Course of Esophageal Strictures in Eosinophilic Esophagitis Using Structured Esophagram Protocol.

Background and Aims: A key unknown in eosinophilic esophagitis (EoE) is the long-term course of esophageal stenosis. Our aim was to evaluate the course of esophageal strictures using structured serial esophagrams and determine predictors of diameter improvement in patients with EoE. Methods: This was a retrospective study of 78 EoE patients who completed 2 structured esophagrams at an academic tertiary referral center between 2003 and 2021. Maximum and minimum esophageal diameters were measured during esophagram using a standardized protocol to reduce measurement errors. Results: The median age at first esophagram was 36.2 (12.9-64.3) years; 60.3% of patients were male; 41 patients had active EoE; and 9 were inactive. Of the patients, 39.7% had allergic rhinitis, asthma (32.1%), and atopic dermatitis (7.7%). Medical therapies at second esophagram and esophagogastroduodenoscopy included proton pump inhibitors (39.5%), swallowed topical steroids (31.6%), diet elimination (13.2%), biologic therapies (1.3%), and clinical trial medications (1.3%). Median maximum diameter significantly increased by 1.0 mm (Q1: -1.0 mm, Q3: 3.0 mm) (P = .034), independent of dilation (P = .744). Increase was most profound in patients starting in the lowest maximum diameter group (9-15 mm) with median increase of 3.0 mm. For patients in disease remission at the second esophagram, there was a significant increase in maximum diameter per year compared to active disease at 0.8 mm (Q1: 0.0 mm, Q3: 5.3 mm) and 0.0 mm (Q1: -0.4 mm, Q3: 0.6 mm) respectively (P = .019). Conclusion: Long-term improvement in esophageal strictures in patients with EoE may occur but is modest and likely occurs over years. Progression also appears to be minimal. Continuous medical treatment may reduce the rate of stricture recurrence and may improve stricture diameter over time.

Long-term Durability Between Parent and Child Patient Reported Outcomes in Eosinophilic Esophagitis.

BACKGROUND: Because young children cannot self-report symptoms, there is a need for parent surrogate reports. While early work suggested parent child alignment for eosinophil esophagitis (EoE) patient reported outcomes (PROs), the longitudinal alignment is unclear. OBJECTIVE: To assess the agreement and longitudinal stability of PROs between children with EoE and their parents. METHODS: 292 parent-child respondents completed 723 completed questionnaires over 5 years in an observational trial in the Consortium of Eosinophilic Gastrointestinal Disease Researchers. The change in and agreement between parent and child Pediatric Eosinophilic Esophagitis Symptom Score version 2 (PEESSv2.0) and Pediatric Quality of Life Eosinophilic Esophagitis Module (PedsQL-EoE) PROs over time were assessed using Pearson correlation and Bland-Altman analyses. Clinical factors influencing PROs and their agreement were evaluated using linear mixed models. RESULTS: The cohort had a median disease duration equalling 3.7 years and was predominantly male (73.6%) and white (85.3%). Child and parent PEESSv2.0 response groups were identified and were stable over time. There was strong correlation between child and parent report (PEESSv2.0 0.83, PedsQL-EoE 0.74) with minimal pairwise differences for symptoms. Longitudinally, parent-reported PedsQL-EoE scores were stable (p ≥ 0.32), whereas child-reported PedsQL-EoE scores improved (p = 0.026). A larger difference in parent and child PedsQL-EoE reports was associated with younger age (p < 0.001) and differences were driven by psychosocial PRO domains. CONCLUSION: There is strong longitudinal alignment between child and parent report using EoE PROs. These data provide evidence that parent report is a stable proxy for objective EoE symptoms in their children.

A practical approach to ineffective esophageal motility.

BACKGROUND AND PURPOSE: Ineffective esophageal motility (IEM) is the most frequently diagnosed esophageal motility abnormality and characterized by diminished esophageal peristaltic vigor and frequent weak, absent, and/or fragmented peristalsis on high-resolution esophageal manometry. Despite its commonplace occurrence, this condition can often provoke uncertainty for both patients and clinicians. Although the diagnostic criteria used to define this condition has generally become more stringent over time, it is unclear whether the updated criteria result in a more precise clinical diagnosis. While IEM is often implicated with symptoms of dysphagia and gastroesophageal reflux disease, the strength of these associations remains unclear. In this review, we share a practical approach to IEM highlighting its definition and evolution over time, commonly associated clinical symptoms, and important management and treatment considerations. We also share the significance of this condition in patients undergoing evaluation for anti-reflux surgery and consideration for lung transplantation.

Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis.

BACKGROUND: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood. OBJECTIVE: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis. METHODS: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms. RESULTS: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden. CONCLUSION: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity.

Current state of rumination syndrome.

Rumination syndrome (RS) is an underdiagnosed behavioral disorder of recurrent regurgitation. Regurgitation occurs in RS due to increased gastric pressure achieved by subconscious contraction of the abdominal musculature wall, reversing the pressure gradient between the esophagus and the stomach. RS is mainly diagnosed clinically by the Rome Criteria with symptoms of regurgitation without retching of recently ingested food into the mouth and subsequent spitting or re-mastication. When the diagnosis is unable to be made clinically, supportive testing including fed impedance manometry can be considered. RS occurs worldwide, affecting patients of all ages, races, and genders with a prevalence of 3.1-5.8%. There is significant overlap with RS and disorders of a gut-brain interaction and upright gastroesophageal reflux driven by aerophagia and supragastric belching. There is also an association with mood disorder, fibromyalgia, and eating disorders. RS may be misdiagnosed as a variety of other syndromes including gastroesophageal reflux disease, gastroparesis, achalasia, and bulimia nervosa. Once RS is diagnosed, the mainstay of treatment is diaphragmatic breathing to lower the intragastric pressure and increase the lower esophageal pressure. Diaphragmatic breathing can be supported with biofeedback and cognitive behavioral therapy as well as medication options for more refractory cases. Response to therapy overtime and changes in symptoms overtime can now be tracked with a validated questionnaire.

Satisfaction With and Adherence to Off-Label Corticosteroids in Adolescents and Adults With Eosinophilic Esophagitis: Results of a Web-Based Survey in the United States.

GOALS: We assessed satisfaction with and adherence to off-label corticosteroids in patients with eosinophilic esophagitis (EoE) in the United States. BACKGROUND: EoE is a chronic inflammatory disease for which there are currently no US Food and Drug Administration-approved swallowed topical corticosteroids. STUDY: This noninterventional, cross-sectional, web-based survey included caregivers of adolescents (aged 11 to 17 y) and adults (aged 18 years or older) with a self-reported [or caregiver-reported (adolescents)] physician diagnosis of EoE who were receiving corticosteroids. Participants were recruited through 2 nonprofit, patient advocacy groups. The 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) was used to assess satisfaction across effectiveness, convenience, and global satisfaction domains (scale: 1 to 100 per domain); higher scores indicated greater satisfaction. The 4-item Morisky Green Levine Medication Adherence Scale (MGL-4) was used to assess adherence; an MGL-4 score of <3 indicated adherence. Participants also reported reasons for nonadherence. RESULTS: Overall, 201 participants (caregivers of adolescents, n=98; adults, n=103) were included in this study. Mean TSQM-9 scores indicated low satisfaction with off-label corticosteroids across all 3 satisfaction domains in adolescents (≤61.1) and adults (≤55.7). Slightly fewer adolescents (37.1%) than adults (40.8%) were considered adherent. Forgetfulness was the most frequently reported reason for nonadherence; some patients chose not to take their medications, owing to poor palatability (adolescents), difficulty taking medications at specific times (adults), or feeling depressed/overwhelmed (adolescents and adults). CONCLUSIONS: Satisfaction with and adherence to off-label corticosteroids were low in this web-based survey of adolescents and adults with EoE in the United States.

Esophageal Self-Dilation in Benign Refractory Esophageal Strictures: Outcomes from a Randomized Controlled Trial and a Prospective Observational Study.

