoms. Laboratory work gave useful background information on pepsin and bile salts. Mean levels in gastric juice were 380llg/ml (range 0-3892) for pepsin and 50llmolll (range 0-8000) for bile salts. Microaspiration may lead to primary bronchial epithelial cell damage and death. Conclusion Reflux/aspiration is prevalent early post-operatively. Pepsin but rarely bile salts were detected in the lavage fluid suggesting pepsin to be a more common biomarker of aspiration. This study suggests that the causes for reflux are not all related to adverse thoracic changes and immunosuppression as surprisingly. despite a lack of a significant increase in immunosuppression levels, reflux indices increased over the first six months. Laboratory based work provides background information on the use of biomarkers and suggests aspiration could lead to cell death. Fundoplication is safe in selected patients and improved quality of life and GORD symptoms. Further studies are required to assess the effects on lung function and survival.EThOS - Electronic Theses Online ServiceEuropean Society for Organ Transplantation : Joint Research Scientific Executive : Scientific Committee of the Newcastle Healthcare Charity (RVIINGH) & Newcastle Upon Tyne Hospitals NHS Charity : British Lung FoundationGBUnited Kingdo

Oesophageal mucosal integrity in non-erosive reflux disease and refractory GORD.

PhDBackground: 20 to 30% of patients with GORD respond inadequately to conventional therapy. Most of these patients belong to the non-­‐erosive reflux disease group. Despite not having oesophagitis, in these patients oesophageal mucosal integrity appears to be impaired. Aims: To study the dynamic in vitro and in vivo properties of oesophageal mucosal integrity in patients with non-­‐erosive reflux disease, and to test the feasibility of a topical mucosal protectant therapy. Methods: In vitro studies of mucosal integrity were done on human oesophageal biopsies using Ussing chambers. Change in transepithelial electrical resistance (TER) on exposure to acidic solutions was measured. Integrity was assessed in vivo by measuring impedance change and subsequent recovery after oesophageal acid perfusion in symptomatic patients. Proximal and distal oesophageal mucosal integrity was assessed in vitro and in vivo. The effect of in vitro topical application of an alginate-­‐based solution on acid-­‐induced changes in mucosal integrity was tested. Results: In vitro exposure of biopsies to acidic and weakly acidic solutions caused a greater impairment of integrity in symptomatic patients than in controls. In vivo oesophageal acid perfusion causes a profound drop in distal oesophageal impedance that is slow to recover. Recovery is slower in patients with non-­‐erosive reClux disease than in patients with functional heartburn, and a low baseline impedance is associated with painful perception of acid. Proximal oesophageal sensitivity appears unrelated to impaired mucosal integrity, but rather to a distinct sensory afferent nerve distribution. Topical pre-­‐treatment with an alginate solution is able to prevent acid-­‐induced changes in integrity in vitro. Conclusion: Patients with non-­‐erosive reClux disease have a distinct mucosal vulnerability to acidic and weakly acidic solutions that may underlie persistent symptoms. A topical therapeutic approach may be a feasible add-­‐on strategy to treat GORD in the future.

Clinical measurement of gastrointestinal motility and function: who, when and which test?

Symptoms related to abnormal gastrointestinal motility and function are common. Oropharyngeal and oesophageal dysphagia, heartburn, bloating, abdominal pain and alterations in bowel habits are among the most frequent reasons for seeking medical attention from internists or general practitioners and are also common reasons for referral to gastroenterologists and colorectal surgeons. However, the nonspecific nature of gastrointestinal symptoms, the absence of a definitive diagnosis on routine investigations (such as endoscopy, radiology or blood tests) and the lack of specific treatments make disease management challenging. Advances in technology have driven progress in the understanding of many of these conditions. This Review serves as an introduction to a series of Consensus Statements on the clinical measurements of gastrointestinal motility, function and sensitivity. A structured, evidence-based approach to the initial assessment and empirical treatment of patients presenting with gastrointestinal symptoms is discussed, followed by an outline of the contribution of modern physiological measurement on the management of patients in whom the cause of symptoms has not been identified with other tests. Discussions include the indications for and utility of high-resolution manometry, ambulatory pH-impedance monitoring, gastric emptying studies, breath tests and investigations of anorectal structure and function in day-to-day practice and clinical management

