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

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).

Factors Associated With Achalasia Treatment Outcomes: Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Identification of factors associated with achalasia treatment outcome might help physicians select therapies based on patient characteristics. We performed a systematic review and meta-analysis to identify factors associated with treatment response. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library through February 21, 2019, for randomized controlled trials and cohort, case-control, and cross-sectional studies that reported patient-specific outcomes of treatment (botulinum toxin injection, pneumatic dilation, peroral endoscopic myotomy, or laparoscopic Heller myotomy). We assessed the methodologic quality of the included studies using the quality in prognosis studies tool. We planned qualitative and quantitative analyses. RESULTS: We analyzed data from 75 studies (8 randomized controlled trials, 27 prospective cohort studies, and 40 retrospective studies) on a total of 34 different factors associated with outcomes (3 demographic, 17 clinical, and 14 diagnostic factors). Qualitative assessment showed age, manometric subtype, and presence of a sigmoid-shaped esophagus as factors associated with outcomes of treatment for achalasia with a strong level of evidence. The cumulative evidence for the association with chest pain, symptom severity, and lower esophageal sphincter pressure was inconclusive. A meta-analysis confirmed that older age (mean difference, 7.9 y; 95% CI, 1.5-14.3 y) and manometric subtype 3 (odds ratio, 7.1; 95% CI, 4.1-12.4) were associated with clinical response. CONCLUSIONS: In a systematic review and meta-analysis, we found age and manometric subtype to be associated with outcomes of treatment for achalasia. This information should be used to guide treatment decisions.

Abnormal Responses to Local Esophageal Food Allergen Injections in Adult Patients With Eosinophilic Esophagitis.

Skin tests and measurement of serum levels of immunoglobulin E do not accurately identify foods for elimination from the diets of patients with eosinophilic esophagitis (EoE). We investigated whether an esophageal prick test, in which the esophageal mucosa is challenged by local injection of allergen extracts, could identify individuals with esophageal sensitization. During endoscopy, 6 allergens were injected in the esophagus of 8 patients with EoE and 3 patients without EoE (controls). A second endoscopy was performed after 24 hours to evaluate delayed responses. Five of the 8 patients with EoE had evidence for an acute response (luminal obstruction and mucosal blanching); 2 other patients had a delayed wheal or flare reaction. No responses were observed in controls. We conclude that esophageal mucosal food allergen injections induce acute and/or delayed responses in patients with EoE but not controls. The esophageal prick test deserves further exploration because it may guide elimination diets.

The natural course of eosinophilic esophagitis and long-term consequences of undiagnosed disease in a large cohort.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammation that may lead to stricture formation. This narrowing can cause major complications including food impactions. Despite increasing interest in EoE accurate data on its natural course is scarce. Therefore, we aimed to investigate the natural course of EoE and to evaluate the association between undiagnosed disease and the occurrence of complications over two decades in a large cohort. METHODS: We retrospectively analyzed charts of patients diagnosed with EoE between 1996 and 2015, collected from 15 hospitals throughout the Netherlands. Histologic, clinical, and endoscopic characteristics were identified and stratified by age and diagnostic delay. RESULTS: We included 721 patients (524 males, 117 children (≤18 years)). Dysphagia and food impactions were more common in adults whereas children more often presented with vomiting and abdominal pain (all p < 0.001). The prevalence of fibrotic endoscopic features was higher in adults (76%) than in children (39%) (p < 0.001). As time with undiagnosed disease progressed the percentage of patients with strictures and food impactions increased from 19% and 24% (diagnostic delay ≤ 2 years) to 52% and 57% (diagnostic delay ≥ 21 years) (p < 0.001), respectively. In a multivariate logistic regression model, diagnostic delay (odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.05-1.13) and male gender (OR = 2.69, 95% CI = 1.61-4.50) were the major risk factors for stricture presence. CONCLUSION: During the natural course of EoE, progression from an inflammatory to a fibrostenotic phenotype occurs. With each additional year of undiagnosed EoE the risk of stricture presence increases with 9%.

Disease activity in eosinophilic esophagitis is associated with impaired esophageal barrier integrity.