BACKGROUND: Patients with benign esophageal strictures may not maintain a response to endoscopic dilation, stenting, incisional or injectional therapies. For patients with these refractory esophageal strictures, esophageal self-dilation therapy (ESDT), performed to maintain luminal patency, may provide persistent symptomatic benefit while reducing patients' reliance on healthcare services and the risk associated with repeated endoscopic procedures. AIMS: The aim of this study was to evaluate the efficacy and safety of EDST in a randomized controlled trial and prospective observational study. METHODS: Twenty-five patients with refractory benign esophageal strictures were recruited at two esophageal clinics between November 2018 and June 2021. Twelve patients participated in the randomized trial and 13 in the prospective observational study. The number of endoscopic dilations, impact of therapy on dysphagia, adverse events, and complications were recorded. RESULTS: In the randomized study, 50% of patients performing ESDT and 100% of controls required endoscopic dilation during follow-up (P = 0.02). In the observational study, the median (IQR) number of endoscopic dilations fell from 7 [7-10] in the 6 months prior to commencing ESDT to 1 [0-2] in the 6 months after (P < 0.0001). Most patients (22/25) were able to learn self-dilation. Few serious adverse events were noted. Dysphagia severity remained unchanged or improved. CONCLUSIONS: ESDT appears to be a safe effective therapy for benign esophageal strictures refractory to endoscopic treatment. CLINICAL TRIAL NUMBER: NCT03738566.

Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis.

BACKGROUND: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE). OBJECTIVE: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both. METHODS: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed. RESULTS: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity. CONCLUSIONS: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation.

Monitoring and modulating the trajectory of eosinophilic esophagitis.

Current treatments of eosinophilic esophagitis (EoE) aim to eliminate esophageal mucosal inflammation and attenuate, stabilize, or reverse stricture formation. However, our ability to study the long-term course of esophageal strictures in patients with EoE is hampered by the short-term existence of this disease. It is unclear to what degree of control of inflammation is needed to prevent stricture formation. Additionally, identified phenotypes of EoE may ultimately dictate different levels of concern and time intervals for developing fibrosis. Currently, multiple methods are used to monitor patients' disease progression to fibrosis, as symptoms alone do not correlate with disease activity. Endoscopic findings and mucosal histology are used to monitor disease activity, but these focus on improvements in inflammation with inconsistent evaluation of underlying fibrosis. The use of functional lumen impedance planimetry, barium esophagraphy, and endoscopic ultrasound continues to expand in EoE. The rapid advancements in EoE have led to an armamentarium of measuring tools and therapies that holistically characterize disease severity and response to therapy. Nevertheless, our ability to evaluate gross esophageal fibrosis and stricture formation from a transmural rather than mucosal view should be a focus of future investigations because it is essential to monitoring and modulating the trajectory of EoE.

Number of Older Biological Siblings and Early-Onset Colorectal Cancer Risk.

Colorectal cancer (CRC) is the third most common cancer in the United States.1 Although CRC incidence has declined in individuals >50 years, incidence is rising in adults <50 years (early onset).1 By 2027, CRC is projected to become the leading cause of cancer mortality in US adults <50 years.2 To combat the rising incidence of early onset CRC (EOCRC), national guidelines recently lowered the screening age from 50 to 45 years for average-risk individuals.3 Understanding the risk profile of EOCRC can help combat the rising burden in young adults, especially in those ineligible for screening.

Questionnaire for diagnosis and response to therapy in rumination syndrome.

Rumination is a behavioral disorder characterized by regurgitation of food without retching. It is diagnosed clinically by the Rome Criteria and treated primarily by diaphragmatic breathing. Despite diagnosis and follow-up being based on symptomatic responses to therapies, there are no published or validated questionnaires. To address this care-gap, a rumination questionnaire was developed and reviewed by two expert esophagologists and five patients diagnosed with rumination. Ultimately, an eight-point questionnaire with scoring ranging from -1 to 10 was finalized. This newly developed questionnaire was implemented on five additional patients diagnosed clinically with rumination syndrome with improvement after interventions noted.

Quality Indicator Development for the Approach to Ineffective Esophageal Motility: A Modified Delphi Study.

GOALS: Develop quality indicators for ineffective esophageal motility (IEM). BACKGROUND: IEM is identified in up to 20% of patients undergoing esophageal high-resolution manometry (HRM) based on the Chicago Classification. The clinical significance of this pattern is not established and management remains challenging. STUDY: Using RAND/University of California, Los Angeles Appropriateness Methods, we employed a modified-Delphi approach for quality indicator statement development. Quality indicators were proposed based on prior literature. Experts independently and blindly scored proposed quality statements on importance, scientific acceptability, usability, and feasibility in a 3-round iterative process. RESULTS: All 10 of the invited esophageal experts in the management of esophageal diseases invited to participate rated 12 proposed quality indicator statements. In round 1, 7 quality indicators were rated with mixed agreement, on the majority of categories. Statements were modified based on panel suggestion, modified further following round 2's virtual discussion, and in round 3 voting identified 2 quality indicators with comprehensive agreement, 4 with partial agreement, and 1 without any agreement. The panel agreed on the concept of determining if IEM is clinically relevant to the patient's presentation and managing gastroesophageal reflux disease rather than the IEM pattern; they disagreed in all 4 domains on the use of promotility agents in IEM; and had mixed agreement on the value of a finding of IEM during anti-reflux surgical planning. CONCLUSION: Using a robust methodology, 2 IEM quality indicators were identified. These quality indicators can track performance when physicians identify this manometric pattern on HRM. This study further highlights the challenges met with IEM and the need for additional research to better understand the clinical importance of this manometric pattern.