Clinical approach to gastro-oesophageal reflux in idiopathic pulmonary fibrosis

MDIdiopathic pulmonary fibrosis is a progressive condition with limited treatment options and median survival of 3-5 years. Gastro-oesophageal reflux (GOR) has been described in up to 90% of patients. Pulmonary aspiration has been suggested to contribute to IPF, with calls for aggressive antireflux therapy. Whilst medical therapy can usually control acid reflux, surgery may be required to control non-acid refluxate, which may also be harmful if aspirated into the lung. The risks of surgery in the IPF population are significant. There is no validated technique with which to measure aspiration in this group and furthermore, patient attitudes towards the treatment of reflux and aspiration in IPF are unknown. As a result, the population that might benefit from antireflux therapy has yet to be defined. The current study comprised two main aims. The first was to characterise reflux and aspiration in an IPF cohort. The second was to evaluate patient attitudes towards the burden of IPF disease as compared to the burden of antireflux therapy. Methods Symptoms of reflux and lung health were assessed using a panel of structured questionnaires. Oesophageal function and gastro-oesophageal reflux were objectively assessed using manometry and pH-impedance monitoring. A standardised bronchoscopy and bronchoalveolar lavage, with biochemical and cytological analysis, was used to assess pulmonary aspiration. A separate group of individuals with IPF participated in an interview study. Respondents’ own health was evaluated using a visual analogue scale, the EuroQOL-5D -3L survey and a standard gamble utility analysis. Vignettes were constructed to describe mild- and moderate-severity IPF health states and adverse outcomes from medical and surgical antireflux therapy. Patient attitudes towards these four health states were assessed with a ranking exercise and a series of standard gambles. Results pH-impedance monitoring demonstrated supranormal levels of gastro-oesophageal reflux in 22 of 36 study subjects (61%). Eleven subjects had pre-existing evidence of gastro- ii oesophageal reflux and questionnaire assessment suggested GORD in 29% of subjects. Oesophageal manometry identified abnormal oesophageal function in 56%. Supranormal levels of pepsin were detected in bronchoalveolar lavage fluid in 16 subjects. The combination of pepsin quantification and oesophageal monitoring identified a subgroup of subjects with evidence of reflux and aspiration, but there was no correlation between levels of reflux and pepsin concentrations. Cytological staining results correlated poorly with gastro-oesophageal reflux. After formal multidisciplinary review, two patients who participated in the current study have undergone fundoplication. Both have enjoyed a stable disease course since surgery. In the interview study, respondents recorded mean utilities of 0.611 to 0.798 for their own health. Amongst 59 respondents, 38 regarded both IPF health states as preferable to the outcomes of either antireflux therapy outcome; the remainder disagreed. An adverse outcome from antireflux surgery was generally regarded as the worst of the health states. Discussion Oesophageal physiology and BAL fluid analysis may be combined to investigate reflux and aspiration in IPF. The current data suggest that reflux is common and frequently asymptomatic. Aspiration may only be significant in the minority of patients. Oesophageal dysmotility, a relative contra-indication to fundoplication, was evident in the majority of subjects. This is the first report of health state utilities for IPF and demonstrates a disease burden comparable to advanced lung cancer. Opinion was divided as to the relative burden associated with IPF disease and the potential outcomes of antireflux therapy. In conclusion, it remains difficult to identify the IPF patients for whom antireflux surgery might be most beneficial. For a proportion, the risks of such treatment will be prohibitive. The complexity of surgical decisions in this group suggests a requirement for a standard of care that includes a multidisciplinary team, informed by objective aerodigestive physiology and imaging.Knowledge Transfer Partnership in collaboration with Innovate UK. Funding originated largely from the Northern Oesophagogastric Unit, with additional support from the Medical Research Counci