Publications by authors named "Albert J Bredenoord"

162 Publications

The tapestry of reflux syndromes: translating new insight into clinical practice.

Br J Gen Pract 2021 Oct 30;71(711):470-473. Epub 2021 Sep 30.

Primary Care and General Practice, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.3399/bjgp21X717329DOI Listing
October 2021

Systematic Review of Outcome Measures Used in Observational Studies of Adults with Eosinophilic Esophagitis.

Int Arch Allergy Immunol 2021 Sep 20:1-25. Epub 2021 Sep 20.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background: Over the last 20 years, diverse outcome measures have been used to evaluate the effectiveness of therapies for eosinophilic esophagitis (EoE). This systematic review aims to identify the readouts used in observational studies of topical corticosteroids, diet, and dilation in adult EoE patients.

Methods: We searched MEDLINE and Embase for prospective and retrospective studies (cohorts/case series, randomized open-label, and case-control) evaluating the use of diets, dilation, and topical corticosteroids in adults with EoE. Two authors independently assessed the articles and extracted information about histologic, endoscopic, and patient-reported outcomes and tools used to assess treatment effects.

Results: We included 69 studies that met inclusion criteria. EoE-associated endoscopic findings (assessed either as absence/presence or using Endoscopic Reference Score) were evaluated in 24/35, 11/17, and 9/17 studies of topical corticosteroids, diet, and dilation, respectively. Esophageal eosinophil density was recorded in 32/35, 17/17, and 11/17 studies of topical corticosteroids, diet, and dilation, respectively. Patient-reported outcomes were not uniformly used (only in 14, 8, and 3 studies of topical corticosteroids, diet, and dilation, respectively), and most tools were not validated for use in adults with EoE.

Conclusions: Despite the lack of an agreed set of core outcomes that should be recorded and reported in studies in adult EoE patients, endoscopic EoE-associated findings and esophageal eosinophil density are commonly used to assess disease activity in observational studies. Standardization of outcomes and data supporting the use of outcomes are needed to facilitate interpretation of evidence, its synthesis, and comparisons of interventions in meta-analyses of therapeutic trials in adults with EoE.
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http://dx.doi.org/10.1159/000516898DOI Listing
September 2021

Letter: is wireless oesophageal pH monitoring the best technique to evaluate night-time reflux? Authors' reply.

Aliment Pharmacol Ther 2021 10;54(7):976

Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, University Medical Centers Amsterdam, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/apt.16586DOI Listing
October 2021

Butyrate and propionate restore interleukin 13-compromised esophageal epithelial barrier function.

Allergy 2021 Aug 30. Epub 2021 Aug 30.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

Background: Eosinophilic esophagitis (EoE) is a food allergen driven disease that is accompanied by interleukin (IL) 13 overexpression and esophageal barrier dysfunction allowing transepithelial food allergen permeation. Nutraceuticals, such as short-chain fatty acids (SCFAs) that restore barrier function and increase immune fitness may be a promising tool in the management of EoE. Here, we investigated the effects of the SCFAs acetate, propionate, and butyrate on an IL-13-compromised human esophageal epithelial barrier, including the mechanisms involved.

Methods: An air-liquid interface culture model of differentiated human EPC2-hTERT (EPC2) was used to study whether SCFAs could restore barrier function after IL-13-induced impairment. Esophageal epithelial barrier function was monitored by transepithelial electrical resistance (TEER) and FITC-dextran paracellular flux, and was further examined by qPCR and immunohistochemical analysis. G protein-coupled receptor (GPR) GPR41, GPR43, GPR109a, or histone deacetylase (HDAC) (ant)agonists were used to assess mechanisms of action of SCFAs.

Results: IL-13 stimulation decreased TEER and increased FITC flux, which was counteracted by butyrate and propionate, but not acetate treatment. Barrier proteins FLG and DSG1 mRNA expression was upregulated following butyrate and propionate treatment, whereas expression of eosinophil chemoattractant CCL26 and protease CAPN14 was downregulated. Similarly, butyrate and propionate restored FLG and DSG1 protein expression. Similar effects were observed with an HDAC antagonist but not with GPR agonists.

Conclusion: Nutraceuticals butyrate and propionate restore the barrier function of esophageal epithelial cells after an inflammatory insult and may be of therapeutic benefit in the management of EoE.
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http://dx.doi.org/10.1111/all.15069DOI Listing
August 2021

The inability to belch syndrome: A study using concurrent high-resolution manometry and impedance monitoring.

Neurogastroenterol Motil 2021 Aug 26:e14250. Epub 2021 Aug 26.

Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, University Medical Centers Amsterdam, Amsterdam, the Netherlands.

Introduction: Although inability to belch has previously been linked to dysfunction of the upper esophageal sphincter (UES), its underlying pathogenesis remains unclear. Our aim was to study mechanisms underlying inability to belch and the effect of UES botulinum toxin (botox) injections in these patients.