A Delphi Method for Development of a Barrett's Esophagus Question Prompt List as a Communication Tool for Optimal Patient-physician Communication.

BACKGROUND METHODS: The question prompt list content was derived through a modified Delphi process consisting of 3 rounds. In round 1, experts provided 5 answers to the prompts "What general questions should patients ask when given a new diagnosis of Barrett's esophagus" and "What questions do I not hear patients asking, but given my expertise, I believe they should be asking?" Questions were reviewed and categorized into themes. In round 2, experts rated questions on a 5-point Likert scale. In round 3, experts rerated questions modified or reduced after the previous rounds. Only questions rated as "essential" or "important" were included in Barrett's esophagus question prompt list (BE-QPL). To improve usability, questions were reduced to minimize redundancy and simplified to use language at an eighth-grade level (Fig. 1). RESULTS: Twenty-one esophageal medical and surgical experts participated in both rounds (91% males; median age 52 years). The expert panel comprised of 33% esophagologists, 24% foregut surgeons, and 24% advanced endoscopists, with a median of 15 years in clinical practice. Most (81%), worked in an academic tertiary referral hospital. In this 3-round Delphi technique, 220 questions were proposed in round 1, 122 (55.5%) were accepted into the BE-QPL and reduced down to 76 questions (round 2), and 67 questions (round 3). These 67 questions reached a Flesch Reading Ease of 68.8, interpreted as easily understood by 13 to 15 years olds. CONCLUSIONS: With multidisciplinary input, we have developed a physician-derived BE-QPL to optimize patient-physician communication. Future directions will seek patient feedback to distill the questions further to a smaller number and then assess their usability.

Roles of swallowing and belching in different phenotypes of gastroesophageal reflux disease.

BACKGROUND: The contributions of swallowing and belching to specific gastroesophageal reflux disease (GERD) phenotypes are unclear. METHODS: This study retrospectively analyzed esophageal pH/impedance studies, comparing reflux events preceded by gastric belching (GB), supragastric belching (SGB), air swallowing, and liquid/solid swallowing based on reflux position, lower esophageal sphincter (LES) pressure, and acid exposure time (AET). KEY RESULTS: 20 GERD patients and 10 controls were studied. Upright GERD patients and controls had a higher proportion of reflux events with a preceding swallow or belch (0.64, 0.64) than the supine group (0.38, p = 0.043). The upright group and controls trended toward a higher proportion of reflux events preceded by overall swallowing (0.61, 0.50) and air swallowing (0.55, 0.48) than the supine group (0.32, 0.31 p = 0.064, p = 0.11), but the three groups had similar rates of liquid/solid swallowing (0.032, 0.024, 0.017, p = 0.69). LES pressure did not correlate with reflux events preceded by swallowing (R2 = 0.021, p = 0.44). There was a higher rate of events preceded by gastric belching in the control group (0.14) than in the upright (0.032) and supine groups (0.066, p = 0.049). LES pressure did not correlate with the rate of events preceded by belching (R2 = 0.000093, p = 0.96). Normal AET patients had a higher rate of events preceded by GB (0.12) than those with increased acid exposure (0.030, p = 0.0083), but the two groups had similar rates of preceding air (0.43, 0.47, p = 0.68), liquid/solid (0.018, 0.032, p = 0.30), and overall swallowing (0.44, 0.53, p = 0.38). CONCLUSIONS AND INFERENCES: Swallowing more than belching is a dominant mechanism for reflux irrespective of GERD position, LES pressure, and AET.

Esophageal Lichen Planus: A Descriptive Multicenter Report.