In eosinophilic esophagitis (EoE), the esophageal barrier integrity is impaired. Integrity can be assessed with different techniques. To assess the correlations between esophageal eosinophilia and various measures of mucosal integrity and to evaluate whether endoscopic impedance measurements can predict disease activity, endoscopies and mucosal integrity measurements were performed in adult EoE patients with active disease (≥15 eosinophils/high-power field) at baseline (n = 32) and after fluticasone (n = 15) and elemental dietary treatment (n = 14) and in controls (n = 19). Mucosal integrity was evaluated during endoscopy using electrical tissue spectroscopy (ETIS) measuring mucosal impedance and transepithelial electrical resistance (TER) and transepithelial molecule-flux through biopsy specimens in Ussing chambers. We included 61 measurements; 32 of patients at baseline and 29 after treatment, 3 patients dropped out. After treatment, 20 patients were in remission (≤15 eosinophils/high-power field) and these measurements were compared with 41 measurements of patients with active disease (at baseline or after failed treatment). All four mucosal integrity measures showed significant impairment in active EoE compared with remission. Eosinophilia was negatively correlated with ETIS and TER and positively with transepithelial molecule flux (P ≤ 0.001). The optimal ETIS cutoff to predict disease activity was 6,000 Ω·m with a sensitivity of 79% [95% confidence interval (CI) 54-94%], specificity of 84% (95% CI 69-94%), positive predictive values of 89% (95% CI 77-95%) and negative predictive values of 71% (95% CI 54-84%). In EoE patients, markers of mucosal integrity correlate with esophageal eosinophilia. Additionally, endoscopic mucosal impedance measurements can predict disease activity.NEW & NOTEWORTHY In adult patients with eosinophilic esophagitis (EoE), the mucosal integrity, measured by making use of four different parameters, correlates strongly with esophageal eosinophilia. The accuracy of endoscopically measured mucosal impedance to distinguish active disease from remission was acceptable with moderate specificity and sensitivity. Mucosal impedance measurements can predict disease activity in adult EoE patients.

Esophageal and Small Intestinal Mucosal Integrity in Eosinophilic Esophagitis and Response to an Elemental Diet.

OBJECTIVES: The esophageal mucosal integrity is impaired in eosinophilic esophagitis (EoE) and it has been suggested that the duodenal permeability is increased. The absence of food allergens may restore the integrity. The aims of this study were to assess duodenal permeability in EoE and to evaluate the effect of an elemental diet on the esophageal and duodenal integrity. METHODS: In this prospective study 17 adult EoE patients and 8 healthy controls (HC) were included. Esophageal biopsy specimens were sampled before and after 4 weeks of elemental diet to measure eosinophil counts and gene expression of tight junction and barrier integrity proteins. Esophageal and duodenal impedance were measured by electrical tissue impedance spectroscopy and Ussing chambers were used to measure transepithelial resistance (TER) and transepithelial molecule flux. Small intestinal permeability was measured using a test, measuring lactulose/mannitol (L/M) ratios. RESULTS: In EoE patients, the esophageal but not the duodenal integrity was impaired, compared with HC. We observed no significant difference between L/M ratios of HC and EoE patients. After diet, eosinophil counts decreased significantly, which was paralleled by normalization of esophageal impedance and transepithelial molecule flux. The esophageal TER improved significantly, but did not reach values seen in HC. Esophageal expression of genes encoding for barrier integrity proteins filaggrin and desmoglein-1 was impaired at baseline and restored after diet. CONCLUSIONS: An elemental diet restores esophageal integrity, suggesting that it is at least partly secondary to allergen exposure. Duodenal integrity seems not to be affected in EoE, and possibly plays a minor role in its pathophysiology.

Histological Response to Fluticasone Propionate in Patients With Eosinophilic Esophagitis Is Associated With Improved Functional Esophageal Mucosal Integrity.