Methods: We prospectively enrolled consecutive patients with symptoms of inability to belch. Patients underwent stationary high-resolution impedance manometry (HRIM) with belch provocation and ambulatory 24-h pH-impedance monitoring before and 3 months after UES botox injection.

Results: Eight patients (four males, age 18-37 years) were included. Complete and normal UES relaxation occurred in response to deglutition in all patients. A median number of 33(15-64) gastroesophageal gas reflux episodes were observed. Despite the subsequent increase in esophageal pressure (from -4.0 [-7.7-4.2] to 8 [3.3-16.1] mmHg; p < 0.012), none of the gastroesophageal gas reflux events resulted in UES relaxation. Periods of continuous high impedance levels, indicating air entrapment (median air presence time 10.5% [0-43]), were observed during 24-h impedance monitoring. UES botox reduced UES basal pressure (from 95.7[41.2-154.0] to 29.2 [16.7-45.6] mmHg; p < 0.02) and restored belching capacity in all patients. As a result, esophageal air presence time decreased from 10.5% (0-43.4) to 0.7% (0.1-18.6; p < 0.02) and esophageal symptoms improved in all patients (VAS 6.0 [1.0-7.9] to 1.0 [0.0-2.5]; p < 0.012).

Conclusion: The results of this study underpin the existence of a syndrome characterized by an inability to belch and support the hypothesis that ineffective UES relaxation, with subsequent esophageal air entrapment, may lead to esophageal symptoms.
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http://dx.doi.org/10.1111/nmo.14250DOI Listing
August 2021

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

J Allergy Clin Immunol 2021 Jul 6. Epub 2021 Jul 6.

Inform Diagnostics, Irving, Tex; Department of Pathology, Baylor College of Medicine, Houston, Tex.

Background: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments.

Objective: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE.

Methods: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists.

Results: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life.

Conclusions: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.001DOI Listing
July 2021

Esophagogastric junction outflow obstruction.

Neurogastroenterol Motil 2021 09 12;33(9):e14193. Epub 2021 Jun 12.

Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, Metrohealth Medical System, Case Western Reserve University, Cleveland, OH, USA.

In the Chicago Classification version 4.0 (CCv4), esophagogastric junction outflow obstruction (EGJOO) is manometrically defined as an elevated median integrated relaxation pressure (IRP) and elevated intrabolus pressure (IBP) during supine wet swallows, and persistently elevated median IRP in the upright position. A clinically relevant conclusive diagnosis of EGJOO requires a manometric diagnosis of EGJOO and associated symptoms such as dysphagia and/or chest pain with at least one of the following supportive investigations (pharmacologic provocation, timed barium esophagogram, and/or endoflip). The Chicago Classification is intended for diagnosis of primary esophageal motor disorders, and thus history and endoscopic evaluation are important to exclude conditions (eg, previous surgery, strictures, or masses) that can secondarily generate the EGJOO pattern on HRM. While a manometric finding of EGJOO is often made and can be an early sign of achalasia, more often it is a manometric finding without clinical implications. The proposed changes in CC4.0 have attempted to make the diagnosis more specific, in order to reduce the number of clinically irrelevant diagnoses and avoid confusion by patients and physicians alike.
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http://dx.doi.org/10.1111/nmo.14193DOI Listing
September 2021

Characterisation of patients with supine nighttime reflux: observations made with prolonged wireless oesophageal pH monitoring.

Aliment Pharmacol Ther 2021 07 11;54(2):144-152. Epub 2021 Jun 11.

Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, University Medical Centers Amsterdam, Amsterdam, the Netherlands.

Background: Although nighttime reflux symptoms are common, the presence of nocturnal reflux is seldom confirmed with a standard 24 hours pH study.

Aim: To study patients with supine nighttime reflux symptoms using prolonged wireless pH monitoring.

Methods: In this retrospective study, patients with typical acid reflux symptoms were studied using 96-h pH monitoring. Patients with nighttime reflux symptoms were compared to those without. Night-to-night variability and diagnostic accuracy of 24-, 48- and 72-hours pH studies compared to the 96-hours "gold standard" were evaluated.

Results: Of the 105 included patients (61.9% females; mean age 46.8 ± 14.4 years), 86 (81.9%) reported nighttime reflux symptoms, of which 67.4% had pathological supine nocturnal acid exposure in at least one night. There was high variance in night-to-night acid exposure (94% [IQR0-144]), which was larger than the variance in upright acid exposure (58% [IQR32-88]; P < 0.001). When analysing the first 24 hours of the pH study, 32% of patients were diagnosed with pathological supine nighttime acid exposure versus 51% of patients based upon the 96-hours pH-test. The diagnostic accuracy and yield improved with study duration (P < 0.001). Reflux episodes with a lower nadir pH or longer acid clearance time were more prone to provoke nightly symptoms.