GOALS: To better understand the characteristics, treatment approaches, and outcomes of patients with esophageal lichen planus (ELP). BACKGROUND: ELP is a rare, often unrecognized and misdiagnosed disorder. Data on this unique patient population are currently limited to small, single-center series. STUDY: A multicenter, retrospective descriptive study was conducted of adults diagnosed with ELP over a 5-year period, between January 1, 2015, and October 10, 2020, from 7 centers across the United States. RESULTS: Seventy-eight patients (average age 65 y, 86% female, 90% Caucasian) were included. Over half had at least 1 extraesophageal manifestation. Esophageal strictures (54%) and abnormal mucosa (50%) were frequent endoscopic findings, with the proximal esophagus the most common site of stricture. Approximately 20% had normal endoscopic findings. Topical steroids (64%) and/or proton pump inhibitors (74%) dominated management; endoscopic response favored steroids (43% vs. 29% respectively). Almost half of the patients required switching treatment modalities during the study period. Adjunctive therapies varied significantly between centers. CONCLUSIONS: Given its at times subtle clinical and endoscopic signs, a high index of suspicion and biopsy will improve ELP diagnosis, especially in those with extraesophageal manifestations. Effective therapies are lacking and vary significantly. Prospective investigations into optimal treatment regimens are necessary.

Barrier Dysfunction in Eosinophilic Esophagitis.

PURPOSE OF REVIEW: Compelling evidence over the past decade supports the central role of epithelial barrier dysfunction in the pathophysiology of eosinophilic esophagitis (EoE). The purpose of this review is to summarize the genetic, environmental, and immunologic factors driving epithelial barrier dysfunction, and how this impaired barrier can further promote the inflammatory response in EoE. RECENT FINDINGS: Common environmental exposures, such as detergents, may have a direct impact on the esophageal epithelial barrier. In addition, the effects of IL-13 on barrier dysfunction may be reduced by 17ß-estradiol, Vitamin D, and the short chain fatty acids butyrate and propionate, suggesting novel therapeutic targets. There are many genetic, environmental, and immunologic factors that contribute to epithelial barrier dysfunction in EoE. This leads to further skewing of the immune response to a "Th2" phenotype, alterations in the esophageal microbiome, and penetration of relevant antigens into the esophageal mucosa, which are central to the pathophysiology of EoE.

H influenzae LPS colocalization with Toll-like receptor 4 in eosinophilic esophagitis.

Background: Patients with eosinophilic esophagitis (EoE) have a unique esophageal microbiome with increased presence of Haemophilus influenzae, but its role in the disease is unclear. Objective: Microbiome-derived bacterial LPS activation of Toll-like receptors (TLR) is a potential mechanism for inducing inflammation in other chronic inflammatory diseases, but it has not been studied in EoE. Our aim was therefore to study microbiome-derived bacterial LPS activation of TLRs in EoE. Methods: We studied 10 patients with active EoE, 9 patients with inactive EoE, and 10 control patients. Esophageal biopsy samples from the controls, patients with active EoE (>15 eosinophils/hpf), and patients with inactive EoE were immunostained for the presence of H influenzae LPS, presence of TLR4, and colocalization of LPS and TLR4. Staining intensity was measured by using confocal laser microscopy and scored on a scale from 0 to 3 as the average score assigned by 2 blinded observers. Results: H influenzae LPS was detected by positive staining in 20 of the 29 patients (69.0%), including 9 of the 10 patients with active EoE (90.0%), 8 of the 9 patients with inactive EoE (89.9%), and 3 of the 10 controls (30%); its level was greater in the patients with active EoE than in the controls (P = .063). TLR4 was detected by positive staining in 19 of the 29 patients (65.5%), including 9 of the 10 patients with active EoE (90.0%), 4 of the 9 patients with inactive EoE (44.4%), and 6 of the 10 controls (60.0%); its level was higher in the patients with active EoE than in those with inactive EoE (P = .096). The result of testing for colocalization of LPS and TLR4 was positive in 8 of 10 patients with active EoE (80.0%), 1 of 9 patients with inactive EoE (11.1%), and 1 of 10 control patients (10.0%), with greater colocalization of H influenzae LPS and TLR4 staining density in the samples from patients with active EoE than in the controls or the patients with inactive EoE (P = .009 and P = .018, respectively). Conclusion: Esophageal microbiome-rich H influenzae LPS colocalizes to TLR4 in active EoE. These data lend further support to a role for the esophageal microbiome in modulating the activity of EoE.