OBJECTIVES: The esophageal mucosal integrity is impaired in patients with eosinophilic esophagitis (EoE). We aimed to evaluate the effect of fluticasone propionate on inflammation and functional and structural markers of esophageal mucosal barrier integrity in adult patients with EoE. METHODS: In this prospective study, we included 15 EoE patients (median age (IQR), 43 (30-45) years). Patients underwent upper endoscopy before and after an 8-week course of swallowed fluticasone propionate 500 µg BID. Several parameters of esophageal mucosal barrier integrity were evaluated: esophageal electrical tissue impedance in vivo during endoscopy, transepithelial electrical resistance (TER) and transepithelial molecule flux in Ussing chambers using esophageal biopsy specimens, and intercellular spaces as a structural marker of permeability using electron microscopy. Esophageal eosinophils and mast cells were counted, and expression of inflammatory cytokines and barrier integrity proteins was investigated using qPCR. Esophageal symptoms and signs were also assessed. RESULTS: Peak eosinophil and mast cell counts decreased significantly after fluticasone propionate treatment. The esophageal mucosal integrity increased substantially during treatment, as shown by increased extracellular impedance and TER (both P<0.01) and decreased transepithelial molecule flux in Ussing chambers (P<0.05). Whereas expression of genes encoding for inflammatory cytokines (IL5, IL13, eotaxin-3, periostin, TSLP) decreased after treatment, expression of genes encoding for barrier integrity proteins (filaggrin and desmoglein-1) increased. CONCLUSIONS: Fluticasone propionate treatment decreases eosinophilic inflammation and improves the esophageal mucosal barrier integrity in adult EoE patients. Improvement of the mucosal barrier integrity correlates with normalization of expression of desmoglein-1 and filaggrin marker genes.

Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis.

BACKGROUND & AIMS: Histologic analysis is used to distinguish patients with proton pump inhibitor-responsive eosinophilia (PPI-REE) from those with eosinophilic esophagitis (EoE). It is not clear whether these entities have different etiologies. Exposure to acid reflux can impair the integrity of the esophageal mucosal. We proposed that patients with EoE and PPI-REE might have reflux-induced esophageal mucosal damage that promotes transepithelial flux of allergens. We therefore assessed the integrity of the esophageal mucosal in these patients at baseline and after PPI. METHODS: We performed a prospective study of 16 patients with suspected EoE and 11 controls. Patients had dysphagia, endoscopic signs of EoE, and esophageal eosinophilia (>15 eosinophils/high-power field [eos/hpf]). All subjects underwent endoscopy at baseline; endoscopy was performed again on patients after 8 weeks of treatment with high-dose esomeprazole. After PPI treatment, patients were diagnosed with EoE (>10 eos/hpf; n = 8) or PPI-REE (≤10 eos/hpf; n = 8). We evaluated the structure (intercellular spaces) and function (electrical tissue impedance, transepithelial electrical resistance, transepithelial molecule flux) of the esophageal mucosal barrier. RESULTS: Compared with controls, electrical tissue impedance and transepithelial electrical resistance were reduced in patients with EoE (P < .001 and P < .001, respectively) and PPI-REE (P = .01 and P = .06, respectively), enabling transepithelial small-molecule flux. PPI therapy partially restored these changes in integrity and inflammation in patients with PPI-REE, but not in those with EoE. CONCLUSIONS: The integrity of the esophageal mucosa is impaired in patients with EoE and PPI-REE, allowing transepithelial transport of small molecules. PPI therapy partially restores mucosal integrity in patients with PPI-REE, but not in those with EoE. Acid reflux might contribute to transepithelial allergen flux in patients with PPI-REE. Trialregister.nl number: NTR3480.

The Effect of STW5 (Iberogast) on Reflux Symptoms in Patients With Concurrent Dyspeptic Symptoms: A Double-blind Randomized Placebo-controlled Crossover Trial.