Conclusions: The majority of patients with nocturnal reflux symptoms had pathological acid exposure in at least one night of the prolonged pH recording. A high night-to-night variability in acid exposure reduces the clinical value and diagnostic yield of pH monitoring limited to 24 hours. Prolonged testing is a more appropriate diagnostic tool for patients with nocturnal reflux symptoms.
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http://dx.doi.org/10.1111/apt.16447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362009PMC
July 2021

Utility of Routine Esophageal Biopsies in Patients With Refractory Reflux Symptoms.

Am J Gastroenterol 2021 04;116(4):816-820

1Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, University Medical Centers Amsterdam, Amsterdam, the Netherlands; 2Department of Gastroenterology and Hepatology, Catharina Hospital Eindhoven, Eindhoven, the Netherlands.

Introduction: This study aimed to assess the diagnostic yield of routine esophageal biopsies in patients with refractory reflux symptoms.

Methods: We prospectively enrolled consecutive patients referred for upper endoscopy and collected histological, clinical, and endoscopic data.

Results: Of the 301 included patients, 14 (4.7%) patients met the clinicopathological diagnostic definition of eosinophilic esophagitis. Presence of dysphagia, food bolus impaction, atopic background, and typical endoscopic features were the factors with the strongest association and diagnostic accuracy for eosinophilic esophagitis. The diagnostic yield in patients lacking symptoms of dysphagia or endoscopic features was negligible (0% and 1.9%, respectively).

Discussion: Routine esophageal biopsy sampling in patients with refractory reflux symptoms has a low diagnostic yield. Esophageal biopsies should only be obtained in patients with refractory reflux symptoms who also present with dysphagia (see Visual abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B792).
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http://dx.doi.org/10.14309/ajg.0000000000001064DOI Listing
April 2021

Long-term outcomes of treatments for achalasia.

Curr Opin Gastroenterol 2021 07;37(4):408-413

Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Purpose Of Review: Idiopathic achalasia is a primary motility disorder of the esophagus that results in dysphagia, weight loss, and impaired quality of life. Several treatment options are available to gastroenterologists, and insights on the long-term outcome of these modalities are discussed.

Recent Findings: Peroral endoscopic myotomy (POEM) represents a novel endoscopic technique in the treatment of achalasia. Studies on long-term outcomes and comparison to other well-known treatment modalities such as laparoscopic Heller myotomy (LHM) and pneumodilation have recently been published. POEM and LHM both have excellent 2-year success rates for relieving achalasia symptoms, but reflux disease and erosive esophagitis are more prevalent following POEM.

Summary: Several treatment modalities with excellent long-term outcomes are available for the treatment of achalasia. The different options should be discussed with patients and treatments should be tailored to their individual needs.
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http://dx.doi.org/10.1097/MOG.0000000000000744DOI Listing
July 2021

Utility of gastric and duodenal biopsy sampling in adult eosinophilic esophagitis patients to rule out other gastrointestinal disorders.

Scand J Gastroenterol 2021 May 9;56(5):613-620. Epub 2021 Apr 9.

Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Rationale: According to consensus guidelines, if eosinophilic esophagitis (EoE) is suspected, not only esophageal but also gastric and duodenal biopsy specimens should be sampled in order to exclude other generalized or eosinophilic gastrointestinal (GI) disorders, such as eosinophilic gastroenteritis or celiac disease. However, the diagnostic yield for this remains unclear.

Aim: To assess the diagnostic yield of biopsy sampling from the stomach and duodenum in adult EoE patients to rule out generalized or eosinophilic GI disorders.

Methods: A retrospective chart-review was conducted in untreated adult EoE patients that underwent upper endoscopy with biopsies sampled from the esophagus, stomach and duodenum. Standardized (electronic) case-report forms were used to extract clinical, endoscopic and histologic data.

Results: In total, 93 adults (71% males, age 36.4 (interquartile range 28.4 - 49.1) years) with untreated EoE (≥15 eosinophils/high-power-field) were included. Symptoms of dysphagia and food impaction were reported in 93% and 58%, respectively of the patients. Typical endoscopic EoE-features were present in 77 (85%) patients. The yield of routinely sampled gastric and duodenal biopsy specimens in our cohort was 3.6% (95% confidence interval: 2.6-4.8%) (n/ = 1/93) for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or gastritis. In total, 62 (67%) patients presented with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions. The diagnostic yield for a relevant generalized or eosinophilic GI disorder in this subgroup was, 4.8% (95%CI 3.4 - 6.7%) (n/ = 1/62).

Conclusion: Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.KEY POINTSEvidence is lacking on the diagnostic value of additional biopsies sampled form the stomach and duodenum to rule out other relevant generalized or eosinophilic gastrointestinal (GI) disorders.The yield of gastric and duodenal biopsies routinely sampled in our cohort was 3.6% for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or gastritis.The diagnostic yield for a relevant generalized or eosinophilic GI disorder in the subgroup of patients (67%) presenting with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions was, 4.8%.Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.
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http://dx.doi.org/10.1080/00365521.2021.1902559DOI Listing
May 2021

Development of quality indicators for the diagnosis and management of achalasia.

Neurogastroenterol Motil 2021 Oct 15;33(10):e14118. Epub 2021 Mar 15.

Division of Gastroenterology, Duke University School of Medicine, Durham, North Carolina, USA.

Background: The management of achalasia has improved due to diagnostic and therapeutic innovations. However, variability in care delivery remains and no established measures defining quality of care for this population exist. We aimed to use formal methodology to establish quality indicators for achalasia patients.

Methods: Quality indicator concepts were identified from the literature, consensus guidelines and clinical experts. Using RAND/University of California, Los Angeles (UCLA) Appropriateness Method, experts in achalasia independently ranked proposed concepts in a two-round modified Delphi process based on 1) importance, 2) scientific acceptability, 3) usability, and 4) feasibility. Highly valid measures required strict agreement (≧ 80% of panelists) in the range of 7-9 for across all four categories.

Key Results: There were 17 experts who rated 26 proposed quality indicator topics. In round one, 2 (8%) quality measures were rated valid. In round two, 19 measures were modified based on panel suggestions, and experts rated 10 (53%) of these measures as valid, resulting in a total of 12 quality indicators. Two measures pertained to patient education and five to diagnosis, including discussing treatment options with risk and benefits and using the most recent version of the Chicago Classification to define achalasia phenotypes, respectively. Other indicators pertained to treatment options, such as the use of botulinum toxin for those not considered surgical candidates and management of reflux following achalasia treatment.

Conclusions & Inferences: Using a robust methodology, achalasia quality indicators were identified, which can form the basis for establishing quality gaps and generating fully specified quality measures.
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http://dx.doi.org/10.1111/nmo.14118DOI Listing
October 2021

Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies.

Annu Rev Immunol 2021 04 1;39:719-757. Epub 2021 Mar 1.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA; email:

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.
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http://dx.doi.org/10.1146/annurev-immunol-093019-125918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317994PMC
April 2021

Pneumatic dilation for persistent dysphagia after antireflux surgery, a multicentre single-blind randomised sham-controlled clinical trial.

Gut 2021 Jan 15. Epub 2021 Jan 15.

Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC Location AMC, Amsterdam, The Netherlands.

Objective: There is no evidence-based treatment for persistent dysphagia after laparoscopic fundoplication. The aim of this study was to evaluate the effect of pneumatic dilation on persistent dysphagia after laparoscopic fundoplication.

Design: We performed a multicentre, single-blind, randomised sham-controlled trial of patients with persistent dysphagia (>3 months) after laparoscopic fundoplication. Patients with an Eckardt symptom score ≥4 were randomly assigned to pneumatic dilation (PD) using a 35 mm balloon or sham dilation. Primary outcome was treatment success, defined as an Eckardt score <4 and a minimal reduction of 2 points in the Eckardt score after 30 days. Secondary outcomes included change in stasis on timed barium oesophagogram, change in high-resolution manometry parameters and questionnaires on quality of life, reflux and dysphagia symptoms.

Results: Forty-two patients were randomised. In the intention-to-treat analysis, the success rates of PD (7/21 patients (33%)) and sham dilation (8/21 patients (38%)) were similar after 30 days (risk difference -4.7% (95% CI (-33.7% to 24.2%) p=0.747). There was no significant difference in change of stasis on the timed barium oesophagogram after 2 min (PD vs sham: median 0.0 cm, p25-p75 range 0.0-4.3 cm vs median 0.0 cm, p25-p75 range 0.0-0.0; p=0.122) or change in lower oesophageal sphincter relaxation pressure (PD vs sham: 10.54±6.25 vs 14.60±6.17 mm Hg; p=0.052). Quality of life, reflux and dysphagia symptoms were not significantly different between the two groups.

Conclusion: Pneumatic dilation with a 35 mm balloon is not superior to sham dilation for the treatment of persistent dysphagia after fundoplication.
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http://dx.doi.org/10.1136/gutjnl-2020-322355DOI Listing
January 2021

The Habitual Diet of Dutch Adult Patients with Eosinophilic Esophagitis Has Pro-Inflammatory Properties and Low Diet Quality Scores.

Nutrients 2021 Jan 13;13(1). Epub 2021 Jan 13.

Department of Pediatrics, OLVG Hospital, 1091 AC Amsterdam, The Netherlands.