Background/Aims: It has been suggested that STW5 (Iberogast) reduces heartburn symptoms in patients with functional dyspepsia, but underlying mechanisms of action are unclear. The aim of this study is to investigate whether STW5 affects esophageal sensitivity or esophageal motility, thereby reducing occurrence and perception of reflux events. Methods: We performed a double-blind, randomized, placebo-controlled, crossover trial in patients with functional dyspepsia (Rome IV) and reflux symptoms. After 4 weeks of treatment with either placebo or STW5, patients were studied with an esophageal acid perfusion test and ambulatory 24-hour pH-impedance monitoring. Results: A total of 18 patients (7 men, median age 54, range [19-76]), were included in the study. Although we found no statistical difference in our primary outcome the total Reflux Disease Questionnaire score 2.33 (0.25-4.33) vs 2.67 (1.17-4.00), P = 0.347, "gastroesophageal reflux disease" and "regurgitation" subscale scores were lower after STW5 treatment compared to placebo (P = 0.049 and P = 0.007). There was no statistical difference in number of reflux events, acid exposure time and acid sensitivity scores between STW5 and placebo. In a subgroup analysis of patients with pH-metry confirmed gastroesophageal reflux disease, treatment with STW5 significantly reduced the total number of acidic reflux events (P = 0.028). Moreover, in patients with reflux esophagitis, the median lag time to acid perception increased after STW5 treatment (P = 0.042). Conclusions: We found some indications pointing towards a beneficial effect of STW5 on reflux symptoms in dyspeptic patients, with reduction of esophageal hypersensitivity as a potential underlying mechanism. Our findings will have to be confirmed in larger studies.

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

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.

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

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.

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

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.

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

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.

PPI-responsive esophageal eosinophilia cannot be distinguished from eosinophilic esophagitis by endoscopic signs.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease histologically characterized by eosinophil-predominant inflammation. One-third of patients respond to proton pump inhibitor (PPI) treatment; this group is identified as having PPI-responsive esophageal eosinophilia (PPI-REE). If we could predict the response to PPIs on the basis of endoscopic signs, futile treatment efforts and additional endoscopies to assess treatment response can be prevented. OBJECTIVE: To determine whether endoscopic signs can distinguish PPI-REE from EoE. METHODS: Endoscopic images of 30 EoE and 30 PPI-REE patients were included. Baseline characteristics were compared between groups. Complete clinical remission after a PPI trial for at least 8 weeks was classified as PPI-REE. Per patient, at least three depersonalized images were incorporated into a slideshow. These images were scored by two experienced endoscopists according to a validated classification system. RESULTS: Characteristics were highly comparable between EoE and PPI-REE patients. Endoscopic signs were similar and did not enable differentiation between EoE and PPI-REE [presence of: rings (P=0.893), white exudates (P=0.209), furrows (P=0.371), edema (P=0.554), crepe paper esophagus (P=1.000), and strictures (P=0.071)]. CONCLUSION: Endoscopic signs at baseline endoscopy cannot distinguish EoE from PPI-REE before a PPI trial; the demographic and clinical characteristics in both groups are similar. Endoscopic features do not enable differentiation between PPI-REE and EoE.

Prevalence of esophageal motility abnormalities increases with longer disease duration in adult patients with eosinophilic esophagitis.

BACKGROUND: During the natural course of eosinophilic esophagitis (EoE), the risk for esophageal stricture formation increases. It remains unknown whether motility abnormalities in EoE also develop over time. We aimed to determine the relationship between disease duration, clinical characteristics, and manometric pattern of EoE patients. METHODS: We compared esophageal high-resolution manometry (HRM) measurements of 31 adult EoE patients with HRM data from 31 GERD controls and 31 healthy controls. Subsequently, we assessed differences in disease duration and clinical characteristics between EoE patients with normal and those with abnormal esophageal motility. KEY RESULTS: In EoE patients, peristaltic integrity was more frequently failed (12 vs 6%) or weak (27 vs 15%; p < 0.001) compared with healthy controls; however, this pattern was also seen in GERD controls (failed 14%, weak 27%). We found no differences regarding symptoms and signs of EoE between EoE patients with normal (42%) and abnormal motility (58%). However, disease duration was longer in EoE patients with abnormal motility than in those with normal motility (13 (6-18) years vs 4 (1-11) years; p < 0.05). In EoE, but not GERD, disease duration was identified as a risk factor for abnormal motility (OR for each year 1.142; 95% CI 1.004-1.299), and with longer disease duration, the prevalence of abnormal motility increased from 36% (duration 0-5 years) to 83% (duration ≥16 years; p < 0.05). CONCLUSIONS & INFERENCES: Weak and failed peristaltic integrity are more often present in adult EoE patients than in healthy controls. The prevalence of manometric abnormalities in EoE patients increases with longer disease duration.