We determined the nutritional adequacy and overall quality of the diets of adult patients with eosinophilic esophagitis (EoE). Dietary intakes stratified by sex and age were compared to Dietary Reference Values (DRV). Overall diet quality was assessed by two independent Diet-Quality-Indices scores, the PANDiet and DHD-index, and compared to age- and gender-matched subjects from the general population. Lastly, food and nutrient intakes of EoE patients were compared to intakes of the general population. Saturated fat intake was significantly higher and dietary fiber intake significantly lower than the DRV in both males and females. In males, the DRV were not reached for potassium, magnesium, selenium, and vitamins A and D. In females, the DRV were not reached for iron, sodium, potassium, selenium, and vitamins A, B2, C and D. EoE patients had a significantly lower PANDiet and DHD-index compared to the general population, although the relative intake (per 1000 kcal) of vegetables/fruits/olives was significantly higher (yet still up to 65% below the recommended daily amounts) and alcohol intake was significantly lower compared to the general Dutch population. In conclusion, the composition of the habitual diet of adult EoE patients has several pro-inflammatory and thus unfavorable immunomodulatory properties, just as the general Dutch population, and EoE patients had lower overall diet quality scores than the general population. Due to the observational character of this study, further research is needed to explore whether this contributes to the development and progression of EoE.
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http://dx.doi.org/10.3390/nu13010214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828600PMC
January 2021

Emerging incidence trends of eosinophilic esophagitis over 25 years: Results of a nationwide register-based pathology cohort.

Neurogastroenterol Motil 2021 07 10;33(7):e14072. Epub 2021 Jan 10.

Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Rationale: Eosinophilic esophagitis (EoE) has emerged from a case-reportable illness in the early 1990s to a distinct clinicopathological entity. Increasing worldwide incidences have been observed, although due to various study designs estimates are inconsistent.

Aim: To determine population-based annual incidence rates over a time period of 25 years.

Methods: A nationwide register-based pathology (PALGA) search was performed to identify reports describing esophageal eosinophilia between 1995 and 2019. EoE was identified if the diagnosis was confirmed by the pathologist. Crude incidence rates were estimated by the number of new EoE cases per year and matched with population data.

Results: Between 1995 and 2019, 7361 unique patients' reports mentioned esophageal eosinophilia, of these 4061 were classified as EoE (71% male, mean age 37.9 ± 18.4 years). In total, 639 (16%) children (<18 years) were diagnosed. The EoE incidence increased from 0.01 in 1995 (95% CI: 0.0 - 0.04) to 3.16 (95% CI: 2.90 - 3.44) per 100.000 inhabitants in 2019. EoE was significantly more prevalent in males (OR 2.48 | 95% CI: 2.32 - 2.65; vs. females p < 0.001) and adults (OR 1.42 | 95% CI: 1.31 - 1.55; vs. children p < 0.001). Highest incidences were observed in 2019, being 4.37 (95% CI: 3.94 - 4.84) vs. 1.97 (95% CI: 1.68 - 2.29) per 100.000 males and females, respectively (p < 0.001). No seasonal variation was observed.

Conclusion: Over the past quarter century, the annual rates of newly diagnosed EoE patients raised dramatically and this increase has not reached a deceleration yet.
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http://dx.doi.org/10.1111/nmo.14072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365671PMC
July 2021

Mental distress among adult patients with eosinophilic esophagitis.

Neurogastroenterol Motil 2021 07 31;33(7):e14069. Epub 2020 Dec 31.

Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Rationale: Data on the prevalence of mental distress among adult eosinophilic esophagitis (EoE) patients are scarce. Also, a significant gap remains in the understanding of which determinants are related to significant psychological symptoms and whether distressed patients require and receive mental care.

Methods: Adult EoE patients were invited to complete standardized measures on anxiety/depressive symptoms (HADS) and general psychopathology (SCL-90-R). All scores were compared to general population norms. Socio-demographic and clinical factors were assessed.

Results: In total, 147 adult EoE patients (61% males, age 43 (IQR 29-52) years were included (response rate 71%). No difference with general population values was found for total anxiety and depressive symptoms (7.8 ± 6.6 vs. 8.4 ± 6.3; p = 0.31). A total of 38/147(26%) patients reported high levels of anxiety and/or depressive symptoms (HADS-A ≥ 8: 35/147(24%) and HADS-D ≥ 8: 14/147(10%)), indicative of a possible psychiatric disorder. In a multivariate analysis, age between 18-35 years was independently associated with high levels of anxiety (HADS-A ≥ 8) (OR 3.0, 95% CI 1.3-6.9; p = 0.01). The SCL-90-R Global Severity Index (GSI) was significantly higher compared to the general population (p < 0.001). Significant signs of general mental distress (GSI ≥ 80th percentile) were observed in 51(36%) EoE patients, of which 29(57%) patients denied having any mental problems and only 8(16%) patients received mental care.

Conclusion: A considerable proportion of adult EoE patients suffers from mental distress, with a 3-fold risk of significant anxiety in those patients younger than 35 years. Therefore, population-based studies are required and a proactive approach in the screening for and treatment of these psychological symptoms in EoE practice seems essential.
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http://dx.doi.org/10.1111/nmo.14069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365712PMC
July 2021

Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0.

Neurogastroenterol Motil 2021 01;33(1):e14058

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.
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http://dx.doi.org/10.1111/nmo.14058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034247PMC
January 2021

Fasted and fed small bowel motility patterns at cine-MRI in chronic intestinal pseudo-obstruction.

Neurogastroenterol Motil 2021 06 27;33(6):e14062. Epub 2020 Dec 27.

Department of Radiology and Nuclear Medicine, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Chronic intestinal pseudo-obstruction (CIPO) is a severe intestinal motility disorder of which the pathophysiology is largely unknown. This study aimed at gaining insight in fasted and fed small bowel motility in CIPO patients using cine-MRI with caloric stimulation.

Methods: Eight adult patients with manometrically confirmed CIPO were prospectively included. Patients underwent a cine-MRI protocol after an overnight fast, comprising fasting-state scans and scans after ingestion of a meal (Nutridrink, 300 kcal). Small bowel motility was quantified resulting in a motility score in arbitrary units (AU) and visually assessed by three radiologists. Findings were compared with those in 16 healthy volunteers.

Key Results: Motility scores (median, IQR) in CIPO patients were 0.21 (0.15-0.30) in the fasting state and 0.23 (0.15-0.27) directly postprandially. In healthy volunteers, corresponding motility scores were 0.15 (0.13-0.18) and 0.22 (0.19-0.25), respectively. The postprandial change in motility score was +1% (-19 to +21%) in CIPO and +39% (+23 to +50%) in healthy volunteers (p = 0.001*). Visual analysis revealed increased small bowel contractility in four, normal in two, and decreased in two CIPO patients.

Conclusions & Inferences: Surprisingly, we found hyperactive small bowel motility in half of the CIPO patients, suggestive of uncoordinated motility. A wide variation in motility patterns was observed, both higher, lower, and comparable contractility compared with healthy subjects. No clear postprandial activation was seen in patients. Cine-MRI helps to gain insight in this complex disease and can potentially impact treatment decisions in the future.
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http://dx.doi.org/10.1111/nmo.14062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244096PMC
June 2021

ESNM/ANMS consensus paper: Diagnosis and management of refractory gastro-esophageal reflux disease.

Neurogastroenterol Motil 2021 04 28;33(4):e14075. Epub 2020 Dec 28.

Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA.

Up to 40% of patients with symptoms suspicious of gastroesophageal reflux disease (GERD) do not respond completely to proton pump inhibitor (PPI) therapy. The term "refractory GERD" has been used loosely in the literature. A distinction should be made between refractory symptoms (ie, symptoms may or may not be GERD-related), refractory GERD symptoms (ie, persisting symptoms in patients with proven GERD, regardless of relationship to ongoing reflux), and refractory GERD (ie, objective evidence of GERD despite adequate medical management). The present ESNM/ANMS consensus paper proposes use the term "refractory GERD symptoms" only in patients with persisting symptoms and previously proven GERD by either endoscopy or esophageal pH monitoring. Even in this context, symptoms may or may not be reflux related. Objective evaluation, including endoscopy and esophageal physiologic testing, is requisite to provide insights into mechanisms of symptom generation and evidence of true refractory GERD. Some patients may have true ongoing refractory acid or weakly acidic reflux despite PPIs, while others have no evidence of ongoing reflux, and yet others have functional esophageal disorders (overlapping with proven GERD confirmed off therapy). In this context, attention should also be paid to supragastric belching and rumination syndrome, which may be important contributors to refractory symptoms.
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http://dx.doi.org/10.1111/nmo.14075DOI Listing
April 2021

What is new in Chicago Classification version 4.0?

Neurogastroenterol Motil 2021 01 19;33(1):e14053. Epub 2020 Dec 19.

Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Since publication of Chicago Classification version 3.0 in 2015, the clinical and research applications of high-resolution manometry (HRM) have expanded. In order to update the Chicago Classification, an International HRM Working Group consisting of 52 diverse experts worked for two years and utilized formally validated methodologies. Compared with the prior iteration, there are four key modifications in Chicago Classification version 4.0 (CCv4.0). First, further manometric and non-manometric evaluation is required to arrive at a conclusive, actionable diagnosis of esophagogastric junction (EGJ) outflow obstruction (EGJOO). Second, EGJOO, distal esophageal spasm, and hypercontractile esophagus are three manometric patterns that must be accompanied by obstructive esophageal symptoms of dysphagia and/or non-cardiac chest pain to be considered clinically relevant. Third, the standardized manometric protocol should ideally include supine and upright positions as well as additional manometric maneuvers such as the multiple rapid swallows and rapid drink challenge. Solid test swallows, postprandial testing, and pharmacologic provocation can also be considered for particular conditions. Finally, the definition of ineffective esophageal motility is more stringent and now encompasses fragmented peristalsis. Hence, CCv4.0 no longer distinguishes between major versus minor motility disorders but simply separates disorders of EGJ outflow from disorders of peristalsis.
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http://dx.doi.org/10.1111/nmo.14053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098672PMC
January 2021

Reply.

Clin Gastroenterol Hepatol 2021 09 26;19(9):1988-1989. Epub 2020 Nov 26.

Amsterdam UMC, University of Amsterdam Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands.

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http://dx.doi.org/10.1016/j.cgh.2020.10.030DOI Listing
September 2021

Use of the Functional Lumen Imaging Probe in Clinical Esophagology.

Am J Gastroenterol 2020 11;115(11):1786-1796

Washington University, St. Louis, St. Louis, Missouri, USA.

The functional lumen imaging probe (FLIP) measures luminal dimensions using impedance planimetry, performed most often during sedated upper endoscopy. Mechanical properties of the esophageal wall and opening dynamics of the esophagogastric junction (EGJ) can be objectively evaluated in esophageal motor disorders, eosinophilic esophagitis, esophageal strictures, during esophageal surgery and in postsurgical symptomatic states. Distensibility index, the ratio of EGJ cross sectional area to intraballoon pressure, is the most useful FLIP metric. Secondary peristalsis from balloon distension can be displayed topographically as repetitive anterograde or retrograde contractile activity in the esophageal body, similar to high-resolution manometry. Real-time interpretation and postprocessing of FLIP metadata can complement the identification of esophageal outflow obstruction and achalasia, especially when findings are inconclusive from alternate esophageal tests in symptomatic patients. FLIP can complement the diagnosis of achalasia when manometry and barium studies are inconclusive or negative in patients with typical symptoms. FLIP can direct adequacy of disruption of the EGJ in achalasia when used during and immediately after myotomy and pneumatic dilation. Lumen diameter measured using FLIP in eosinophilic esophagitis and in complex strictures can potentially guide management. An abbreviated modification of the Grading of Recommendations Assessment, Development, and Evaluation was used to determine the quality of available evidence and recommendations regarding FLIP utilization. FLIP metrics that are diagnostic or suggestive of an abnormal motor pattern and metrics that define normal esophageal physiology were developed by consensus and are described in this review.
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http://dx.doi.org/10.14309/ajg.0000000000000773DOI Listing
November 2020

Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world.

Gut 2020 Oct 9. Epub 2020 Oct 9.

Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.

Objective: Limitations of existing impedance-pH thresholds include small sample size of normative studies, inclusion of artefactual pH drops and incorrect identification of impedance reflux events. We aimed to obtain new impedance-pH thresholds from expert consensus analysis of tracings from a large number of healthy subjects.

Design: Of 541 studies performed worldwide using two different systems (Diversatek, USA, and Laborie, Netherlands), 150 tracings with oesophageal diagnoses, behavioural disorders and study-related artefacts were excluded. The remainder studies were subject to two reviewer consensus analysis, in-person or through video conference, consisting of editing meals and pH drops, identification of impedance reflux and postreflux swallow-induced peristaltic wave (PSPW) using strict pre-established criteria and measurement of distal mean nocturnal baseline impedance (MNBI).

Results: Consensus analysis was performed in 391 tracings (age 32.7 years, range 18-71, 54.2% female). Normative thresholds were significantly different between Diversatek and Laborie (total acid exposure time: 2.8% and 5%; reflux episodes: 55 and 78; MNBI at 3 cm: 1400 and 1500 ohms, at 5 cm: 1400 and 1800 ohms). Males had higher acid exposure, more reflux episodes and lower MNBI. Significant regional differences were identified, including higher PSPW scores in Western countries, and higher MNBI in Asia using Diversatek, and higher acid exposure in the Netherlands, higher MNBI in Asia and South Africa, and lower MNBI in Turkey using Laborie.

Conclusion: Normal impedance-pH monitoring thresholds have regional and system-related differences. Clinical interpretation needs to use normal thresholds valid for the system used and world region, following careful editing of the tracings.
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http://dx.doi.org/10.1136/gutjnl-2020-322627DOI Listing
October 2020

Investigator initiated research in times of COVID-19: Let's go digital!

Neurogastroenterol Motil 2020 11 6;32(11):e14011. Epub 2020 Oct 6.

Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/nmo.14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646011PMC
November 2020

Non-surgical treatment of esophageal perforation after pneumatic dilation for achalasia: a case series.

Scand J Gastroenterol 2020 Oct 13;55(10):1248-1252. Epub 2020 Sep 13.

Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Esophageal perforation is the most serious complication of pneumatic dilation for achalasia and is traditionally managed by conservative therapy or surgical repair. We present four achalasia patients who underwent pneumatic dilatation, complicated by an esophageal perforation. All patients were treated successfully with endoscopic treatment: two patients with Eso-SPONGE vacuum therapy, in the other two patients, esophageal defects were closed endoscopically using Endoclips. The time between dilatation and detection of the perforation was less than 24 h in all cases. Non-surgical treatment resulted in a relatively short hospital stay, ranging from 5 to 10 days, and an uneventful recovery in all patients. Based on our experience, endoscopic clipping and/or vacuum therapy are relatively new, valuable, minimally invasive techniques in the management of patients with small, well-defined esophageal tears with contained leakage and should be considered as primary therapeutic option for iatrogenic perforation in achalasia.
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http://dx.doi.org/10.1080/00365521.2020.1817541DOI Listing
October 2020

The natural course of giant paraesophageal hernia and long-term outcomes following conservative management.

United European Gastroenterol J 2020 12 24;8(10):1163-1173. Epub 2020 Aug 24.

Amsterdam UMC, University of Amsterdam, Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands.

Background: Accurate information on the natural course of giant paraesophageal hernia is scarce, challenging therapeutic decisions whether or not to operate.

Objective: We aimed to investigate the long-term outcomes, including hernia-related deaths and complications (e.g. volvulus, gastrointestinal bleeding, strangulation) of patients with giant paraesophageal hernia that were conservatively managed, and to determine factors associated with clinical outcome.

Methods: We retrospectively analysed charts of patients diagnosed with giant paraesophageal hernia between January 1990 and August 2019, collected from a university hospital in The Netherlands. Included patients were subdivided into three groups based on primary therapeutic decision at diagnosis. Radiological, clinical and surgical characteristics, along with long-term outcomes at most recent follow-up, were collected.

Results: We included 293 patients (91 men, mean age 70.3 ± 12.4 years) with a mean duration of follow-up of 64.0 ± 58.8 months. Of the 186 patients that were conservatively treated, a total hernia-related mortality of 1.6% was observed. Hernia-related complications, varying from uncomplicated volvulus to strangulation, occurred in 8.1% of patients. Only 1.1% of patients included in this study required emergency surgery. Logistic regression analysis revealed the presence of symptoms (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.8-20.6), in particular obstructive symptoms (vomiting, OR 15.7, 95% CI 4.6-53.6; epigastric pain, OR 4.4, 95% CI 1.2-15.8 and chest pain, OR 6.1, 95% CI 1.8-20.6) to be associated with the occurrence of hernia-related complications.

Conclusions: Hernia-related death and morbidity is low in conservatively managed patients. The presence of obstructive symptoms was found to be associated with the occurrence of complications during follow-up. Conservative therapy is an appropriate therapeutic strategy for asymptomatic patients.
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http://dx.doi.org/10.1177/2050640620953754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724529PMC
December 2020

The Role of Symptom Association Analysis in Gastroesophageal Reflux Testing.

Am J Gastroenterol 2020 12;115(12):1950-1959

Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, the Netherlands.

Gastroesophageal reflux disease is characterized by the reflux of gastric contents into the esophagus with an estimated worldwide prevalence of 8%-33%. The current paradigm in gastroesophageal reflux disease diagnosis relies on recognition of symptoms and/or the presence of mucosal disease at the time of esophagogastroduodenoscopy. Recognition of symptoms, however, can arise with challenges, particularly when patients complain of less typical symptoms. Since first reported in 1969 by Spencer et al., the application of prolonged intraesophageal pH monitoring to identify pathologic reflux has evolved considerably. Utility of pH monitoring aims to investigate the degree of acid burden and frequency of reflux episode, and the relationship between symptoms and acid reflux events. This relationship is represented by either the Symptom Index, Symptom Sensitivity Index, Symptom Association Probability, or Ghillebert Probability Estimate. This article reviews symptom-association analysis during esophageal reflux testing, covering the literature on current methods of reflux testing, interpretation of symptom association, and practical issues that can arise during symptom analysis.
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http://dx.doi.org/10.14309/ajg.0000000000000754DOI Listing
December 2020

Normative reference values for esophageal high-resolution manometry in healthy adults: A systematic review.

Neurogastroenterol Motil 2021 01 26;33(1):e13954. Epub 2020 Jul 26.

Department of Gastroenterology and Hepatology, University Medical Centers Amsterdam, Amsterdam, The Netherlands.

Background And Purpose: Establishing normative values of high-resolution esophageal manometry is necessary for accurate interpretation and comparison of measurements. In this systematic review, we aimed to summarize normal values for different esophageal high-resolution manometry systems. Moreover, we assessed the effect of body position, bolus consistency, and provocative maneuvers on these normative thresholds. We searched Medline, Embase, and the Cochrane Library from January 1st, 2006, to January 20th, 2020, for studies that reported normative data of high-resolution manometry in healthy volunteers. We assessed methodological quality of the included studies and planned a descriptive analysis. We analyzed data from 54 articles describing normative thresholds in high-resolution manometry using solid-state or water-perfused systems. Forty-six studies performed the manometry study in the supine position with liquid swallows, whereas sixteen studies described normative values in the upright position. Twelve studies assessed normative values for different bolus consistencies, and nine studies evaluated different provocative maneuvers. There is a considerable variety of normative values for esophageal high-resolution manometry depending on the equipment used and the protocols performed to obtain measurements. This should be taken into account when evaluating measurements in clinical practice and when comparing results of published research studies.
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January 2021
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